A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIG®) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)
Phase: PHASE3
Conditions: ALK+ Advanced NSCLC
Sponsor: Takeda

For non-commercial use only

 
 
CONFIDENTIAL
PROTOCOL
A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIG®) Versus Alectinib 
(ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung 
Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)
Sponsor:
Takeda Development Center Americas, Inc (TDCA) 
95 Hayden Avenue 
Lexington, MA 02421, USA
Telephone: +1 (617) 679-7000
Study Number:
Brigatinib-3001
IND Number:
IND 110,935
EudraCT Number:
2018-001957-29
Compound:
Brigatinib (AP26113) 
Date:
08 March 2021
Amendment Number:
4
Amendment History:
Date
Amendment Number
Amendment Type
Region
08 March 2021
4
Substantial
Global
09 March 2020
3
Substantial
Global
07 June 2019
2
Substantial
Global
11 January 2019
1
Nonsubstantial
Germany
15 May 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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CONFIDENTIAL
1.0
ADMINISTRATIVE 
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE) 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 the 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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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatories can be found on the 
signature page.
Electronic Signatures may be found on the last page of this document.
, MD
Oncology Clinical Research, 
, 
Date
, PhD
Oncology Statistics, 
Date
MD
Oncology Clinical Research, 
, 
Clinical Study Lead
Date
, PhD
Quantitative Clinical Pharmacology, 
 
Date
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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 SAEs 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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1.3
Protocol Amendment Summary of Changes
Protocol Amendment 4 Summary and Rationale
This section describes the changes in reference to the protocol incorporating Amendment 4. The 
primary reasons for this amendment are to:

Add futility analysis to be performed with the planned interim analysis.

Add precautions for photosensitivity to sunlight.

Update the dose modification guidance for creatine phosphokinase (CPK) elevation to align
with the current Company Core Data Sheet (CCDS) V3 recommendations.

Provide updated brigatinib storage conditions.

Add the descriptions of direct-to-patient (DTP) drug delivery during the pandemic of
coronavirus disease 2019 (COVID-19).

Add criteria to terminate central blinded Independent Review Committee (BIRC) assessment
if the primary endpoint is met at the interim analysis (IA) or primary analysis, or not met at the
primary analysis.

Add description of remote source document verification during the pandemic of COVID-19.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Description
Rationale
Section 2.0 STUDY SUMMARY
Section 6.3.1 Duration of an 
Individual Patient’s Study 
Participation
Section 13.1.3.2 Primary Efficacy 
Endpoint Analyses
Section 13.2 IA
A futility analysis will be performed 
with the interim analysis. 
Due to strategic considerations, a 
futility analysis is added to the 
interim analysis so that the study 
could be terminated early if the real 
efficacy of alectinib and brigatinib in 
the study population significantly 
deviates from the study assumption.
Section 8.3 Recommended Dosing 
and Dose Modification Guidelines
Updated the creatine phosphokinase
(CPK) dose modification guidance.
Aligned protocol with the current 
CCDS V3 dose modification 
guidance for CPK elevation. 
An analysis was performed using 
data from Studies 301 and 201 to 
evaluate the relationship of CPK 
increase, brigatinib treatment 
duration and muscular toxicities. The 
results suggested that CPK increase 
was associated with longer duration 
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Description
Rationale
of treatment and did not seem to be 
associated with the frequency of 
muscular toxicity. Also, review of 
individual patient data from Studies 
301 and 201 showed only 1 report of 
patient with a Grade 3 CPK elevation 
as well as a Grade 3 muscular 
toxicity (Preferred Term: muscular 
toxicity). 
Additionally, many of the 49 patients 
from pooled Studies 301 and 201 
with a Grade ≥3 CPK elevation did 
not report a muscular toxicity event 
(any grade or Grade ≥3). 
Based on these analyses, it was 
concluded that the dose modification 
for CPK elevations of Grade 3 and 4, 
without concurrent muscular 
toxicity, is not warranted and 
therefore the guidance was modified 
accordingly. 
Section 8.6 Precautions and 
Restrictions
Added precautions for 
photosensitivity to sunlight.
Mitigation of photosensitivity to 
sunlight, which has been observed in 
patients treated with brigatinib.
Section 8.10 Storage, Handling, and 
Accountability
Updated the storage condition of 
brigatinib to “Store at controlled 
room temperature of 20°C to 25°C 
with excursions permitted between 
15°C to 30°C.”
Update of the storage condition of 
brigatinib to be consistent with 
Investigational Medicinal Product 
Dossier and other documents.
Section 8.11 Preparation and 
Dispensing
Added the description of DTP drug 
delivery during the COVID-19
pandemic.
Because of the impact of the 
COVID-19 pandemic, travel 
restrictions were executed in most of 
the countries participating in the 
study, and some of the study centers 
were temporarily closed. Instructions 
were provided to establish the DTP 
process to facilitate the direct 
delivery of the drugs from the study 
site to the patient’s home to make 
sure the patients are able to continue 
the treatment without physically 
going to the study center.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Description
Rationale
Section 9.8 Posttreatment Follow-up 
Assessments (Progression-Free 
Survival and Overall Survival) and 
Appendix A Schedule of Events
Provided clarification that the 
collection of tumor assessment data 
is not required if the patient has 
progressed and has started treatment 
beyond progression during the 
posttreatment follow-up.
Although the tumor assessment is 
still a requirement, collection of these 
data is not required if the patient has 
progressed and has started treatment 
beyond progression.
Section 11.2 IRC
Added criteria to terminate BIRC 
assessment if the primary endpoint is 
met at the IA or primary analysis, or 
not met at the primary analysis. 
Tumor assessment by BIRC is no 
longer warranted after primary 
analysis, and assessment of ongoing 
patients will continue to be 
performed by investigators.
Section 14.1 Study-Site Monitoring 
Visits
Added description of remote source 
document verification during the 
COVID-19 pandemic.
Because of the impact of the 
COVID-19 pandemic, travel 
restrictions were executed in most of 
the countries participating the study,
and some of the study centers were 
temporarily closed or limiting 
entrance of nonpatient personnel. 
This made the on-site SDV 
impossible in some of the sites. To
ensure data integrity, remote source 
data verification was allowed and 
conducted in a small number of sites.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment Summary of Changes...............................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Principal Investigator...............................................................................................18
3.3
List of Abbreviations ...............................................................................................19
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.1.1
Epidemiology and Pathology ...........................................................................21
4.1.2
ALK+ NSCLC.................................................................................................21
4.1.3
Current Treatment for ALK+ NSCLC..............................................................22
4.1.4
Unmet Medical Need.......................................................................................23
4.2
Rationale for the Proposed Study.............................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Objectives................................................................................................................25
5.1.1
Primary Objective............................................................................................25
5.1.2
Secondary Objectives ......................................................................................25
5.1.3
Exploratory Objectives ....................................................................................25
5.2
Endpoints.................................................................................................................26
5.2.1
Primary Endpoint.............................................................................................26
5.2.2
Secondary Endpoints .......................................................................................26
5.2.3
Safety Endpoints..............................................................................................26
5.2.4
Exploratory Endpoints .....................................................................................26
6.0
STUDY DESIGN..........................................................................................................27
6.1
Overview of Study Design.......................................................................................27
6.2
Number of Patients ..................................................................................................29
6.3
Duration of Study ....................................................................................................29
6.3.1
Duration of an Individual Patient’s Study Participation....................................29
6.3.2
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......30
6.3.3
Total Study Duration .......................................................................................31
7.0
STUDY POPULATION................................................................................................31
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7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................33
8.0
STUDY DRUG .............................................................................................................35
8.1
Study Drug Administration......................................................................................35
8.2
Treatment With Study Drug Beyond Radiological Disease Progression ...................35
8.3
Recommended Dosing and Dose Modification Guidelines.......................................36
8.4
Permitted Concomitant Medications and Procedures................................................43
8.5
Excluded Concomitant Medications and Procedures ................................................43
8.6
Precautions and Restrictions ....................................................................................44
8.6.1
Pregnancy, Breastfeeding, and Contraception ..................................................45
8.6.2
Additional Precautions and Restrictions for Alectinib ......................................47
8.7
Blinding and Unblinding..........................................................................................47
8.8
Description of Investigational Agents ......................................................................47
8.9
Packaging and Labeling...........................................................................................47
8.10
Storage, Handling, and Accountability.....................................................................48
8.11
Preparation and Dispensing......................................................................................48
8.12
Other Protocol-Specified Materials ..........................................................................49
9.0
STUDY CONDUCT......................................................................................................49
9.1
Study Personnel and Organizations..........................................................................49
9.2
Arrangements for Recruitment of Patients................................................................49
9.3
Treatment Group Assignments.................................................................................49
9.3.1
Informed Consent ............................................................................................50
9.3.2
Screening.........................................................................................................50
9.3.3
Visit Windows.................................................................................................50
9.3.4
Enrollment.......................................................................................................50
9.3.5
Medical History...............................................................................................51
9.3.6
Tumor Tissue Samples.....................................................................................51
9.3.7
Physical Examination ......................................................................................52
9.3.8
ECOG Performance Status...............................................................................52
9.3.9
Patient Height and Weight ...............................................................................52
9.3.10
Vital Signs.......................................................................................................52
9.3.11
Concomitant Medications and Procedures........................................................53
9.3.12
AEs .................................................................................................................53
9.3.13
ECG ................................................................................................................53
9.3.14
Clinical Laboratory Evaluations.......................................................................53
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9.3.15
Pregnancy Test ................................................................................................54
9.3.16
Disease Assessment.........................................................................................54
9.3.17
Confirmation of ALK Positivity.......................................................................55
9.3.18
PK Measurements............................................................................................55
9.3.19
Circulating DNA Measurements......................................................................56
9.3.20
Dosing Diary ...................................................................................................56
9.3.21
Quality of Life Assessment: Cancer (EORTC QLQ-C30, QLQ-LC13, and 
QLQ-BN20) ....................................................................................................56
9.3.22
Quality of Life Assessment: EQ-5D-5L Measurement .....................................57
9.3.23
Health Resource Utilization Data Collection....................................................57
9.3.24
End-of-Treatment Visit....................................................................................57
9.3.25
30 Days After Last Dose..................................................................................57
9.3.26
Follow-up Period.............................................................................................58
9.4
Completion of Study Treatment (for Individual Patients) .........................................58
9.5
Completion of Study (for Individual Patients)..........................................................58
9.6
Discontinuation of Treatment With Study Drug .......................................................58
9.7
Study Compliance....................................................................................................59
9.8
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)..................................................................................................................59
10.0
ADVERSE EVENTS ....................................................................................................60
10.1
Definitions...............................................................................................................60
10.1.1
Pretreatment Event Definition..........................................................................60
10.1.2
AE Definition ..................................................................................................60
10.1.3
SAE Definition................................................................................................61
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................61
10.3
Monitoring of AEs and Period of Observation .........................................................62
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........63
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................63
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........64
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
11.1
Steering Committee .................................................................................................64
11.2
IRC..........................................................................................................................64
11.3
Independent Data Monitoring Committee ................................................................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65
12.1
eCRFs......................................................................................................................65
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12.2
Record Retention .....................................................................................................66
13.0
STATISTICAL METHODS..........................................................................................66
13.1
Statistical and Analytical Plans ................................................................................66
13.1.1
Analysis Sets ...................................................................................................66
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................67
13.1.3
Efficacy Analysis.............................................................................................67
13.1.4
PK Analysis.....................................................................................................69
13.1.5
Analysis of PRO and Health Resource Utilization Data ...................................69
13.1.6
Safety Analysis................................................................................................70
13.2
IA............................................................................................................................70
13.3
Determination of Sample Size..................................................................................71
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................71
14.1
Study-Site Monitoring Visits ...................................................................................71
14.2
Protocol Deviations..................................................................................................71
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................72
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB and/or IEC Approval ........................................................................................72
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................74
15.4.1
Publication.......................................................................................................74
15.4.2
Clinical Trial Registration................................................................................75
15.4.3
Clinical Trial Results Disclosure......................................................................75
15.5
Insurance and Compensation for Injury....................................................................76
16.0
REFERENCES..............................................................................................................77
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................31
Table 8.a
Recommended Brigatinib Dose Reduction Levels..............................................37
Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs.....37
Table 8.c
Alectinib Dose Reduction Schedule ...................................................................41
Table 8.d
Alectinib Dose Modification Recommendations for Treatment-Related AEs......42
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................54
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LIST OF IN-TEXT FIGURES
Figure 6.a
Study Design......................................................................................................28
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................81
Appendix B
Responsibilities of the Investigator.....................................................................85
Appendix C
Investigator Consent to Use of Personal Information..........................................87
Appendix D
ECOG Scale for Performance Status ..................................................................88
Appendix E
RECIST (Version 1.1)........................................................................................89
Appendix F
Modification of Diet in Renal Disease Equation for Estimated Glomerular 
Filtration Rate....................................................................................................92
Appendix G
Protocol History.................................................................................................93
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc (TDCA) 
Compound:
Brigatinib (AP26113)
Title of Protocol: A Phase 3 Randomized Open-label 
Study of Brigatinib (ALUNBRIG®) Versus Alectinib 
(ALECENSA®) in Advanced Anaplastic Lymphoma 
Kinase-Positive Non–Small-Cell Lung Cancer Patients 
Who Have Progressed on Crizotinib (XALKORI®)
IND No.: 
IND 110,935
EudraCT No.:
2018-001957-29
Study Number: Brigatinib-3001
Phase: 3
Study Design: 
A phase 3, randomized, open-label, comparative, multicenter, international study of patients with anaplastic 
lymphoma kinase-positive (ALK+) non–small-cell lung cancer (NSCLC) who have progressed on crizotinib
Primary Objective:
To compare the efficacy of brigatinib to that of alectinib in patients with ALK+ locally advanced or metastatic NSCLC 
who have progressed on crizotinib as evidenced by progression-free survival (PFS) as assessed by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Secondary Objectives:
1.
To compare the efficacy of brigatinib to that of alectinib as evidenced by overall survival (OS), PFS as assessed
by the investigator, objective response rate (ORR), time to response, and duration of response (DOR) (all as
assessed by RECIST v1.1).
2.
To compare the efficacy of brigatinib in the central nervous system (CNS)to that of alectinib as evidenced by
intracranial objective response rate (iORR), intracranial duration of response (iDOR), and time to intracranial
progressive disease (iPD) without prior systemic progression as assessed by modified RECIST criteria.
3.
To assess the safety and tolerability of brigatinib in comparison with alectinib.
4.
To collect plasma concentration-time data for brigatinib to contribute to population pharmacokinetic (PK)
analyses.
5.
To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organization
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (v3.0) and its
Quality of Life Lung Cancer Module (QLQ-LC13), in patients treated with brigatinib compared with those treated
with alectinib.
Exploratory Objectives: 
1.
To compare the efficacy in the CNS of brigatinib to that of alectinib as evidenced by iORR, iDOR, and time to
iPD, per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
2.
To explore the molecular determinants of efficacy and safety with brigatinib and alectinib.
3.
To evaluate health resource utilization.
4.
To use patient reported outcomes to assess morbidity related to CNS symptoms.
Subject Population: Adult patients with locally advanced or metastatic ALK+ NSCLC whose disease has progressed 
on crizotinib.
Number of Subjects:
Approximately 246 expected 
Number of Sites: 
100-120 globally.
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Dose Level(s):
Arm A: Brigatinib 180 mg once daily (QD) with a 7-day 
lead-in at 90 mg QD. Brigatinib can be taken with or 
without food.
Arm B: Alectinib 600 mg orally twice daily with food.
Route of Administration:
Oral
Duration of Treatment:
Patients will continue to be treated with brigatinib or 
alectinib until they experience objective disease 
progression by the investigator’s assessment per RECIST 
v1.1 or until any other discontinuation criterion is met. 
Continuation of brigatinib and alectinib beyond 
progression is permitted, at the investigator’s discretion, 
if there is evidence of continued clinical benefit.
Period of Evaluation: 
The total estimated duration of the study is 
approximately 5 years, including approximately 2 years 
to accrue patients, with approximately 3 years for 
treatment and follow-up of the last patient. 
Main Criteria for Inclusion:

Male or female, aged 18 years or older or of local legal adult age.

Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC.

Must meet one of the following criteria:
–
Have documentation of anaplastic lymphoma kinase (ALK) rearrangement by a positive result from 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.
–
Have documented ALK rearrangement by a different test and be able to provide a tumor sample to the central 
laboratory. (Note: central laboratory ALK rearrangement testing results are not required to be obtained before 
randomization.)

Had progressive disease while on crizotinib, as assessed by the investigator or treating physician. (Note: crizotinib 
does not need to be the last therapy a patient received. The patient may have received chemotherapy as his/her last 
systemic anticancer therapy.)

Treatment with crizotinib for at least 4 weeks before progression.

Have had no other ALK inhibitor other than crizotinib.

Have had no more than 2 prior regimens of systemic anticancer therapy in the locally advanced or metastatic 
setting (other than crizotinib).
(Note: a systemic anticancer therapy regimen will be counted if it is administered for at least 1 complete cycle at 
least 1 cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen. Neoadjuvant 
or adjuvant systemic anticancer therapy will be counted as a prior regimen if disease progression/recurrence 
occurred within 12 months upon completion of this neoadjuvant or adjuvant therapy.
*Systemic therapy followed by maintenance therapy will be considered as one regimen if the maintenance 
therapy consists of a drug or drugs that were used in the regimen that immediately preceded maintenance.

Have Eastern Cooperative Oncology Group performance status of 0 to 2.

Have at least 1 measurable (ie, target) lesion per RECIST v1.1.

Have recovered from toxicities related to prior anticancer therapy to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 grade ≤1. (Note: treatment-related alopecia or 
peripheral neuropathy that are grade >1 are allowed, if deemed irreversible.)

Have adequate organ function, as determined by:
–
Total bilirubin ≤1.5 times the upper limit of the normal range (ULN).
–
Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2, using the modification of diet in renal disease 
equation.
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–
Alanine aminotransferase/aspartate aminotransferase ≤2.5 × ULN; ≤5 × ULN is acceptable if liver 
metastases are present.
–
Serum lipase ≤1.5 × ULN.
–
Platelet count ≥75 × 109/L.
–
Hemoglobin ≥9 g/dL.
–
Absolute neutrophil count ≥1.5 × 109/L.

Suitable venous access for study-required blood sampling (ie, including PK and laboratory safety tests).

Have the willingness and ability to comply with scheduled visit and study procedures.

For female patients of childbearing potential, have a negative pregnancy test documented before randomization.

For female and male patients who are fertile, agree to use a highly effective form of contraception with their 
sexual partners during the dosing period and for a period of at least 120 days after the end of treatment with 
brigatinib, or alectinib.
(Note: Given that, globally, the patient population that has received crizotinib as the sole ALK inhibitor is decreasing, 
Takeda reserves the right to amend the inclusion criteria to include crizotinib intolerant patients and/or patients who 
have progressed on or been found intolerant to ALK inhibitors other than crizotinib, brigatinib, or alectinib.)
Main Criteria for Exclusion:

Participation in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L)

Received crizotinib within 7 days before randomization.

Have a history or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation 
pneumonitis.

Have uncontrolled hypertension. Patients with hypertension should be under treatment for control of blood 
pressure upon study entry.

Received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, moderate CYP3A inhibitors, 
strong CYP3A inducers, or moderate CYP3A inducers within 14 days before randomization. 

Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, 
before randomization.

Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated 
nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or patients 
with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the 
diagnosis of the other primary malignancy.

Received chemotherapy or radiation therapy within 14 days before randomization except for stereotactic 
radiosurgery or stereotactic body radiation therapy.

Received anticancer monoclonal antibodies within 30 days of randomization.

Had major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or 
minimally invasive biopsies, are allowed.

Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (patients with asymptomatic 
brain metastases or who have stable symptoms that did not require an increased dose of corticosteroids to control 
symptoms in the 7 days before randomization will be enrolled). 
(Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to 
complete local therapy and be neurologically stable [with no requirement for an increasing dose of corticosteroids 
or use of anticonvulsants] for at least 7 days before randomization.)

Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). 
Patients with leptomeningeal disease and without cord compression are allowed.

Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to the 
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following: 
1.
Myocardial infarction within 6 months before randomization.
2.
Unstable angina within 6 months before randomization.
3.
New York Heart Association Class III or IV heart failure within 6 months before randomization.
4.
History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as 
determined by the treating physician.
5.
Any history of clinically significant ventricular arrhythmia.

Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of study drug.

Have malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the 
study drug.

Have an ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics.

Have a known history of HIV infection. Testing is not required in the absence of history.

Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. Testing is not 
required in the absence of history.

Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, potentially 
compromise patient safety or interfere with the completion of treatment according to this protocol.

Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.

Life-threatening illness unrelated to cancer.
Main Criteria for Evaluation and Analyses:
Primary Endpoint:
The primary endpoint is PFS as assessed by the blinded Independent Review Committee (BIRC) per RECIST v1.1.
Key Secondary Endpoint:
OS.
Other Secondary Endpoints:
1.
PFS, as assessed by the investigator per RECIST v1.1.
2.
ORR, as assessed by the investigator and BIRC per RECIST v1.1.
3.
DOR, as assessed by the investigator and BIRC.
4.
Time to response, as assessed by the investigator and BIRC.
5.
iORR, as assessed by BIRC per modified RECIST v1.1 (as described in protocol and BIRC charter).
6.
iDOR, as assessed by the BIRC per modified RECIST v1.1.
7.
Time to iPD, as assessed by the BIRC per modified RECIST v1.1.
8.
HRQoL assessed with the global health status/quality of life and other function and symptom domains from 
EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13.
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Safety Endpoints:
Safety assessments will include physical and laboratory examinations, vital signs, and electrocardiograms. Adverse 
events will be graded according to the NCI CTCAE v4.03.
Exploratory Endpoints:
1.
CNS efficacy outcomes as assessed by the BIRC per RANO-BM criteria (iORR, iDOR, and time to iPD).
2.
Molecular determinants of efficacy and safety with brigatinib and alectinib.
3.
HRQoL measured by EuroQoL–5 Dimensions–5 Levels (EQ-5D-5L) questionnaires.
4.
Items from the EORTC Quality of Life Brain Cancer Module (QLQ-BN20) used to assess morbidity related to 
CNS symptoms.
5.
To evaluate health resource utilization.
Statistical Considerations:
The primary analysis of the primary endpoint will be performed using a 2-sided stratified log-rank test (stratification 
factors: presence of intracranial CNS metastases at baseline [yes vs no] and best prior response to crizotinib therapy as 
assessed by the investigator [complete response/partial response vs any other response/status unknown]) to compare 
BIRC-assessed PFS of patients randomized to brigatinib with the BIRC-assessed PFS of patients randomized to 
alectinib. The overall (2-sided) type I error rate will be controlled at 0.05. The primary analysis will be based on the 
intent-to-treat population. The Kaplan Meier (K-M) survival curves and K-M estimates (if estimable), along with their 
2-sided 95% CIs, will be provided for each treatment group. Additionally, hazard ratios will be estimated using the 
stratified Cox regression model with the stratification factors.
The interim analysis (IA) for efficacy and futility will be performed after the first 115 events have been observed, and 
the final analysis of the primary endpoint will be performed after 164 events have been observed. An 
O’Brien-Fleming Lan-DeMets alpha spending function will be used to control the overall alpha level at 0.05 2-sided. 
A gamma spending function will be used for the futility stopping boundary. Futility is nonbinding. OS, the key 
secondary endpoint, will be formally tested for statistical significance only once when PFS per BIRC is statistically 
significant. 
Further details of statistical analyses including the data handling rules will be provided in the statistical analysis plan.
Sample Size Justification: 
For the purposes of this sample size calculation, the median PFS for alectinib is estimated as 9 months and the PFS for 
brigatinib is estimated to be 15 months on the basis of the outcomes observed in previous single-arm studies. 
Approximately 246 patients will be randomized in a 1:1 fashion to receive brigatinib or alectinib. A total of 164 events 
(progression or death among the randomized patients) will provide 90% power to detect a 6-month improvement in 
PFS (hazard ratio=0.60). This power projection is based on a 2-sided log-rank test, and is controlled at the 2-sided 0.05 
level, adjusting for the proposed IA plan. The number of events is fixed, but the enrollment number may change based 
on an assessment of the overall event rate pooled across treatment groups before the close of enrollment.
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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, 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
BIRC
blinded Independent Review Committee
CFR
Code of Federal Regulations
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CR
complete response
CT
computed tomography
CYP
cytochrome P-450
DOR
duration of response
DTP
direct-to-patient
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EOPE
early onset pulmonary events
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
EuroQoL–5 Dimensions–5 Levels
EQ VAS
EQ 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
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
ICH
International Conference on Harmonisation
ICF
informed consent form
IDMC
Independent Data Monitoring Committee
iDOR
intracranial duration of response
IEC
independent ethics committee
iORR
intracranial objective response rate
iPD
intracranial progression without prior systemic progression 
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IRC
Independent Review Committee
IRB
institutional review board
ITT
intent-to-treat
LD
longest diameter(s)
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
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
QD
once daily
QLQ-BN20
Quality of Life Brain Cancer Module
QLQ-C30
Quality of Life Questionnaire-Core 30
QLQ-LC13
Quality of Life Lung Cancer Module
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SLD
sum of the longest diameters
SRS
stereotactic radiosurgery
SUSAR
suspected unexpected serious adverse reaction
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
US
United States
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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 or 
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 the end of 2018, and 154,050 deaths are estimated to occur due to the disease [3]. In 
the EU, lung cancer is ranked as the fourth most frequent cancer; approximately 313,000 new 
cases were diagnosed in 2012 with 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 (ganjoho.jp/reg_stat/statistics/index.html, Accessed 
07 March 2018 [in Japanese]). Most lung cancer cases are diagnosed at advanced stages and about 
78% of newly diagnosed patients have regional/distant disease [1,6].
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 more than 80% of all lung cancers 
[7,8], and includes a number of subtypes such as adenocarcinoma, squamous cell carcinoma, large 
cell carcinoma, and bronchioloalveolar carcinoma [9]. More recently, attention has turned to 
stratifying patients with lung cancer 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, ALK receptor tyrosine kinase (ALK) rearranged, ROS 
proto-oncogene 1, receptor tyrosine kinase (ROS1) rearranged, or B-Raf proto-oncogene, 
serine/threonine kinase (BRAF) V600E mutant NSCLC. The focus herein is on NSCLC that 
contain oncogenic rearrangements in the ALK gene, and the role of brigatinib, a novel small 
molecule inhibitor, in the treatment of anaplastic lymphoma kinase-positive (ALK+) NSCLC. 
4.1.2
ALK+ NSCLC
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase encoded on chromosome 2 and is 
primarily involved in developmental processes and expressed at low levels in adults [10]. The first 
genetic rearrangement of ALK seen in NSCLC involved a fusion between the echinoderm 
microtubule associated protein like 4 gene (EML4) and the ALK tyrosine kinase domain. 
EML4-ALK has the capacity to transform fibroblasts grown in culture and as subcutaneous 
xenografts to induce tumor formation [11]. 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 [12,13]. 
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Estimates of the frequency of ALK rearrangement in the overall population of patients with 
NSCLC range from 2% to 7% [14,15], which represent, based on proportionality of total 
populations in the US and EU, approximately 7000 to 25,000 patients in the US and 5800 to 
20,000 patients in the EU with ALK+ NSCLC 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 KRAS proto-oncogene, GTPase (KRAS) [10]. 
4.1.3
Current Treatment for ALK+ NSCLC
While the standard treatment algorithm for patients with unselected NSCLC 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 [16]. The efficacy of crizotinib has been confirmed in a randomized study of crizotinib 
versus chemotherapy [16,17].
ALK-dependent mechanisms of resistance, observed in approximately 30% of patients [18], 
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 [19,20]. The central nervous system (CNS) is the first site of progression in 
approximately 50% of patients treated with crizotinib [21,22], 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 [23] and alectinib [24], have become available for 
patients with NSCLC with ALK rearrangements. Both drugs are effective in patients previously 
treated with crizotinib. Ceritinib demonstrated significantly improved progression-free survival 
(PFS) vs chemotherapy (hazard ratio [HR] 0.55) [25] whereas alectinib demonstrated significantly 
improved PFS vs crizotinib (HR 0.34-0.47) [26,27] 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 [17,26-29]. 
More recently, the investigational agent lorlatinib has been evaluated in a phase 1/2 study showing
responses after ≥1 prior ALK tyrosine kinase inhibitor (TKI) (25% [11 of 44] objective response 
rate [ORR] in patients with 2 prior ALK TKI and 31% [4 of 13] ORR in patients with 3 prior ALK 
TKI). The most common treatment-related adverse events (AEs) were hypercholesterolemia (90%) 
and hypertriglyceridemia (72%) [28]. 
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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 after crizotinib with over 50% of these patients 
developing brain metastases. The impact of progression is seen in the quality of life of patients as 
well as their survival. Despite 2 ALK inhibitors (ie, ceritinib and alectinib) being available for 
crizotinib failures, the majority of patients currently treated with ALK inhibitors in second-line 
therapy progress within 1 year. ALK secondary mutations associated with clinical resistance and 
treatment failure to crizotinib, ceritinib, and alectinib have been identified. The alternative 
treatments for these patients include chemotherapy and checkpoint inhibitors (PD-1 or PD-L1 
antibody). The efficacy of platinum doublet chemotherapy is not impacted by prior TKI treatment; 
however, the benefits of doublet therapy are limited with response rates about 30% and median 
PFS about 4 months [29]. Checkpoint inhibitors have recently become available 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 [30], possibly related to 
the low mutation burden in this population. Of note, patients with ALK+ NSCLC are often 
nonsmokers, which may help to explain the low mutation burden [31].
Clinicians treating patients with ALK+ NSCLC with metastatic disease need to know the benefit, 
in months, of one next generation ALK inhibitor versus another in terms of PFS, time to 
intracranial progression without prior systemic progression (iPD), duration of response (DOR), 
and intracranial duration of response (iDOR). These measures represent time free of interventions 
such as radiotherapy or surgery. The likelihood of response as assessed by PFS as assessed by the 
investigator, ORR, and intracranial objective response rate (iORR) are also important factors in 
clinical decision making. Given that the majority of these patients will have had CNS metastases, 
the intracranial data obtained from this study will be of particular value in determining the best 
therapeutic option for that large subset of patients with brain metastases present at the initiation of 
therapy. This study (the primary analysis) will provide the CNS data to address this unmet medical 
need. 
Brigatinib
Brigatinib (AP26113) is a novel, orally administered 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 >100-fold selectivity over ALK-negative lines. 
In clinical studies, 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 mentioned 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 DOR was 15.7 months (95% CI: 12.8, 21.8 event rate: 54.8%) and median PFS 
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was 16.7 months (95% CI: 11.6, 21.4, event rate: 49.1%). High IRC-assessed iORR (66.7%, 12/18, 
95% CI: 41.0, 86.7) with a median 16.6 month (95% CI: 3.7, not reached) iDOR 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 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or 
are intolerant of crizotinib. 
4.2
Rationale for the Proposed Study
Crizotinib has been approved by both the FDA and European Medicines Agency (EMA) for 
first-line treatment of advanced ALK+ NSCLC, after 2 phase 3 clinical studies demonstrated a 
significant PFS benefit over chemotherapy [32,33]. Since crizotinib was approved for first-line 
treatment of advanced ALK+ NSCLC, several newer ALK inhibitors with greater efficacy and 
tolerability have been developed and approved for this patient population. 
The newer ALK inhibitors, ceritinib, alectinib, and brigatinib, have been shown to be of benefit in 
a postcrizotinib setting. Ceritinib received accelerated approval by the FDA in April 2014, and was 
approved in the EU in May 2015, in patients previously treated with crizotinib [34-36]. In a phase 
2 study of ceritinib, patients who had progressed on crizotinib showed an ORR of 38.6% and a 
median PFS of 5.7 months [35]. In patients with intracranial brain metastases, the iORR was 33% 
[35]. Alectinib was granted accelerated approval in the US in December 2015 for patients with 
ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In 2017, alectinib received 
conditional marketing authorization from the EMA in patients with ALK+ NSCLC previously 
treated with crizotinib. In 1 clinical studies, alectinib has been shown to be well tolerated by 
patients. The ORR based on IRC assessment was 38% and 44% in studies 1 and 2, respectively 
[37-39]. Median PFS was approximately 9 months [38]. In patients with intracranial CNS 
metastases (N = 51), the iORR was 61%, with a median duration of CNS response of 9.1 months 
[24]. Brigatinib received accelerated approval by the FDA in April 2017 for the treatment of 
patients with metastatic ALK+ NSCLC who have progressed on or are intolerant of crizotinib. 
Brigatinib’s accelerated approval was based on efficacy seen in a 2-arm, open-label, multicenter 
trial (NCT02094573 [ALTA]). In this study, patients with ALK+ NSCLC who had progressed on 
crizotinib demonstrated an IRC assessed ORR of 51% in patients given 90 mg QD (Arm A; 
N = 112) and 55% in patients who were given 180 mg QD with a 7-day lead in at 90 mg QD 
(Arm B; N = 110). The IRC-assessed median DOR was 13.8 months in Arm A and 14.8 months in 
Arm B. IRC-assessed PFS was 9.2 months in Arm A and 16.7 months in Arm B. In patients with 
measurable brain metastases, the iORR was 50% (N = 26) in Arm A and 67% (N = 18) in Arm B, 
and median iDOR was not reached in Arm A and was 16.6 months in Arm B. Both doses were well 
tolerated in this study. Based on these results, the recommended dosing regimen of brigatinib is 
180 mg QD with 7-day lead-in at 90 mg QD. 
Both brigatinib and alectinib are being or have been compared directly with crizotinib as first line 
therapy in separate phase 3 open-label studies. Alectinib demonstrated a PFS advantage in 
previously untreated advanced ALK+ NSCLC; HR for disease progression or death, 0.47 [95% CI, 
0.34 to 0.65]; p<0.001 [26]. Brigatinib is being compared with crizotinib in patients with advanced 
ALK+ NSCLC treated with 1or fewer lines of systemic chemotherapy in the phase 3 randomized 
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open-label ALTA-1L study. ALTA-1L completed enrollment in August 2017, with follow-up 
ongoing. 
There is a need for a head-to-head comparison of the newer ALK inhibitors in this patient 
population. This study will provide a direct comparison of brigatinib with alectinib. This study will 
be conducted in the postcrizotinib setting rather than in the ALK inhibitor naïve setting, because 
the sample size required for a head-to-head study in the first-line setting would be prohibitive. 
Alectinib has been chosen as the comparator, because it is more widely prescribed than ceritinib or 
lorlatinib. Data also suggest alectinib has the best PFS in this setting; although at this time, 
lorlatinib data is still maturing.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to compare the efficacy of brigatinib to that of alectinib in patients with 
ALK+ locally advanced or metastatic NSCLC who have progressed on crizotinib as evidenced by 
PFS as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
5.1.2
Secondary Objectives
The secondary objectives are:
1. To compare the efficacy of brigatinib with that of alectinib as evidenced by overall survival 
(OS), PFS as assessed by the investigator, ORR, DOR, and time to response (all as assessed by 
RECIST v1.1).
2. To compare the efficacy of brigatinib in the CNS to that of alectinib as evidenced by iORR, 
iDOR, and time to iPD as assessed by modified RECIST criteria. 
3. To assess the safety and tolerability of brigatinib in comparison with alectinib.
4. To collect plasma concentration-time data for brigatinib to contribute to population 
pharmacokinetic (PK) analyses.
5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) (v3.0) and its Quality of Life Lung Cancer Module 
(QLQ-LC13), in patients treated with brigatinib compared with those treated with alectinib.
5.1.3
Exploratory Objectives
The exploratory objectives are:
1. To compare the efficacy in the CNS of brigatinib to that of alectinib as evidenced by iORR, 
iDOR, and time to iPD, per the Response Assessment in Neuro-Oncology Brain Metastases 
(RANO-BM) criteria.
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2. To explore the molecular determinants of efficacy and safety with brigatinib and alectinib.
3. To evaluate health resource utilization.
4. To use patient reported outcomes to assess morbidity related to CNS symptoms.
5.2
Endpoints
5.2.1
Primary Endpoint

The primary endpoint is PFS as assessed by the blinded Independent Review Committee 
(BIRC) per RECIST v1.1.
5.2.2
Secondary Endpoints
Key Secondary Endpoint:

OS.
Other Secondary Endpoints:
1. PFS, as assessed by the investigator per RECIST v1.1.
2. ORR, as assessed by the investigator and BIRC per RECIST v1.1.
3. DOR, as assessed by the investigator and BIRC.
4. Time to response, as assessed by the investigator and BIRC.
5. iORR, as assessed by BIRC per modified RECIST v1.1 (as described in protocol and BIRC 
charter).
6. iDOR, as assessed by the BIRC per modified RECIST v1.1.
7. Time to iPD, as assessed by the BIRC per modified RECIST v1.1.
8. HRQoL assessed with the global health status/quality of life and other function and symptom 
domains from EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13.
5.2.3
Safety Endpoints
The safety endpoint assessments will include physical and laboratory examinations, vital signs, 
and electrocardiograms (ECGs). AEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. 
5.2.4
Exploratory Endpoints
The exploratory endpoints are:
1. CNS efficacy outcomes as assessed by the BIRC per RANO-BM criteria (iORR, iDOR, 
and time to iPD).
2. Molecular determinants of efficacy and safety with brigatinib and alectinib as uncovered by 
genetic alterations noted on tumor tissue DNA or plasma samples of circulating tumor DNA.
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3. HRQoL measured by EuroQoL–5 Dimensions–5 Levels (EQ-5D-5L) questionnaires.
4. To evaluate healthcare resource utilization.
5. Items from the EORTC Quality of Life Brain Cancer Module (QLQ-BN20) used to assess 
morbidity related to CNS symptoms.
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a phase 3, randomized, open-label, comparative, multicenter, international study in which 
patients with ALK+ NSCLC who have progressed on crizotinib will be randomized in a 
1:1 fashion to receive brigatinib in Arm A or alectinib in Arm B. Patients will be stratified by the 
presence of intracranial CNS metastases at baseline (Yes versus No) and best prior response to 
crizotinib therapy as assessed by the investigator (complete response [CR]/partial response [PR] 
vs any other response/status unknown). 
Patients will be treated on each arm until they experience progressive disease (PD) assessed by the 
investigator or intolerable toxicity, or until any other discontinuation criterion is met. On each arm, 
treatment will be given continuously. For logistical convenience, every 28 days is defined as 
1 cycle. Continuation of study drug beyond progression is permitted, if there is potential for 
continued clinical benefit (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). 
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The primary endpoint of the study is to compare the efficacy of brigatinib with that of alectinib in 
patients with ALK+ locally advanced or metastatic NSCLC who have progressed on crizotinib as 
evidenced by BIRC-assessed PFS. An interim analysis (IA) to assess the primary endpoint will be 
conducted once 70% of PFS events have been observed. It is expected that enrollment will be 
completed before reaching IA. 
AEs will be assessed from the time a patient signs the informed consent form (ICF) until 30 days 
after last dose of the study drug a patient receives. Patients’ signs and symptoms, laboratory values, 
vital signs, ECGs, and any other relevant special examinations as clinically indicated will be 
obtained to evaluate the safety and tolerability of brigatinib. For patients randomized to the 
brigatinib arm of the study (Arm A), sparse PK samples will be collected during the study to 
measure plasma concentrations of brigatinib as outlined in Appendix A, PK Sampling Schedule. 
Before randomization, ALK status must be confirmed with documentation from a pathology report 
of ALK+ tumor tissue. If the determination of ALK positivity was made by a non-FDA-approved 
test, tumor tissue (archival or new biopsy) must be submitted to a central laboratory for ALK
rearrangement testing. Central laboratory results of ALK testing are not required to be available 
before randomization. Given that all patients are required to have received therapy with crizotinib, 
it is not deemed necessary that central laboratory tests be in agreement with local ALK tests (it is 
anticipated that the central laboratory will have an intrinsic false negative rate).
For patients for whom there is available formalin-fixed, paraffin-embedded (FFPE) tumor tissue 
that was acquired after progression on crizotinib, a sample will be requested for exploratory 
molecular genetic analysis. In patients without such tissue available, an optional biopsy for 
exploratory molecular genetic analysis may be obtained during screening if the patient has an 
amenable lesion. An optional biopsy will be obtained at the time of disease progression for patients 
who consent to the procedure and genetic testing of the sample. FFPE tumor tissue will be used for 
exploratory molecular genetic analysis. For all patients, blood samples will be obtained for 
exploratory biomarker studies, including molecular genetic analysis, according to the Schedule of 
Events (Appendix A).
Toxicity will be evaluated according to NCI CTCAE, Version 4.03, effective date 
14 June 2010 [40].
6.2
Number of Patients
The expected number of patients is 246 enrolled at 100 to 120 sites globally (a patient is 
considered to be enrolled in the study once the ICF is signed, all screening evaluations are 
completed and the patient has been randomized).
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will continue to be treated with brigatinib or alectinib until they experience objective 
disease progression by the investigator’s assessment per RECIST v1.1 or until any other 
discontinuation criterion is met. Continuation of brigatinib and alectinib beyond progression is 
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permitted, at the investigator’s discretion, if there is evidence of continued clinical benefit (see 
Section 8.2). 
The follow-up period for survival begins after a patient has permanently discontinued study drug 
and continues until that 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. All new systemic anticancer therapies initiated in the 
follow-up period should be reported.
An IA for efficacy and futility to assess the primary endpoint will be conducted once 70% of PFS 
events have been observed. This corresponds to 115 PFS events. 
The primary analysis for the primary endpoint will be conducted when 164 events have been 
observed, which is approximately 30 months after the first patient has enrolled. 
The final analysis for OS and HRQoL endpoints will occur approximately 5 years after the first 
patient has enrolled. The study will end after the final analysis has been performed. The sponsor 
may also terminate the study prematurely due to safety or administration reasons.
This study will begin to enroll patients in May 2019. The overall timeframe will depend upon the
actual enrollment rate and event rate.
6.3.2
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Maximum Timeframe
Primary:
PFS as assessed by the BIRC per RECIST v1.1.
Up to 5 years
Key Secondary:
OS.
Up to 5 years
Other Secondary:
1.
PFS, as assessed by the investigator per RECIST v1.1. 
Up to 5 years
2.
ORR, as assessed by the BIRC per RECIST v1.1.
Up to 5 years
3.
DOR, as assessed by the investigator and BIRC.
Up to 5 years
4.
Time to response, as assessed by the investigator and BIRC.
Up to 5 years
5.
iORR, as assessed by BIRC per modified RECIST v1.1 (as described in 
protocol and BIRC charter).
Up to 5 years
6.
iDOR, as assessed by the BIRC per modified RECIST v1.1.
Up to 5 years
7.
Time to iPD, as assessed by the BIRC per modified RECIST v1.1.
Up to 5 years
8.
HRQoL assessed with the global health status/quality of life and other 
function and symptom domains from EORTC QLQ-C30 (v3.0), and 
EORTC QLQ-LC13.
Up to 5 years after FPI
Abbreviations: BIRC, blinded Independent Review Committee; EORTC, European Organization for Research and 
Treatment of Cancer; FPI, first patient in; HRQoL, health-related quality of life; iDOR, intracranial duration of 
response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; QLQ-C30, Quality of 
Life Questionnaire-Core 30; QLQ-LC13, Quality of Life Lung Cancer Module; RECIST, Response Evaluation 
Criteria in Solid Tumors.
6.3.3
Total Study Duration
The time for completion of the clinical study report analyzing the primary and secondary 
endpoints will be approximately 5 years. The time for completion of the entire study 
(eg, completion of clinical study report reporting OS and HRQoL results) will be approximately 
5 years.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be randomized:
1. Male or female, aged 18 years or older or of local legal adult age.
2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
3. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or 
stage IV NSCLC.
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4. Must meet one of the following criteria:
a) Have documentation of ALK rearrangement by a positive result from 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. 
b) Have documented ALK rearrangement by a different test and be able to provide tumor 
sample to the central laboratory. (Note: central laboratory ALK rearrangement testing 
results are not required to be obtained before randomization.)
5. Had PD while on crizotinib, as assessed by the investigator or treating physician. (Note: 
crizotinib does not need to be the last therapy a patient received. The patient may have received 
chemotherapy as his/her last therapy.)
6. Treatment with crizotinib for at least 4 weeks before progression.
7. Have had no other ALK inhibitor other than crizotinib.
8. Have had no more than 2 prior regimens of systemic anticancer therapy (other than crizotinib) 
in the locally advanced or metastatic setting*.
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. Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior 
regimen if disease progression/recurrence occurred within 12 months upon completion of this 
neoadjuvant or adjuvant therapy. 
*Systemic therapy followed by maintenance therapy will be considered as one regimen if the 
maintenance therapy consists of a drug or drugs that were used in the regimen that immediately 
preceded maintenance.
9. Have at least 1 measurable (ie, target) lesion per RECIST v1.1.
10. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v4.03 grade 
≤1. (Note: treatment-related alopecia or peripheral neuropathy that are grade >1 are allowed, if 
deemed irreversible.)
11. Have adequate organ function, as determined by:
a) Total bilirubin ≤1.5 times the upper limit of normal (ULN).
b) Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2, using the modification of diet 
in renal disease equation (Appendix F).
c) Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN; ≤5 × 
ULN is acceptable if liver metastases are present.
d) Serum lipase ≤1.5 × ULN.
e) Platelet count ≥75 ×109/L.
f)
Hemoglobin ≥9 g/dL.
g) Absolute neutrophil count ≥1.5 × 109/L.
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12. Suitable venous access for study-required blood sampling (ie, including PK and laboratory 
safety tests).
13. Have the willingness and ability to comply with scheduled visits and study procedures.
14. For female patients of childbearing potential, have a negative pregnancy test documented 
before randomization.
15. Female patients of childbearing potential and male patients with partners of childbearing 
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 120 days after the end of 
treatment with either brigatinib or alectinib (Section 8.6.1.1).
16. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days (or if the drug has a very long half-life, for 90 days plus five 
half-lives) after the last dose of study drug, or
b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (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.)
c) Do not donate semen or sperm during treatment and for 90 days after the last dose of study 
therapy.
17. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
(Note: Given that, globally, the patient population who has received crizotinib as the sole ALK 
inhibitor is decreasing, Takeda reserves the right to amend the inclusion criteria to include 
crizotinib intolerant patients and/or patients who have progressed on or been found intolerant to 
ALK inhibitors other than crizotinib, brigatinib, or alectinib.)
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be randomized to treatment:
1. Participation in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L).
2. Received crizotinib within 7 days before randomization.
3. Have a history or presence at baseline of pulmonary interstitial disease, drug-related 
pneumonitis, or radiation pneumonitis.
4. Have uncontrolled hypertension. Patients with hypertension should be under treatment for 
control of blood pressure upon study entry.
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5. Received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, moderate 
CYP3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days 
before randomization (refer to Section 8.5 for a list of example medications).
6. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, 
whichever is longer, before randomization.
7. Have been diagnosed with another primary malignancy other than NSCLC, except for 
adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated 
nonmetastatic prostate cancer; or patients with another primary malignancy who are 
definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary 
malignancy.
8. Received chemotherapy or radiation therapy within 14 days before randomization except for 
stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
9. Received antineoplastic monoclonal antibodies within 30 days of randomization.
10. Had major surgery within 30 days of randomization. Minor surgical procedures, such as 
catheter placement or minimally invasive biopsies, are allowed.
11. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (patients 
with asymptomatic brain metastases or patients who have stable symptoms and did not require 
an increased dose of corticosteroids to control symptoms within 7 days before randomization 
will be enrolled). Note: If a patient has worsening neurological symptoms or signs due to CNS 
metastasis, the patient needs to complete local therapy and be neurologically stable (with no 
requirement for an increasing dose of corticosteroids or use of anticonvulsants) for at least 7 
days before randomization.
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by 
radiographic imaging). Patients with leptomeningeal disease and without cord compression are 
allowed.
13. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not 
restricted to the following: 
a) Myocardial infarction within 6 months before randomization.
b) Unstable angina within 6 months before randomization.
c) New York Heart Association Class III or IV heart failure within 6 months before 
randomization.
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.
14. Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of 
study drug. 
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15. Have malabsorption syndrome or other gastrointestinal illness or condition that could affect 
oral absorption of the study drug. 
16. Have an ongoing or active infection, including but not limited to, the requirement for 
intravenous antibiotics.
17. Have a known history of HIV infection. Testing is not required in the absence of history.
18. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. 
Testing is not required in the absence of history.
19. Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, 
potentially compromise patient safety or interfere with the completion of treatment according 
to this protocol.
20. Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.
21. Life-threatening illness unrelated to cancer.
22. Female patients who are lactating and breastfeeding.
23. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
8.0
STUDY DRUG
8.1
Study Drug Administration
Arm A: brigatinib 180 mg QD with 7-day lead-in at 90 mg QD. Brigatinib can be taken with or 
without food.
Arm B: alectinib 600 mg orally twice daily with food. 
The dose regimens are described fully in Section 8.3.
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). 
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded (see Schedule of Events [Appendix A] for site staff review of diary card). 
Complete instructions for completing the diary card will be provided with the study manual.
8.2
Treatment With Study Drug Beyond Radiological Disease Progression
When radiological disease progression assessed by the investigator is identified, patients may 
continue to receive study drug at the current dose, if they are still benefiting from it as determined 
by the 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 
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study treatment). In this scenario, the medical monitor delegated by the sponsor shall review and 
approve the case and an informed consent shall be obtained from the patient.
Missed Doses of Either Brigatinib or Alectinib
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. 
The patient shall take the next dose of study drug at the scheduled time.
8.3
Recommended Dosing and Dose Modification Guidelines
BRIGATINIB RECOMMENDED DOSING
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 of Cycle 1 will be expected to increase their 
dose to 180 mg QD continuously, beginning on Day 8. Brigatinib may be taken with or without 
food at approximately the same time every day, and patients will take their prescribed dose with 
water (recommended 240 mL). 
The patient’s daily dose of brigatinib should not be increased to 180 mg if any of the following 
AEs are experienced during treatment at 90 mg QD:

Interstitial lung disease/pneumonitis (any grade).

Symptomatic bradycardia (Grade 2 or greater).

Grade 2 or higher visual disturbance.

Any other Grade 3 or higher adverse reaction.
Once the decision not to increase the dose to 180 mg QD is made, it should not be increased in the 
future even if the AE has resolved.
The investigator should carefully evaluate the safety of the patients before making the decision to 
escalate the dose to 180 mg QD.
Brigatinib Dose Modifications for Adverse Reactions
The allowable daily doses of brigatinib in this study are 180 mg, 120 mg, 90 mg, and 60 mg. In 
cases where 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.
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Table 8.a
Recommended Brigatinib Dose Reduction Levels
Dose
Dose Reduction Levels
First
Second
Third
Fourth
90 mg QD
60 mg QD
Permanently 
discontinue
Not applicable
Not applicable
180 mg QD
120 mg QD
90 mg QD
60 mg QD
Permanently 
discontinue
Abbreviation: QD, once daily.
Guidelines for dose modification of brigatinib treatment-related AEs are outlined in Table 8.b. 
Unless otherwise noted, reduce dose as below, if one or more dose reductions are necessary 
because of AEs of Grade 3 or 4 severity, as defined by NCI CTCAE v4.03.
Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs
Adverse Reaction
Severity a
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.
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs
Adverse Reaction
Severity a
Dose Modification
Hypertension 
Grade 3 hypertension (SBP 
greater than or equal to 
160 mm Hg or DBP greater 
than or equal to 
100 mm Hg, medical 
intervention indicated, 
more than 1 
antihypertensive drug, or 
more intensive therapy than 
previously used indicated)

Withhold brigatinib until hypertension has 
recovered to baseline or SBP less than 140 mm Hg 
and DBP less than 90 mm Hg, 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 (or 
SBP less than 140 mm Hg and DBP less than 
90 mm Hg), 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 HR of 
60 bpm or above, with frequent monitoring as 
clinically indicated. 

Recurrence: permanently discontinue brigatinib.
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
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs
Adverse Reaction
Severity a
Dose Modification
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 
(less than or equal to 2.5 × ULN) or to baseline, then 
resume brigatinib at same dose.

If 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 (less 
than or equal to 2.5 × ULN) or to baseline, then 
resume at the next lower dose level per Table 8.a.
Lipase/amylase elevation 
Grade 3 lipase or amylase 
elevation (greater than 2.0 
× 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 same dose.

If Grade 3 elevation of lipase and amylase recurs, 
brigatinib should be withheld until recovery to Grade 
1 or less (less than or equal to 1.5 × ULN) or to 
baseline, then resume at the next lower dose level per
Table 8.a.
Grade 4 lipase or amylase 
elevation (greater than 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 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; SBP, systolic blood pressure; ULN, upper limit of normal.
a Graded per NCI CTCAE v4.03.
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 used to determine appropriate management of the 
patient for any AE experienced while participating in this study.
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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.
Reintroducing Brigatinib After Dose Interruption
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 their previous treatment 
dose, 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 baseline after dose interruption for more 
than 28 days, the sponsor’s medical monitor must be contacted before the study drug can be 
resumed.
Re-escalation of Brigatinib After Dose Reduction
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.
Pulmonary Adverse Reactions and Other AEs
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 early onset pulmonary events (EOPE).
In the ALTA study (AP26113-13-201) for brigatinib, as of 21 February 2017, of 219 treated 
patients, there were 14 cases of EOPE (6.4%). 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 onset of EOPE was 
Day 2 (range: 1-9). Eleven of these 14 cases were reported as SAEs. Seven patients had events that 
were Grade ≥3, all of whom permanently discontinued brigatinib because of these events. One 
patient had an EOPE that was Grade 5 (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, specifically 
with hypoxia and ground glass opacity on radiographic imaging indicative of interstitial lung 
disease or pneumonitis, could suggest a relationship to brigatinib after other etiologies, including 
pulmonary embolism, rapid disease progression, and infectious pneumonia are ruled out. If no 
evidence of other etiology is identified, a causal relationship to brigatinib may 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 work up for infectious or other etiology, with high dose 
corticosteroids, supplemental oxygen therapy, and empiric antibiotics as indicated. After drug 
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interruption and workup of symptoms, if ILD/pneumonitis is suspected, dose modification should 
be accomplished according to the recommendations in Table 8.b.
See Section 6 of the current version of the investigator’s brochure for detailed information on 
EOPE, late onset pneumonitis and other AEs, including bradycardia, hypertension, vision 
impairment, blood creatine kinase increased, pancreatic enzymes elevation, hyperglycemia, and 
other adverse drug reactions observed in the clinical studies with brigatinib.
ALECTINIB RECOMMENDED DOSING
Alectinib should be taken 600 mg orally twice daily with food at approximately the same time 
every day. If a dose of alectinib is missed or vomiting occurs after taking a dose of alectinib, take 
the next dose at the scheduled time.
Alectinib Dose Modifications for Adverse Reactions
The allowable daily doses of alectinib in this study are 600 mg taken orally twice daily, 450 mg 
taken orally twice daily, and 300 mg taken orally twice daily. Treatment needs to be discontinued 
if patients are unable to tolerate the 300 mg twice daily dose. In cases where the patient is 
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.c.
Table 8.c
Alectinib Dose Reduction Schedule
Dose Reduction Schedule
Dose Level
Starting dose
600 mg taken orally twice daily
First dose reduction
450 mg taken orally twice daily
Second dose reduction
300 mg taken orally twice daily
Guidelines for dose modification of alectinib treatment-related AEs are outlined in Table 8.d. 
Unless otherwise noted, reduce dose as below, if one or more dose reductions are necessary 
because of adverse reactions of Grade 3 or 4 severity, as defined by NCI CTCAE v4.03.
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Table 8.d
Alectinib Dose Modification Recommendations for Treatment-Related AEs
NCI CTCAE Grade
Alectinib Treatment
ILD/pneumonitis of any severity grade
Immediately interrupt and permanently discontinue 
alectinib if no other potential causes of ILD/pneumonitis 
have been identified.
ALT or AST elevation of Grade ≥3 (>5 × ULN) with total
bilirubin in ≤2 times ULN
Temporarily withhold until recovery to baseline or 
≤Grade 1 (≤3 × ULN), then resume at reduced dose (see 
Table 8.c)
ALT or AST elevation of Grade ≥2 (>3 × ULN) with total 
bilirubin elevation >2 × ULN in the absence of 
cholestasis or haemolysis
Permanently discontinue alectinib
Bradycardia a Grade 2 or Grade 3 (symptomatic, may be 
severe and medically significant, medical intervention 
indicated)
Temporarily withhold until recovery to ≤Grade 1 
(asymptomatic) bradycardia or to a heart rate of ≥60 bpm. 
Evaluate concomitant medicinal products known to cause 
bradycardia, as well as antihypertensive medicinal 
products.
If a contributing concomitant medicinal product is 
identified and discontinued, or its dose is adjusted, 
resume at previous dose upon recovery to ≤Grade 1 
(asymptomatic) bradycardia or to a heart rate of ≥60 bpm.
If no contributing concomitant medicinal products is 
identified, or if contributing concomitant medicinal 
products are not discontinued or dose modified, resume at 
reduced dose (see Table 8.c) upon recovery to ≤Grade 1 
(asymptomatic) bradycardia or to a heart rate of ≥60 bpm.
Bradycardia a Grade 4 (life-threatening consequences, 
urgent intervention indicated)
Permanently discontinue if no contributing concomitant 
medicinal product is identified.
If a contributing concomitant medicinal product is 
identified and discontinued, or its dose is adjusted, 
resume at reduced dose (see Table 8.c) upon recovery to 
≤Grade 1 (asymptomatic) bradycardia or to a heart rate of 
≥60 bpm, with frequent monitoring as clinically 
indicated.
Permanently discontinue in case of recurrence.
CPK elevation >5 × ULN
Temporarily withhold until recovery to baseline or to 
≤2.5 × ULN, then resume at the same dose.
CPK elevation >10 × ULN or second occurrence of CPK 
elevation of >5 × ULN
Temporarily withhold until recovery to baseline or to 
≤2.5 × ULN, then resume at reduced dose as per 
Table 8.c.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; bpm, beats per minute; CPK, 
creatine phosphokinase; ILD, interstitial lung disease; NCI CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events; ULN, upper limit of normal.
a Heart rate less than 60 bpm.
For Grade 3 toxicities (both hematologic and nonhematologic toxicities) not listed in Table 8.d: 

First occurrence: withhold alectinib until recovery to baseline, then resume at same dose.
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
Recurrence: withhold alectinib until recovery to baseline, then resume at next lower dose 
(Table 8.c) or discontinue alectinib. 
For Grade 4 toxicities (both hematologic and nonhematologic toxicities) not listed in Table 8.d:

First occurrence: either withhold alectinib until recovery to baseline and resume at next lower 
dose (Table 8.c) or permanently discontinue.

Permanently discontinue alectinib for recurrence.
Re-escalation of Alectinib After Dose Reduction
Re-escalation of alectinib 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.
In order for a patient to be a candidate for dose re-escalation, the AE that led to dose modification 
must not have reoccurred after alectinib was resumed at the decreased dose, and the patient must 
have had no other Grade 3/4 AEs in the past 28 days.
Reintroducing Alectinib After Dose Interruption
Alectinib may be resumed at the same dose if alectinib was held for reasons other than an adverse 
reaction. If an AE does not resolve to baseline after dose interruption for more than 28 days, the 
sponsor’s medical monitor must be contacted before the study drug can be resumed.
8.4
Permitted Concomitant Medications and Procedures 
Any medication, given for any reason, during any time period from the time a patient signs the ICF 
up to 30 days after the final treatment with study drug will be considered a concomitant medication. 
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.
8.5
Excluded Concomitant Medications and Procedures
Systemic treatment with the following medications should be avoided during the study for patients 
taking brigatinib due to the risk of drug-drug interactions:

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 QD 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 
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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. If 
concomitant use of a moderate CYP3A inducer cannot be avoided and after discussion with the 
Takeda medical monitor/designee, the dose of brigatinib may be increased in 30 mg 
increments after 7 days of treatment with the current brigatinib dose as tolerated, up to a 
maximum of twice the brigatinib dose that was tolerated before initiation of the moderate 
CYP3A inducer. After discontinuation of a moderate CYP3A inducer, brigatinib should be 
resumed at the dose that was tolerated before initiation of the moderate CYP3A inducer.
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. 
Refer to the local prescribing information for drug-drug interaction information for alectinib.

The following medications and procedures are also prohibited before radiological disease 
progression is observed:
–
Any other systemic anticancer therapy including, but not limited to: chemotherapeutic 
agents, immunotherapy, biological response modifiers (excluding growth factors), 
radiotherapy, and/or systemic hormonal therapy (with the exception of local therapies, 
such as SRS, 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.

Any illicit substance. (Note: medical use of cannabis is allowed if it is legal where the patient 
resides and no alternative treatment is available. The case must be reviewed and agreed to by 
the medical monitor. Nonmedicinal use of cannabis if legal is discouraged).

Use of alternative or herbal therapy must be approved by the sponsor in advance and be 
documented.
8.6
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, P-glycoprotein [P-gp]) 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.
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Brigatinib is an in vitro inhibitor of P-gp, 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.
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 ultraviolet A (UVA)/ultraviolet B (UVB) 
sunscreen and lip balm (SPF [sun protection factor] 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 accordingly (see the “other” AE in the dose modification 
guidelines in Table 8.b).
8.6.1
Pregnancy, Breastfeeding, and Contraception
8.6.1.1
Brigatinib
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 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 non-hormonal method 
(see list below) and 1 additional effective (barrier) method of contraception at the same time, 
from the time of signing of the ICF through at least 120 days after the last dose of study drug, 
or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient, from the time of signing of the ICF through at least 120 days 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.)
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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 120 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient, from the time of signing of the ICF through at least 120 days 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.
8.6.1.2
Alectinib
Refer to the current local prescribing information for alectinib for full details regarding pregnancy, 
breastfeeding, and contraception.
Female Patients
Based on animal studies and its mechanism of action, alectinib can cause fetal harm when 
administered to a pregnant woman. There are no available data on alectinib use in pregnant women. 
Female patients of reproductive potential should use effective contraception during treatment with 
alectinib and for 1 week after the final dose.
There are no data on the presence of alectinib or its metabolites in human milk, the effects of 
alectinib on the breastfed infant, or its effects on milk production. Because of the potential for 
serious adverse reactions in breastfed infants from alectinib, advise a lactating woman not to 
breastfeed during treatment with alectinib and for 1 week after the final dose.
Male Patients
Based on genotoxicity findings, male patients with female partners of reproductive potential 
should use effective contraception during treatment with alectinib and for 3 months following the 
final dose.
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8.6.2
Additional Precautions and Restrictions for Alectinib
Refer to the local prescribing information for alectinib for full details regarding precautions/ 
restrictions for its use. If local prescribing information is not available, the latest edition of the 
alectinib Summary of Product Characteristics should be consulted.
8.7
Blinding and Unblinding
This is an open-label study. A double-blind design was not implemented due to lack of feasibility 
based on the following considerations:

Brigatinib is given once daily with no food restriction while alectinib is given twice daily with 
food.

Brigatinib is provided in tablet form whereas alectinib is provided in capsule form that leads to 
easy identification.

Different safety profiles between the 2 drugs would likely unblind patients/investigators to 
treatment assignments.
It should be noted that of the multiple randomized phase 3 studies completed with ALK inhibitors 
to date, not one has utilized a double blind design.
Of note, primary and several secondary efficacy endpoints will be assessed by the BIRC 
(Section 11.2).
8.8
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. 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 
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.
Alectinib drug product will be supplied as hard capsules containing 150 mg of alectinib active 
pharmaceutical ingredient.
8.9
Packaging and Labeling
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.
Alectinib will be supplied in the commercial package, the carton 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.
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8.10
Storage, Handling, and Accountability
Brigatinib is to be stored at controlled room temperature of 20°C to 25°C, with excursions 
permitted between 15°C to 30°C. Do not refrigerate or freeze.
Alectinib will be stored per local prescribing instructions. If local prescribing instructions do not 
exist or do not address storage, then alectinib will be stored as advised in the latest version of the
Summary of Product Characteristics.
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 
re-dispensed.
No other use of brigatinib or alectinib 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 
or returned to the study sponsor if this is not possible. Please refer to the study manual for 
additional details regarding storage, handling, and disposal of study drug.
8.11
Preparation and Dispensing
The study pharmacist or designee at the site will be responsible for handling and dispensing 
brigatinib and alectinib and completing associated documentary paperwork. Supplies are shipped 
to the investigative site at appropriate intervals, depending on patient accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor or an acceptable substitute 
used by the site. Each time study medication is dispensed for a patient, the following information 
must be recorded: the patient’s initials, the patient’s study number, drug product strength (eg, 120 
mg), quantity dispensed with the corresponding lot number, date of dispensation, and the initials of 
the person dispensing the drug. These logs are to be maintained by the study pharmacist in the 
pharmacy throughout the duration of the study and will be periodically verified by a representative 
of the sponsor.
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. 
Additional study drug may be dispensed during a scheduled study visit or study drug may be 
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shipped directly from investigational sites to participants’ residences by a contracted logistics 
provider or distributor (DTP shipment) in compliance with national laws or temporary national 
emergency measures and Takeda processes. The details of the instructions are provided in the 
Direct to Patient Shipment of Clinical Trial Material document.
8.12
Other Protocol-Specified Materials
Details are provided in the 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 
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 institutional review board 
(IRB)/independent ethics committee (IEC). 
9.3
Treatment Group Assignments
This is an open-label study. Patients will be randomized in a 1:1 fashion to receive either brigatinib 
in Arm A or alectinib in Arm B. Patients will be stratified by:

The presence of intracranial CNS metastases at baseline (Yes vs No).

Best prior response to crizotinib therapy as assessed by the investigator (CR/PR vs any other 
response/status unknown).
Patients will be treated on each arm until they experience PD as assessed by the investigator or 
intolerable toxicity, or until any other discontinuation criterion is met. 
Study Procedures
Refer to the Schedule of Events (Appendix A) for timing of assessments immediately after 
randomization. Additional details are provided as necessary in the sections that follow.
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9.3.1
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.
Patient Demographics
The date of birth (outside European Economic Area) or age (in European Economic Area), race, 
ethnicity (optional depending on country), and sex of the patient are to be recorded during 
screening.
9.3.2
Screening
Screening assessments must be performed no more than 28 days before Cycle 1 Day 1, with the 
exception of tumor imaging assessment, where the allowable window is 21 days before first dose 
of study drug (Cycle 1, Day 1) and pregnancy testing which must be completed within 7 days of 
Cycle 1 Day 1. However, 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.
Vital signs should be repeated on Cycle 1, Day 1 before the first dose, regardless of the time from 
screening. Physical examination, ECOG performance status assessments, hematology, chemistry, 
insulin, and pregnancy tests do not need to be repeated on Cycle 1, Day 1 if they were performed 
for screening within 7 days before Cycle 1, 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, the result 
should be obtained before the treatment is started.
Any patient who is re-screened after screen failure must, in addition to the failed test, repeat only 
those screening tests that have fallen outside the specified screening period, as outlined in the SOE 
(Appendix A).
9.3.3
Visit Windows
The day the first dose of brigatinib or alectinib is administered is defined as Day 1. Following 
visits 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. Mid cycle day 15 visits also have a ±3 
day window. There is no window for Cycle 1 Day 8. 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.
9.3.4
Enrollment
A patient is considered to be enrolled in the study once the ICF is signed, all screening evaluations 
are completed, and the patient has been randomized.
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9.3.5
Medical History
A complete medical history, including cancerous and noncancerous disease, will be collected at 
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 by which ALK+ status was determined shall also be recorded.
Diagnosis and Cancer History
The initial cancer diagnosis and the current cancer stage at the time of screening, along with tumor 
histology and all sites of disease, should be recorded per The American Joint Committee on 
Cancer (AJCC), 8th edition (http://www.cancerstaging.com). 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, neoadjuvant, 
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.
In addition, concomitant medications will be recorded as specified in Section 9.3.11.
9.3.6
Tumor Tissue Samples
Mandatory Tumor Tissue at Screening From Those Patients Without a Prior ALK+ Result 
From an FDA-Approved Test
Patients entering the study must have a history of a positive results from a FDA approved test. 
Otherwise, they must have 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 
central laboratory is not required before enrollment. Specifications regarding handling and 
processing of tissue for central laboratory analysis are described below in Tumor Tissue Samples 
and in the study manual.
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Optional Tumor Tissue at Screening From All Patients
For all patients enrolled on the study, collection of FFPE tumor tissue obtained after progression 
on crizotinib is highly encouraged. These samples will be used for exploratory biomarker studies. 
Tissue can be obtained as part of Standard of Care or as an optional screening biopsy in this study.
Optional Tumor Tissue at Time of Disease Progression
For patients who consent, a fresh biopsy will be performed at the time of progression on brigatinib 
or alectinib. Biopsies are requested, but not mandatory, at progression. Formalin fixed tumor 
tissues should be sent to the central laboratory. This tumor tissue will be used for exploratory 
molecular genetic analysis.
9.3.7
Physical Examination
A complete physical examination must be performed at screening and at the end-of-treatment visit, 
the extent of which should be consistent with medical history and the patients’ underlying disease. 
Subsequent physical examinations, including the 30 days after last dose physical examination may 
be directed to relevant findings described in the Schedule of Events (Appendix A). Of note:

Assessment for early pulmonary symptoms must be performed during the visit on Day 8 before 
receiving study drug. If new pulmonary or worsening pulmonary symptoms are detected, 
conditions leading to worsening pulmonary function should be ruled out (eg, pneumonia, 
pulmonary embolism, congestive heart failure, worsening NSCLC) before attributing the 
pulmonary symptoms to study drug.

Due to 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.
9.3.8
ECOG Performance Status
The ECOG Performance Status will be assessed at screening and with every physical examination 
as outlined in the Schedule of Events (Appendix A).
9.3.9
Patient Height and Weight
Height will be measured only during screening. Weight will be measured during screening and at 
every scheduled visit.
9.3.10
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 the first dose, regardless of the 
time from screening. Vital signs will also be assessed per the Schedule of Events (Appendix A).
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9.3.11
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the date of informed consent up to 30 days after the last dose of study 
drug. See Sections 8.4 and 8.5 for a list of medications and therapies that are prohibited and/or 
allowed during the study. Concomitant medications will be recorded through 30 days after the last 
dose of last study drug.
9.3.12
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
9.3.13
ECG
A 12-lead ECG will be administered at Screening and at the end-of-treatment visit. Additional 
ECGs may be performed at the investigator’s discretion to ensure patient safety.
9.3.14
Clinical Laboratory Evaluations
Clinical laboratory 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 frequency of the laboratory test are defined in the Schedule of Events 
(Appendix A). The results shall be recorded in eCRF. The attending physicians may order 
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 study drug 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 study drug. Hematology laboratory are listed in Table 9.a.
Serum chemistry tests are listed in Table 9.a and include amylase, lipase, magnesium, creatine 
kinase and insulin in addition to other electrolytes and liver function tests.
Day 15 Liver Function Testing
For Cycles 1, 2 and 3, the Day 15 chemistry serum testing will include only AST, ALT, and total 
bilirubin (see the Schedule of Events, Appendix A for details).
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Albumin
ALP
ALT and AST
Amylase
Bilirubin (total)
Blood urea nitrogen
Calcium
CPK
Creatinine
Chloride
Glucose
LDH
Lipase
Magnesium
Phosphate
Potassium
Sodium
Insulin
Abbreviations: ANC, absolute neutrophil count; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase.
9.3.15
Pregnancy Test
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 first study drug administration (Cycle 1, Day 1).
The pregnancy tests must be a beta-human chorionic gonadotropin test, and either urine or serum 
can be used. Women of childbearing potential at study start must also complete the pregnancy test 
once every 12 weeks (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.
9.3.16
Disease Assessment
Tumor response assessments will be determined per RECIST v.1.1 by the investigator and an 
independent radiological review committee. Patients must have at least 1 measurable lesion per 
RECIST v1.1. 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.
At screening, disease assessment must include imaging of the chest and abdomen (including 
adrenal glands), using appropriate radiological procedures (computed tomography [CT] scans or 
magnetic resonance imaging [MRI] with contrast, unless contrast media is contraindicated). 
Contrast-enhanced MRI of the brain (such as gadolinium) is required at screening for all patients, 
unless medically contraindicated. If contrast for MRI is contraindicated, use CT with contrast. All 
radiographic images (eg, CT scan, MRI) performed during the study will be submitted to the 
imaging core laboratory for central review. Imaging of chest, abdomen, and brain will occur at 
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each assessment for all patients. Disease assessment by CT and MRI scans will be performed at 
screening (this may be up to 21 days before Cycle 1, Day 1) and at 8-week intervals thereafter 
using C1D1 as the starting point (on Day 28 [±7 days] of every even-numbered cycle), through 
Cycle 12 after the initial dose of study drug, and every 3 cycles thereafter until end of treatment. 
More frequent imaging is recommended at any time if clinically indicated; confirmation of CR or 
PR should be performed at least 4 weeks after initial response. If confirmatory imaging occurs 
4 weeks after the initial response it is preferred, but not required. that regular imaging resume at 
the original schedule (eg, on Day 28 of every even cycle or Day 28 of each original 3-cycle block). 
Imaging assessment will also be performed at end of treatment if more than 4 weeks have passed 
since the last imaging assessment. The same imaging modality at the same institution should be 
used at each assessment, if possible.
For patients who discontinue the study drug because of a reason other than PD by investigator’s 
assessment, additional tumor assessment should be documented, if available, until disease 
progression or start of subsequent systemic anticancer therapy. 
9.3.17
Confirmation of ALK Positivity
All patients are required to have documentation of ALK rearrangement before randomization. If 
the documentation is a positive result from either the Vysis ALK Break-Apart FISH Probe Kit or 
the Ventana ALK (D5F3) CDx Assay or Foundation Medicine’s FoundationOne CDx, then 
confirmation by a central laboratory is not required.
If the patient has documented ALK rearrangement by a different test (other than 1 of the 2 listed 
above), the patient must provide a tumor sample to the central laboratory before randomization. A 
pathologist should assess the tissue sample to ensure adequate tumor tissue is available based on 
the minimum requirements described in the study manual. (Note: central laboratory ALK
rearrangement testing results are not required to be obtained before randomization.)
9.3.18
PK Measurements
Patients randomized to the brigatinib arm of the study (Arm A) must provide blood samples 
(approximately 3 mL per sample) for measurement of plasma concentrations of brigatinib. Patients 
must be instructed not to take the day’s dose of brigatinib until after the predose blood sample is 
collected. Predose samples should be collected as close as possible to 24 hours after the prior 
brigatinib dose. The administration date and time of the prior 2 brigatinib doses must be recorded. 
On the PK sampling day, the collection time of the predose PK sample along with time of 
brigatinib dosing should be recorded. Blood samples for the determination of plasma 
concentrations of brigatinib will be collected as indicated in Appendix A, PK Sampling Schedule. 
The exact date and time of each PK sample collection should be recorded.
Plasma concentrations of brigatinib will be measured using a validated liquid chromatography 
tandem-mass spectrometry assay. Details regarding the preparation, handling, and shipping of the 
PK samples are provided in the study manual. 
For patients randomized to the alectinib arm of the study (Arm B), no PK samples will be collected 
at any time point during the study.
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9.3.19
Circulating DNA Measurements 
Circulating tumor DNA will be obtained at 3 time points for all patients: (1) Screening and 
(2) Cycle 3, Day 1, and at (3) the end-of-treatment visit. A blood sample (approximately 60 mL in 
total) will be collected for exploratory biomarker studies, including molecular genetic analysis of 
ALK and other genes implicated in tumor biology. 
9.3.19.1
Biomarker Sample Retention
Biomarker samples will be stored at Takeda-designated laboratories for up to 15 years after the 
date of study completion as identified in the clinical study report, and then will be discarded. 
Tumor tissue samples will be stored at refrigeration temperature, and other samples will be stored 
at -70°C. If patients withdraw consent, the samples will be discarded.
9.3.20
Dosing Diary
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded. Complete instructions will be provided with the study manual. The schedule for 
when the diary card will be reviewed with site staff is presented in the Schedule of Events 
(Appendix A).
The dosing diary will be reviewed as per the Schedule of Events.
9.3.21
Quality of Life Assessment: Cancer (EORTC QLQ-C30, QLQ-LC13, and 
QLQ-BN20)
The HRQL assessments (EORTC QLQ-C30, QLQ-LC13, and QLQ-BN20) will be completed by 
the patient as specified in the Schedule of Events (Appendix A). The EORTC QLQ-C30 
incorporates 5 functional scales (physical functioning, role functioning, emotional functioning, 
cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales 
(fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).
The lung cancer specific module QLQ-LC13 comprises 13 questions assessing lung cancer 
associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side 
effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. 
This will be administered subsequent to the EORTC QLQ-C30.
To reduce the clinical site and respondent burden, 5 items from the brain cancer module 
QLQ-BN20 will be used to assess morbidity related to CNS symptoms, including headaches (item 
4), coordination (item 15), and communication deficit (items 11, 12, and 13). This will be 
administered subsequent to the EORTC QLQ-C30 and QLQ-LC13.
The time recall period for the instruments is 1 week (the week immediately preceding the 
assessment). These are reliable and valid measures of HRQoL in patients with cancer and take 
about 15 minutes to administer. The instruments have been validated and used in many countries.
The patient-reported outcomes (PRO) questionnaires (EORTC QLQ-C30, QLQ-LC13, and 
QLQ-BN20) will be administered at specified scheduled visits and at the visit 30 days after the last 
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dose of study drug. The PRO questionnaire should be administered to patients when they arrive for 
their scheduled visits, before other assessments are performed before any clinical measurements, 
assessments, evaluations, or study drug is taken procedures being performed. 
9.3.22
Quality of Life Assessment: EQ-5D-5L Measurement
The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual analogue 
scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression), each rated on 5 levels. The EQ VAS records 
the respondent’s self-rated health on a 20-cm, vertical, visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state). The EQ-5D-5L will be administered 
as specified in the Schedule of Events (Appendix A); at time points when a clinic visit is not 
required, the EQ-5D-5L questionnaire may be administered for at least 1 or more complete cycles
over the telephone, and site staff may enter the data from the patient.
9.3.23
Health Resource Utilization Data Collection
During the treatment and follow-up periods indicated in the Schedule 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 scheduled visit of each cycle, during the 
end-of-treatment visit, and the 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.
9.3.24
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, and insulin), and ECG 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.
9.3.25
30 Days After Last Dose
The 30 days after last dose assessments must be performed 30 days (±7 days) after the last dose of 
study drug. Physical examinations and laboratory tests (hematology, chemistry, and insulin) 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 the patient has the 
last dose equals or is more than 30 days before the decision of permanent discontinuation from 
study treatment, the end-of-treatment visit and 30 days after last dose visit can be combined as 1 
visit. If patients permanently discontinued study treatment before radiological disease progression 
is observed, this visit may occur before the end-of-treatment visit.
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9.3.26
Follow-up Period
The follow-up period for a patient begins after end of treatment (ie, when all study drug has been 
discontinued) and continues until patient contact ceases. The follow-up assessments 
(ie, contacting the patient for survival and subsequent anticancer therapy) must be performed 
every 12 weeks (±14 days) after the last dose of the study treatment. The allowable window for 
follow-up assessments is 14 days. All new systemic anticancer therapies should be reported. Also, 
the EQ-5D-5L will be obtained in this period every 12 weeks (±14 days) (the questionnaires 
should be administered to patients when they arrive for their scheduled visits, before any clinical 
measurements, assessments, evaluations, or procedures being performed).
9.4
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 study drug (either brigatinib or alectinib) because of disease 
progression by the investigator’s assessment, intolerance, investigator discretion, or if they die 
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 the date the patient has the last dose equals or is 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. 
9.5
Completion of Study (for Individual Patients)
All patients who have discontinued study drug(s) shall be followed for survival, regardless of the 
reason of discontinuation. The survival follow-up will continue until the patient dies or the study 
ends. Patients will be considered to have completed the study if they died before the time of data 
cut. Patients lost to follow-up or who have withdrawn consent before study completion are not 
counted in number of patients completing this study.
9.6
Discontinuation of Treatment With Study Drug 
Study drug must be permanently discontinued for patients meeting any of the following criteria:

PD assessed by the investigator as defined by RECIST v1.1.
–
Note: Treatment of patients with brigatinib or alectinib may be continued, despite 
progression by RECIST v1.1, at the discretion of the investigator, if there is still evidence 
of clinical benefit. In this scenario, the medical monitor shall be contacted to approve these 
cases. Patients shall sign an additional ICF before the treatment continues.

Intolerable toxicity as determined by the investigator.
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Treatment with study drug may also be discontinued for any of the following reasons:

Significant protocol deviations that will jeopardize safety surveillance and pose a significant 
threat to the safety of the patient.

Study terminated by sponsor.

Withdrawal by subject.
In cases in which patients request to discontinue the study drug, the investigator should assess 
if this is due to study drug related toxicity. This election is only applicable if the patients are 
not having intolerable toxicity by 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 the study.

By investigator discretion it is in the best interests of the patient to discontinue. 
If investigator discretion is based on intolerable toxicity, the reason of discontinuation shall be 
recorded as due to intolerable toxicity. Before discontinuing a patient because it is in the best 
interests of the patient the investigator should contact the study sponsor to discuss the matter. 

Lost to follow-up.

Pregnancy.

Other.
Once study drug has been discontinued, all study procedures outlined for the end-of-treatment visit 
will be completed as specified in the Schedule of Events (Appendix A). The primary reason for 
study drug discontinuation will be recorded in the eCRF.
9.7
Study Compliance
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded. Complete instructions will be provided with the study manual.
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.
9.8
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)
After end of treatment, all patients will be followed for OS until death or study end. The survival 
follow-up can be conducted by remote method (eg, telephone call). At each visit, the survival 
status and information about subsequent anticancer therapy, such as 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. 
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If disease progression is already reported and the patient receives the study drug beyond initial 
disease progression, the tumor assessment will continue to occur at the same schedule; however,
the sponsor does not require further tumor assessment data to be collected. 
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event 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 does not need to be reported as 
AEs.
AE Severity
The severity of AEs will be assessed according to the NCI CTCAE v4.03 (see the study manual). If 
the AE is not defined in the NCI CTCAE, the investigator will determine the severity of the AE 
based on 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.
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10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, severity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 4.03, effective date 14 June 2010 [40]. 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 
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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 of the 
completed Takeda paper-based SAE form will be sent. In case of fax, site personnel need to 
confirm successful transmission of all pages and include an e-mail address on the fax cover sheet 
so that an acknowledgment of receipt can be returned via e-mail within 1 business day. 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 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 4.03, effective date 14 June 2010 [40]. The criteria are provided in 
the study manual.
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. AEs that occur 
between the ICF and the first dose of study drug will be captured as pretreatment events or 
medical history.
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
SAEs:
–
Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to first dose of study 
drug, and will also be recorded in the eCRF. 
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug and recorded in the eCRF. After
this period, only related SAEs must be reported to the Takeda Global Pharmacovigilance 
department or designee. SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Product
Call center
Phone number
E-mail
Fax
Brigatinib
Dohmen Life 
Science Services, 
or DLSS 
(formerly known 
as MedComm)
1-844-662-8532
Non-toll-free number: 
1-510-740-1273
GlobalOncologyMedinfo@t
akeda.com 
1-800-881-6092
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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 EMA 
investigators and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as an expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues 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 comprised 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
IRC
A central BIRC with no knowledge of the patients’ status on treatment will evaluate all images 
collected during the study for the primary endpoint of PFS per RECIST v1.1, as well as several 
secondary endpoints such as time to iPD, as per modified RECIST v1.1. An IRC charter defines 
the procedures used by the committee.
The central BIRC assessment may be terminated if the primary endpoint is met at the IA or 
primary analysis, or not met at the primary analysis. The tumor assessment of on-going patients 
will only be performed by investigators thereafter.
11.3
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) supported by an independent statistician 
will review safety and efficacy data at the planned primary analysis and IA for PFS. The IDMC 
will be composed of 3 medical oncologists with expertise in NSCLC and 2 statisticians. They will 
make recommendations on study conduct if needed. Study accrual will not be interrupted because 
of the scheduled safety reviews. The IDMC or Brigatinib-3001 study team may request an ad hoc 
meeting for any reason, including a significant unexpected safety event, follow-up of an 
observation during a planned IDMC meeting, or a report external to the study, such as publication 
of study results from a competing product. At each review, subject incidence rates of AEs 
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(including all SAEs, treatment-related AEs, serious treatment-related AEs, and AEs requiring the 
discontinuation of study therapy) will be tabulated by system organ class, preferred term, and 
severity grade. Listings and/or narratives of on-study deaths and other serious and significant AEs, 
including any early withdrawals because of AEs, will be provided. Records of all meetings will be 
archived. The IDMC will communicate major safety concerns and recommendations regarding 
study modification or termination to Takeda. Further details including frequency of IDMC 
meetings will be provided in the IDMC charter.
12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, contract research 
organization partners, and regulatory authorities. Investigative sites must complete eCRFs in 
English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
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12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic 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 subject’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 statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1
Analysis Sets
Full Analysis Set
The full analysis set is based on the intent-to-treat (ITT) principle and includes all patients 
randomized to each regimen regardless of whether they are ALK+ by the Vysis ALK Break Apart 
FISH Probe Kit or the Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s 
FoundationOneCDx or a local test other than FISH and immunohistochemistry, or whether they 
receive study drug or adhere to the assigned dose. The primary analyses of efficacy will be based 
on the full analysis set.
Safety Analysis Set
The safety analysis set for each regimen includes all patients receiving at least 1 dose of study drug. 
Safety will be analyzed using the safety analysis set.
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Per-Protocol Analysis Set
The per-protocol analysis set will exclude all patients in the safety 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.
Additional analyses may also be performed excluding patients who were not confirmed as ALK+ 
(locally or centrally) by an FDA approved test. 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 at the time of randomization will be summarized using 
descriptive statistics for the full analysis set according to the randomly assigned treatment. 
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 re-categorizing existing 
categorical variables. 
13.1.3
Efficacy Analysis
13.1.3.1
Definitions of Efficacy Endpoints
The primary endpoint, PFS assessed by BIRC, is defined as the time interval from the date of 
randomization until the first date at which disease progression is objectively documented via 
RECIST v1.1, 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 at the last valid tumor 
response assessment.
Secondary efficacy endpoints for this study are defined as follows (unless otherwise stated, 
secondary efficacy endpoints of response will use BIRC assessments with sensitivity analyses 
performed using the investigator assessments):

OS is defined as the time interval from the date of randomization 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.

PFS as assessed by the investigator.

ORR is defined as the proportion of the patients who have achieved CR or PR using RECIST 
v1.1 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 or PR (whichever is first recorded) until the first date that the PD is objectively 
documented or death.
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
Time to response is defined as the time interval from randomization until the initial 
observation of CR or PR. Time to response will be summarized using descriptive statistics in 
patients with objective response.

iORR, as assessed by the BIRC, is defined as the proportion of the patients who have achieved 
CR or PR in the CNS per a modification RECIST v1.1 after the initiation of study treatment in 
patients with CNS metastases at baseline.

iDOR, as assessed by the BIRC, is defined as the time interval from the time that the 
measurement criteria are first met for CR or PR in the CNS (whichever is first recorded) until 
the first date that the PD in the CNS is objectively documented or death.

Time to iPD, as assessed by the BIRC, is defined as the time interval from the date of 
randomization until the first date at which intracranial disease progression is objectively 
documented via a modification of RECIST v1.1. Time to iPD will be censored for patients 
without documented intracranial disease progression at the last valid intracranial tumor 
response assessment. 
Exploratory efficacy endpoints include CNS efficacy via RANO-BM on initial treatment, 
molecular determinants of efficacy and safety with brigatinib and alectinib, HRQoL endpoints and 
health resource utilization endpoints. Detailed definitions of these exploratory efficacy endpoints 
will be provided in the SAP.
13.1.3.2
Primary Efficacy Endpoint Analyses
The primary analysis of the primary endpoint will be performed using a 2-sided stratified log-rank 
test (stratification factors: presence of intracranial CNS metastases at baseline [yes vs no], and best 
prior response to crizotinib therapy as assessed by the investigator [CR/PR vs any other 
response/status unknown]) to compare the BIRC-assessed PFS of patients randomized to 
brigatinib with the BIRC-assessed PFS of patients randomized to alectinib. The overall (2-sided) 
type I error rate will be controlled at 0.05. The primary analysis will be based on the full analysis 
set. PFS will be estimated for each treatment arm using the Kaplan-Meier method [41]. 
Additionally, HRs will be estimated using the stratified Cox regression model with the 
stratification factors.
Sensitivity analyses of the primary endpoint of PFS will also be performed in the following 
populations:

Per-protocol population, as assessed by the BIRC.

FDA approved ALK test population, as assessed by the BIRC.
Subgroup analyses will be performed by baseline prognostic factors.
BIRC-assessed PFS will be tested at the IA after 115 PFS events have been observed. If the 
observed HR doesn’t meet the prespecified stopping rules for efficacy or futility at the IA then a 
primary analysis will be conducted after 164 events are observed. 
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13.1.3.3
Secondary Efficacy Endpoint Analyses
OS, the key secondary endpoint, will be formally tested for statistical significance only once PFS 
per BIRC is statistically significant. OS will be assessed in the full analysis set. 
PFS as assessed by the investigator and ORR will be assessed in the full analysis set. iORR will be 
assessed in patients in the full analysis set with measurable brain metastases. The percentage 
responding and the associated 2-sided 95% CI will be calculated. A Mantel-Haenszel (using the 
stratification factors) test will be performed to compare each endpoint between the 2 arms.
The analysis of time to iPD, as assessed by the BIRC, will be performed using a 2-sided stratified 
log-rank test (using the stratification factors) to compare the BIRC-assessed time to iPD of patients 
randomized to brigatinib with the BIRC-assessed time to iPD of patients randomized to alectinib. 
The analysis will be based on patients in the full analysis set. Time to iPD will be estimated for 
each treatment arm using the Kaplan-Meier method [41]. Additionally, HRs will be estimated 
using the stratified Cox regression model with the stratification factors. Additional analyses in 
patients with measurable brain metastases and in patients without brain metastases will also be 
performed in a similar manner.
DOR will be assessed among responders in the full analysis set. iDOR will be assessed among 
patients with brain metastases with an intracranial response in the full analysis set. For each time to 
event endpoint, values and 2-sided 95% CIs will be estimated using Kaplan-Meier method 
according to the initially assigned treatment. Stratified log-rank tests (using the stratification 
factors) will be performed to compare each endpoint between the 2 arms. Survival probabilities at 
12 months and the associated 2-sided 95% CIs will be calculated.
Time to response will be summarized only for responders using descriptive statistics.
13.1.4
PK 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 
analysis plans for these analyses will be separately developed and the results reported separately.
13.1.5
Analysis of PRO and Health Resource Utilization Data
Analyses of PRO data will be performed using the PRO-ITT population, which will be defined as 
patients with baseline and at least 1 postbaseline measurement in the ITT population. The global 
health status/quality of life and functions from EORTC QLQ-C30 and symptoms measured by 
QLQ-LC13 will be of special interest.
The descriptive statistics of the actual value and change from baseline of the EORTC QLQ-C30, 
QLQ-LC13, and QLQ-BN20 scores will be summarized by treatment group over time. The change 
from baseline scores will be analyzed using linear mixed models to compare 2 treatment groups. 
The number and percentage of patients with improved, stable and worsened quality of life scores 
will be analyzed by treatment group over time. Time to quality of life worsening will also be 
summarized and compared by treatment group. 
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EQ-5D-5L scores will be summarized by treatment group over time using descriptive statistics. 
Details of scoring and initial handling of missing item scores are included in the EORTC 
QLQ-C30, QLQ-LC13, QLQ-BN20, and EQ-5D-5L scoring guidelines. Further investigation on 
patterns of missing data and subsequent sensitivity analysis may be conducted. EORTC QLQ-C30, 
QLQ-LC13, QLQ-BN20, and EQ-5D-5L questionnaires compliance will be summarized by 
treatment arm at each time point (and overall).
Health resource utilization will be summarized using descriptive statistics by treatment group in 
the ITT population.
More details will be described in the SAP.
13.1.6
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 
v4.03. All patients who receive at least 1 dose of either study treatment (alectinib or brigatinib) 
will be evaluated for safety. The proportion of patients with at least 1 treatment-emergent AE, 
treatment-related AEs, and treatment-emergent SAEs 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 NCI 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.
13.2
IA
One IA for efficacy and futility is planned after approximately 70% of the total expected events 
(progression or death) have been observed. An O’Brien-Fleming Lan-DeMets [42] alpha spending 
function will be used to control the overall alpha level at 0.05 2-sided. A gamma spending function 
[43] will be used for the futility stopping boundary. Futility is nonbinding. The IA is planned to be 
performed after the 115 events have been observed. If the observed HR doesn’t meet the 
prespecified stopping rule for efficacy or futility at the IA then the primary analysis will be 
conducted after 164 events are observed. The efficacy and futility stopping boundaries used in the 
analysis will be adjusted based on the actual number of events observed at each analysis using the 
O’Brien-Fleming Lan-DeMets [42] alpha spending function and gamma spending function [43]. 
Details of the stopping boundaries will be described in the SAP.
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13.3
Determination of Sample Size
For the purposes of this sample size calculation, the median PFS for alectinib is estimated as 
9 months and the PFS for brigatinib is estimated to be 15 months on the basis of the outcomes 
observed in previous single-arm studies (AP26113-13-201 and AP26113-11-101). Approximately 
246 patients will be randomized in a 1:1 fashion to receive brigatinib or alectinib. A total of 164 
events (progression or death among the randomized patients) will provide 90% power to detect a 
6-month improvement in PFS (HR=0.60). This power projection is based on a 2-sided log-rank 
test, and is controlled at the 2-sided 0.05 level, adjusting for the proposed IA plan. The number of 
events is fixed, but the enrollment number may change based on an assessment of the overall event 
rate pooled across treatment groups (before the close of enrollment).
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 (contract research organization) and by the IRB or IEC.
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches, such as remote source data verification or telephone contact,
may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local health authority and 
permitted by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. 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 subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
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misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. Refer to the study manual for specific information on protocol deviations.
The investigator should document all protocol deviations.
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, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB 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 Investigator’s Brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB 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 
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screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The sponsor will notify site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the study. Until the site receives notification no protocol activities, 
including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, 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.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, 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 EC. 
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be signed 
and dated by the subject at the time of consent and before the subject entering into the study. The 
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subject should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The investigator must also sign and date the ICF 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 in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, 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 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2
Clinical Trial Registration
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. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
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.
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15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
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12. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of 
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fusion oncokinase identified by an immunohistochemistry-based diagnostic system for 
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lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 
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15. Wong H, Belvin M, Herter S, Hoeflich KP, Murray LJ, Wong L, et al. Pharmacodynamics of 
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18. 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 
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19. Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in 
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anaplastic lymphoma kinase inhibitor crizotinib. Journal of Clinical Oncology 
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22. 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 
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23. ZYKADIA (ceritinib). Prescribing Information. East Hanover, NJ, USA: Novartis 
Pharmaceuticals Corporation, 6/2017.
24. ALECENSA (alectinib). Prescribing Information. South San Francisco, CA: Genentech USA, 
Inc., November 2017.
25. 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.
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. 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.
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28. 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).
29. 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.
30. 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.
31. 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.
32. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus 
chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368(25):2385-94.
33. Mok T, Kim D, Wu Y, Solomon B, Nakagawa K, Mekhail T, et al. First-line crizotinib versus 
pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive 
non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 
1014). Journal of Clinical Oncology 2014;32(15_suppl):8002.
34. Felip E, Kim D, Mehra R, Tan D, Chow L, Camidge D, et al. Efficacy and safety of ceritinib in 
patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) 
non-small cell lung cancer (NSCLC). Annals of Oncology 2014;25(suppl_4):iv426-70. 1295P.
35. Mok T, Spigel D, Felip E, deMarinis F, Ahn M-J, Groen H, et al. ASCEND-2: A single-arm, 
open-label, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged 
(ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and 
crizotinib (CRZ). 2015 ASCO Annual Meeting Abstract. J Clin Oncol 2015;33(suppl).
36. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged 
non-small-cell lung cancer. N Engl J Med 2014;370(13):1189-97.
37. Alecensa (alectinib). Prescribing Information. San Francisco, CA, US: Genentech USA, Inc., 
Revised November 2016.
38. 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.
39. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, 
crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. 
Lancet Oncol 2016;17(2):234-42.
40. 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.
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41. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53:457-81.
42. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13(13-14):1341-52; discussion 53-6.
43. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med 1990;9(12):1439-45.
44. 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
Schedule of Events
Schedule of Events
Screening Period
Treatment Through 30 Days After Last Dose
Follow-up
Period
Assessment
Screening
(Note: Tumor 
assessments must 
be 21 days before 
Day 1)
Cycle 1 a
Cycles 
2 and 3
Day 1 of 
Every 
Cycle
Starting 
C4D1
Every
2 Cycles
End-of-Treatment b
30 Days 
After Last 
Dose
Follow-up
Day
D -28 to D0
D1
D8
D15
D1
D15
Informed consent (may be 28 days 
before D1)
X
Demographics
X
Medical/surgical history
X
Diagnosis and cancer history c
X
Prior cancer therapy
X
Archival (banked) tumor tissue 
sample (patients with local non–
FDA-approved ALK testing and 
patients who agree to optional genetic 
testing)
X
Fresh FFPE tumor tissue biopsy 
sample d
X (only if archival 
tumor tissue is not 
available)
X e, m
(optional at time of 
progression)
Plasma sample for ctDNA (DNA for 
NGS analysis including but not 
limited to ALK mutations)
X
C3D1
only
X m
(at time of 
progression)
PE (screening and end-of-treatment 
will be complete PE, rest may be 
symptom directed) f
X
X
X g
X
X
X
X
Height
X
Weight
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
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Screening Period
Treatment Through 30 Days After Last Dose
Follow-up
Period
Assessment
Screening
(Note: Tumor 
assessments must 
be 21 days before 
Day 1)
Cycle 1 a
Cycles 
2 and 3
Day 1 of 
Every 
Cycle
Starting 
C4D1
Every
2 Cycles
End-of-Treatment b
30 Days 
After Last 
Dose
Follow-up
Day
D -28 to D0
D1
D8
D15
D1
D15
Hematology
X
X
X
X
X
X
Chemistry
X
X
X h
X
X h
X
X
X
Insulin (fasting, if possible)
X
X
X
X
X
X
ECG
X
X
Brigatinib (Arm A only)
ONCE DAILY ORAL DOSE
Alectinib (Arm B only)
TWICE-DAILY ORAL DOSE (with food)
AEs
Throughout study g
Concomitant medications
Throughout study
Pregnancy test i (must be within 7 
days before D1)
X
X
X (every 
12 weeks)
X
Disease assessment (this may be 
21 days before D1)
X
X (every 8 weeks 
through Cycle 12 
then every 12 
weeks thereafter)
X n
Plasma sample for brigatinib PK (Arm 
A only)
Please refer to Appendix A, PK Sampling Schedule
PRO assessment j and HRU
X
X
X
X
X
X
EQ-5D-5L 
only
Review patient diary with patient k
X k
X
X
Subsequent anticancer therapy 
/survival l
X (every 
12 
weeks) l
For details regarding any item on the Schedule of Events, please refer to Section 9.3, Study Procedures, of this protocol.
Abbreviations: AE, adverse event; ALK, anaplastic lymphoma kinase; C, Cycle; ctDNA, circulating tumor DNA; D, Day; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D-5L, EuroQoL–5 Dimensions–5 Levels; FDA, Food and Drug Administration; 
FFPE, formalin-fixed, paraffin-embedded; HRU, health resource utilization; NGS, Next Generation Sequencing; PE, physical examination; PK, pharmacokinetics; PRO, 
patient-reported outcomes; QD, once daily; QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-LC13, Quality of Life Lung Cancer Module; QLQ-BN20, Quality of Life Brain 
Cancer Module.
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a 1 cycle = 28 days. The allowed visit day window is ±3 days, starting from Cycle1 Day 15, with the exception of disease assessment. There is no window for C1D8.
b This visit shall be scheduled with a ±7-day window. If patient’s last dose equals or is 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.
c The medical history needs to include the detail of prior treatment, starting and ending time, and the best response to each treatment. The assay and sample type of prior ALK test will 
also be collected.
d Exploratory biomarker studies (including ALK mutation status) will be performed on tissue biopsy obtained after progression on crizotinib but before start of study treatment. Tissue 
can be obtained as part of standard of care or as an optional screening biopsy in this study. The collection of this tissue is not mandatory, but highly encouraged. An optional biopsy 
will also be taken at time of progression on brigatinib and alectinib for patients who consent to the procedure and test. FFPE tumor tissue will be used for exploratory molecular 
genetic analysis.
e Exploratory biomarker studies (including ALK mutation status) will be performed on tissue biopsy, taken at time of progression on brigatinib and alectinib for patients who consent 
to the procedure and test. FFPE tumor tissue will be used for exploratory molecular genetic analysis.
f Physical examination, ECOG performance status assessments, hematology, chemistry, insulin, and pregnancy tests do not need to be repeated on Cycle 1, Day 1 if they were 
performed for screening within 7 days before Cycle 1, Day 1 and, in the opinion of the investigator, there is no reason to believe they have substantially changed.
g Assessment for early pulmonary symptoms must be performed during the visit on Day 8 before receiving study drug.
h Only aspartate aminotransferase/alanine aminotransaminase and total bilirubin will be evaluated at this visit.
i Pregnancy tests will be performed for women of childbearing potential at screening. The test must be known to be negative before the study drug administration and be performed 
within 7 days before first study drug administration (Cycle 1, Day 1). The pregnancy tests must be a beta-human chorionic gonadotropin test, and either urine or serum can be used. 
Women of childbearing potential at study start must also complete the pregnancy test once every 12 weeks (3 cycles) ±7 days thereafter and at the end-of-treatment visit. Additional 
pregnancy testing should be performed if recommended or required per local guidelines or regulations.
j PRO assessments: EORTC QLQ-C30 (v3.0) and its lung cancer module, QLQ-LC13, items of QLQ-BN20, and EQ-5D-5L questionnaires will be administered at baseline, per the 
Schedule of Events throughout the study, and at the 30 days after last dose visit. The questionnaires should be administered to patients when they arrive for their scheduled visits, 
before any clinical measurements, assessments, evaluations, or procedures being performed. The EQ-5D-5L will be administered in the follow-up period.
k On C1D1 site staff will explain to the patient how to complete the patient diary. 
l Survival follow-up shall be scheduled with a ±14-day window.
m If study treatment is stopped for a reason other than disease progression, the re-biopsy or plasma for ctDNA shall be collected after confirmed disease progression occurs.
n 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 continue to occur at the same schedule; however, the sponsor does not require further tumor assessment data to be collected.
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PK Sampling Schedule (Arm A only)
The PK samples outlined in the schedule below are to be collected in all patients randomized to the brigatinib arm (Arm A) of the study. 
For patients randomized to the alectinib arm of the study (Arm B), no PK samples are to be collected at any time point during the study.
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 hours before dosing)
X
X
X
X
X
1 hour postdose (±15 minutes)
X
X
X
4 hours postdose (±30 minutes)
X
X
X
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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:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to 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.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
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.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. (This responsibility lies on 
the appropriate individual, designated by the site in Japan.)
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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Appendix E
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.
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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)
Abbreviations: GFR, glomerular filtration rate; Scr, serum creatinine.
Levey et al, 2006 [44]. 
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Appendix G
Protocol History
Date
Amendment Number
Amendment Type
Region
08 March 2021
4
Substantial
Global
09 March 2020
3
Substantial
Global
07 June 2019
2
Substantial
Global
11 January 2019
1
Nonsubstantial
Germany
15 May 2018
Initial Protocol
Not applicable
Global
Rationale for Amendment 3
This document describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment are to:

Change the legal entity of the sponsor and the name of study lead due to a company level 
change. 

Incorporate the recommendation from the United States (US) Food and Drug Administration 
(FDA) for the endpoint of “time to intracranial disease progression (iPD),” which will no 
longer be a key secondary endpoint and was removed from hierarchical testing. The ordering 
of secondary objectives and endpoints were revised to reflect this change.

Provide clarification for some of the protocol language.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Changes in Amendment 3
The following is a summary of changes made in the amendment:

Updated sponsor information from ARIAD Pharmaceuticals, Inc to Takeda Development 
Center Americas, Inc.

Changed the clinical study lead to 
, MD, on signatory page.

Removed “time to intracranial progressive disease (iPD)” from the key secondary endpoints 
and revised the order of other secondary endpoints. The order of secondary objectives was 
revised to match the order of key and other secondary endpoints.

Clarified throughout the protocol that the treatment will continue until “progressive disease 
(PD) assessed by the investigator.”

Removed statements about “End of Study/Study Completion Definition, and Planned 
Reporting,” “Primary Completion/Study Completion,” and “Study Completion,” and unified 
the terms in Section 6.3.1 for the definition of “End of Study” and “Primary Completion.”

Specified that timing for exclusion criteria 2 (crizotinib use) and 7 (chemotherapy or radiation 
therapy) was before randomization.
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
Added new exclusion criterion 7 (other primary malignancies other than NSCLC) and
renumbered subsequent criteria.

Clarified that timing for exclusion criterion 11 (symptomatic central nervous system
metastases; formerly exclusion criterion 10) was a minimum of 7 days.

Clarified the required test to support protocol exclusion criteria 18 (formerly exclusion
criterion 17) for an active hepatitis B virus/hepatitis C virus infection.

Clarified requirement that both brigatinib and alectinib be administered at approximately the
same time every day and added detail regarding dose-limiting AEs.

Clarification for dose modification for AEs and clarifications that if the brigatinib dose cannot
be escalated to 180 mg QD due to AE, 90 mg QD should be administered throughout the study.

Clarification for pulmonary events occurring within the first 7 days of treatment regarding
ruling out other etiologies including rapid disease progression for assessing relation to
treatment.

Clarification for alectinib dose discontinuation due to AEs.

Provided additional information regarding the use of moderate CYP3A inducers and
alternative or herbal therapy after consultation with and approval by the sponsor.

Clarification for disease assessment in patients who discontinue study drug for reasons other
than PD.

Corrected total blood volume collection for DNA measurements.

Added requirement for acknowledgment of receipt when reporting AEs and SAEs by
facsimile.

The secondary endpoint analyses were revised to reflect that iPD will no longer be a key
secondary endpoint and was removed from hierarchical testing.

Minor editorial revisions were made for clarification throughout the document.
Rationale for Amendment 2
This document describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to:

Change the current secondary endpoint for intracranial progression-free survival (iPFS) to
time to intracranial progression (iPD) without prior systemic progression per advice from the
United States Food and Drug Administration (US FDA).

To clarify the dose modification table for treatment-related adverse events (Table 8.b) and
provide consistency with the Company Core Data Sheet (CCDS) for brigatinib and to provide
clarity on allowed dose levels.
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
To add an additional week of testing of aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) and bilirubin levels (Cycle 3 Week 15) to align with the latest 
Summary of Product Characteristics (SmPCs) for both brigatinib and alectinib.
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 title to reflect brigatinib (Alunbrig®) registration.

Changed the terminology from intracranial progression-free survival (iPFS) to time to 
intracranial progressive disease (iPD) without prior systemic progression or death.

Updated the date that patient enrollment began.

Updated inclusion criterion #1 to clarify gender and age eligibility requirements.

Clarified inclusion criterion #8 regarding prior systemic anticancer therapy.

Updated the guidance regarding female contraception.

Updated Dose Modification Table 8.b. 

Updated Excluded Medications to include moderate CYP3A inhibitors and to provide further 
guidance to investigators. 

Added information regarding administration of brigatinib with certain concomitant 
medications.

Provided explanation for not implementing double-blind design.

Clarified screening procedures and visit windows. 

Provided additional guidance regarding clinical laboratory evaluations.

Clarified procedures related to confirmatory imaging.

Added Biomarker Sample Retention section.

Clarified health-related quality of life assessment for follow-up period.

Provided additional guidance regarding posttreatment follow-up assessments.

Revised AE Definition section.

Removed the term “confirmed” from references to the ORR endpoint and remove the term 
"median" from references to study endpoints to be estimated using the Kaplan-Meier method.

Removed Japan-specific instructions.

Corrected Schedule of Event Column Heading for Cycles 2 and 3 and Cycle 4.

Added footnotes to Appendix A regarding biomarker sample collection and disease 
assessment after confirmed disease progression occurs.
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
Added Appendix F Modification of Diet in Renal Disease Equation for Estimated Glomerular 
Filtration Rate.
Protocol Amendment 1 was a local amendment and is not applicable to the global protocol.
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