A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors
Phase: PHASE1
Conditions: Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors
Sponsor: Takeda




Title: A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate 
Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors
NCT Number: NCT03420742
Protocol Approve Date: 13 May 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

1.0 TITLE PAGE
PROTOCOL
A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam 
in Patients With ALK-Positive or ROS1-Positive Solid Tumors
Sponsor:
ARIAD Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Study Number:
Brigatinib-1001
IND Number:
IND 110,935
EudraCT Number:
2018-001624-19
Compound:
Brigatinib (ALUNBRIG) 
Date:
13 May 2019
Amendment Number:
01
Version Number:
1.0
Amendment History
Date
Amendment Number
Type
Region
14 November 2017
Initial protocol
Not applicable
Global
13 May 2019
01
Substantial
Global
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Study No. Brigatinib-1001
Page 2 of 79
Protocol Incorporating Amendment No. 01
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
Takeda Development Center–sponsored 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 Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual.
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Study No. Brigatinib-1001
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Protocol Incorporating Amendment No. 01
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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 Council 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, as applicable) can 
be found on the signature page.
Electronic signatures may be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, 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 Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Protocol Incorporating Amendment No. 01
13 May 2019
1.3
Protocol Amendment 01 Summary of Changes
Rationale for Amendment 01
This document describes the changes to the protocol incorporating Amendment 01. The primary 
reason for this amendment is to update the dose modification table (Table 8.b Brigatinib Dose 
Modification Recommendations for Treatment-Related Adverse Events) for consistency with the 
Company Core Data Sheet (CCDS) for brigatinib and provide clarity on allowed dose levels. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E. 
Changes in Amendment 01
1. Update Table 8.a (Recommended Brigatinib Dose Reduction Levels)
2. Update Table 8.b (Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events).
3. Update Excluded Concomitant Medications and Procedures (Section 8.3) to include moderate 
cytochrome P450 (CYP) 3A inhibitors in Part B of the study and to provide further guidance to 
investigators.
4. Add information regarding administration of brigatinib with certain concomitant medications 
to Precautions and Restrictions (Section 8.5).
5. Update adverse event (AE) definition (Section 10.1.2) to provide guidance on reporting of 
disease progression.
6. Update Schedule of Events (Appendix E) to include laboratory tests on Day 15 of Cycle 1.
7. Update Schedule of Events (Appendix E) to include laboratory tests on Day 15 of Cycles 2 to 
3.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 01 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................18
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................19
5.1
Objectives................................................................................................................19
5.1.1
Primary Objective ..............................................................................................19
5.1.2
Safety Objective.................................................................................................19
5.1.3
........................................................................................19
5.2
Endpoints.................................................................................................................19
5.2.1
Primary Endpoints .............................................................................................19
5.2.2
Secondary Endpoints..........................................................................................19
5.2.3
Safety Endpoints................................................................................................19
5.2.4
.......................................................................................20
6.0
STUDY DESIGN..........................................................................................................21
6.1
Overview of Study Design.......................................................................................21
6.1.1
Part A ................................................................................................................21
6.1.2
Part B.................................................................................................................23
6.2
Number of Patients ..................................................................................................23
6.3
Duration of Study ....................................................................................................23
6.3.1
Duration of an Individual Patient’s Study Participation ......................................23
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................24
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.......24
6.3.4
Total Study Duration..........................................................................................24
6.3.5
Posttrial Access..................................................................................................24
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7.0
STUDY POPULATION................................................................................................26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................27
8.0
STUDY DRUG .............................................................................................................30
8.1
Study Drug Administration......................................................................................30
8.2
Dose Modification Guidelines..................................................................................31
8.2.1
Recommended Dosing .......................................................................................31
8.2.2
Dose Modifications for Treatment-Related AEs.................................................31
8.2.3
Reescalation After Dose Reduction....................................................................34
8.2.4
Reintroducing Brigatinib After Dose Interruption...............................................35
8.3
Excluded Concomitant Medications and Procedures ................................................35
8.4
Permitted Concomitant Medications and Procedures................................................36
8.5
Precautions and Restrictions ....................................................................................37
8.5.1
Brigatinib...........................................................................................................37
8.5.2
Midazolam.........................................................................................................38
8.6
Management of Selected Treatment-Related Clinical Events....................................38
8.6.1
Nausea and/or Vomiting.....................................................................................38
8.6.2
Diarrhea.............................................................................................................38
8.6.3
Pneumonitis .......................................................................................................38
8.6.4
Hypertension......................................................................................................39
8.6.5
Bradycardia........................................................................................................39
8.6.6
Visual Disturbance.............................................................................................39
8.7
Blinding and Unblinding..........................................................................................39
8.8
Description of Investigational Agents ......................................................................39
8.9
Dispensation of Study Drug .....................................................................................40
8.10
Packaging and Labeling...........................................................................................40
8.11
Storage, Handling, and Accountability.....................................................................40
9.0
STUDY CONDUCT......................................................................................................41
9.1
Study Personnel and Organizations..........................................................................41
9.2
Arrangements for Recruitment of Patients................................................................41
9.3
Study Procedures.....................................................................................................41
9.3.1
Informed Consent...............................................................................................41
9.3.2
Enrollment .........................................................................................................41
9.3.3
Patient Demographics ........................................................................................42
9.3.4
Medical History .................................................................................................42
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9.3.5
ECOG Performance Status.................................................................................42
9.3.6
Physical Examination.........................................................................................42
9.3.7
Patient Height and Weight .................................................................................42
9.3.8
Vital Signs .........................................................................................................42
9.3.9
Pregnancy Test...................................................................................................43
9.3.10 Concomitant Medications and Procedures..........................................................43
9.3.11 Adverse Events ..................................................................................................43
9.3.12 ECG...................................................................................................................43
9.3.13 Patient Dosing Diary..........................................................................................43
9.3.14 Clinical Laboratory Evaluations .........................................................................43
9.3.15 Disease Assessment ...........................................................................................44
9.3.16 PK Measurements..............................................................................................45
9.4
Completion of Study Treatment (for Individual Patients) .........................................45
9.5
Completion of Study (for Individual Patients)..........................................................45
9.6
Discontinuation of Treatment With Study Drug and Withdrawal From the Study.....45
9.7
Study Compliance....................................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions...............................................................................................................47
10.1.1 Pretreatment Event Definition............................................................................47
10.1.2 AE Definition ....................................................................................................47
10.1.3 SAE Definition ..................................................................................................47
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................48
10.3
Monitoring of AEs and Period of Observation .........................................................49
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........49
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................49
10.6
Safety Reporting to Investigators, IRBs or Independent Ethics Committees, and 
Regulatory Authorities.............................................................................................50
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................51
12.0
DATA HANDLING AND RECORDKEEPING............................................................52
12.1
eCRFs......................................................................................................................52
12.2
Record Retention .....................................................................................................52
13.0
STATISTICAL METHODS..........................................................................................54
13.1
Statistical and Analytical Plans ................................................................................54
13.1.1 Analysis Sets......................................................................................................54
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................54
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13.1.3 PK Analysis .......................................................................................................54
13.1.4 Safety Analysis ..................................................................................................55
13.1.5 Efficacy Analysis...............................................................................................56
13.2
Analyses For Parts A and B and Criteria for Early Termination ...............................56
13.3
Determination of Sample Size..................................................................................57
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................58
14.1
Study-Site Monitoring Visits ...................................................................................58
14.2
Protocol Deviations..................................................................................................58
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................59
15.1
IRB Approval ..........................................................................................................59
15.2
Subject Information, Informed Consent, and Subject Authorization .........................60
15.3
Subject Confidentiality ............................................................................................61
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................61
15.4.1 Publication.........................................................................................................61
15.4.2 Clinical Trial Registration..................................................................................62
15.4.3 Clinical Trial Results Disclosure ........................................................................62
15.5
Insurance and Compensation for Injury....................................................................62
16.0
REFERENCES..............................................................................................................63
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................24
Table 8.a
Recommended Brigatinib Dose Reduction Levels..............................................31
Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs.....32
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................44
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Design for Part A (Cycle 1: PK Cycle).....................................................22
LIST OF APPENDICES
Appendix A
Schedule of Events and PK Sampling Schedule..................................................65
Appendix B
Responsibilities of the Investigator.....................................................................70
Appendix C
Investigator Consent to Use of Personal Information..........................................72
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Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status ..................73
Appendix E
Detailed Description of Amendments to Text.....................................................74
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2.0
STUDY SUMMARY
Name of Sponsor(s):
ARIAD Pharmaceuticals, Inc, a wholly owned subsidiary of
Takeda Pharmaceutical Company Limited
Compound:
Brigatinib
Title of Protocol: A Phase 1 Drug-Drug Interaction Study 
Between Brigatinib and the CYP3A Substrate Midazolam 
in Patients With ALK-Positive or ROS1-Positive Solid 
Tumors
IND No. 110,935
EudraCT No. 2018-001624-19
Study Number: Brigatinib-1001
Phase: 1
Study Design:
This study will consist of 2 parts: Part A (Cycle 1: pharmacokinetics [PK] cycle) and Part B (Cycle 2 and beyond: 
treatment cycles). Part A of the study will use a fixed-sequence design over a single 28-day treatment cycle. Patients 
will receive a 3 mg oral dose of midazolam on Day 1 of Part A, with serial PK sampling performed over 24 hours 
postdose to characterize the PK of midazolam in the absence of brigatinib. Brigatinib 90 mg will then be orally 
administered once daily (QD) on Days 2 through 8. If the 90 mg QD brigatinib dose is tolerated by the patient, the 
brigatinib dose will be increased to 180 mg QD, starting on Day 9 and continuing through Day 28 (in accordance with 
the United States [US] prescribing information). For patients who have escalated to brigatinib 180 mg QD, a 3 mg oral 
dose of midazolam will be administered on Day 21 of Part A, with serial PK sampling performed over 24 hours 
postdose to characterize the PK of midazolam in the presence of brigatinib. 
Any patients in Part A who are not PK evaluable will be replaced. Patients will be considered PK evaluable if they 
receive the protocol-specified dosing regimen during Part A (including the 180 mg QD brigatinib dose) without dose 
reductions or interruptions through the completion of PK sampling (Day 22); do not receive any excluded concomitant 
medications through the completion of PK sampling; and have sufficient midazolam concentration-time data to permit 
the reliable estimation of PK parameters by noncompartmental analysis methods.
After completion of Part A, patients may continue to Part B to receive the potential therapeutic benefits of brigatinib. 
Any patients who are replaced because they are not PK evaluable in Part A will also be eligible to continue into Part B. 
The starting dose of brigatinib in Part B will be the dose that was tolerated by the patient at the end of Part A. Part B of 
the study will include 28-day treatment cycles in which brigatinib will continue to be dosed QD at the highest tolerated 
dose (up to 180 mg QD) until disease progression (PD), intolerable toxicity, or another discontinuation criterion is 
met. Patients who cannot escalate to 180 mg QD in Part A will be maintained at 90 mg QD or lower. The available 
brigatinib daily oral doses for Part A and Part B will include 180, 120, 90, and 60 mg, allowing patients to have their 
dose reduced in cases of intolerability. 
Disease assessments by the investigator, using Response Evaluation Criteria in Solid Tumors, version 1.1, and 
evaluated by computed tomography and/or magnetic resonance imaging, will be performed during Screening; at 
8-week intervals during treatment (ie, on Day 28 [±3 days] of every even-numbered cycle) through Cycle 14; and 
every 12 weeks (ie, every 3 cycles) thereafter, and at end of treatment (EOT). Safety will be assessed throughout the 
study, including adverse event reporting through the 30-day follow-up period after EOT. Subsequent therapy will also 
be collected during the 30-day follow-up period.
Primary Objective: To characterize the effect of repeat-dose administration of brigatinib 180 mg QD on the 
single-dose PK of midazolam.
Other Objectives:
Safety: To assess the safety and tolerability of brigatinib in patients with ALK-positive or ROS1-positive solid tumors.
Subject Population: Adult cancer patients with locally advanced or metastatic solid tumors who meet 1 of the 
following 4 criteria: 1) patients with locally advanced or metastatic ALK-positive NSCLC who have progressed on 
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Protocol Incorporating Amendment No. 01
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treatment with at least 1 other ALK inhibitor, 2) patients with ALK-positive nonlung solid tumors that are locally 
advanced or metastatic and for whom no standard, nonexperimental therapy is available, 3) patients with locally 
advanced or metastatic ROS1-positive NSCLC who have progressed with crizotinib therapy or are intolerant to 
crizotinib, or 4) patients with ROS1-positive nonlung solid tumors that are locally advanced or metastatic and for 
whom no standard, nonexperimental therapy is available. 
Number of Subjects: approximately 20 enrolled patients to 
achieve 15 PK-evaluable patients
Number of Sites: Approximately 16 sites in Europe
Dose Level(s): 
Brigatinib: 180, 120, 90, 60 mg
Midazolam: 3 mg (Part A only)
Route of Administration: oral
Duration of Treatment:
Part A: 
Midazolam: 2 single 3 mg doses on Day 1 and Day 21.
Brigatinib: 90 mg QD×7 days, followed by 180 mg QD× 
20 days. 
Part B: Brigatinib at highest tolerated dose (180, 120, 90, 
or 60) QD×28 days per cycle. During Part B, patients may 
receive up to 23 months of treatment, or treatment until PD, 
intolerable toxicity, or another discontinuation criterion is 
met. If patients are still continuing to receive benefit at 
23 months, they may have the option to continue brigatinib 
monotherapy at the same dose.
Period of Evaluation:
Part A: 28 days
Part B: up to 23 28-day cycles through the 30-day 
Follow-up period following EOT 
(A maximum period of evaluation of 25 months)
Main Criteria for Inclusion:
!
Adult patients with cancer aged 18 years and older.
!
Patients with locally advanced or metastatic solid tumors who meet 1 of the following 4 criteria: 1) patients with 
locally advanced or metastatic ALK-positive NSCLC who have progressed on treatment with at least 1 other ALK
inhibitor; 2) Patients with ALK-positive nonlung solid tumors that are locally advanced or metastatic and for 
whom no standard, nonexperimental therapy is available; 3) Patients with locally advanced or metastatic 
ROS1-positive NSCLC who have progressed with crizotinib therapy or are intolerant to crizotinib, or 4) patients 
with ROS1-positive nonlung solid tumors that are locally advanced or metastatic and for whom no standard, 
nonexperimental therapy is available. Note: ALK or ROS1 positivity does not need to be diagnosed by a US 
FDA-approved test.
!
Total bilirubin ≤1.5 times the upper limit of the normal range.
!
Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2.
Main Criteria for Exclusion:
!
Systemic treatment with strong or moderate cytochrome P450 3A inhibitors or inducers within 14 days before 
enrollment.
!
Prior therapy with brigatinib. 
Endpoints and Assessments:
!
Primary: Midazolam PK parameters in the presence and absence of brigatinib, including:
–
Area under the concentration-time curve from time 0 to infinity (AUC∞)
–
Maximum observed concentration (Cmax)
–
Time of first occurrence of Cmax (tmax).
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Protocol Incorporating Amendment No. 01
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duration of response, and progression-free survival in the 4 subgroups of patients.
Statistical Considerations: Midazolam PK parameters in the presence and absence of brigatinib will be summarized 
descriptively. For the estimation of the effect of brigatinib on midazolam PK, the ratios of geometric mean midazolam 
AUC∞and Cmax (with vs without brigatinib coadministration) and the associated 2-sided 90% CIs will be calculated on 
the basis of the within-patient variance using a mixed-effects analysis of variance. Analyses for Part A of the study 
will be performed when all patients have completed Cycle 1 (PK cycle) and will include analyses of PK and safety.
Descriptive statistics will be presented for continuous safety variables (laboratory test values, vital signs, weight) by 
scheduled time point. Shift tables for laboratory parameters will be generated to show changes in National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.03, grade from Baseline to the worst 
post-Baseline value.
Sample Size Justification: It is anticipated that approximately 20 patients will be enrolled to obtain approximately 
15 PK-evaluable patients. The sample size calculation was based on the expected 2-sided 90% CI for the difference in 
the paired, log-transformed AUC∞means of midazolam in the absence and presence of brigatinib. The within-patient 
coefficient of variation for midazolam AUC∞was estimated to be 28% on the basis of a pooled analysis of data from 
5 drug-drug interaction studies with midazolam conducted in patients with cancer [1-5]. Assuming that the AUC∞
ratio for midazolam in the presence versus absence of brigatinib is 1, with a sample size of 15, the 90% CI for the 
AUC∞ratio is expected to be 0.84 to 1.19 on the basis of the variance assumptions. If the AUC∞ratio for midazolam in 
the presence versus absence of brigatinib is X, with a sample size of 15, the 90% CI for the AUC∞ratio is expected to 
be 0.84X to 1.19X on the basis of the variance assumptions.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities, with the exception of those identified in the 
clinical study supplier list or equivalent. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator 
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity
CCDS
Company Core Data Sheet
CK
creatine kinase
Cmax
maximum observed concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOT
end of treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
HDPE
high-density polyethylene
ICH
International Council on Harmonisation
ILD
interstitial lung disease
IRB
institutional review board
IRT
interactive response technology
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
PD
progressive disease
PFS
progression-free survival
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P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PR
partial response
PTA
posttrial access
QD
once daily
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SBP
systolic blood pressure
SRS
stereotactic radiosurgery
SUSAR
suspected unexpected serious adverse reaction
tmax
time of first occurrence of maximum observed concentration
ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
3.4
Corporate Identification 
ARIAD
ARIAD Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
TDC Americas
Takeda Development Center Americas, Inc.
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4.0
INTRODUCTION
4.1
Background
Lung cancer is the leading cause of cancer death in the United States (US) and Europe. 
Approximately 78% of patients have regional/distance metastases at diagnosis [6], and the 5-year 
survival rates are low (17.7% and 13.0%, respectively) [7]. In the United States, an estimated 
222,500 new cases of lung and bronchial cancer will be diagnosed by the end of 2017, with an 
estimated 155,870 deaths occurring due to the disease [8].
Historically, lung cancers have been stratified on the basis of histologic criteria and are generally 
divided into 2 categories: small-cell lung cancer and non–small-cell lung cancer (NSCLC). 
NSCLC is the most prevalent histologic class, accounting for nearly 85% of all lung cancers 
[9,10], and includes a number of subtypes such as adenocarcinoma, squamous cell carcinoma, 
large-cell carcinoma, and bronchioloalveolar carcinoma [11]. In recent years, attention has turned 
to stratifying patients with lung cancer on the basis of molecular alterations. This is because 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 
EGFR-mutant and ALK-rearranged NSCLC. NSCLC and other solid tumors that contain 
oncogenic rearrangements in the ALK gene and the ROS1 gene are potential targets for brigatinib.
Brigatinib is an orally administered tyrosine kinase inhibitor whose primary targets are activated, 
mutant forms of ALK and ROS1, which play important roles in NSCLC and other solid tumors. 
ALK is a tyrosine kinase encoded on chromosome 2 and is primarily involved in developmental 
processes and expressed at low levels in adults [12]. A series of in vitro and in vivo studies to 
characterize the pharmacodynamic profile of brigatinib have demonstrated that brigatinib potently 
inhibits activated variants of ALK, such as EML4-ALK, and variants of ALK, including the 
L1196M gatekeeper mutation that confers resistance to crizotinib. No ALK mutations that confer 
resistance to brigatinib at clinically achievable concentrations have been identified in in vitro
mutagenesis assays, and brigatinib has been shown to potently inhibit activated variants of ROS1
kinase. Brigatinib also inhibits certain mutant variants of EGFR and IGF1R without affecting the 
insulin receptor.
Brigatinib (marketed as ALUNBRIG) was granted accelerated approval by the US Food and Drug 
Administration (FDA) on 28 April 2017 for the treatment of patients with metastatic ALK-positive 
NSCLC who have progressed on or are intolerant to the ALK inhibitor crizotinib. The 
recommended dose of brigatinib is 90 mg orally once daily (QD) for the first 7 days, and if 
tolerated, the dose is to be increased to 180 mg QD. Approval was based on the phase 2 
Study AP26113-13-201, which compared the brigatinib 90 mg QD dosing regimen to the 
90 mg→180 mg QD dosing regimen (90 mg QD for 7 days followed by escalation to 180 mg QD) 
in patients who had progressed on crizotinib. Brigatinib is designated an orphan drug for the 
treatment of ALK-positive, ROS1-positive, and EGFR-positive NSCLC.
In ongoing Study AP26113-13-201, patients were stratified for randomization by brain metastases 
at Baseline and best response to prior treatment with crizotinib. Based on data from a clinical 
database extraction date of 21 February 2017, brigatinib is highly effective in the 
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crizotinib-refractory, ALK-positive NSCLC population, with confirmed investigator-assessed 
objective response rates (ORRs) of 45.5% and 55.5% for the 90 mg QD and 90 mg→180 mg QD 
regimens, respectively, and investigator-assessed progression-free survival (PFS) of 9.2 months 
and 15.6 months, respectively. In patients with measurable brain metastases at Baseline, the 
IRC-assessed intracranial ORR was 50.0% and 66.7% for patients receiving the 90 mg QD and 
90 mg→180 mg QD regimens, respectively. 
In ongoing phase 1/2 Study AP26113-11-101, 2 of the 4 patients with ROS1-positive NSCLC who
were enrolled had confirmed partial responses (PRs) to brigatinib, with durations of response 
(DORs) of 22.5 and 22.8 months; both patients were crizotinib naïve.
Also ongoing is the phase 3, randomized Study AP26113-13-301, which is evaluating brigatinib 
versus crizotinib in patients with locally advanced or metastatic ALK-positive NSCLC who have 
had no prior therapy with an ALK inhibitor.
4.2
Rationale for the Proposed Study
In vitro studies using human hepatocytes have indicated that brigatinib, at clinically relevant 
concentrations of 1 to 2.5 μM, caused an increase in CYP3A4 messenger RNA levels (see the 
Investigator’s Brochure for further details). Therefore, brigatinib may have the potential for 
pharmacokinetic (PK) drug interactions with substrates of CYP3A through induction of 
expression of this enzyme, potentially leading to decreased systemic exposures of its substrates. 
The primary purpose of this study (Brigatinib-1001) is to evaluate the effect of repeated doses of 
brigatinib on the single-dose PK of midazolam, a sensitive CYP3A probe substrate, to determine if 
brigatinib, at therapeutic doses, produces clinically meaningful CYP3A induction in vivo, and if 
so, to inform strategies for the management of potential drug-drug interactions (DDIs) between 
brigatinib and substrates of CYP3A. Midazolam is an established sensitive substrate of CYP3A 
that is commonly used in clinical DDI studies to assess the effect of a coadministered drug on 
CYP3A activity [13,14]. Oral doses of midazolam ranging from 2 to 7.5 mg have generally been 
used in clinical DDI studies [1,2,15-17]. A 3 mg oral dose of midazolam was selected for use in 
this study to allow for adequate PK characterization of midazolam after administration in both the 
absence (ie, baseline CYP3A expression levels) and presence (ie, possibly induced CYP3A 
expression levels) of brigatinib.
 In addition to ALK-positive patients with NSCLC, patients with
ROS1-positive NSCLC, and patients with ALK-positive or ROS1-positive nonlung solid 
tumors—all with locally advanced or metastatic disease—are eligible for enrollment, 
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to characterize the effect of repeat-dose administration of 
brigatinib 180 mg QD on the single-dose PK of midazolam.
5.1.2
Safety Objective
The safety objective of this study is to assess the safety and tolerability of brigatinib in patients 
with ALK-positive or ROS1-positive solid tumors.
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints of this study are midazolam PK parameters in the presence and absence of 
brigatinib, including:
!
Area under the concentration-time curve from time 0 to infinity (AUC∞). 
!
Maximum observed concentration (Cmax).
!
Time of first occurrence of Cmax (tmax).
5.2.2
Secondary Endpoints
There are no secondary endpoints for this study.
5.2.3
Safety Endpoints
The endpoints for assessing safety and tolerability of brigatinib will include:
!
AEs.
!
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis [Part B only]).
!
Vital signs.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This open-label, multicenter, phase 1 study will enroll approximately 20 patients with 
ALK-positive or ROS1-positive solid tumors, including NSCLC, and will consist of 2 parts: Part A 
(Cycle 1: PK cycle) and Part B (Cycle 2 and beyond: treatment cycles). 
6.1.1
Part A
Part A will use a fixed-sequence design over a single 28-day treatment cycle (Figure 6.a). All 
patients will receive a 3 mg oral dose of midazolam on Day 1, with serial PK sampling performed 
over the 24 hours following dosing to characterize the PK of midazolam in the absence of 
brigatinib. Brigatinib 90 mg QD will then be orally administered on Days 2 through 8. If the 90 mg 
brigatinib dose is tolerated by the patient, the brigatinib dose will be increased to 180 mg QD, 
starting on Day 9 and continuing through Day 28 (in accordance with the US prescribing 
information). For patients escalating to brigatinib 180 mg QD, a 3 mg oral dose of midazolam will 
be administered on Day 21 of Part A, with serial PK sampling performed over the 24 hours 
following dosing to characterize the PK of midazolam in the presence of brigatinib. 
Any patients in Part A who are not PK evaluable will be replaced. Patients will be considered PK 
evaluable if they receive the protocol-specified dosing regimen during Part A (including the 
180 mg QD brigatinib dose) without dose reductions or interruptions through the completion of 
PK sampling (Day 22); do not receive any excluded concomitant medications through the 
completion of PK sampling; and have sufficient midazolam concentration-time data to permit the 
reliable estimation of PK parameters by noncompartmental analysis methods. 
Serial blood samples for determination of plasma concentrations of midazolam will be obtained 
during Part A (Cycle 1: PK cycle) at prespecified time points up to 24 hours postdose, as described 
in Appendix A Table 1 and Appendix A Table 2. Predose blood samples will also be collected on 
Days 21 and 22 of Part A and on Day 1 of Cycle 2 (Part B) to measure trough plasma 
concentrations of brigatinib.
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CONFIDENTIAL
Figure 6.a
Study Design for Part A (Cycle 1: PK Cycle)
Study Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Midazolam 3 mg
X
X
Brigatinib 90 mg
X X X X X X X
Brigatinib 180 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sampling for 
Midazolam PK
X X
X
X
Note: Red, green, and blue shading indicate dosing days for midazolam 3 mg, brigatinib 90 mg, and brigatinib 180 mg, respectively.
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6.1.2
Part B
After completion of Part A, patients may continue to Part B to receive the potential therapeutic 
benefits of brigatinib. Any patients who are replaced because they are not PK evaluable in Part A 
will also be eligible to continue into Part B. The starting dose of brigatinib in Part B will be the 
dose that was tolerated by the patient at the end of Part A. Part B of the study will include 28-day
treatment cycles in which brigatinib will continue to be dosed QD at the highest tolerated dose (up 
to 180 mg QD) up to 23 cycles of treatment, or until PD, intolerable toxicity, or another 
discontinuation criterion is met. 
Patients who cannot escalate to 180 mg QD in Part A will be maintained at 90 mg QD or 
60 mg QD. The brigatinib daily oral doses administered during Part A and Part B may include 
180 mg or lower. Doses of 120, 90, and 60 mg may be offered as options to allow patients to have 
their dose reduced in cases of intolerability.
Drug safety and tolerability will be evaluated during the study by AE monitoring, clinical 
laboratory tests, vital sign measurements, and physical examinations. An electrocardiogram 
(ECG) will be performed at Screening, Day 1 of Part B, and at the end of treatment (EOT). The 
study will include a 30-day follow-up period after EOT for reporting of AEs and subsequent 
therapy. Toxicity will be evaluated according to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010 [18]. 
6.2
Number of Patients
Approximately 20 patients with locally advanced or metastatic ALK-positive or ROS1-positive 
solid tumors, including NSCLC, will be enrolled in this study to achieve approximately 15 
PK-evaluable patients for assessment of the effect of brigatinib on the PK of midazolam.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Following the single 28-day PK cycle in Part A of the study, patients may enter Part B and 
continue daily treatment with brigatinib in 28-day repeated cycles at their highest tolerated dose 
(up to 180 mg QD) for up to 23 months of treatment or until PD, intolerable toxicity, or another 
discontinuation criterion is met. All patients will be assessed for safety and subsequent therapy
during the 30-day follow-up period after EOT. 
The maximum duration of study participation for an individual patient will be approximately 
26 months (which includes screening period, the Part A PK cycle, a maximum of 23 cycles in 
Part B, and the 30-day follow-up period after EOT).
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6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion
The estimated time frame for primary completion of the study is 13 to 15 months, which includes 
an estimated 12- to 14-month enrollment period and Part A of the study. The clinical study report 
(CSR) analyses for the primary endpoint will be conducted after all PK-evaluable patients 
complete Part A of the study, and will include analyses of PK and safety.
Other Planned Analyses
A CSR addendum for safety
is planned for when all enrolled patients 
have completed Part B of the study (approximately 2 years after enrollment of the last patient).
Study Completion
The estimated time frame for overall study completion is approximately 3 years. 
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for the primary endpoint.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
The primary endpoints of this study 
are midazolam PK parameters in the 
presence and absence of brigatinib, 
including:
!
AUC∞. 
!
Cmax.
!
tmax.
Midazolam AUC∞, Cmax, tmax
For an individual patient, from 
predose up to 24 hours postdose on 
Days 1 and 21, for a total time 
frame of 22 days.
There are no secondary endpoints for 
this study.
6.3.4
Total Study Duration
Part A will consist of a single 28-day PK cycle. Part B will consist of repeated 28-day treatment 
cycles up to 23 months of treatment (24 months in total, including Part A), or until PD, intolerable 
toxicity, or discontinuation due to other reasons. The total duration of the study is anticipated to be 
up to approximately 3 years, including the enrollment period, Part A PK cycle, Part B treatment 
cycles, and follow-up period.
6.3.5
Posttrial Access
Currently, there is no posttrial access (PTA) protocol available in the brigatinib development 
program. If an open-label, rollover, PTA study should become an option, and the investigator and 
sponsor agree that a patient would derive benefit from continued treatment or would be harmed 
CCI
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without continued access to brigatinib, the patient may be given the opportunity to enter the 
rollover study and continue receiving brigatinib.
In the event of a rollover PTA study, continued access to brigatinib for study participants will be 
terminated for those individuals who no longer benefit from treatment (eg, they have completed 
the recommended course of therapy or their disease has improved or resolved), the benefit-risk 
profile no longer favors the individual, or an appropriate alternative therapy becomes available. If 
patients are placed in a rollover PTA study, they will be considered to have completed Study 
Brigatinib-1001. PTA may be terminated in a country or geographical region where the 
development of brigatinib has been suspended or stopped by the sponsor or brigatinib can no 
longer be supplied.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Adult patients with cancer aged 18 years and older.
2. Patients with locally advanced or metastatic solid tumors who meet 1 of the following 4 
criteria: 1) patients with locally advanced or metastatic ALK-positive NSCLC who have 
progressed on or are intolerant to treatment with at least 1 other ALK inhibitor, 2) patients with 
ALK-positive nonlung solid tumors that are locally advanced or metastatic and for whom no 
standard, nonexperimental therapy is available, 3) patients with locally advanced or metastatic 
ROS1-positive NSCLC who have progressed on crizotinib therapy or are intolerant to 
crizotinib, or 4) patients with ROS1-positive nonlung solid tumors that are locally advanced or 
metastatic and for whom no standard, nonexperimental therapy is available. Note: ALK or 
ROS1 positivity does not need to be diagnosed by a US FDA-approved test.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Have at least 1 target lesion per RECIST version 1.1.
5. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE version 4.03 
Grade ≤1. Note: Treatment-related alopecia and peripheral neuropathy that are Grade >1 are 
allowed, if deemed irreversible.
6. Adequate organ function as determined by:
–
Total bilirubin ≤1.5 times the upper limit of the normal range (ULN).
–
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5×ULN; ≤5×ULN 
is acceptable if liver metastases are present.
–
Estimated glomerular filtration rate (eGFR) ≥30 mL/minute/1.73 m2, calculated using the 
Modification of Diet in Renal Disease equation: 
eGFR (mL/min/1.73 m2)=175×(serum creatinine in mg/dL)-1.154×(age in 
years)-0.203×(0.742 if female)×(1.212 if African American).
–
Serum lipase/amylase ≤1.5×ULN.
–
Absolute neutrophil count (ANC) ≥1.5×109/L.
–
Platelet count ≥75×109/L.
–
Hemoglobin ≥10 g/dL.
7. Female patients who:
–
Are postmenopausal for at least 1 year before the screening visit, or
–
Are surgically sterile, or
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–
If they are of childbearing potential, agree to practice 1 highly effective nonhormonal
method of contraception and 1 additional effective (barrier) method at the same time, from 
the time of signing the informed consent through 4 months after the last dose of study drug, 
or
–
Agree to practice true abstinence during the entire study treatment period through 4 months 
after the last dose of study drug, 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.)
8. Male patients, even if surgically sterilized (ie, postvasectomy), who:
–
Agree to practice effective barrier contraception during the entire study treatment period 
through 4 months after the last dose of study drug, or
–
Agree to practice true abstinence during the entire study treatment period through 4 months 
after the last dose of study drug, 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.)
9. Suitable venous access for study-required blood sampling (ie, including PK and laboratory 
safety tests).
10. Have the willingness and ability to comply with scheduled visits and study procedures.
11. Provide signed and dated informed consent indicating that the patient has been informed of all 
pertinent aspects of the study, including the potential risks, and is willingly participating. 
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.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Systemic treatment with strong or moderate CYP3A inhibitors or inducers within 14 days 
before enrollment. (See Section 8.3 for lists of strong and moderate CYP3A inhibitors and 
inducers.)
2. Prior therapy with brigatinib. 
3. Received prior ALK-inhibitor therapy within 7 days before the first dose of study drug.
4. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, 
whichever is longer, before the first dose of study drug.
5. Received chemotherapy or radiation therapy within 14 days before the first dose of study drug, 
except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
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6. Received antineoplastic monoclonal antibodies within 30 days before the first dose of study 
drug.
7. Had major surgery within 30 days before the first dose of study drug. Minor surgical 
procedures, such as catheter placement or minimally invasive biopsies, are allowed.
8. Have symptomatic central nervous system (CNS) metastases (parenchymal or leptomeningeal) 
at Screening or asymptomatic disease requiring an increasing dose of corticosteroids to control 
symptoms within 7 days before study enrollment. 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 7 days before study enrollment.
9. Have current spinal cord compression (symptomatic or asymptomatic and detected by 
radiographic imaging). Patients with leptomeningeal disease and without cord compression are 
allowed.
10. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not 
restricted to:
–
Myocardial infarction within 6 months before the first dose of study drug.
–
Unstable angina within 6 months before the first dose of study drug.
–
Congestive heart failure (ie, New York Heart Association Class III or IV) within 6 months 
before the first dose of study drug.
–
History of clinically significant atrial arrhythmia (including clinically significant 
bradyarrhythmia), as determined by the treating physician.
–
Any history of ventricular arrhythmia.
–
Cerebrovascular accident or transient ischemic attack within 6 months before the first dose 
of study drug.
11. Have uncontrolled hypertension. Patients with hypertension should be under treatment for 
control of blood pressure upon study entry.
12. Female patients who are pregnant, planning a pregnancy, or breastfeeding.
13. Have a history or presence at Baseline of pulmonary interstitial disease, drug-related 
pneumonitis, or radiation pneumonitis.
14. Have an ongoing or active infection, including but not limited to, the requirement for 
intravenous antibiotics.
15. Have a known history of HIV infection. Testing is not required in the absence of history.
16. Have a known or suspected hypersensitivity to brigatinib or midazolam or their excipients.
17. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral 
absorption or tolerance of midazolam or brigatinib, including difficulty swallowing or diarrhea 
Grade >1, despite supportive therapy.
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18. 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.
19. Life-threatening illness unrelated to cancer.
20. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
21. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection.
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
study drug administration. Study drug will be dispensed only to eligible patients under the 
supervision of the investigators or identified subinvestigators.
On Day 1 of Part A (Cycle 1: PK cycle), all enrolled patients will report to the clinic and receive a 
3 mg oral solution dose of midazolam on an empty stomach (ie, at least 1 hour before or at least 
2 hours after food). Immediately after administration of the oral midazolam dose, patients will 
consume approximately 8 ounces (240 mL) of water. Following collection of the 24-hour 
midazolam PK sample on Day 2 of Part A, patients will be dispensed brigatinib for administration 
of 90 mg QD on Days 2 through 8. Patients will return to the clinic on Day 9 for a study visit, and 
if the 90 mg QD brigatinib dose was tolerated on Days 2 through 8, the brigatinib dose will be 
increased to 180 mg QD. Patients will be instructed to administer each brigatinib dose at 
approximately the same time each day, approximately 24 hours apart, and as close as possible to 
the anticipated time of midazolam administration on Day 21 (ie, in the morning). Brigatinib may 
be taken with or without food on Days 2 through 20 of Part A. Patients will take the prescribed 
dose of brigatinib with approximately 8 ounces (240 mL) of water. On Days 21 and 22 of Part A, 
the 180 mg QD brigatinib dose will be administered in the clinic as described below.
On Day 21 of Part A, patients receiving the 180 mg daily dose of brigatinib will return to the 
clinic. Following collection of the Day 21 midazolam and brigatinib predose PK samples, patients 
will take 180 mg of brigatinib in the clinic together with 3 mg of oral midazolam on an empty 
stomach (ie, at least 1 hour before or at least 2 hours after food). The 3 mg oral solution dose of 
midazolam should be administered first, immediately followed by administration of the 180 mg 
dose of brigatinib with approximately 8 ounces (240 mL) of water.
Following collection of the PK samples on Day 22 (ie, 24-hour midazolam PK sample and predose 
brigatinib PK sample), QD administration of brigatinib will continue on Days 22 through 28 of 
Part A. Patients will continue on their highest tolerated dose of brigatinib (up to 180 mg QD) 
through Day 28 of Part A. Patients will be instructed to take brigatinib doses with or without food 
at approximately the same time each day and approximately 24 hours apart. Patients will take the 
prescribed dose of brigatinib with approximately 8 ounces (240 mL) of water.
Patients continuing into Part B of the study will visit the clinic on Day 1 of Cycle 2. The Cycle 2 
Day 1 brigatinib dose will be administered in the clinic after collection of a predose brigatinib PK 
sample. Patients will continue into Part B at the brigatinib dose that they were receiving (and 
tolerating) at the end of Part A (180, 120, 90, or 60 mg) and will continue treatment until PD, 
unacceptable toxicity, or another discontinuation criterion is met. Brigatinib doses during Part B 
may be taken with or without food and should be taken at approximately the same time each day 
(ie, approximately 24 hours apart). Patients will take the prescribed dose of brigatinib with 
approximately 8 ounces (240 mL) of water.
During Part A, the date and time of brigatinib administration should be recorded in the patient’s 
dosing diary. A diary will not be used in Part B of the study. If a patient fails to take the brigatinib 
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dose within the time frame specified (ie, within ±4 hours of the initial dosing time), that dose 
should be omitted and considered a missed dose. The patient should record any missed doses in the 
dosing diary. If emesis occurs after study drug administration, the patient should simply adhere to 
the dosing schedule and resume dosing at the next scheduled dosing time with the prescribed 
dosage. The timing of emesis relative to study drug administration should be recorded. Patients 
should not repeat a dose, try to make up a dose, or “double up” doses. In the case of a missed dose 
or emesis in Part A, patients may be considered not PK evaluable and may be replaced.
8.2
Dose Modification Guidelines
8.2.1
Recommended Dosing
In Part A, patients who have tolerated the 90 mg starting dose on Days 2 through 8 of Cycle 1 will 
be expected to increase their daily dose to 180 mg, beginning on Day 9 and continuing through 
Day 28. The patient’s daily dose of brigatinib should not be increased to 180 mg if any of the 
following adverse drug reactions are experienced during treatment with 90 mg QD:

Interstitial lung disease (ILD)/pneumonitis (any grade).

Symptomatic bradycardia (Grade 2 or higher).

Visual disturbance (Grade 2 or higher).

Any other Grade 3 or higher adverse drug reaction.
If a patient did not experience any of the above adverse drug reactions, but dose escalation did not 
occur during Part A, dose escalation may be permitted during Part B following approval from the 
medical monitor. The brigatinib daily dose must not exceed 180 mg daily.
8.2.2
Dose Modifications for Treatment-Related AEs
The allowable daily doses of brigatinib in this study are 180, 120, 90, and 60 mg. 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.a.
Table 8.a
Recommended Brigatinib Dose Reduction Levels
Dose
Dose Reduction Levels
First
Second
Third
Fourth
90 mg QD
(first week of 
treatment)
60 mg QD
Permanently 
discontinue
Not applicable
Not applicable
180 mg QD
120 mg QD
90 mg QD
60 mg QD
Permanently 
discontinue
Recommendations for dose modification of brigatinib for the management of treatment-related 
AEs are provided in Table 8.b and are based on the CCDS for brigatinib (ALUNBRIG). Unless 
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otherwise noted, reduce the dose as indicated in Table 8.b if 1 or more dose reductions are 
necessary because of Grade 3/4 treatment-related AEs (as defined by NCI CTCAE version 4.03).
Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs
AE
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. If 
ILD/pneumonitis is suspected, resume at next lower dose (Table 
8.a); otherwise, resume at same dose. 

If ILD/pneumonitis recurs, permanently discontinue brigatinib.
Grade 3 or 4
Permanently discontinue brigatinib for ILD/pneumonitis.
Hypertension
Grade 3 hypertension 
(SBP ≥160 mmHg or 
DBP ≥100 mmHg, 
medical intervention 
indicated, more than 1 
antihypertensive drug, or 
more intensive therapy 
than previously used 
indicated)

Withhold brigatinib until hypertension has recovered to Grade 1 
or less (SBP less than 140 mmHg and DBP less than 90 mmHg), 
then resume brigatinib at same dose. 

Recurrence: Withhold brigatinib until recovery to Grade 1 or 
less, then resume at next lower dose or permanently discontinue 
treatment.
Grade 4 hypertension 
(life-threatening 
consequences, urgent 
intervention indicated)

Withhold brigatinib until recovery to Grade 1 or less (SBP less 
than 140 mmHg and DBP less than 90 mmHg), then resume at 
next lower dose (Table 8.a) or permanently discontinue 
treatment. 

Recurrence: Permanently discontinue brigatinib for recurrence of 
Grade 4 hypertension.
Footnotes are on last table page.
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related AEs 
(continued)
AE
Severity (a)
Dose Modification
Bradycardia (HR 
<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 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 upon recovery to asymptomatic bradycardia or to a resting 
heart rate of 60 bpm or above, with frequent monitoring as 
clinically indicated. 

Recurrence: Permanently discontinue brigatinib.
Visual 
disturbance
Grade 2 or 3 visual 
disturbance
Withhold brigatinib until recovery to Grade 1 or baseline, then resume 
at the next lower dose
Grade 4 visual 
disturbance
Permanently discontinue brigatinib.
CPK elevation
Grade 3 CPK elevation 
(>5.0×ULN)

Withhold brigatinib until recovery to Grade 1 or less 
(≤2.5×ULN) or to baseline, then resume brigatinib at same dose.

If Grade 3 elevation of CPK recurs, brigatinib should be withheld 
until recovery to Grade 1 or less (less than or equal to 2.5 x ULN) 
or to baseline, then resume at the next lower dose level per Table 
8.a.
Grade 4 CPK elevation 
(>10.0×ULN) 

Withhold brigatinib until recovery to Grade 1 or less 
(≤2.5×ULN) or to baseline, then resume brigatinib at next lower 
dose.

If Grade 4 elevation of CPK recurs, permanently discontinue 
brigatinib.
Lipase/amylase 
elevation
Grade 3 lipase or 
amylase elevation 
(>2.0×ULN)

Withhold brigatinib until recovery to Grade 1 or less 
(≤1.5×ULN) or to baseline, then resume brigatinib at same dose.

If Grade 3 elevation of lipase and amylase recurs, brigatinib 
should be witheld 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.
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AE
Severity (a)
Dose Modification
Grade 4 lipase or 
amylase elevation 
(>5.0×ULN) 

Withhold brigatinib until recovery to Grade 1 or less 
(≤1.5×ULN) or to baseline, then resume brigatinib at next lower 
dose

If Grade 4 elevation of lipase/amylase recurs, permanently 
discontinue brigatinib. 
Hyper-
glycemia
Grade 3 (>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 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.
Grade 4

First occurrence: either withhold brigatinib until recovery to 
baseline and resume at next lower dose or permanently 
discontinue. 

Permanently discontinue brigatinib for recurrence.
Source: US prescribing information, April 2017.
Bpm=beats per minute, CPK=creatine phosphokinase, DBP=diastolic blood pressure, HR=heart rate, SBP=systolic blood 
pressure.
(a) Graded per NCI CTCAE version 4.03.
Grade 3 nonhematologic toxicities attributed to brigatinib that do not require dose reduction 
include:

Grade 3 or greater nausea and/or emesis in the absence of optimal antiemetic prophylaxis. 
(Optimal antiemetic prophylaxis is defined as an antiemetic regimen that employs both a 
5-HT3 antagonist and a corticosteroid given in standard doses and according to standard 
schedules.)

Grade 3 or greater diarrhea that occurs in the absence of optimal supportive therapy.

Grade 3 fatigue.
8.2.3
Reescalation After Dose Reduction
Reescalation of brigatinib after dose modification for AEs is discouraged; however, if in the 
opinion of the treating investigator, reescalation is warranted, this must be undertaken after 
consultation with the sponsor. 
For a patient to be a candidate for dose reescalation, the AE that led to dose modification must not
have reoccurred, and the patient must have had no other Grade 3/4 AEs in the past 28 days. 
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8.2.4
Reintroducing Brigatinib After Dose Interruption
If brigatinib treatment is interrupted for less than 14 days, patients may resume treatment at the 
current dose, provided the patient does not meet any of the criteria to reduce their dose by 1 dose 
level (as indicated in Table 8.b).
If brigatinib treatment is interrupted for 14 days or more, with the interrupted dose being greater 
than 90 mg QD, patients should resume brigatinib treatment at 90 mg QD for 7 days before 
escalating the dose to 120 mg QD or 180 mg QD; however, the dose should not be escalated 
higher than the dose level before treatment was interrupted.
8.3
Excluded Concomitant Medications and Procedures
Systemic treatment with the following medications is prohibited for 14 days before study 
enrollment and during Part A (Cycle 1: PK cycle) of the study: 

Strong CYP3A inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, 
grapefruit-containing products including grapefruit juice, idelalisib, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole.

Moderate CYP3A inhibitors: amprenavir, aprepitant, atazanavir, ceritinib, cimetidine, 
ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, diltiazem, erythromycin, 
fluconazole, fluvoxamine, fosamprenavir, imatinib, and verapamil. 

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.
Systemic treatment with the following medications should be avoided during Part B of the study:

Strong CYP3A inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, 
grapefruit-containing products including grapefruit juice, idelalisib, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole. If concomitant use of a strong CYP3A inhibitor cannot be 
avoided in Part B of 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 the strong CYP3A inhibitor was initiated.

Moderate CYP3A inhibitors: amprenavir, aprepitant, atazanavir, ceritinib, cimetidine, 
ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, diltiazem, erythromycin, 
fluconazole, fluvoxamine, fosamprenavir, imatinib, and verapamil. If concomitant use of a 
moderate CYP3A inhibitor cannot be avoided during the study, reduce the brigatinib QD dose 
by approximately 40% (ie, from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). 
After discontinuation of a moderate CYP3A inhibitor, resume the brigatinib dose that was 
tolerated before the moderate CYP3A inhibitor was initiated.
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
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.
Because the above lists are not exhaustive, the investigator should consult the prescribing 
information for any medication under consideration for use to assess if it is a strong CYP3A 
inhibitor, moderate CYP3A inhibitor, strong CYP3A inducer, or moderate CYP3A inducer.
The following medications and procedures are prohibited during the study:

Any investigational agent other than brigatinib, including agents that are commercially 
available for indications other than ALK-positive or ROS1-positive NSCLC and other solid 
tumors that are under investigation for the treatment of NSCLC and other solid tumors.

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.
8.4
Permitted Concomitant Medications and Procedures
During Part A of the study, no new concomitant therapy is allowed unless approved by the medical 
monitor, with the exception of concomitant medications found necessary by the investigator to 
treat severe or life-threatening conditions. Patients will be allowed to continue concomitant 
medications that they were taking during study screening, as long as the medications are not strong 
or moderate CYP3A inhibitors or inducers or other excluded medications, as described in Section 
8.3.
During Part B, palliative therapy and supportive care are permitted during the study for 
management of symptoms and underlying medical conditions that may develop during the study. 
Once a patient has begun treatment, a condition may arise that requires the initiation of a new 
concomitant treatment. Patients with CNS lesions requiring local radiotherapy such as SRS are 
allowed to continue study drug after appropriate interruption, as determined by the investigator 
with sponsor agreement; however, these patients will be considered to have PD.
Concomitant medications for all ongoing medical history conditions or AEs, as well as 
prophylactic treatments and supplements, must be reported from the date the informed consent is 
signed through the 30-day follow-up period after EOT. All concomitant medications related to 
serious or study-drug–related toxicities must be reported until the medication is no longer taken or 
until patient contact ceases.
Radiation therapy for the disease under study is allowed but will be considered evidence of PD; 
therefore, such patients will be considered to have PD at or before the initiation of radiation 
therapy.
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8.5
Precautions and Restrictions
8.5.1
Brigatinib
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.
Brigatinib is an in vitro inhibitor of P-gp, breast cancer resistance protein, organic cation 
transporter 1, multidrug and toxin extrusion protein 1 and 2K. 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.
If a patient experiences a brigatinib-related side effect, the investigator will advise the patient of 
any precautions or restrictions.
It is not known what effects brigatinib may have 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.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective nonhormonal method 
and 1 additional effective (barrier) method of contraception from the time of signing the 
informed consent form through 4 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject during the dosing period through 4 months after the last dose of study drug. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
Male patients with female partners of reproductive potential, even if surgically sterilized (ie, 
postvasectomy), must agree to 1 of the following:
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
Agree to practice effective barrier contraception during the entire study treatment period and 
through 4 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject, from the time of signing the informed consent form through 4 months after the last 
dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used together.)
8.5.2
Midazolam
Midazolam is a short-acting benzodiazepine that depresses activity of the CNS and has been 
associated with respiratory depression, most often when used concomitantly with other CNS 
depressants (eg, opioids and other benzodiazepines). Therefore, all patients will be closely 
monitored for respiratory and cardiac function (ie, pulse oximetry) after administration of 
midazolam on Days 1 and 21 of Part A of the study. Immediate availability of reversal agents (eg, 
flumazenil), resuscitative drugs, equipment for ventilation and intubation, and personnel trained in 
their use and skilled in airway management should be assured. Please refer to the midazolam 
prescribing information for full details regarding the use of midazolam.
Midazolam causes sedation. Patients should not drive, operate dangerous tools or machinery, or 
engage in any other potentially hazardous activity that requires full alertness and coordination after 
receiving midazolam on Day 1 and Day 21 of Part A of the study. 
8.6
Management of Selected Treatment-Related Clinical Events
8.6.1
Nausea and/or Vomiting
Although this study will not initially employ prophylactic antiemetics, there is no prohibition 
against their use in the management of a patient who develops nausea and/or vomiting. As in the 
prophylactic setting, 5-HT3 receptor antagonists and corticosteroids should be tried first.
8.6.2
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. Management of diarrhea will be at the 
discretion of the investigator. Fluid intake should be maintained to avoid dehydration.
8.6.3
Pneumonitis
Pneumonitis and ILD are known side effects of tyrosine kinase inhibitors used in NSCLC, 
generally occurring later in the course of therapy. Drug-related pneumonitis may be associated 
with signs and symptoms such as dyspnea, hypoxia, cough, hemoptysis, and fever, and radiologic 
evidence of parenchymal or interstitial changes.
The diagnosis of pneumonitis and determination of causal relationship to the drug is often 
confounded by the underlying disease (especially lymphangitic carcinomatosis) and other factors, 
such as lung infection and radiation effects due to nonspecific signs and symptoms, and similar 
radiological appearance. Pneumonitis should be suspected when such signs and symptoms 
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develop, or in asymptomatic patients when a new ground glass opacity or interstitial infiltration is 
noted in imaging studies. If a patient is considered to have the potential diagnosis of drug-related 
pneumonitis, physical examination, assessment of oxygen saturation, evaluation for infectious 
etiologies, and thoracentesis, bronchoscopy, or open-lung biopsy should be considered to reach a 
diagnosis. If the causality is at least possibly related to the study drug, management of 
pneumonitis, including dose interruption and potential discontinuation, is required (see Table 8.b).
8.6.4
Hypertension
Blood pressure should be monitored and recorded at each visit. Hypertension detected by at least 2 
blood pressure measurements should be graded according to NCI CTCAE, version 4.03, which 
defines hypertension as a disorder characterized by a pathological increase in blood pressure: a 
repeated elevation in blood pressure exceeding 140 mmHg for systolic blood pressure (SBP) and 
90 mmHg for diastolic blood pressure (DBP). For patients who either develop hypertension or 
experience worsening hypertension during treatment with study drug, antihypertensive medication 
should be initiated or optimized to achieve target blood pressure before interruption or dose 
reduction of the study drug. If hypertension is persistent despite adequate antihypertensive 
therapy—including titration of antihypertensive medication or introduction of additional 
antihypertensive medications—or if Grade 4 hypertension develops, dose interruption and 
reduction is recommended (see Table 8.b).
8.6.5
Bradycardia
Heart rate should be monitored and recorded at each visit. Brigatinib should be avoided in 
combination with other agents known to cause bradycardia (eg, β-blockers, nondihydropyridine 
calcium-channel blockers, clonidine, and digoxin) to the extent possible. For symptomatic 
bradycardia, dose interruption and reduction is recommended (see Table 8.b).
8.6.6
Visual Disturbance
In patients with new onset or worsening severe (Grade ≥3) visual disturbance, ophthalmological 
evaluation should be performed. Visual disturbance should be managed as described in Table 8.b.
8.7
Blinding and Unblinding
As this is an open-label study, there will be no study drug blinding.
8.8
Description of Investigational Agents
Brigatinib will be supplied as film-coated tablets in the following strengths of active 
pharmaceutical ingredient: 30, 90, and 180 mg, with all strengths being dose to weight 
proportional. The inactive ingredients (excipients) will include lactose monohydrate, 
microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, and 
hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl 
alcohol, and titanium dioxide. Brigatinib is manufactured under current Good Manufacturing 
Practice in accordance with approved procedures.
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Midazolam is a short-acting benzodiazepine that is a probe substrate of CYP3A. Midazolam oral 
syrup (2 mg/mL) will be obtained from commercial sources. The dose regimen for midazolam in 
this study is 3 mg orally on Day 1 and Day 21 of Part A (ie, 1.5 mL of the 2 mg/mL syrup). 
Midazolam will be administered on an empty stomach (ie, at least 1 hour before or at least 2 hours 
after food). The dose of midazolam should be administered using an oral syringe. Patients will 
consume approximately 8 ounces (240 mL) of water immediately after administration of 
midazolam. The precautions, warnings, contraindications, and AEs associated with midazolam 
therapy are included in the midazolam prescribing information.
8.9
Dispensation of Study Drug
Brigatinib is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling it. Brigatinib will be supplied to the study sites as film-coated tablets (30, 
90, and 180 mg) in high-density polyethylene (HDPE) bottles with child-resistant caps. 
Midazolam hydrochloride oral syrup, at a concentration of 2 mg/mL, will be obtained 
commercially and administered to patients on Days 1 and 21 of Part A.
Additional details regarding study drug dispensation are provided in the study manual.
8.10
Packaging and Labeling
Brigatinib film-coated tablets will be supplied to the study sites in strengths of 30, 90, and 180 mg 
in white HDPE bottles with induction sealed, polypropylene child-resistant caps. Each bottle of 
brigatinib will be labeled with pertinent study information, country-specific requirements, and a 
caution statement. Brigatinib will be dispensed directly to the patients without repackaging.
8.11
Storage, Handling, and Accountability
Brigatinib tablets should be stored at controlled room temperature (20°C-25°C; 68°F-77°F), with 
excursions permitted from 15°C to 30°C (59°F-86°F); refrigeration or freezing is not permitted. 
Storage area temperature conditions must be monitored and recorded daily. All temperature 
excursions must be reported to the sponsor for assessment and determination for continued use. 
Brigatinib tablets should remain in the original bottle provided to the study site for dispensation to 
patients. The drug supply must be kept in an appropriate, limited access, secure place until it is 
dispensed to the enrolled patients.
A record is to be kept at the study site documenting the amount of study drug received from the 
sponsor, the amount dispensed to individual patients, and the amount returned to the site by the 
patients.
Midazolam hydrochloride oral syrup, 2 mg/mL, will be obtained from commercial sources and 
should be stored in accordance with the product’s prescribing information. 
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council on Harmonisation (ICH) guidelines.
9.1
Study Personnel and Organizations
Contact information for the project clinician, laboratory conducting the analysis of PK samples, 
coordinating investigator, interactive response technology (IRT) provider, and contract research 
organization (CRO) team may be found in the study manual. The 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). 
9.3
Study Procedures
During Part A of the study (Cycle 1: PK cycle), clinic visits will take place on Days 1, 2, 9, 15, 21, 
and 22. Blood sampling for midazolam PK characterization will take place over the 24-hour 
postdose period beginning on Days 1 and 21. Patients will be closely monitored for respiratory and 
cardiac function (ie, pulse oximetry) after administration of midazolam on Days 1 and 21.
During Part B, clinic visits will take place on Day 1 of each cycle (±3 days) for assessment of 
ECOG performance status, physical examination, weight and vital signs measurements. 
Laboratory tests will be conducted on Day 1 (± 3 days) and Day 15. Imaging assessments will be 
conducted on Day 28 (± 3 days) of every even-numbered cycle up to Cycle 14, and on Day 28 
(±3 days) for every 3 cycles thereafter.
For the timing of assessments, please refer to the Schedules of Events in Appendix A (Table 1 for 
Part A and Table 3 for Part B). The timing of midazolam PK assessments is specified in Appendix 
A Table 2. Additional details are provided as necessary in the sections that follow.
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. The 
informed consent form will be signed during Screening.
9.3.2
Enrollment
A patient is considered enrolled in the study once they sign the informed consent form for study 
participation. 
Procedures for completing enrollment information are described in the study manual.
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9.3.3
Patient Demographics
Patient demographic characteristics will be collected at Screening and will include date of birth, 
sex, race, and ethnicity.
9.3.4
Medical History
A complete medical history will be recorded for each patient during Screening. The history will 
describe the background, progress, and stage of the patient’s malignancy, and will include a 
description of prior therapies. In addition, concomitant medications will be recorded, as specified 
in Section 9.3.10. 
9.3.5
ECOG Performance Status
ECOG performance status will be assessed and recorded at Screening, on Day 1 of each cycle, and 
at EOT. See Appendix D for the ECOG scale.
9.3.6
Physical Examination
A physical examination will be completed in accordance with the study site’s standard of care at 
the times specified in the Schedules of Events (Appendix A Table 1 and Table 3). Additional 
symptom-directed evaluations may be performed.
A complete physical examination must be performed at Screening, the extent of which should be 
consistent with the patient’s medical history and underlying disease. Subsequent physical 
examinations may be directed to relevant findings. Of note, because of adverse reactions reported 
during treatment with crizotinib and brigatinib, investigators are cautioned to monitor patients for 
signs of vision dysfunction. For new or worsening severe vision disorders, ophthalmological 
evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical 
coherence tomography, and other evaluations should be performed. 
The Part B EOT physical examination should be a complete physical examination. The physical 
examination at the end of the 30-day follow-up period may be directed to any relevant findings.
9.3.7
Patient Height and Weight
The patient’s height will be measured during Screening (within 28 days before the first dose of 
study drug). 
The patient’s weight will be obtained on Day 1 of each cycle and at EOT.
9.3.8
Vital Signs
Vital sign measurements will be taken at each visit after 3 to 5 minutes in the supine position and 
will include measurements of DBP, SBP, heart rate, and body temperature.
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9.3.9
Pregnancy Test
A serum or urine pregnancy test will be performed for women of childbearing potential during 
Screening and within 7 days before the first dose of study drug on Day 1 of Cycle 1. The test 
results must be negative and available before the first dose of study drug is administered. 
Pregnancy testing must be conducted every 12 weeks thereafter and at EOT. Additional pregnancy 
testing may be required or recommended according to local guidelines and regulations. 
9.3.10 Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded in the electronic case report form 
(eCRF) from Screening through the 30-day follow-up period following EOT. See Section 8.3 for a 
description of prohibited medications and procedures, and Section 8.4 for a description of 
permitted medications and procedures during the study.
9.3.11 Adverse Events
AE monitoring will be conducted throughout the study as shown in the Schedules of Events in 
Appendix A Table 1 (for Part A) and Appendix A Table 3 (for Part B). 
Refer to Section 10.0 for details regarding definitions, documentation, and reporting of AEs and 
serious adverse events (SAEs). 
9.3.12
ECG
A 12-lead ECG will be performed at Screening (Part A), on Cycle 2 Day 1 (Part B), and at EOT 
(Part A or Part B). The ECGs will be performed at the sites and read locally.
9.3.13 Patient Dosing Diary
A patient dosing diary will be filled out only during Part A of the study. During Part A, patients are 
to bring unused brigatinib and the dosing diary with them to each clinic visit. The study center staff 
will check the diary and the patient’s supply of brigatinib to assess adherence to the treatment 
regimen. 
Refer to the study manual for complete instructions.
9.3.14
Clinical Laboratory Evaluations
Clinical laboratory evaluations for safety will be performed locally, with reference ranges 
provided in the electronic data capture (EDC) system.
Instructions for handling and shipping clinical laboratory samples are provided in the 
study manual.
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9.3.14.1 Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in Table 
9.a will be obtained as specified in the Schedules of Events for Part A (Appendix A Table 1) and 
Part B (Appendix A Table 3).
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry

Hematocrit.

Hemoglobin.

WBC count with 5-part differential 
(lymphocytes, monocytes, 
neutrophils, eosinophils, basophils).

Platelet count.

Albumin and total protein.

ALP.

ALT.

AST.

Amylase.

Bilirubin (total and direct/indirect).

BUN.

Calcium.

Bicarbonate (HCO3; may be listed on 
chemistry panel as CO2).

Creatine kinase.

Creatinine.

Chloride.

Glucose.

LDH.

Lipase.

Phosphate.

Magnesium (a).

Potassium.

Sodium.

Urate (a).
ALP=alkaline phosphatase; BUN=blood urea nitrogen; LDH=lactate dehydrogenase; WBC=white blood cell.
(a) Analyzed only during Part A.
Urinalysis will be performed only during Part A of the study.
9.3.15
Disease Assessment
Patients will undergo CT and MRI scanning to monitor and assess disease progression using 
modified RECIST version 1.1.
Contrast CT scans of the chest, abdominal cavity, and pelvis will be obtained at Screening. For 
patients whose primary tumor or metastases are present in the head and neck or extremities, a CT 
scan of these regions is to be included. For patients with lung cancer and those with known brain 
metastases, MRI of the brain, with contrast, should be performed at Baseline (ie, during Screening) 
and repeated post-Baseline for patients with CNS metastases. 
When possible, the same qualified physician will interpret results to reduce variability. 
Radiographic images will be maintained at the site, and test results and physicians’ findings will be 
filed in patient source documents.
Disease assessment by CT or MRI scan will be performed at Screening (ie, as close as possible to 
Day 1 of Cycle 1, but no more than 28 days before the first dose of brigatinib on Day 2 of Cycle 1), 
and at 8-week intervals thereafter (ie, on Day 28 [±3 days] of every even-numbered cycle) through 
14 cycles after the initial dose of brigatinib, and every 3 cycles thereafter until PD (see Appendix 
A Table 3).
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More frequent imaging is recommended at any time, if clinically indicated; confirmation of CR or 
PR may be performed at least 4 weeks after the initial response.
In the event of antitumor response, the sponsor may request electronic images for those patients 
who demonstrate tumor reduction.
9.3.16
PK Measurements
Plasma concentrations of midazolam and brigatinib will be measured using validated liquid 
chromatography-tandem mass spectrometry assays. Details regarding the preparation, handling, 
and shipping of the PK samples are provided in the Study Manual.
Blood samples for the determination of plasma concentrations of midazolam will be collected on 
Days 1, 2, 21, and 22 of Part A (Cycle 1: PK cycle) as described in Appendix A Table 2. Blood 
samples for the determination of trough plasma concentrations of brigatinib will be collected 
predose on Days 21 and 22 of Part A (Appendix A Table 1) and on Day 1 of Cycle 2 in Part B.
The exact date and time of each PK sample collection should be recorded.
9.4
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they experience PD or intolerable 
toxicity despite dose reduction.
Patients may continue brigatinib treatment for up to 23 cycles during Part B.
9.5
Completion of Study (for Individual Patients)
A patient will be considered to have completed the study if they:

Complete Part A; and

Receive up to 23 cycles of brigatinib treatment during Part B; or 

Are withdrawn from treatment because of PD or intolerable toxicity, despite dose reduction; 
and

Complete the 30-day follow-up period after EOT.
9.6
Discontinuation of Treatment With Study Drug and Withdrawal From the Study
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Intolerable toxicity, as determined by the investigator.

PD requiring an alternate therapy.

Entry into another therapeutic clinical study or start of new anticancer therapy.

Significant deviation from the protocol or eligibility criteria, in the opinion of the investigator 
or the sponsor’s medical monitor.

Noncompliance with the study or follow-up procedures.
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
Pregnancy.

Patient withdrawal of consent or decision to discontinue study participation.

Termination of the study by the sponsor.

Any other reason that, in the opinion of the investigator, would justify removal of the patient 
from the study.

Lost to follow-up.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedules of Events (Appendix A Table 1 for Part A; Appendix A
Table 3 for Part B). The patient will be followed for 30 days after the EOT visit for drug safety and 
subsequent therapy. The primary reason for study drug discontinuation will be recorded in the 
eCRF.
9.7
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing. Patients should be encouraged to administer their brigatinib 
dose at approximately the same time each day.
During Part A of the study, each patient will be required to complete a patient diary detailing the 
dates and times of each dose of brigatinib. In addition to recording their daily doses in the diary, 
patients in Part A will be required to return unused brigatinib to the clinic for assessment of 
compliance.
During Part B, patients will be required to return unused brigatinib to the clinic at each visit (ie, 
beginning of each cycle) for assessment of compliance. Any patient who receives <80% or >120% 
of their prescribed doses will be considered noncompliant.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
the informed consent to participate in a study, but which occurs before administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs in the 
appropriate section of the eCRF. Disease progression assessed by measurement of malignant 
lesions on radiographs or other methods should not be reported as an AE.
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, 
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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, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [18]. 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 decrease in white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) by 
the investigator to the Takeda Global Pharmacovigilance department or designee within 24 hours 
of becoming aware of the event. This will be done by transmitting an 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. 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.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [18]. 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 (EOT) and recorded in the eCRFs. 
SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from the 
signing of informed consent through 30 days after administration of the last dose of study drug and 
recorded in the eCRF. After this period, only treatment-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 transmitting a completed pregnancy form to the Takeda 
Global Pharmacovigilance department or designee. 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 transmitting a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
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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 email addresses provided below. 
Call Center
Phone Number
Email
Fax
Dohmen Life Science 
Services, or DLSS 
(formerly known as 
MedComm)
1-844-662-8532 
Non–toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com
1-800-881-6092
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported.
10.6
Safety Reporting to Investigators, IRBs or Independent Ethics Committees, and 
Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs. 
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 in accordance with national regulations. 
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who receives study drug.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator 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 informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
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 
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(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.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
A data review will be conducted before database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
13.1.1 Analysis Sets
13.1.1.1 Safety Population
The safety population is defined as all patients who received at least 1 dose of any study drug 
(brigatinib or midazolam). The safety population will be used for all safety analyses.
13.1.1.2 PK-Evaluable Population
The PK-evaluable population is defined as patients who:

Received the protocol-specified dosing regimen during Part A (including the 180 mg 
brigatinib dose) without dose reductions or interruptions through the completion of PK 
sampling.

Did not receive any excluded concomitant medications through the completion of PK 
sampling.

Have sufficient midazolam concentration-time data to permit the reliable estimation of PK 
parameters by noncompartmental analysis methods.
The PK-evaluable population will be used for PK analyses. Patients who are not PK evaluable may 
be replaced.
13.1.1.3 Response-Evaluable Population
The response-evaluable population is defined as all patients who had measurable disease at 
Baseline, received at least 1 dose of any study drug, and had at least 1 post-Baseline response 
assessment.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
The demographic and baseline characteristics will be summarized, including sex, age, race, 
weight, height, and other parameters as appropriate.
13.1.3 PK Analysis
The PK-evaluable population will be used for all PK analyses.
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Individual and mean plasma midazolam concentration data after dosing on Day 1 and Day 21 of 
Part A (Cycle 1) will be plotted over time and listed with and without brigatinib coadministration. 
Plasma PK parameters of midazolam administered in the absence and presence of brigatinib for 
individual patients will be calculated using noncompartmental analysis methods. Descriptive 
statistics for plasma midazolam concentrations and PK parameters (including but not limited to 
Cmax, tmax, and AUC∞) will be calculated with and without brigatinib coadministration.
For the estimation of the effect of brigatinib on midazolam PK, the ratios of geometric mean 
midazolam AUC∞and Cmax (with vs without brigatinib coadministration) and the associated 
2-sided 90% CIs will be calculated on the basis of the within-patient variance calculated via a 
mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or 
without brigatinib coadministration). Patient will be treated as a random effect in the model. After 
log transformation, AUC∞and Cmax will be separately analyzed. Point estimates and adjusted 90% 
CIs for the difference in treatment will be calculated and then exponentially back transformed to 
provide point and CI estimates for the ratios of interest.
Predose plasma concentrations of brigatinib on Days 21 and 22 of Part A (Cycle 1) and on Day 1 
of Cycle 2 (Part B) will be listed and summarized using descriptive statistics. Individual and mean 
predose plasma concentrations of brigatinib will be plotted over time. 
13.1.4 Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
Baseline in the patient’s clinical laboratory results, weight, and vital signs using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of any study drug and 
through 30 days after the last dose of brigatinib will be tabulated.
AEs will be tabulated according to MedDRA and will include, but are not limited to, the following 
subsets:

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.

The most commonly reported treatment-emergent AEs (ie, those events occurring in ≥10% of 
all patients).

Treatment-emergent AEs resulting in study drug dose reduction.

Treatment-emergent AEs resulting in study drug dose modification (as defined as dose 
interruption, dose reduction, or permanently discontinued).

SAEs.
A listing of treatment-emergent AEs resulting in study drug discontinuation will be provided.
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Descriptive statistics for the actual values (and/or change from Baseline) in clinical laboratory
parameters, weight, and vital signs will be tabulated by scheduled time point. Mean or median key 
laboratory parameters over time will be plotted. Shift tables for laboratory parameters will be 
generated to show changes in NCI CTCAE grade from the Baseline value to the worst 
post-Baseline value.
All concomitant medications collected from Screening through the study period will be classified 
to generic terms according to the WHO Drug Dictionary.
Additional safety analyses may be determined to most clearly enumerate rates of toxicities and to 
further define the safety profile of brigatinib.
13.2
Analyses For Parts A and B and Criteria for Early Termination
Analyses for Part A of the study will be performed when all patients have completed Cycle 1 (PK 
cycle) and will include analyses of PK and safety.
Analyses for Part B of the study will be performed when all patients have completed the study and 
will included analyses of safety and efficacy. 
CCI
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13.3
Determination of Sample Size
It is anticipated that approximately 20 patients will be enrolled to obtain approximately 
15 PK-evaluable patients. The sample size calculation was based on the expected 2-sided 90% CI 
for the difference in the paired, log-transformed AUC∞means of midazolam in the absence and 
presence of brigatinib. The within-patient coefficient of variation for midazolam AUC∞was 
estimated to be 28% on the basis of a pooled analysis of data from 5 DDI studies with midazolam 
conducted in patients with cancer [1-5]. Assuming that the AUC∞ratio for midazolam in the 
presence versus absence of brigatinib is 1, with a sample size of 15, the 90% CI for the AUC∞ratio 
is expected to be 0.84 to 1.19 on the basis of the variance assumptions. If the AUC∞ratio for 
midazolam in the presence versus absence of brigatinib is X, with a sample size of 15, the 90% CI 
for the AUC∞ratio is expected to be 0.84X to 1.19X on the basis of the variance assumptions.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB.
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 informed consent forms), 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 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. Significant 
deviations include, but are not limited to, those that involve fraud or misconduct, increase the 
health risk to the subject, or confound interpretation of the primary study assessment. A protocol 
deviation form should be completed by the site and signed by the sponsor or designee for any 
significant deviation from the protocol.
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 the US FDA. If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and institution guarantee access for quality assurance auditors to all study documents 
as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, 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 investigator responsibilities listed in Appendix B. The principles of 
Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable state and local requirements. The sponsor or 
designee will require documentation noting all names and titles of members who make up the 
respective IRBs. If any member of the IRB has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained. Those sites 
unwilling to provide names and titles of all members due to privacy and conflict of interest 
concerns should instead provide a Federal Wide Assurance Number or comparable number 
assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the IRBs for the 
protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the informed 
consent form, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB for approval. The IRB’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. If required 
by either country or regional regulations or procedures, approval from the competent regulatory 
authority will be obtained before commencement of the study or implementation of a substantial 
amendment. The sponsor will notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation, and when applicable, the sponsor has received permission from the US 
FDA to begin the trial. Until the site receives notification, no protocol activities, including 
screening, may occur.
Sites must adhere to all requirements stipulated by their IRB. This may include notification to the 
IRB regarding protocol amendments, updates to the informed consent form, recruitment materials 
intended for viewing by subjects, local safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to the IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
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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 informed consent form, 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 informed consent form 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 informed consent form 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 approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved 
by both the IRB and the sponsor before use.
The informed consent form, 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 informed consent 
form, 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. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form 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 informed consent form, 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 informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
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 the US 
FDA, the sponsor’s designated auditors, and the appropriate IRBs to review the subject’s original 
medical records (source data or documents), including, but not limited to, laboratory test result 
reports, ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original medical 
records requires the specific authorization of the subject as part of the informed consent process 
(see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda policy/standard. Takeda contact 
information, along with investigator’s city, 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 and clinicaltrialsregister.eu, as 
well as or other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda policy/standard, applicable laws and/or regulations. 
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Morcos PN, Cleary Y, Guerini E, Dall G, Bogman K, De Petris L, et al. Clinical Drug-Drug 
Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor 
Alectinib. Clin Pharmacol Drug Dev 2017;6(3):280-91.
2. Stroh M, Talaty J, Sandhu P, McCrea J, Patnaik A, Tolcher A, et al. Lack of meaningful effect 
of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model prediction 
and clinical confirmation. J Clin Pharmacol 2014;54(11):1256-62.
3. Han TH, Gopal AK, Ramchandren R, Goy A, Chen R, Matous JV, et al. CYP3A-mediated 
drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug 
conjugate, in patients with CD30-positive hematologic malignancies. J Clin Pharmacol 
2013;53(8):866-77.
4. Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, et al. 
Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet 
2015;54(10):1057-69.
5. Clinical Pharmacology and Biopharmaceutics Review: Crizotinib, Application No. 
202570Orig1s000. Center for Drug Evaluation and Research. March 2011.
6. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 
v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. 
Published 2013.
7. Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Altekruse S, et al. SEER Cancer 
Statistics Review, 1975-2013. National Cancer Institute 2016.
8. Siegel R, Miller K, Jemal A. Cancer Statistics, 2017. CA Cancer Journal for Clinicians 
2017;67:7-30.
9. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer Version 4. 
NCCN. 2016.
10. Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S, et al. Metastatic 
non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii27-39.
11. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: 
epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83(5):584-94.
12. Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future 
challenges. Nature Reviews Clinical Oncology 2012;9(5):268-77.
13. Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, Implications 
for Dosing, and Labeling Recommendations. U.S. Department of Health and Human Services 
Food and Drug Administration: Center for Drug Evaluation and Research. 2012.
14. Guideline on the investigation of drug interactions. European Medicines Agency, Committee 
for Human Medicinal Products.
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15. Stockis A, Watanabe S, Scheen AJ. Effect of brivaracetam on CYP3A activity, measured by 
oral midazolam. J Clin Pharmacol 2015;55(5):543-8.
16. Calvert H, Twelves C, Ranson M, Plummer R, Fettner S, Pantze M, et al. Effect of erlotinib on 
CYP3A activity, evaluated in vitro and by dual probes in patients with cancer. Anticancer 
Drugs 2014;25(7):832-40.
17. Hilli J, Sailas L, Jyrkkio S, Pyrhonen S, Laine K. NCT01110291: induction of CYP3A activity 
and lowered exposure to docetaxel in patients with primary breast cancer. Cancer Chemother 
Pharmacol 2011;67(6):1353-62.
18. 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.
19. 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 A
Schedule of Events and PK Sampling Schedule
Table 1
Schedule of Events for Part A (Cycle 1, 28-Day PK Cycle)
Assessment
Screening
Visits
Day 28
(EOT 
Part A)
Day 1
Day 2
Day 9
Day 15
Day 21
Day 22
Informed consent
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history
X
Physical examination 
(a)
X
X
X
X (b)
ECOG Performance 
Status
X
X
X (b)
Height
X
Weight
X
X (b)
Midazolam 3 mg 
single dose
X
X (c)
Pulse oximetry (d)
X
X
Brigatinib 
90 mg/180 mg (or 
highest tolerated dose) 
QD
X (e)
X (f)
X (f)
X (f)
X (f)
Pregnancy test (g)
X
X
X (b)
Imaging assessments 
(h)
X
12-lead ECG
X
X (b)
Vital signs
X
X
X
X
X
X
X (b)
Laboratory tests (i)
X
X (j)
X (k)
X (b)
Adverse event 
reporting 
Recorded from the signing of the informed consent form through 30 days after the last dose 
of study drug
Serious adverse events will be reported from the signing of the informed consent form 
through 30 days after the last dose of study drug.
Monitoring of 
concomitant 
medications and 
procedures 
Recorded from the signing of the informed consent form through 30 days after the last dose 
of study drug
Serial PK sampling for 
midazolam PK (l)
X
X
X
X
Predose PK sample for 
brigatinib PK (m)
X
X
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
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CK=creatine kinase; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOT=End of Treatment; β-HCG=β-human chorionic gonadotropin; LDH=lactate dehydrogenase; MRI=magnetic resonance 
imaging; PK=pharmacokinetic(s); QD=once daily.
(a) A complete physical examination will be performed during Screening, with symptom-directed physical examinations performed 
on Day 1 and Day 22, and at EOT (for patients who discontinue the study during Part A).
(b) For patients who discontinue from the study during Part A.
(c) To be administered only to patients who have escalated to brigatinib 180 mg QD.
(d) Performed after administration of midazolam on Days 1 and 21.
(e) Brigatinib 90 mg QD (or highest tolerated dose) from Day 2 through Day 8.
(f) Brigatinib 180 mg QD (or highest tolerated dose) from Day 9 through Day 28.
(g) β-HCG test (urine or serum) within 7 days before first dose of study drug for all women of childbearing potential.
(h) Baseline disease assessments during Screening should be performed as close to Cycle 1 Day 1 as possible and will consist of CT 
scans of the chest, abdomen, and pelvis for all patients. A CT scan of the head and neck or extremities is to be included if the 
primary tumor or metastases are present in the head, neck, and/or extremities. An MRI scan of the brain should be performed at 
Baseline for lung cancer patients and patients with known brain metastases.
(i) Laboratory tests to include hematology (complete blood count with 5-part differential and platelet count); serum chemistry 
(sodium, potassium, chloride, bicarbonate [or total carbon dioxide], BUN [or urea], albumin and total protein, creatinine, bilirubin 
[at least total and direct or total and indirect], ALT, AST, ALP, magnesium, phosphate, calcium, LDH, CK, uric acid, amylase, 
lipase, and glucose); and urinalysis.
(j) Before dosing on Day 1.
(k) Laboratory tests to include ALT, AST, and total bilirubin.
(l) Refer to Appendix A Table 2 (Sampling Schedule for Midazolam PK in Part A) for PK sample collection times.
(m) A predose PK sample to measure trough concentrations of brigatinib will be collected within 1 hour before brigatinib 
administration on Days 21 and 22 of Part A.
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Table 2
Sampling Schedule for Midazolam PK in Part A
PK Sampling Time
Part A (Cycle 1)
Day 1
Day 2
Day 21
Day 22
Predose (within 1 hour before dosing)
X
0.25 hours postdose (±3 minutes)
X
0.5 hours postdose (±5 minutes)
X
1 hour postdose (±15 minutes)
X
1.5 hours postdose (±15 minutes)
X
2 hours postdose (±15 minutes)
X
4 hours postdose (±30 minutes)
X
6 hours postdose (±1 hour) 
X
8 hours postdose (±1 hour)
X
10 hours postdose (±1 hour)
X
24 hours postdose (±2 hours)
X
Predose (within 1 hour before dosing)
X
0.25 hours postdose (±3 minutes)
X
0.5 hours postdose (±5 minutes)
X
1 hour postdose (±15 minutes)
X
1.5 hours postdose (±15 minutes)
X
2 hours postdose (±15 minutes)
X
4 hours postdose (±30 minutes)
X
6 hours postdose (±1 hour) 
X
8 hours postdose (±1 hour)
X
10 hours postdose (±1 hour)
X
24 hours postdose (±2 hours)
X
PK=pharmacokinetic(s).
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CONFIDENTIAL
Table 3
Schedule of Events for Part B (Repeat 28-day Treatment Cycles)
Assessment
Treatment Cycles (a)
EOT
Follow-up 
(b)
Cycle
Cycle 2
Cycle 3
Cycle 4 and Every Cycle 
Thereafter Through 
EOT
Cycle Days
Day 1
Day 15
Days 2-28
Day 1
Day 15
Days 2-28
Day 1
Days 2-28
ECOG 
Performance 
Status
X
X
X
X
Symptom-directed 
physical exam
X
X
X
X (c)
X
Weight
X
X
X
X
Pregnancy test (d)
X (d) 
X
Vital signs (e)
X
X
X
X
Laboratory tests (f)
X
X (g)
X
X (g)
X
X
12-lead ECG
X
X
Adverse event 
reporting
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug
Serious adverse events will be reported from the signing of the informed consent form through 30 days after the last dose of study drug.
Monitoring of 
concomitant 
medications and 
procedures
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug
Imaging 
assessments (h)
X (i)
X (i)
X
Brigatinib once 
daily
X
X
X
X
X
X
Predose PK 
sample for 
brigatinib PK (j)
X
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CK=creatine kinase; CT=computed tomography; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End of Treatment; β-HCG=β-human chorionic gonadotropin; LDH=lactate dehydrogenase; 
MRI=magnetic resonance imaging; PK=pharmacokinetics.
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CONFIDENTIAL
(a) Treatment cycles are 28 days, and are to continue until disease progression, intolerable toxicity, or another discontinuation criterion is met.
(b) The 30-day follow-up period after EOT will capture adverse events and subsequent therapy.
(c) Complete physical examination at EOT.
(d) For women of childbearing potential, β-HCG pregnancy test using urine or serum, performed within 7 days before first dose of study drug (Cycle 1 Day 1, Part A), every 12 weeks 
(~3 cycles) thereafter, and at EOT. Additional pregnancy testing may be required or recommended based on local guidelines or regulations.
(e) Vital signs measurements are to be performed just before dosing on Day 1 of each cycle, as needed, and at EOT.
(f) Laboratory tests for drug safety are to be performed on Day 1 of each cycle before dosing and at EOT. They are to include hematology (complete blood count with 5-part 
differential and platelet count); and serum chemistry (sodium, potassium, chloride, bicarbonate [or total carbon dioxide], BUN [or urea], albumin and total protein, creatinine, 
bilirubin [at least total and direct or total and indirect], ALT, AST, ALP, phosphate, calcium, LDH, CK, amylase, lipase, and glucose). 
(g) Laboratory tests to include ALT, AST, and total bilirubin.
(h) CT/MRI to be conducted every 8 weeks, at the end of every even-numbered cycle (ie, 2, 4, 6, etc) up to Cycle 14, and every 3 cycles thereafter and at EOT. Imaging assessments 
will consist of CT scans of the chest, abdomen, and pelvis for all patients. For patients whose primary tumor or metastases are present in the head, neck, or extremities, a CT scan of 
the head and neck or extremities is to be included. Brain MRI should be performed at Baseline (ie, during Screening) for patients with lung cancer and patients with known brain 
metastases. Brain MRI, CT of the head/neck or extremities should be repeated every 8 weeks for the first 14 cycles and every 3 cycles thereafter, if disease is present in these sites at 
Screening/Baseline.
(i) To be performed on Day 28 (±3 days).
(j) A predose PK sample to measure the trough concentration of brigatinib will be collected within 1 hour before brigatinib administration on Day 1 of Cycle 2 of Part B.
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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 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. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. 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.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/independent ethics 
committee (IEC) that conform to 21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, and issue 
a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each 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. Each informed consent form 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 informed consent form 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM et al, 1982 [19].
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Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 01 are indicated. The 
corresponding text has been revised throughout the protocol.
Change 1: Update Table 8.a (Recommended Brigatinib Dose Reduction Levels)
The primary change occurs in Section 8.2.2 Dose Modifications for Treatment-Related AEs.
Description of change: An additional column was added to Table 8.a to describe a fourth dose 
reduction. 

In the row 90 mg QD (first week of treatment), the following text was added: Not applicable.

In the row 180 mg QD, the following text was added: Permanently discontinue.
Rationale for Change: To provide guidance to sites on the fourth dose reduction.
Change 2: Update Table 8.b (Brigatinib Dose Modification Recommendations for 
Treatment-Related Adverse Events).
The primary change occurs in Section 8.2.2 Dose Modifications for Treatment-Related AEs.
Initial 
wording
Recommendations for dose modification of brigatinib for the management of 
treatment-related AEs are provided in Table 8.b and are based on the US Prescribing 
Information for brigatinib (ALUNBRIG). Unless otherwise noted, reduce the dose 
as indicated in Table 8.b if 1 or more dose reductions are necessary because of Grade 
3/4 treatment-related AEs (as defined by NCI CTCAE version 4.03).
Amended 
text:
Recommendations for dose modification of brigatinib for the management of 
treatment-related AEs are provided in Table 8.b and are based on the US Prescribing 
Information CCDS for brigatinib (ALUNBRIG). Unless otherwise noted, reduce 
the dose as indicated in Table 8.b if 1 or more dose reductions are necessary because 
of Grade 3/4 treatment-related AEs (as defined by NCI CTCAE version 4.03).
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Description 
of change:
Text has been modifed to Table 8.b as follows:
In the row Hypertension the following text was amended: 

Withhold brigatinib until hypertension has recovered to Grade 1 or less (SBP 
less than 140 mmHg and DBP less than 90 mmHg), then resume brigatinib at 
next lowersame dose.
In the row CPK elevation, Grade 3 CPK elevation (>5.0×ULN) the following text 
was added:

If Grade 3 elevation of CPK recurs, brigatinib should be withheld until recovery to Grade 
1 or less (less than or equal to 2.5 x ULN) or to baseline, then resume at the next lower dose 
level per Table 8.a.
In the row CPK elevation, Grade 4 CPK elevation (>10.0×ULN) the following text 
was amended:
or recurrence of Grade 3 elevation

If Grade 4 elevation of CPK recurs, permanently discontinue brigatinib.
In the row Lipase/amylase elevation, Grade 3 lipase or amylase elevation 
(>2.0×ULN) the following text was added:

If Grade 3 elevation of lipase and amylase recurs, brigatinib should be witheld 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.
In the row Lipase/amylase elevation, Grade 4 lipase or amylase elevation 
(>5.0×ULN) the following text was amended:
or recurrence of Grade 3 elevation

If Grade 4 elevation of lipase/amylase recurs, permanently discontinue brigatinib.
Rationale for Change: To align brigatinib dose modification for treatment-related adverse events 
with the CCDS.
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Change 3: Update Excluded Concomitant Medications and Procedures (Section 8.3) to include 
moderate cytochrome P450 (CYP) 3A inhibitors in Part B of the study and to provide further 
guidance to investigators.
The primary change occurs in Section 8.3 Excluded Concomitant Medications and Procedures
Added text: 
Moderate CYP3A inhibitors: amprenavir, aprepitant, atazanavir, 
ceritinib, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, 
dronedarone, diltiazem, erythromycin, fluconazole, fluvoxamine, 
fosamprenavir, imatinib, and verapamil. If concomitant use of a moderate 
CYP3A inhibitor cannot be avoided during the study, reduce the brigatinib 
QD dose by approximately 40% (ie, from 180 mg to 120 mg, 120 mg to 90 
mg, or from 90 mg to 60 mg). After discontinuation of a moderate CYP3A 
inhibitor, resume the brigatinib dose that was tolerated before the 
moderate CYP3A inhibitor was initiated.
...
Because 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.
Rationale for Change: To include moderate CYP3A inhibitors to list of excluded medications 
and to provide further guidance to investigators regarding classification of excluded medications.
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Change 4: Add information regarding administration of brigatinib with certain concomitant 
medications to Precautions and Restrictions (Section 8.5).
The primary change occurs in Section 8.5 Precautions and Restrictions
Added text: 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.
Brigatinib is an in vitro inhibitor of P-gp, breast cancer resistance protein, 
organic cation transporter 1, multidrug and toxin extrusion protein 1 and 2K. 
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.
Rationale for Change: To clarify that brigatinib may induce other enzymes and transporters via 
the same mechanism responsible for induction of CYP3A and to provide guidance to investigators 
regarding monitoring of patients who may be receiving certain concomitant medications.
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Change 5: Update adverse event (AE) definition (Section 10.1.2) to provide guidance on reporting 
of disease progression.
The primary change occurs in Section 10.1.2 AE Definition
Added text: AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product 
whether or not it is related to the medicinal product. This includes any newly 
occurring event, or a previous condition that has increased in severity or frequency 
since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads 
to discontinuation or delay in treatment, dose modification, therapeutic intervention, 
or is considered by the investigator to be a clinically significant change from 
baseline. 
Worsening of signs and symptoms of the malignancy under study should be 
reported as AEs in the appropriate section of the eCRF. Disease progression 
assessed by measurement of malignant lesions on radiographs or other 
methods should not be reported as an AE.
Rationale for Change: To provide guidance on reporting of disease progression.
Change 6: Update Schedule of Events (Appendix E) to include laboratory tests on Day 15 of 
Cycle 1.
The primary change occurs in Appendix A Schedule of Events and PK Sampling Schedule
Description of 
change:

Day 15 column added for Table 1: Schedule of Events for Part A (Cycle 1, 
28-Day PK Cycle).

Laboratory tests added for Day 15.
Added text 
in footnotes 
for Schedule 
of Events 
Table
(k) Laboratory tests to include ALT, AST, and total bilirubin.
Rationale for Change: To be consistent with Summary of Product Characteristics.
Section 9.3 also contains this change.
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Change 7: Update Schedule of Events (Appendix E) to include laboratory tests on Day 15 of 
Cycles 2 to 3.
The primary change occurs in Appendix A Schedule of Events and PK Sampling Schedule
Description of 
change:

Day 15 column added for Cycles 1 and 2 in Table 3 Schedule of Events for Part 
B (Repeat 28-day Treatment Cycles).

Laboratory tests added for Day 15.
Added text 
in footnotes 
for Schedule 
of Events 
Table
(g) Laboratory tests to include ALT, AST, and total bilirubin. 
Rationale for Change: To be consistent with Summary of Product Characteristics.
Section 9.3 also contains this change.
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