Clinical trial NCT02706626
Conditions: Non-Small Cell Lung Cancer
Sponsor: Criterium, Inc.
Start date: 2017-03-09; Completion date: 2021-04-01
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of this investigational drug, brigatinib (AP261136) in patients with advanced non-small cell lung cancer Non-small cell lung cancer (NSCLC) who have had first-line treatment for their cancer and it still got worse, even after, or while taking drugs called ALK inhibitors, or anti-cancer drugs that act on tumors. Some examples of these anti-cancer drugs are: KEYTRUDA® or ALECENSA®).

Detailed description:
A significant population of Anaplastic Lymphoma Kinase (ALK) plus Non-small cell lung cancer patients exist that have progressed on or who were intolerant of second generation anaplastic lymphoma kinase inhibitor (e.g. ceritinib or alectinib). Brigatinib has demonstrated activity in patients who have progressed on crizotinib, but the activity of brigatinib in patients who have progressed on ceritinib, alectinib, or other second generation anaplastic lymphoma kinase inhibitors is unknown. Based on the preclinical data. 3, , brigatinib has activity against known secondary anaplastic lymphoma kinase mutations suggesting it may retain activity after second-generation anaplastic lymphoma kinase inhibitors.

Patients enrolled in ARI-AT-002 must have previously received a second generation Anaplastic lymphoma kinase inhibitor other than brigatinib. We have chosen 20% as a clinically meaningful response rate that would justify further study of brigatinib in previously treated anaplastic lymphoma kinase plus disease.

Arms: arm 1: Brigatinib until progressive disease, unacceptable toxicity, withdrawal of consent. Patients enrolled regardless the number of lines of therapy arm 2: Brigatinib until progressive disease, unacceptable toxicity, withdrawal of consent. Patients enrolled after first-line alectinib arm 3: Brigatinib at 240 mg daily until progressive disease, unacceptable toxicity, withdrawal of consent. Patients enrolled after treatment on brigatinib at the standard dose brigatinib
Interventions: intervention 1: brigatinib
Intervention descriptions: intervention 1: Single arm phase 2 trial to investigate the clinical activity in patients with advanced non-small cell lung cancer

Protocol documents:
ICF_002.pdf: 
Consent To Participate In A Research Study
Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after 
Treatment with Next-Generation ALK inhibitors in 
Refractory ALK Rearranged NSCLC
Page 1 of 2                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Consent Addendum
You are being asked to read, sign and date this addendum consent form before you may continue to 
receive study drug brigatinib. You are being asked because you have consented to participate in the 
main study (brigatinib) and your disease has worsened. If the study drug is working, you may continue 
for as long as you receive benefit or until you decide to stop the study. Once study drug has been 
discontinued, the follow up visits begin as described in the main study consent. All foreseeable risks or 
discomforts and other alternative treatment options as described in the main informed consent form are 
still applicable.  If you are interested in learning more about his study, please continue reading below.
Accumulating evidence indicates a small number of subjects who receive brigatininb may derive clinical 
benefit despite initial growth of their tumor(s); therefore if you are eligible you may continue to receive 
study drug brigatinib, at a higher dose, by signing and dating this consent form.
Brigatinib has been approved by the FDA for patients with metastatic non-small cell lung cancer 
(NSCLC) and alterations in the ALK gene whose cancer has progressed during their initial therapy.
The uses of Brigatinib in this study have not been approved by the FDA, therefore Brigatinib is 
considered an investigational drug. The word “investigational” means the study drug is still being tested 
in research studies and is not approved by the U.S. Food and Drug Administration (FDA).
This document provides you with new information/ additional information about the study.
All parts of the informed consent that you have signed before remain valid, as does your consent to it, 
except any that are specifically revised by this document.
If you agree to be in this study, you will be asked to sign and date this consent form.  You will be 
permitted to continue receiving the study drug, brigatinib, beyond your initial tumor growth as long as 
you meet the following criteria: 
•
Your doctor has assessed the potential clinical benefit of continuing the study drug, brigatinib
•
You do not have rapid tumor growth or clinical deterioration
•
The symptoms you are having from your disease are stable
•
You can tolerate brigatinib
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent To Participate In A Research Study
Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after 
Treatment with Next-Generation ALK inhibitors in 
Refractory ALK Rearranged NSCLC
Page 2 of 2
                                                  *
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
If you agree to continue to receive the study drug, we will need to determine if you are eligible for 
Cohort C. You will undergo all screening procedures listed previously in the Main ICF, and will be 
required to undergo a fresh tumor tissue biopsy, to evaluate your tumor to see if your non-small cell lung 
cancer has transformed/mutated into small cell lung cancer. 
A biopsy would only be performed if it was considered safe and feasible.
If your cancer has mutated, it would not be beneficial for you to continue study treatment, and you study 
doctor will discuss other options with you. 
__________________________________________
___________     ___________
Signature of Subject
Date
     Time
__________________________________________
Printed Signature of Subject 
__________________________________________
___________      ___________
Signature of Person Obtaining Consent
Date
     Time
__________________________________________
Printed Signature of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021

Prot_SAP_000.pdf: 
Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 1 of 82 
 
 
 
 
Title: Phase 2 Trial of Brigatinib after Treatment with Next-Generation ALK 
inhibitors in Refractory ALK Rearranged NSCLC 
 
 
 
 
 
Protocol Number: ARI-AT-002  
Study Collaborator: Takeda Oncology 
 
IND# 128883 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 2 of 82 
Study Contacts:  
 
Principal Investigator USA 
Thomas E. Stinchcombe, MD  
Duke University 
DUMC 3198 
25177 Morris Building  
Durham, NC 27710 
Phone 919-681-9509 Fax 919-681-9599 
E-mail: Thomas.stinchcombe@duke.edu 
 
Principal Investigator Canada 
Geoffrey Liu, MD 
Princess Margaret Cancer Centre 
610-7-124 University Ave.  
Toronto, ON Canada 
M5G2M9 
Phone: (416) 946-2000 
E-mail: Geoffrey.Liu@uhn.ca 
 
Principal Co-Investigator  
Ross Camidge MD, PhD  
University of Colorado  
12605 E 16th Avenue  
Aurora CO 80045 
Phone: 720-848-0449 Fax: 720-848-0465 
E-mail: Ross.Camidge@cuanschutz.edu 
 
 
Biostatistician  
Xiaofei Wang, PhD  
Duke University 
Dept.of Biostatistics & Bioinformatics  
Hock Plaza, 2424 Erwin Rd 
Durham, NC 27710 
Phone: (919) 681-5406 
E-mail: Xiaofei.wang@duke.edu 
 
 
Criterium, Inc. (Project Management) 
358 Broadway, Suite 201  
Saratoga Springs, NY 12866 
E-Mail: ARIAT002PM@criteriuminc.com 
 
 
 
Sponsor: Criterium, Inc. dba ATOMIC 
Funding Source: Takeda Oncology 
Protocol History: 
Original: September 17, 2015 
Amendment 1 (Version 2): May 26, 2016 
Amendment 2 (Version 3): October 4, 2016 
Amendment 3 (Version 4): December 06, 2017 
Amendment 4 (Version 5) April 18, 2018 
Amendment 4 (Version 5.1) November 29, 2018 
Amendment 5 (Version 6) May 20, 2019 
Amendment 6 (Version 7) April 20, 2020 
 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 3 of 82 
 
Version 
Main Changes 
1 
     Original 
2 
• Removal of Co-Investigators, updates to study collaborators and  
contact information, addition of IND #; 
• Clarifications, formatting, and spelling updates throughout; 
• Section 1.3.5 updated with new findings; 
• Mechanism of resistance added to exploratory findings; 
• Inclusion 7 updated to allow study entry for subjects who cannot 
undergo a biopsy; 
• Exclusion criteria 2 added to exclude patients who received prior 
brigatinib treatment; 
• Addition of ctDNA blood sample collection at C1D1 and D1 of odd 
cycles; 
• SAE and pregnancy reporting process updated; 
• Addition of overdose reporting; 
• Updates to section 9.2: Required documentation for site opening; 
• Updates to enrollment procedures; 
• Updates to section 9.4 due to change in EDC system and monitoring 
of data. 
• Addition of Criterium Project manager’s role throughout the protocol. 
• Removal of Unanticipated problems; 
• Updated Appendix B Model Patient Diary. 
3 
• Background and Rationale updated with new data 
• Updates throughout removing references to UNC and LCCC 1523 to 
reflect the transition of responsibilities to ATOMIC and Duke        
Principal Investigator; 
• Change of the Protocol number to ARI-AT-002; 
• Update to study team and contact information; 
• Addition of protocol signature page; 
• Clarifications, formatting, and spelling updates throughout; 
• New background information added; 
• Update to Inclusion 7; 
• Update to Exclusion 6 to include wash out period; 
• Removal of therapy actions related to QTc Interval prolongation; 
• Update to treatment modifications due to pneumonitis; 
• Update to prohibited medications and medications to be used with  
caution due to updated safety profile; 
• Update to management of adverse events of note to reflect current safety 
profile; 
• Removal of treatment beyond disease progression; 
• Updates to Time and Events table and footnotes; 
• Clarification of tumor biopsy requirement; 
• Updates to SAE and Serious SAR reporting; 
• Updates to Data Safety Monitoring Plan; 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 4 of 82 
• Updated to data analysis plan 
• Removal of institution specific IRB reporting requirements; 
• Removal of single patient/subject exception. 
• Removal of appendix Drugs with a Risk of Torsades de Pointes 
4 
• 
Revision to title of protocol 
• 
The addition of 2 cohorts (one for patients who have only received 
alectinib and one for patients who have tolerated brigatinib and 
experienced disease progression and then will receive brigatinib 240 
mg daily 
• 
Increased number of patients enrolled to 120 (40  per cohort) 
• 
Addition of information from the updated IB which included updated 
information about the randomized  phase 2 trial 
• 
Updated information about the drug-drug interactions 
• 
Additional changes were administrative to clarify questions    
investigators have had over eligibility or tests. 
• 
Inclusion criteria for previous therapies revised to reflect cohorts A, B, C 
• 
Dose administration for Cohort C added 
• 
Toxicities and dose modifications for Cohort C were  added 
• 
Contact information was updated for safety reporting 
• 
Product complaint/medication error instructions were  added 
• 
Length of study revised to two years from amendment approval 
5 
• Inclusion criteria 3.1.11 – Revised contraception language; removed 
hormonal contraception as an effective method of  birth control 
• Appendix C - Added information regarding co-administration of brigatinib 
with CYP3A substrates 
• Pregnancy reporting language updated. 
5.1 
• Page 2 (Study Contacts) adds Principal Investigator of Canada site. 
• Section 9.7 (Record Retention) updated to comply with Canadian law.  
• Appendix B and C removed from protocol by University Health Network 
Research Ethics Board request, to be presented as auxiliary material for 
the patient. 
6 
• Corrected Table of Content including page numbering. 
• Administrative changes throughout to correct vertical spacing (reduced 
number of pages to this document); section formatting and numbering; 
sections headings; and page  numbering in footer. 
• Clarified that no EOT visit is required with cohort changes  from A or B to 
C in Sections (Section 3.2.4. 3.3.3 and 6.4). 
• Clarifies dose modification regarding Grade 4 Non- Hematologic  
Treatment Related AEs during Brigatinib  180mg Daily than Pneumonitis 
(Section 4.4.3).  
• Corrected section references related to Concomitant Medications/ 
Juices/Herbal Supplements (within Section 4.6). 
• Clarifies timeframe of Duration of Follow-up (Section 4.7, see also  
footnote 4 Section 6.1). 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 5 of 82 
• Clarifies Section 6, including Schedule of Events (Section  6.1) and 
Treatment Assessments (Section 6.3), Assessment of Efficacy  
(Section 6.8) as follows: 
- 
collection of information regarding prior cancer  therapy;  
- 
clarifies CT scans requirements. 
- 
Clarifies CT scan and brain MRI requirements and measurements. 
- 
Clarifies no EOT visit required with cohort changes from A or B  
to cohort C.  
- 
Clarifies timeframe of Duration of Follow-up. 
- 
Clarifies that biopsies are required for patients treated on cohorts A  
or B and enrolling in C. 
- 
Specifies prior cancer therapy to be captured. 
- 
Clarifies tissue acquisition requirements.  
7 
• Updated to maintain one protocol version for all participating sites  
(merging v5.1 and v6). 
• Adjusts left margins per ICH required minimum, and includes some 
right margin readjustments. 
• Updates References throughout to identify by authors (vs. numbers) 
• Page 2 (Study Contacts) adds Canadian Site PI and updates some other 
addresses 
• Section 1.1 updated with recent research findings regarding brigatinib, 
clarifies each cohort is evaluated independently 
• Section 1.2 adds Canadian health systems use of IHC testing method 
and recent FDA approval of loritinib for patients with disease  
progression. 
• Sections 1.3 and 1.4 adds current and clarifies brigatinib information.  
• EOT visit clarified that EOT not needed for cohort changes from A or 
B to C in Sections 3.2.4. 3.3.3 and 6.4. 
• Inclusion criteria Sections updated to confirm ALK positive status  
allows CLIA or test approved for use in Canada (3.1.2); correct  
subsection numbering (3.1.7 - 3.1.13); reference progressing on  
lorlatinib for cohort A (3.2.1); and clarify no EOT visit for cohort A or  
B participants entering cohort C; and biopsy required for cohort C 
participants (3.2.4). 
• Exclusion criteria Sections revisions include no washout for A or  
cohort B participants entering cohort C (3.3.6); adds “as determined by     
the investigator” to Clinically significant atrial arrhythmia (3.3.7); adds  
new section “Another primary malignancy for which the patient is    
currently receiving therapy” (3.3.8), and readjusts subsequent  
subsection numbers (3.3.9 - 3.3.13) 
• Section 6.1 (Time/Events Table) expands columns to 12 cycles adding  
new footnote 14 reference; updates “X” at Medical History (removes at 
C1D1 & D8), all D1 cycle visits (adds for physical exam/vital signs,   
ECOG, CBC/serum blood tests, and AEs); all D1 cycles for patient  
diary and concomitant meds (add “Review”); and brain MRI timepoints 
(moves to each 3rd cycle from each odd cycle – revised with protocol  
v6) visit. 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 6 of 82 
• Section 6.1 (Keynotes to footnotes) updates FN 9 to clarify ctDNA  
blood samples collected only while patient receives treatment and adds  
FN 14 allowing some telemedicine visits, at treating physician’s  
discretion, for non-scan even cycle visits. 
• Section 6.2 revised that patient diary (Appendix B) is a stand-alone 
auxiliary patient document. 
• Section 6.3 (Treatment Assessments) updates include adds paragraph 
clarifying each odd day cycles (at 6.3.3) and each 3rd cycle (new 6.3.4)  
visit assessments; updates odd day cycles (6.3.3); adds new subsection  
for each 3rd cycle visit (6.3.4); and adds new subsection for non-scan  
even cycles allowing some telemedicine visits (6.3.5). 
• Section 6.4 (EOT Visit) revisions adds clarity for consistency with data 
collection across participating centers (new paragraph 2); for AEs,  
ctDNA blood sample collection; and for cohort C (previously cohort A  
or B) participants. 
• Section 6.5 (Post-treatment/Follow-up Assessments) adds clarity for 
recording data of EOT visit and long-term follow-ups. 
• Section 7.3 (Documentation of non-serious AEs or SARs) adds clarity  
for data recording with participants as both cohort A or B and cohort C. 
• Section 9.1, and throughout, updated references to IRB to include REB 
• Section 9.4 (Data Management) clarifies all data for each cohort is  
captured independently from time of entry into cohort.  
• Section 9.5.2 (Protocol Deviations) adds clarity for data capture and 
regulatory reporting of missed assessments with use of telemedicine  
visits. 
• Section 9.7 (Record Retention) adds Canada’s required record retention 
period per protocol v5.1 
• Section 10 (Appendices) removes Appendix B and Appendix C per  
protocol v5.1  
 
 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
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Page 7 of 82 
 
ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with Second-Generation  
ALK inhibitors in Refractory ALK Rearranged NSCLC 
 
 
Amendment 7: April 20, 2020 
 
 
Principal Investigator - USA  
Thomas E. Stinchcombe, MD  
Duke University 
DUMC 3198 
25177 Morris Building  
Durham, NC 27710 
Phone 919-681-9509 Fax 919-681-9599 
E-mail: Thomas.stinchcombe@duke.edu 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
Principal Investigator (PI) Name:   
 
 
 
PI Signature:  
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 8 of 82 
 
PROTOCOL SIGNATURE PAGE 
Study Protocol Number: 
ARI-AT-002 
Study Protocol Title: 
Phase 2 Trial of Brigatinib after Treatment with Second-
Generation ALK inhibitors in Refractory ALK Rearranged 
NSCLC 
 
SIGNATURES 
 
Principal Investigator: 
 
 
 
 
Thomas E. Stinchcombe, MD 
Date 
 
Director of ATOMIC 
 
 
 
 
 
Ross Camidge, MD, PhD 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6/23/2020
7/1/2020


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 9 of 82 
TABLE OF CONTENTS 
1.0 BACKGROUND AND RATIONALE ....................................................................... 12 
1.1 
Study Synopsis ...................................................................................................... 12 
1.2 
Non-small Cell Lung Cancer (NSCLC) ................................................................ 13 
1.3 
Brigatinib (AP26113) ............................................................................................ 15 
1.4 
Rationale ............................................................................................................... 35 
1.5 
Correlative Studies to Explore Mechanisms of Resistance ................................... 36 
2.0 STUDY OBJECTIVES ............................................................................................... 37 
2.1 
Primary Objective ................................................................................................. 37 
2.2 
Secondary Objectives ............................................................................................ 37 
2.3 
Exploratory Objectives ......................................................................................... 38 
2.4 
Primary Endpoint .................................................................................................. 38 
2.5 
Secondary Endpoints ............................................................................................. 38 
3.0 PATIENT ELIGIBILITY ........................................................................................... 39 
3.1 
Inclusion Criteria for all cohorts ........................................................................... 39 
3.2 
Inclusion criteria for cohort assignment ............................................................... 40 
3.3 
Exclusion Criteria for cohorts A, B, and C ........................................................... 41 
4.0 TREATMENT PLAN .................................................................................................. 42 
4.1 
Schema for cohorts A and B ................................................................................. 42 
4.2 
Schema for cohort C ............................................................................................. 42 
4.3 
Treatment Dosage and Administration ................................................................. 43 
4.4 
Toxicities and Dosing Delays/Dose Modifications for cohorts A and B .............. 43 
4.5 
Toxicities and dose modifications for cohort C .................................................... 47 
4.6 
Concomitant Medications/Juices/Herbal Supplements ......................................... 49 
4.7 
Prohibitive Palliative Radiotherapy ...................................................................... 49 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 10 of 82 
4.8 
Prohibited Systemic Therapy ................................................................................ 49 
4.9 
Prohibited Medications/Juices/Herbal Supplements ............................................ 49 
4.10 
Duration of Therapy .............................................................................................. 49 
4.11 
Duration of Follow-up........................................................................................... 50 
4.12 
Removal of Patients from Protocol Therapy ......................................................... 50 
4.13 
Study Withdrawal ................................................................................................. 50 
5.0 DRUG INFORMATION ............................................................................................. 50 
5.1 
Investigational Agent Description and Management ............................................ 50 
6.0 EVALUATIONS AND ASSESSMENTS................................................................... 53 
6.1 
Time and Events Table ......................................................................................... 53 
6.2 
Pre-Study Assessments ......................................................................................... 55 
6.3 
Treatment Assessments ......................................................................................... 56 
6.4 
EOT Visit .............................................................................................................. 58 
6.5 
Post-Treatment/Follow-up Assessments ............................................................... 59 
6.6 
Correlative Studies Procedures ............................................................................. 59 
6.7 
Assessment of Safety ............................................................................................ 64 
6.8 
Assessment of Efficacy ......................................................................................... 64 
7.0 ADVERSE EVENTS ................................................................................................... 66 
7.1 
Intentionally Blank ............................................................................................... 66 
7.2 
Definitions ............................................................................................................ 66 
7.3 
Documentation of non-serious AEs or SARs ........................................................ 68 
7.4 
SAEs or Serious SARs .......................................................................................... 69 
7.5 
Data and Safety Monitoring Plan .......................................................................... 72 
8.0 STATISTICAL CONSIDERATIONS ....................................................................... 72 
8.1 
Study Design/Study Endpoints.............................................................................. 72 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
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Page 11 of 82 
8.2 
Sample Size and Accrual ...................................................................................... 73 
8.3 
Data Analysis Plans .............................................................................................. 73 
9.0 STUDY MANAGEMENT .......................................................................................... 74 
9.1 
Institutional Review Board (IRB) / Research Ethics Board REB)                                                
Approval and Consent ........................................................................................... 74 
9.2 
Required Documentation....................................................................................... 75 
9.3 
Enrollment Procedures .......................................................................................... 75 
9.4 
Data Management and Monitoring/Auditing ........................................................ 76 
9.5 
Adherence to the Protocol ..................................................................................... 76 
9.6 
Amendments to the Protocol ................................................................................. 78 
9.7 
Record Retention .................................................................................................. 78 
9.8 
Obligations of Investigators .................................................................................. 78 
10.0 
APPENDICES ..................................................................................................... 79 
Appendix A: ECOG Performance Status 
Appendix B:  Patient Diary for Brigatinab (see as auxiliary patient document)   
Appendix C:  Prohibited Drugs, Juices and Herbal Supplements, and 
Medications to be used with Caution (see as auxiliary patient  
document)   
11.0     REFERENCES ...................................................................................................... 80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Drug Substance: brigatinib  
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Page 12 of 82 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This multicenter phase II trial will evaluate brigatinib (AP261136) in patients  
with advanced non-small cell lung cancer (NSCLC) harboring an anaplastic  
lymphoma kinase (ALK) rearrangement, previously treated with a next generation  
ALK inhibitor such as ceritinib or alectinib.(Shaw et al. 2014; Soria et al. 2017; Peters 
et al. 2017; Hida et al. 2017). Ceritinib and alectinib are referred to as ‘next generation,”  
and are approved by the Food and Drug Administration (FDA) for patients with a 
confirmed ALK rearrangement (referred to as ALK+) who have progressed on or are 
intolerant of crizotinib, and alectinib and ceritinib is approved for treatment naïve  
patients. Alectinib, ceritinib, and crizotinib currently are recommended by the National 
Comprehensive Cancer Network (NCCN) as first- line therapy with category 1 
recommendations; alectinib is the preferred therapy.( ) In addition, multiple other next 
generation inhibitors are in development. Brigatinib has also demonstrated significant 
activity in patients who have progressed on crizotinib, with responses reported for both 
intracranial and extracranial disease.(Kim et al. 2017) The activity of brigatinib in  
patients who have disease progression after ceritinib or alectinib has not been 
prospectively investigated. Brigatinib was compared to crizotinib in phase 3 trial of 
treatment naïve patients, and was found a statistically significant improvement in 
progression-free survival.  
 
There is increasing concern that patients who have been exposed to multiple 
therapies may have multiple mechanisms of resistance, including ALK dependent 
and ALK independent mechanisms of resistance. Therefore, patients will be 
divided into cohorts (A) patients who have progressed on multiple lines (>1) of 
ALK directed therapy, including at least one licensed or experimental next 
generation therapy (B) patients who have progressed on only alectinib.8 In an 
exploratory cohort (C) patients who tolerate but progress on 180mg brigatinib (as a 
part of the trial or as part of routine clinical care) will be treated with 240 mg 
brigatinib daily to determine if intra-patient dose escalation is safe and tolerable 
and is associated with greater activity at the higher doses. 
 
Rationale for post alectinib cohort 
Brigatinib is predicted to maintain activity against all ALK resistance mutations, and 
such resistance mutations are associated with progression in approximately 50% of 
patients treated with alectinib.(Gainor et al. 2016; Shaw et al. 2019; Lin, Riely, and 
Shaw 2017) Brigatinib inhibits ALK with approximately 2-fold greater potency 
than alectinib in vitro. Steady-state levels of exposure of brigatinib in patients 
treated with 90 mg daily for 7 days followed by 180 mg daily regimen of brigatinib 
are at least 2-fold higher than those achieved in patients treated with alectinib (600 
mg twice daily), suggesting that brigatinib may also be less susceptible to 
pharmacologic resistance than alectinib.(Zhang et al. 2016) The mechanisms of 
resistance and resistance mutations may be unique for alectinib. Investigating 
brigatinib in patients who have progressed on only alectinib will create a more 
homogenous cohort, and there is a clinical need to assess the activity of other ALK 
inhibitors as alectinib is adopted as a first-line therapy. 
 
 


Drug Substance: brigatinib  
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Rationale for dose escalation cohort.  
The rationale for escalation to 240 mg daily at disease progression is to attempt to 
overcome potential pharmacologic resistance at 180 mg daily brigatinib (i.e. to 
increase brigatinib exposure in order to have better activity against a given ALK 
resistance mutation may be dose dependent or for increased exposure in the CNS 
to treat CNS disease progression). A higher dose of brigatinib may have inhibitory 
activity against resistance mutations, and better CNS penetration which is 
clinically relevant since many patients experience progressive CNS disease. In the 
phase 1/2 dose-limiting toxicities (DLT) were grade 3 alanine aminotransferase 
(ALT) in one patient at 240 mg daily and grade 4 dyspnea in one patient at 300 
mg daily.(Gettinger et al. 2016) The maximum tolerated dose was not established. 
In patients who were treated with 240 mg daily, 300 mg daily or 120 mg twice 
daily (n=15) the grade 3 or 4 adverse events observed at (>5%) were fatigue 
(13%), diarrhea (13%), headache (7%), vomiting (14%), increased lipase (13%), 
hypertension (7%), and pyrexia (7%). Since exposure to lower starting doses of 
brigatinib has now been associated with an abrogation of early onset pulmonary 
symptoms at escalation to a higher dose (e.g. 90 mg for 7 days before increasing 
to 180mg as in ALTA), re-exploration of the tolerability and efficacy of 240 mg 
QD after tolerable exposure to 180 mg is appropriate clinical question for further 
study. 
 
Study design 
The study will enroll up to 40 patients in each of the cohorts, using a Simon two- 
stage design, with a primary endpoint of objective response (complete response 
(CR) + partial response (PR)) as assessed by the investigator. Each cohort is 
evaluated independently. Secondary objectives include estimating duration of 
response, progression free survival (PFS), intracranial and extracranial PFS, and 
overall survival (OS). Exploratory objectives include intracranial ORR among 
patients with measurable CNS disease. If the trial meets the primary efficacy end-
point an exploratory evaluation of molecular predictors of response and resistance, 
using both tumor tissue samples and circulating tumor DNA (ctDNA) from 
peripheral blood samples will be conducted. 
 
1.2 
Non-small Cell Lung Cancer (NSCLC) 
Factors that determine treatment for non-small cell lung cancer (NSCLC) include 
histology, age, comorbidities, and presence or absence of driver mutations or 
rearrangements. One such oncogenic driver that influences treatment is the novel 
fusion oncogene resulting from an inversion in chromosome 2 of two genes: the 
echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic 
lymphoma kinase (ALK) gene. ALK rearrangements are more commonly (but not 
exclusively) detected in NSCLC patients with adenocarcinoma, patients with a history 
of light or never smoking, and younger patients. The prevalence among patients with 
adenocarcinoma is estimated to be 8% (95% confidence interval (CI), 6 to 10%).(Kris 
et al. 2014; Barlesi et al. 2016). Given that ALK rearrangements are not exclusively 
found in these groups, current practice guidelines recommend reflexive testing in all 
patients with non-squamous NSCLC. Current FDA approved methods of  detecting 
ALK rearrangements are the fluorescence in situ hybridization (FISH), and more 
recently immunohistochemistry (IHC) testing. (Lindeman et al. 2018) Additional  


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methods that can detect ALK fusions include PCR-based methods and more recently 
DNA- and RNA-based next generation sequencing (NGS) assays from tumor and/or 
ctDNA. The Canadian health system has adopted an IHC testing method nationally, 
and there is increasing adoption of tumor and ctDNA NGS testing methods. 
(Lindeman et al. 2018; Cutz et al. 2014; Wynes et al. 2014) 
 
Crizotinib, an ALK inhibitor, is a standard first-line treatment for NSCLC patients 
with this genetic rearrangement, so called ALK+ disease. This is based on 
superior objective response rates (ORR) and progression free survival (PFS) in 
phase 3 trials of crizotinib compared to chemotherapy in the first and second line 
treatment of advanced ALK+ NSCLC patients.   A phase 3 trial compared ceritinib 
to platinum-pemetrexed and demonstrated a statistically significant improvement 
in PFS as assessed by the independent review committee (IRC) (HR of 0.55, 95% 
CI, 0.42-0.73, p<0.00001; median PFS 16.6 and 8.1 months, respectively) and 
superior ORR (72.5% vs 26.7%) with ceritinib.(Soria et al. 2017) The most 
common grade 3 or 4 AE’s were ALT (31%), and AST (17%). The median 
relative dose intensity was 78.4%. 
 
Two phase 3 trials have compared alectinib to crizotinib in ALK therapy naïve 
patients, and have demonstrated a superior ORR and PFS with alectinib.  A phase 
3 trial in Japan compared alectinib to crizotinib in patients with ALK + NSCLC 
who had not previously been treated with an ALK inhibitor. (Hida et al. 2017; 
Peters et al. 2017) The independent data monitoring committee stopped 
enrollment to the trial early since alectinib had demonstrated a statistically 
significant improvement in PFS.4 Patients assigned to alectinib compared to 
crizotinib had a statistically higher ORR (92% vs 79%), a lower rate of grade 3 or 
4 AE’s (26% vs 52%), treatment discontinuations due to AE’s (9% vs 20%), and a 
longer PFS (hazard ratio (HR) of 0.34; 95% CI, 0.17 to 0.71; p<0.0001; median 
not reached and 10.2 months, respectively). An international trial compared 
alectinib to crizotinib and revealed a superior ORR by investigator (82.9% vs 
75.5%, p=0.09), and PFS by IRC (HR of 0.50, 95% CI, 0.36 to 0.70; p<0.001; 
median PFS of 25.7 and 10.4 months, respectively). The grade 3 to 5 AE’s were 
lower in the alectinib than the crizotinib arms (41% vs 51%). The time to CNS 
disease progression was significantly longer in the alectinib arm compared to the 
crizotinib arm (HR of 0.16, 95% CI, 0.10-0.28, p<0.001), and the 12-month rate 
of CNS progression was 9.4% and 41.4%, respectively 
 
The current NCCN recommend crizotinib, ceritinib, and alectinib as first-line 
therapies (category 1) with alectinib being the preferred therapy.6 These phase 3 
trials and the NCCN guidelines have led to the adoption of second-generation ALK 
TKI’s as first-line therapy. 
 
Recently lorlatinib was approved by the FDA for patients with disease progression after 
alectinib, after ceritinib, or crizotinib and one other ALK TKI.(Solomon et al. 2018) 
 
Brigatinib, a next generation ALK inhibitor with broad activity against crizotinib 
resistance mutations and promising CNS activity. It was approved by the FDA  
for patients who have progressed on or were intolerant of crizotinib. Brigatinib 
was investigated in a two-arm randomized phase 2 trial of 90 mg daily and 90 mg 


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daily for 7 days followed by 180 mg daily.(Kim et al. 2017) The primary end-
point was ORR, and secondary end-points were PFS and CNS response. In the  
90 mg daily arm the ORR by IRC was 48% (95% CI, 39-58%), and the median 
PFS was 9.2 months (95% CI, 7.4 to not reached). In the 90 mg daily followed by 
180 mg daily the ORR by IRC was 53% (95% CI, 43-62%), and the median PFS 
was 15.6 months (95% CI, 11.0 to not reached). The intracranial response rate in 
patients with measurable CNS disease by independent radiological review on the 
90 mg daily arm (n=26) was 42% (95% CI, 23-635), and in the 90 mg daily 
followed by 180 mg daily arm (n=18) was 67% (95% CI, 41%-87%). In the 90 
mg daily followed by 180 mg daily the grade ≥3 AE’s observed at a rate of ≥ 2% 
of patients were: dyspnea (2%), back pain (2%), increase phosphokinase (9%), 
rash (3%), and hypertension (6%). Episodes of QT prolongation were not 
observed. 
 
At this time the activity of brigatinib after ceritinib, or alectinib has not been  
prospectively studied. 
 
1.3 
Brigatinib (AP26113) 
Brigatinib (AP26113) is a novel, orally-active tyrosine kinase inhibitor (TKI) 
discovered and developed by ARIAD Pharmaceuticals, a subsidiary of Takeda 
Oncology. Primary targets are activated, mutant forms of anaplastic lymphoma 
kinase (ALK) and c-ros oncogene 1 (ROS1), which play important roles in non- 
small cell lung cancer (NSCLC) and other cancers. 
 
1.3.1 
Pharmacology Summary 
A series of in vitro and in vivo studies have been performed to characterize the 
pharmacodynamic profile of brigatinib. These studies have demonstrated that 
brigatinib potently inhibits activated variants of ALK, such as echinoderm 
microtubule-associated protein like (EML4)-ALK, and variants of ALK,  
including the L1196M gatekeeper mutation, that confers resistance to crizotinib. 
No ALK mutations have been identified in in vitro mutagenesis assays that confer 
resistance to brigatinib at clinically achievable concentrations. Overall, the data 
established that brigatinib has a promising profile as an antitumor agent, and they 
provided a strong rationale for conducting a clinical development program in 
cancer patients. 
 
1.3.2 
Absorption, Distribution, Metabolism, and Excretion (ADME) Summary 
Brigatinib is bioavailable after oral administration in multiple animal species,  
and in rats and monkeys has been shown to be a low clearance compound that is 
extensively distributed in extravascular compartments. In vitro, brigatinib was 
moderately bound to plasma proteins in mouse, rat, monkey and human and also 
did not show preferential partitioning into red blood cells (RBCs). Brigatinib is a 
Permeability-glycoprotein (P-gp) substrate. 
 
Overall, the metabolism of brigatinib in rats, monkeys, and humans (both in vitro 
and in vivo) was qualitatively similar with no unique human metabolites  
observed. N-demethylation leading to AP26123 was identified as the main 
biotransformation pathway in liver microsomes and hepatocytes. Other minor 


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metabolites were present in insignificant amounts in hepatocyte incubations and 
did not contribute substantially to brigatinib metabolism. Analysis of rat, monkey, 
and human urine, and feces of rats by liquid chromatography/tandem mass 
spectrometry (LC/MS/MS) showed that AP26123 also was the principal 
metabolite in these matrices. In [14C]-brigatinib ADME studies in rats, monkeys, 
and humans, the majority of the circulating radioactivity was attributed to the 
parent drug brigatinib (>60%). The metabolite AP26123 accounted for <10% of 
circulating radioactivity. 
 
In vitro studies suggest that brigatinib and its metabolite, AP26123, do not inhibit 
CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 at therapeutically relevant drug 
concentrations. Thus, clinical DDIs due to inhibition of CYPs by brigatinib and 
AP26123 are highly unlikely. 
1.3.3 
Toxicology Summary 
The nonclinical safety and toxicity profile of brigatinib was characterized in acute 
toxicity studies in mice and rats, range-finding and 28-day Good Laboratory 
Practice (GLP) toxicology studies in rats and cynomolgus monkeys, in vitro 
genotoxicity studies, and a phototoxicity study in rats. A summary of toxicology 
observations is summarized in the investigator brochure.  
 
A single oral dose of brigatinib was tolerated in mice at doses up to 75 mg/kg and 
in rats at doses up to 125 mg/kg. Dose-dependent increases in mortality occurred 
at dose levels ≥125 mg/kg in mice and ≥250 mg/kg in rats. 
 
In the 28-day GLP oral toxicology/toxicokinetics study in rats, oral 
administration of brigatinib at doses of 30 or 60 mg/kg/day resulted in a dose-
dependent increase in mortality, which led to the cessation of dosing in the 60 
mg/kg/day dose group toward the end of Week 1. A clear spectrum of clinical 
signs of toxicity preceded the deaths of the animals. The key histopathological 
findings in rats at the 30 and 60 mg/kg/day dose levels that died prematurely and 
in some 30 mg/kg/day rats that survived the 28-day treatment period were 
minimal to marked hematopoietic hypocellularity in the bone marrow in 
conjunction with lymphoid depletion in the spleen, thymus and other lymphoid 
tissues, which raise the potential for immunosuppressive effects of brigatinib. 
Other notable brigatinib-related gross anatomic or microscopic findings, 
including bone and gastrointestinal pathologies, were seen primarily in rats that 
died prematurely. Brigatinib was physically well tolerated by rats in the 15 
mg/kg/day dose group, and by most rats in the 30 mg/kg/day dose group. 
Reversible, dose-related reductions in group mean body weight, body weight 
gain, and food consumption were noted at these dose levels from Day 7 until the 
end of the dosing period. Based on the incidence and severity of gross anatomic 
and microscopic lesions and mortality observed at the 30 mg/kg/day brigatinib 
dose level, the no-observed adverse effect level (NOAEL) of brigatinib was 
considered to be 15 mg/kg/day, which corresponded to a Cmax of 1437 ng/mL 
and 1527 ng/mL, and AUC0-24 of 21716 h•ng/mL and 23550 h•ng/mL on Day 
28 for males and females, respectively. 
 


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In the 28-day GLP monkey oral toxicology/toxicokinetic study, clinical signs of 
toxicity, moribundity, and mortality were evident beginning on Day 3 after daily 
oral administration of 45 mg/kg/day brigatinib. Consequently, dosing of all 
animals in the 45 mg/kg/day dose group was stopped on Day 7 or 8. The cause of 
premature death was attributed to brigatinib-related gastrointestinal toxicity, which 
involved all segments of the gastrointestinal tract, but was most severe in the 
stomach and small intestines. Other prominent histopathological findings in 
monkeys that died prematurely and in animals treated with 15 and 45 mg/kg/day 
brigatinib that survived to the terminal sacrifice on Day 30 were generally similar 
to those seen in rats, including lymphoid atrophy/necrosis and bone marrow 
hypocellularity. No brigatinib-related changes were seen at terminal sacrifice in 
the 7.5 mg/kg/day treatment group, or in any dose group at the end of the 28-day 
recovery period. Based on these results, the NOAEL was considered to be 7.5 
mg/kg/day brigatinib, corresponding to a Cmax of 526 ng/mL and 560 ng/mL,  
and AUC0-24 of 3408 h•ng/mL and 3358 h•ng/mL on Day 28 for males and 
females, respectively. 
 
No evidence of cutaneous phototoxicity or ocular phototoxicity was observed in 
rats after a single oral administration of brigatinib at doses as high as 60 mg/kg. A 
bacterial reverse mutation assay and a chromosomal aberration test in human 
peripheral blood lymphocytes revealed no evidence of brigatinib genotoxic 
activity. 
 
In summary, the nonclinical safety and toxicity profile of brigatinib was 
adequately characterized in appropriate animal and in vitro models to inform the 
design of clinical studies of brigatinib, determine potential risks associated with 
its administration to patients, and provide recommendations for clinical 
monitoring. 
 
1.3.4 
Preclinical data 
The activity of brigatinib against 293 recombinant human protein kinases was 
analyzed in an in vitro kinase assay. At a concentration of 1 μM, brigatinib was 
found to inhibit the activity of 36 kinases (12%) by at least 90%. More detailed 
analysis of the kinases with greatest sensitivity showed that 1 kinase, ALK, was 
inhibited with a 50% inhibitory concentration (IC50) <1 nM. Eleven kinases, 
including ROS1, FAK, FLT3, CHK2, and EGFR-L858R were inhibited with IC50 
values between 1 nM and 10 nM. Nineteen kinases, including EGFR- 
L858R/T790M, ERBB2, and CHK1, were inhibited with IC50 values between 
10 nM and 50 nM. Twelve kinases, including IGF-1R and native EGFR, were 
inhibited with IC50 values between 50 nM and 100 nM 
 
These studies demonstrated that brigatinib potently inhibited the kinase activity of 
ALK, and inhibited the activity of ROS1, mutant EGFR, and to a lesser extent 
IGF-1R, prompting further analysis of these kinases in non-clinical experiments. 
 
1.3.5 
Anaplastic Lymphoma Kinase Inhibitory Activity of Brigatinib 
In nonclinical studies, brigatinib has been shown to: 


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• Inhibit growth of ALK+ human tumor-derived cell lines with potency and 
selectivity approximately 10-fold greater than that of crizotinib 
• Potently inhibit ALK variants with secondary mutations that confer resistance 
to crizotinib, ceritinib, or alectinib 
• Suppress the emergence of any resistant ALK mutant in an in vitro 
mutagenesis assay, at concentrations that can be achieved clinically 
• Induce regressions or inhibit growth of tumor xenografts driven by native 
ALK or mutant variants that confer clinical resistance 
• Prolong survival of mice in an ALK-dependent orthotopic brain tumormodel 
 
1.3.6 
In Vitro Activity in Human Tumor-derived Cell Lines 
In a panel of 7 anaplastic large cell lymphoma (ALCL) and NSCLC cell lines that 
express nucleophosmin-ALK (NPM-ALK) or EML4-ALK fusions, the 
concentration of brigatinib that inhibited growth by 50% (GI50) ranged from 4 nM 
to 31 nM, and the concentration that inhibited ALK phosphorylation by 50%  
(IC50) ranged from 1.5 nM to 12 nM. Across 3 ALK-negative ALCL and  
NSCLC cell lines, the GI50 values for brigatinib ranged from 503 nM to 2387 nM. 
Overall, brigatinib potently inhibited ALK activity and proliferation in all ALK+ 
cell lines tested, and exhibited >100-fold selectivity over ALK-negative lines. In 
contrast, crizotinib exhibited 10-fold lower potency compared to brigatinib in 
ALK+ cell lines, and only approximately 10-fold selectivity over ALK-negative 
lines. AP26123, the principal metabolite of brigatinib in vivo, was included in a 
subset of these studies and found to have slightly reduced anti-ALK activity 
compared to brigatinib. 
 
The cellular activity of brigatinib was also compared to that of crizotinib, 
ceritinib, and alectinib in Ba/F3 cells whose viability was dependent on activity of 
a native EML4-ALK fusion, or fusions containing mutations in the ALK kinase 
domain that have been previously been associated with resistance in clinical or 
nonclinical studies.10,12,13 Brigatinib inhibited the viability of cells expressing 
native EML4-ALK with potency 8-fold greater than that of crizotinib (IC50 of 14 
nM versus 107 nM). Brigatinib also inhibited the viability of cells expressing all 
17 ALK mutants (IC50 values of 9 to 184 nM), with potency substantially greater 
than that of crizotinib (IC50 values of 170 to 1109 nM) for all 17 mutants except 
L1198F, which has been associated with resistance to ceritinib but not crizotinib. 
 
The relationship between TKI potency in these cellular assays and levels of TKI 
exposure in patients (mean steady state plasma concentrations), corrected 
for the functional effects of protein binding, was analyzed (Figure 1). For 
crizotinib, drug levels in patients exceed the IC50 for native EML4-ALK, but did 
not exceed, by at least 2-fold, the IC50 for variants that have been associated with 
crizotinib resistance. In contrast, based on PK data from the ongoing phase 1/2 
trial, brigatinib plasma concentrations in patients dosed at 90 or 180 mg daily 
were found to exceed the IC50 values for native EML4-ALK and all 17 resistance 
mutants by at least 2-fold, with the exception of the G1202R mutant, whose IC50 
was substantially exceeded by brigatinib levels achieved at 180 mg but not 90 mg 
daily dosing. 
 


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A similar analysis of ceritinib and alectinib revealed that certain mutations 
increased the inhibitory concentrations to levels that were not exceeded, by at least 
2-fold, by steady state plasma concentrations at the recommended phase 2 doses 
(Figure 1). These include T1151Tins, L1152R, L1152P, L1198F, and G1202R for 
ceritinib, and T1151Tins, I1171N, V1080L, and G1202R for alectinib. 
 
Finally, a cell-based accelerated mutagenesis assay was performed to more broadly 
assess the mutational liabilities of brigatinib and crizotinib. While this assay 
successfully identified mutations that cause clinical resistance to crizotinib, no 
mutations in ALK were identified that had an IC50 that exceeded the concentrations 
of brigatinib achieved in patients dosed with 90 or 180 mg. Taken together, these 
results demonstrate that brigatinib has pan-ALK inhibitory activity in vitro and is 
the only ALK TKI predicted to retain potent activity against all secondary ALK 
mutants described to date. (Figure 1). 
Figure 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure source.(Zhang et al. 2016) 
 
 
50% maximal inhibitory concentration (IC50) values of Ba/F3 cells dependent on 
expression of EML4 ALK (native) or kinase domain mutated EML4 ALK 
variants (n=17). Data for each cell line are derived from at least 3 independent 
experiments (error bars=standard deviation). 
 
Dashed horizontal lines indicate the mean steady state (SS) concentrations of each 
drug (expressed as the average plasma drug concentration over the dosing interval 
determined by dividing: AUC0-24, ss by 24 h, or Cave,ss) corrected for the functional 
L1198F 
G1202R
I1171N 
V1180L 
G1202R 


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effects of protein binding (2.7, 2.7, 4.1, and 2.0-fold for crizotinib, ceritinib, alectinib, 
and brigatinib, respectively;10, 14,15 at the recommended phase 2 doses: 
 
a: Crizotinib: 250 mg BID, 266 nM (Cave,ss [719 nM]/2.7)  
b: Ceritinib: 750 mg QD, 456 nM (Cave,ss [1232 nM]/2.7)1  
c: Alectinib: 600 mg BID, 302 nM (Cave,ss [1120]/3.7)  
d: Brigatinib 180 mg QD, 724 nM (Cave,ss [1477 nM]/2.0) and 90 mg QD, 291 nM 
(Cave,ss [582 nM]/2.0) (Data on file,Takeda Pharmaceuticals, Inc.) 
 
For each TKI, mutants for which the clinically effective concentration did not 
exceed the  IC50 by at least 2-fold are indicated in red text. *For brigatinib, G1202R 
met this criterion based on exposure in patients dosed with 90 mg daily, but no 
mutants met this criterion based on exposure in patients dosed with 180 mg daily. 
 
1.3.7 
In Vivo Activity in ALK-dependent Subcutaneous Xenografts 
The in vivo activity of brigatinib was examined in ALK+ KARPAS-299 (ALCL)  
and H3122 (NSCLC) xenograft models. Daily oral administration of brigatinib   
(10, 25, and 50 mg/kg) led to a dose-dependent inhibition of tumor growth in both 
models, with a dose level of 25 mg/kg inhibiting tumor growth by 89% in the 
KARPAS-299 model and inducing tumor regression by >90% in the H3122 model. 
In both models, a prolonged inhibition of ALK signaling was observed after 
administration of 25 mg/kg brigatinib, with >90% and >60% reductions in levels of 
phosphorylated ALK observed 10 and 24 hours after dosing, respectively. 
 
Additional in vivo tumor studies were conducted using Ba/F3 cell lines engineered  
to express native EML4-ALK, a crizotinib-resistant variant (L1196M), and the most 
recalcitrant mutant identified in in vitro assays (G1202R). Mice bearing  
subcutaneous tumors expressing native EML4-ALK or EML4- ALK/L1196M were 
administered vehicle, brigatinib, or crizotinib orally once daily. Crizotinib induced  
the regression of tumors expressing native EML4- ALK at the highest dose tested  
(200 mg/kg), but did not show antitumor activity in the EML4-ALK/L1196M  
model at this same dose. In contrast, brigatinib (50 mg/kg) induced tumor  
regression in both models. In mice bearing tumors expressing EML4-  
ALK/G1202R, brigatinib (50 mg/kg) inhibited tumor growth by 88%, while  
crizotinib (200 mg/kg) inhibited tumor growth by 46%. Doses of ceritinib (50  
mg/kg) and alectinib (60 mg/kg) that strongly inhibited growth of native EML4-  
ALK tumors (by >95%) had little to no impact on growth of EML4- ALK/G1202R 
tumors (≤15% inhibition of tumor growth). 
 
1.3.8 
In Vivo Activity in ALK-dependent Orthotopic Brain Tumor Model 
Activity of brigatinib in the CNS was assessed in vivo using an orthotopic brain 
tumor model. ALK+ H2228 (NSCLC) cells were injected intracranially to form 
tumors in the brain and tumor-bearing mice were treated with vehicle, crizotinib or 
brigatinib. Daily oral administration of crizotinib at 100 mg/kg extended median 
survival to 48 days compared to 28 days in vehicle-treated mice (Figure 2).  
 
 


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Compared to crizotinib-treated mice, daily oral dosing with 25 and 50 mg/kg 
brigatinib significantly prolonged median survival to 62 days and >65 days, 
respectively (Figure 2). Histological findings demonstrated a significant reduction  
in tumor burden in the brains of mice treated with 50 mg/kg brigatinib compared  
with crizotinib-treated mice.10 
 
Figure 2:  
Brigatinib Enhances Survival of Mice Bearing H2228 
Brain Tumors Compared with Crizotinib 
 
 
1.3.9 
Clinical Data 
As of 01 August 2017, 634 patients have been enrolled in Takeda-sponsored clinical 
trials of brigatinib in cancer patients (phases 1, 2, and 3), and 263 subjects have  
been enrolled in clinical pharmacology studies. 
 
Three company-sponsored clinical studies with brigatinib are being conducted in 
adult cancer patients as of August 2017: 
• A phase 1/2 study of the safety, tolerability, PK and preliminary antitumor 
activity of brigatinib in advanced malignancies, including ALK+ NSCLC (Study 
AP26113-11-101). 
• A pivotal phase 2 study in patients with locally advanced or metastatic ALK+ 
NSCLC whose disease has progressed on therapy with crizotinib (Study  
AP26113- 13-201; ALTA). 


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• A pivotal randomized phase 3 study of brigatinib versus crizotinib in patients    
with locally advanced or metastatic ALK+ NSCLC and no previous treatment  
with an ALK inhibitor (Study AP26113-13-301; ALTA 1L). 
 
An EAP (Study AP26113-16-901) to provide brigatinib to patients with ALK+  
NSCLC who are resistant or intolerant to at least 1 prior ALK TKI and for whom 
brigatinib therapy is requested by the investigator was initiated in 2016 and was  
closed after brigatinib was granted accelerated approval in the US in April 2017. A 
similar EAP is ongoing in Europe. As of 25 July 2017, approximately 139 patients 
have been exposed to brigatinib in the Post-Marketing setting in the US and as of  
14 July 2017, 265 patients have been exposed to brigatinib through EAP in the US  
and Europe. 
 
The following clinical pharmacology studies have been completed or are ongoing: 
• 
An ethnobridging study to determine the PK of orally administered brigatinib 
in healthy Japanese and Caucasian subjects (Study AP26113-13-102). 
• 
A study to provide a preliminary assessment of the effect of a high-fat meal on  
the relative bioavailability and PK of a single dose of brigatinib administered  
orally to healthy subjects (Study AP26113-13-103). 
• 
An ADME study with [14C]brigatinib (Study AP26113-13-104). 
• 
A DDI study evaluating the effects of rifampin, itraconazole, and gemfibrozil 
on the PK of brigatinib in healthy subjects (Study AP26113-15-105). 
• 
A BE study between 30 mg brigatinib tablets and 90 mg brigatinib tablets in 
healthy subjects (Study AP26113-15-106). 
• 
A study evaluating the PK of brigatinib in subjects with chronic hepatic 
impairment and matched healthy subjects (Study AP26113-15-107). This study  
• 
is ongoing. 
• 
A study evaluating the PK of brigatinib in subjects with chronic renal   
impairment and matched healthy subjects (Study AP26113-15-108). This study  
is ongoing. 
• 
A study to provide a definitive assessment of the effect of a high-fat meal on the 
relative bioavailability and PK of a single dose of brigatinib administered orally  
to healthy subjects (Study AP26113-16-109). 
• 
A BE study between 30 mg brigatinib tablets and 180 mg brigatinib tablets in 
healthy subjects (Study AP26113-16-110). 
Detailed information about these studies is provided in Section 5.2. 
 
Clinical Pharmacology Studies 
An overview is presented of the final PK and safety results for the 7 completed 
clinical pharmacology studies performed in healthy subjects: Study AP26113-13- 
102 (Ethnobridging), Study AP26113-13-103 (Preliminary Food-Effect), Study 
AP26113-13-104 (ADME), Study AP26113-15-105 (DDI), Study AP26113-15-106 
(30 mg vs 90 mg tablet BE), Study AP26113-16-109 (Pivotal Food-Effect) and 
Study AP26113-16-110 (30 mg vs 180 mg tablet BE) Study descriptions for the 2 
ongoing clinical pharmacology studies in subjects with impaired end-organ function 
are also described although results are not available: Study AP26113-15-107 
(Hepatic Impairment) and Study AP26113-15-108 (Renal Impairment). 


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Ethnobridging Study (Study AP26113-13-102) 
This was a double-blind, randomized, placebo-controlled, single ascending dose 
study of PO- administered brigatinib in healthy subjects (24 Japanese and 24 
Caucasian subjects). Three of the 6 cohorts consisted of 8 Japanese (6 active:2 
placebo) subjects each and the other 3 cohorts consisted of 8 Caucasian (6 active:2 
placebo) subjects each. The single doses of brigatinib tested were 90 mg, 120 mg, 
and 180 mg administered under fasting conditions. Each dose was tested in 2 
cohorts, 1 of Caucasian subjects and 1 of Japanese subjects. 
 
Following single PO doses, plasma brigatinib concentrations reached a maximum at 
approximately 2.0 to 3.5 hours and then declined in a multi-exponential manner 
with all subjects showing quantifiable concentrations up to 72 hours postdose. The 
arithmetic mean Cmax increased with an increase in dose from 401.8 ng/mL and 
451.3 ng/mL for Japanese and Caucasian subjects at 90 mg, respectively, to 640.3 
ng/mL and 712.3 ng/mL for Japanese and Caucasian subjects at 180 mg, 
respectively. Although the mean peak concentration generally appeared higher for 
the Caucasian population, there was also higher intersubject variability with this 
population when compared with the Japanese population. The GeoMean coefficient 
of variation (CV%) Cmax with Caucasian subjects ranged from 41.2% to 65.2% 
across treatments when compared with the GeoMean CV% Cmax for Japanese 
subjects, which ranged from 26.6% to 37.0% across treatments. The mean AUC0-∞ 
increased from 6064 h•ng/mL and 6783 h•ng/mL for Japanese and Caucasian 
subjects at 90 mg, respectively, to 9910 h•ng/mL and 12149 h•ng/mL for Japanese 
and Caucasian subjects at 180 mg, respectively. Similar to the observation with 
Cmax, AUC0-∞ estimated for Caucasian subjects generally appeared higher with 
higher variability when compared with Japanese subjects. Given the variability, 
assessment of race on single dose PK parameters of brigatinib indicated that 
Caucasian and Japanese subjects had comparable systemic exposure at the studied 
dose levels. A could not be ruled out due to variability. Mean t½ was comparable 
across populations and dose levels and ranged from approximately 20 to 26 hours 
following single dose administration. Brigatinib was safe and well tolerated in 
healthy male and female Caucasian and Japanese subjects in this study after single 
PO dose administration of 90, 120, and 180 mg. 
 
Based on these single-dose PK findings, the PK of brigatinib appears to be similar 
between Japanese and Caucasian subjects. 
 
Preliminary Food-Effect Study (Study AP26113-13-103) 
The objective of this randomized, open-label study was to rule out a clinically 
significant food effect by assessing the effect of high-fat conditions on the PK and 
relative bioavailability of brigatinib as compared to fasting conditions. This study was 
designed to be a preliminary food-effect assessment intended to guide further 
development of brigatinib. Healthy male or female (of non-childbearing potential) 
adult subjects were eligible for study participation. Doses were administered in the 
fasting state or after the completion of a standard high-fat meal. Ten healthy subjects 
were enrolled (evaluable for safety) and 8 subjects were considered evaluable for all 
PK comparisons. Single PO doses of brigatinib 180 mg (6 x 30 mg tablets) were 


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administered on Day 1 and subjects remained at the research site until at least 96 
hours postdose (Day 4). 
 
When administered under fasting conditions, the median (range) time to reach first 
Cmax (Tmax) for brigatinib was 2.5 hours (range: 1 to 6 hours) after intake of the 
180 mg brigatinib dose. After administration following a high-fat meal, median 
(range) Tmax was 6 hours (range: 1 to 8 hours). GeoMean Cmax for the fasted and 
high-fat regimens were 804.5 ng/mL and 612 ng/mL, respectively, representing a 
24% decrease under fed conditions. Importantly, GeoMean AUC0-∞ values for the 
fasted and high-fat regimens were similar at 15607 h•ng/mL and 15488 h•ng/mL, 
respectively.The limits of the 90% CIs of the estimated GeoMean ratios of Cmax 
(67.766, 85.401) did not fall within the 80% to 125% margin, suggesting the 
presence of an effect of food on  brigatinib absorption. However, the limits of the 
90% CIs of the estimated GeoMean ratios for both AUC0-∞ (88.163, 113.479) and 
AUC0-t (88.086, 107.147) fell within the 80% to 125% margins required to support 
the absence of a clinically relevant effect of food intake on brigatinib PK. 
 
Brigatinib was well tolerated in healthy subjects under both fasted and fed conditions. 
 
[14C]ADME Study (Study AP26113-13-104) 
This was an open-label, non-randomized, mass balance study performed in 6 
healthy male subjects to investigate the absorption, metabolism, and excretion of 
brigatinib. On Day 1, each subject received a single 180 mg PO dose of 
[14C]brigatinib (approximately 100 µCi). Serial PK sampling (blood, urine, feces) 
and safety assessments were conducted up to 216 hours postdose (morning of Day 
10) or until the release criterion was met.[14C]radioactivity concentrations in 
plasma above the detectable level were observed up to 96 hours postdose in all 6 
subjects, and in 4 of 6 subjects at 120 hours postdose. Brigatinib plasma 
concentrations were observed up to 240 hours postdose in all 6 subjects and in 5 of 
the 6 subjects who were still in the study at 264 hours postdose. Plasma brigatinib 
concentrations closely followed the plasma radioactivity concentrations. GeoMean 
plasma Cmax for both total radioactivity and brigatinib was approximately 1,000 
ng/mL (Cmax for [14C]brigatinib equivalents was 7.6% higher than Cmax for 
brigatinib), and the median Tmax was 2 hours. The GeoMean exposure to total 
radioactivity in terms of AUC0-t and AUC0-∞ was close to approximately 20,000 
h•ng/mL and only marginally higher (3.5% and 6.4% higher, respectively), than the 
values for brigatinib. The respective exposure PK parameter values (Cmax, Tmax, 
AUC) in plasma were very similar for brigatinib and TRA, indicating that 
concentrations of metabolites, if any, were negligible compared to those of 
brigatinib. The mean (±SD) total recovery of the administered radioactivity was 
89.75±1.44%, of which 24.99±1.89% and 64.76±2.36% were recovered in urine and 
feces, respectively, indicating that feces was the major route of excretion of dosed 
[14C]brigatinib, although urinary excretion also contributed to drug elimination. 
Most of the radioactivity (approximately 80% of the dose) had been recovered by 
120 hours postdose. 
 
Following PO administration of [14C]brigatinib, parent brigatinib was the major 
circulating radioactive component accounting for 91.5% of the plasma radioactivity. 


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AP26123 was the principal metabolite observed and was present at 3.5% in the 
plasma. No other metabolites greater than 2% of the total plasma radioactivity were 
observed. Similarly in 0 to 240 hours pooled urine, parent brigatinib was the major 
species observed (85.57%) with AP26123 being the sole metabolite detected 
(6.17%). The major radioactive component in 0 to 240 hours pooled feces was 
brigatinib, accounting for 40.91% of the fecal TRA. Metabolites identified in feces 
were M36 (N-desmethyl brigatinib; AP26123), M28 (brigatinib cysteine conjugate), 
M25 (brigatinib N-oxide; AP32830), and M27 (monooxy-brigatinib), accounting for 
39.13%, 14.03%, 1.04%, and 0.59% of the fecal TRA, respectively. 
 
Overall, the metabolism of brigatinib in humans was qualitatively similar to 
nonclinical toxicology species (rat and monkey) with no unique human metabolites 
observed. 
 
A single 180 mg PO dose of [14C]brigatinib was safe and well tolerated in the 
healthy male subjects in this study. 
 
DDI Study of Brigatinib with Gemfibrozil, Rifampin, and Itraconazole (Study 
AP26113-15-105) 
In vitro studies demonstrated that brigatinib is primarily metabolized by CYP2C8 
and CYP3A4, and is a substrate of the efflux transporter P-gp. This study was 
conducted to determine whether strong inhibitors of CYP2C8 or CYP3A4 
(gemfibrozil and itraconazole, respectively) and a strong inducer of both enzymes, 
as well as P-gp, (rifampin) alter the single dose PK of brigatinib in healthy subjects.  
 
This was a single-center, 3-part, open-label, single-dose, 1-sequence, crossover study 
evaluating the effects of gemfibrozil (Part 1), rifampin (Part 2), and itraconazole 
(Part 3) on brigatinib PK in healthy subjects. In each part of the study, subjects 
received a single PO dose of brigatinib indose-proportional relationship treatment 
period 1. In treatment period 2, subjects were pretreated with the CYP inhibitor or 
inducer for either 4 or 6 days prior to co-administration with brigatinib.  
Subjects received the following treatments: 
• 
Part 1:  Gemfibrozil DDI Study Treatment period 1: 90 mg brigatinib.  
Treatment period 2: 600 mg gemfibrozil twice daily (BID) + 90 mg brigatinib. 
• 
Part 2:  Rifampin DDI Study Treatment period 1: 180 mg brigatinib.  
Treatment period 2: 600 mg rifampin QD + 180 mg brigatinib. 
• 
Part 3:  Itraconazole DDI Study Treatment period 1: 90 mg brigatinib. Treatment 
period 2: 200 mg itraconazole BID + 90 mg brigatinib. 
 
Subjects received the single doses of brigatinib following an overnight fast of at 
least 10 hours at approximately the same time on each dosing day. During treatment 
period 2, the CYP inducer or inhibitor was administered first for either 4 or 6 days, 
followed by co-administration with brigatinib. A washout period of at least 16 days 
between brigatinib doses was implemented and blood samples for brigatinib plasma 
PK characterization were collected for at least 120 hours following each brigatinib 
dose for all 3 study parts. 


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Part 1 Gemfibrozil DDI Study 
Twenty healthy subjects were enrolled in Part 1 of the study and received at least 1 
dose of the study drug in the treatment phase, and were included in the PK and 
safety populations. One subject was discontinued from the study due to vomiting 
within 4 hours of dosing in treatment period 2 and therefore, 19 subjects were 
evaluable for statistical PK comparisons. 
 
Median Tmax of brigatinib was similar for the 2 treatment periods. Compared with 
brigatinib administered alone, co-administration with gemfibrozil reduced the Cmax 
of brigatinib by 41% and the AUC0-∞ and AUC0-120 of brigatinib were decreased 
by 11.5% and 14.7%, respectively. The percent GeoMean ratio for Cmax was 
59.086% with a 90% CI of 53.847 to 64.835. The percent GeoMean ratios and 90% 
CI for AUC0-∞ and AUC0-120 were 88.469% (83.186, 94.088) and 85.339% 
(80.036, 90.993), respectively. 
 
Although exposure to brigatinib was reduced following gemfibrozil administration, 
the degree of decrease for each parameter is well within the typical observed 
interpatient PK variability for brigatinib in patients under SS conditions. Therefore, 
CYP2C8 does not appear to contribute meaningfully to the clearance of brigatinib 
in vivo. No dose modification is required for brigatinib during co-administration 
with strong CYP2C8 inhibitors. Single PO doses of 90 mg brigatinib alone and 
when co-administered with gemfibrozil were well tolerated. No deaths or serious 
adverse events (SAEs) occurred during the study. 
 
Part 2 Rifampin DDI Study 
Twenty healthy subjects were enrolled in Part 2 of the study and all subjects 
received at least 1 dose of the study drug in the treatment phase, and were included 
in the PK and safety populations. One subject was discontinued from the study due 
to elevated liver enzymes approximately 21 days after dosing in treatment period 2 
and therefore, 19 subjects were evaluable for statistical PK comparisons. 
Median Tmax of brigatinib was similar for both treatment periods. Compared with 
brigatinib administered alone, co-administration with rifampin reduced the Cmax of 
brigatinib by 59.5%; AUC0-∞ and AUC0-120 were decreased by 80.4% and 80.0%, 
respectively. The percent GeoMean ratio for Cmax was 40.478% with 90% CI 
(36.833, 44.484). The GeoMean ratios and 90% CI for AUC0-∞ and AUC0-120  
were 19.582% (18.151, 21.127) and 20.021% (18.562, 21.594), respectively. 
 
Co-administration of multiple 600 mg daily doses of rifampin with a single 180 mg 
brigatinib dose resulted in a statistically significant decrease in brigatinib Cmax by 
59.5%. A 5-fold higher apparent oral clearance after extravascular administration, 
calculated using the observed value of the last quantifiable concentration (CL/F) of  
brigatinib was observed, and brigatinib AUC0-∞ and AUC0-120 were decreased by 
80.4% and 80.0%, respectively, relative to a single 180 mg brigatinib dose given 
alone. Therefore, the concomitant use of strong and moderate CYP3A inducers with 
brigatinib should be avoided. Single PO doses of 180 mg brigatinib alone and when 
co-administered with rifampin were well tolerated. No deaths or serious AEs 
occurred during Part 2 of the study. 


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Part 3 Itraconazole DDI Study 
Twenty healthy subjects were enrolled in Part 3 of the study and all subjects 
received at least 2 doses of study drug and completed the treatment phase, and were 
included in the PK and safety populations. 
 
The median Tmax of brigatinib was similar for the 2 treatments. Compared with 
brigatinib administered alone, co-administration with itraconazole resulted in an 
increase in brigatinib Cmax. The GeoMean ratio for brigatinib Cmax was 121.165% 
with an associated 90% CI of 113.318 to 129.554. AUC0-∞ and AUC0-120 GeoMean 
ratios (90% CI) were 201.165% (183.917, 220.030) and 182.069% (171.579, 
193.201), demonstrating increases by 101.2% and 82.1 respectively, in the presence 
of itraconazole. The t½ of brigatinib was prolonged from 30 to 45   hours in the 
presence of itraconazole. 
 
Itraconazole, a strong CYP3A4 and a P-gp inhibitor, had a moderate effect on the 
PK of brigatinib. Co-administration of multiple 200 mg BID doses of itraconazole 
with a single 90 mg brigatinib dose resulted in a statistically significant increase in 
brigatinib Cmax by 21.2%. A 2-fold decrease in CL/F of brigatinib was observed 
and brigatinib AUC0-∞ and AUC0-120 were increased by brigatinib dose given 
alone. Accordingly, the concomitant use of strong CYP3A inhibitors with brigatinib 
should be avoided. If concomitant use of strong CYP3A inhibitors cannot be 
avoided, the dose of brigatinib should be reduced by approximately 50% (ie, from 
180 mg to 90 mg or from 90 mg to 60 mg considering the available tablet 
strengths). After discontinuation of a strong CYP3A inhibitor, the brigatinib dose 
that was tolerated prior to the initiation of the strong CYP3A inhibitor should be 
resumed.Single PO doses of 90 mg brigatinib alone and when co-administered with 
itraconazole were well tolerated. No deaths or SAEs occurred during Part 3 of the 
study, and no subject was discontinued from the study due to an AE.101.2% (2- 
fold) and 82.1% (<2-fold), respectively, relative to a single 90 mg 
 
Hepatic Impairment Study (Study AP26113-15-107) 
This study is an open-label, single-dose, parallel-group, inpatient, non-randomized 
study conducted in patients with chronic hepatic impairment and matched healthy 
subjects. A total of approximately 27 participants will be enrolled into the study, 
including 18 patients with hepatic impairment (6 each with Child-Pugh classes  A, B, 
and C) and approximately 9 matched healthy controls. Patients with hepatic 
impairment will be matched with healthy subjects by age, sex, body mass index 
(BMI), and, if possible, smoking habits. Each participant will receive a single 90 mg 
PO dose of brigatinib in the morning of study Day 1 under fasting conditions and 
will remain in the clinic to complete PK sampling through 192 hours. This study is 
ongoing. 
 
Renal Impairment Study (Study AP26113-15-108) 
This study is an open-label, parallel-group, inpatient, non-randomized, single-dose 
study conducted in patients with severe renal impairment and matched healthy 
subjects with normal renal function Approximately 8 subjects with severe renal 


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impairment are planned to be enrolled along with 8 matched healthy subjects with 
normal renal function. Patients with renal impairment will be matched to the 
greatest extent possible with healthy subjects by age, sex, BMI and, if possible, 
smoking habits. Each participant will receive a single 90 mg PO dose of brigatinib 
in the morning of study Day 1 under fasting conditions and will remain in the clinic 
to complete blood and urine PK sampling through 168 hours. This study is ongoing. 
 
Pivotal Food-Effect Study (Study AP26113-16-109) 
Study AP26113-16-109 was conducted to provide a definitive assessment of the 
effect of a high-fat meal on the PK of a single PO dose of brigatinib, administered 
using the commercial 90 mg tablet formulation, in healthy subjects. This was a 
single-dose, randomized, open-label, 2-period, 2-sequence crossover study in healthy 
subjects. Single PO doses of brigatinib 180 mg (2 x 90 mg tablets) were 
administered after consumption of a high-fat meal or under fasting conditions. Each 
study drug administration was separated by a washout interval of at least  
16 days. PK blood samples were collected and safety assessments were conducted 
at designated time points from predose until 168 hours postdose. 
 
A total of 24 subjects were randomized and were administered at least 1 dose of 
study drug and were included in the safety and PK populations. Three subjects were 
discontinued from the study prior to treatment period 2; therefore, 21 subjects 
completed the study and are included in the final statistical analyses. Two subjects 
were withdrawn early due to positive breath carbon monoxide test results; and 1 
subject was withdrawn early due to noncompliance with clinic rules. 
 
Median brigatinib Tmax was 2 hours after dosing brigatinib 180 mg in the fasted 
state and 5.0 hours after dosing brigatinib in the fed state. The observed GeoMean 
Cmax was approximately 13% lower after dosing in the fed state (604.6 ng/mL) 
than after dosing in the fasted state (701.3 ng/mL). GeoMean values for AUC0-t 
were similar for both fasted and fed treatments (13054 h•ng/mL and 12742 h•ng/mL 
after dosing in the fasted and fed states, respectively). GeoMean values for AUC0-∞ 
were similar after dosing in the fasted state and fed state (13261 h•ng/mL and 12944 
h•ng/mL, respectively).The results of the analyses conducted to evaluate the effect of 
a high-fat meal on brigatinib Cmax, AUC0-t, and AUC0-∞, demonstrated that the 
limits of the 90% CI of the estimated mean ratio of AUC0-t (89.396, 107.399) and 
AUC0-∞ (89.430, 107.386) fell within the 80% to 125% margins, but the lower 
bound of the 90% CI for Cmax (78.261, 96.752) fell below the 80% lower margin 
required to conclude BE between the fasted and fed treatments, with food intake 
reducing the GeoMean Cmax (estimated mean ratio was 87.016%) by  
approximately 13%. Brigatinib median Tmax was delayed by 3 hours after dosing 
in the fed state compared to the fasted state. Overall, the observed 13% decrease in 
plasma Cmax following a high-fat meal was small relative to typical variability in 
Cmax observed for brigatinib in patients under SS conditions (approximately 60% 
CV). Without a corresponding decrease in AUC when brigatinib is administered with 
a high-fat meal, these changes in Cmax are not considered to be clinically important 
for the safety and efficacy of brigatinib. 
 
Therefore, brigatinib may be administered without regard to food intake. 


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Concentration-QTc Analysis 
Electrocardiogram (ECG) and time-matched PK data were available from a subset  
of the 137 patients enrolled in Study AP26113-11-101. Specifically, a total of 110 
patients administered brigatinib doses ranging from 30 mg to 240 mg QD 
contributed PK time -matched ECG data to this concentration-QTc analysis, with 29 
patients receiving the recommended 90 mg to 180 mg QD dose regimen. Therefore, 
data over a wide concentration range, including concentrations higher than those 
observed with the recommended dose regimen, contributed to the analysis, and 
brigatinib had no clinically significant effect on cardiac repolarization as assessed 
by concentration-QTc analysis. The one-sided upper 95% confidence bound of the 
predicted change from baseline in QTc corrected by Fridericia's formula (QTcF) 
was -4.7 milliseconds 
 
Phase 2 Study AP26113-13-201 (ALTA) 
This is a pivotal phase 2, randomized, multicenter, international study of brigatinib 
in patients with ALK+ NSCLC who previously progressed on crizotinib. A total of 
222 patients were randomized 1:1 to receive brigatinib in 1 of 2 different dosing 
regimens: (A) 90 mg QD, continuously, or (B) 90 mg QD for 7 days, then 180 mg 
QD, continuously (90 mg to180 mg QD). For both treatment regimens, dose 
modifications (dose interruptions, dose reductions) were allowed. Eligible patients 
had histologically or cytologically confirmed locally advanced or metastatic 
NSCLC with documented ALK rearrangement by a positive result from the Vysis® 
ALK. Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or 
documented ALK positivity by a different test and tissue available for the Vysis® 
FISH test to be performed centrally. Patients were required to have progressive 
disease (PD) while on crizotinib. The first patient was randomized in June 2014 
and the last patient was randomized in September 2015. Treatment and follow up 
are ongoing. The primary endpoint of this study was confirmed ORR as assessed 
by the investigator, per RECIST, Version 1.1. Secondary endpoints include 
confirmed ORR as assessed by a central IRC; CNS response assessed by an IRC 
(ORR and PFS in patients who had active brain metastases); time to response; 
DOR; time on treatment; disease control rate (DCR); PFS; OS; safety and 
tolerability; SS plasma level of brigatinib for use in population PK modeling; and 
patient-reported symptoms of lung cancer and health-related quality of life scores, 
assessed with the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ-C30, Version 3.0). The study is 
being conducted at approximately 100 study centers in 18 countries in North 
America, Europe, Asia, and Australia. Overall, 222 patients were enrolled into the 
study in 18 countries; 105 patients at 38 sites in 12 countries in Europe (Austria, 
Belgium, Denmark, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, 
Switzerland, and the United Kingdom); 68 patients at 17 sites in 4 countries in the 
Asian Pacific region (Australia, Hong Kong, Republic of South Korea, and 
Singapore); and 49 patients at 16 sites in North America (Canada and US). 
 
Overall, the median age was 54.0 years (range: 18 to 82); over half the patients 
were female (56.8%, 126/222), while 23.5% were ≥65 years. At baseline, the 
ECOG performance status was 2 for 7.2% (16/222) of all patients (6.3% [7/112] in 
Arm A and 8.2% [9/110] in Arm B). The NSCLC histopathological classification 


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was adenocarcinoma for the majority (96.8% [215/222]) of all patients (95.5% 
[107/112] in Arm A and 98.2% [108/112] in Arm B). The majority of patients had 
a local or centrally confirmed ALK Vysis FISH test result (89.2% [198/222] of all 
patients; 89.3% [100/112] in Arm A and 89.1% [98/110] in Arm B). Crizotinib  
was the most recent prior systemic therapy at baseline for 95.9% (213/222) of all 
patients (95.5% [107/112] in Arm A and 96.4% [106/110] in Arm B). 
 
The best response to the prior crizotinib therapy was a partial response (PR) for 
60.8% (135/222) of all patients (58.0% [65/112] in Arm A and 63.6% [70/110] in 
Arm B), and 3.2% (7/222) of all patients had achieved a complete response (CR) 
with crizotinib (4.5% [5/112] in Arm A and 1.8% [2/110] in Arm B). The majority 
of patients had received prior chemotherapy (73.9% [164/222] of all patients; 
74.1% [83/112] in Arm A and 73.6% [81/110] in Arm B) and prior platinum-based 
chemotherapy (73.4% [163/222] of all patients; 74.1% [83/112] in Arm A and 
72.7% [80/110] in Arm B). Brain metastases at baseline, as assessed by the 
investigator, were present in 69.4% (154/222) of all patients (71.4% [80/112] in 
Arm A and 67.3% [74/110] in Arm B) 
 
Objective response rate 
The investigator-assessed confirmed ORR was 45.5% (51/112) of patients in Arm 
A and 55.5% (61/110) of patients in Arm B. The best overall response was a 
confirmed PR for 43.8% (49/112) of patients in Arm A and 50.9% (56/110) of 
patients in Arm B, and a confirmed CR for 1.8% (2/112) of patients in Arm A and 
4.5% (5/110) of patients in Arm B. 
 
Prospectively defined criteria for efficacy stated that a treatment regimen will be 
considered to have achieved the primary objective when the investigator-assessed 
ORR is shown to be significantly higher than 20% at a two-sided alpha level of 
0.025 at the primary analysis for that regimen; the lower limit of the 97.5% CI rules 
out an alternate rate of 20% when the true rate is 35% or higher. Therefore, these 
prospectively defined criteria for efficacy were met (the lower limit of the 97.5% 
CI exceeds 20%) with statistical significance for investigator-assessed ORR in both 
arms: 45.5% for Arm A (97.5% CI: 34.8, 56.5) and 55.5% for Arm B (97.5% CI: 
44.3, 66.2). The IRC-assessed confirmed ORR was 50.9% (57/112) of patients in 
Arm A and 54.5% (60/110) of patients in Arm B. IRC-assessed confirmed CR was 
observed in 5.4% (6/112) of patients in Arm A and 5.5% (6/110) of patients in Arm 
B 
 
Progression-free survival 
Investigator-assessed PFS in the ITT population is presented in Figure XX. Median 
(KM estimate) for investigator-assessed PFS was 9.2 months (95% CI: 7.4, 11.1) 
in Arm A and 15.6 months (95% CI: 11.1, 19.4) in Arm B. In Arms A and B, 
73/112 (65%) and 55/110 (50%) events have been observed, respectively. The 
hazard ratio observed between the two arms is 0.64 (95% CI: 0.45, 0.91). Median 
(KM estimate) for IRC-assessed PFS was 9.2 months (95% CI: 7.4, 12.8) in Arm 
A and 16.7 months (95% CI: 11.6, NE) in Arm B. In Arms A and B, 60/112 
(53.6%) and 45/110 (40.9%) events have been observed, respectively. The hazard 
rat in between the two arms is 0.69 (95% CI: 0.47, 1.02). 
 


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Overall survival 
OS by arm is shown in Figure 5.n. Median OS has not been reached in Arm A 
(95% CI: 20.2, NE) and is 27.6 months (95% CI 27.6, NE) in Arm B, with 42/112 
(37.5%) and 32/110 (29.1%) events observed in Arm A and Arm B, respectively. 
The hazard ratio observed between the 2 arms is 0.67 (95% CI: 0.42, 1.06). 
 
CNS Efficacy 
To evaluate the potential for brigatinib anti-tumor activity in the CNS, an additional 
IRC assessment was performed to assess efficacy endpoints in the intracranial CNS 
in randomized patients with active brain metastases assessed by MRI at enrollment. 
Contrast -enhanced brain MRI scans were analyzed by neuroradiologists in an 
independent central review. The reviewers were blinded to investigator assessment 
and treatment assignment. Up to 5 measurable brain metastases could be chosen as 
target lesions by the independent reviewers. Response in patients with at least 1 
measurable brain lesion (≥10 mm) was defined as a ≥30% decrease in the sum of 
the longest diameters of target lesions and nonprogression in non-target lesions. 
Response in patients with only nonmeasureable brain metastases was defined as 
disappearance of all lesions (CR). 
 
Of the 222 patients in the ITT population, 217 patients had baseline MRI scans of the 
brain read by IRC, and 153 patients had brain metastases identified by IRC at 
baseline. 
• 
44 patients with measurable lesions; of which, 34 patients had at least 1 
active brain metastasis at baseline identified by the investigator (with ‘active’ 
defined as no prior history of radiation to the brain or clear progression after local 
radiotherapy). 
• 
109 patients had only nonmeasureable lesions at baseline; of which, 67 
patients who had a least 1 active brain metastasis at baseline identified by the 
investigator. 
 
The IRC database extraction included a last scan date of 28 February 2017 for all 
patients with brain metastases at baseline and 24 January 2017 for patients with 
measurable brain metastases at baseline. 
 
Intracranial ORR 
Patients with Measureable Brain Metastases at Baseline 
At this database extraction, the IRC-assessed confirmed intracranial ORR was 
50.0% (13/26) for patients in Arm A and 66.7% (12/18) for patients in Arm B for 
patients with measurable brain metastases at baseline. Confirmed intracranial CR 
was the best response for 7.7% (2/26) of patients in Arm A and for no patients 
(0/18) in Arm B. Confirmed intracranial PR was the best response for 42.3% 
(11/26) of patients in Arm A and 66.7% (12/18) of patients in Arm B. 
 
The intracranial DCR for patients with measureable brain metastases at baseline 
was 84.6% (22/26) of patients in Arm A and 83.3% (15/18) of patients in Arm B. 
 
Patients with Only Nonmeasurable Brain Metastases at Baseline 
For patients with only non-measureable brain metastases at baseline, intracranial 


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ORR was observed in 7.4% (4/54) of patients in Arm A and 18.2% (10/55) of 
patients in Arm B. Intracranial response for patients with only non-measureable 
brain metastases is defined for purposes of this study as complete radiographic 
disappearance of lesions and is the only response possible for patients with only 
non-measureable lesions. 
 
The intracranial DCR for patients with non-measureable brain metastases at 
baseline was 74.1% (40/54) of patients in Arm A and 87.3% (48/55) of patients in 
Arm B. 
 
Phase 2 Study AP26113-13-201 (ALTA) Safety 
TEAEs that occurred in >20% of patients overall were nausea (42.5%), diarrhea 
(35.6%), cough (34.2%), headache (32.9%), vomiting (32.9%), fatigue (27.9%), 
dyspnea (25.6%), blood creatine phosphokinase (CPK) increased (25.6%), 
decreased appetite (24.7%), hypertension (22.4%), and constipation (21.0%). The 
most common TEAE in both Arm A and Arm B was nausea (occurring in 37.6% 
and 47.3% of patients, respectively). 
 
Grade ≥3 TEAEs and Treatment-Related Grade ≥3 TEAEs 
Treatment-emergent AEs Grade ≥3 occurred in 62.1% (136/219) of patients 
overall and in similar proportions in Arm A and in Arm B (58.7% [64/109] and 
65.5% [72/110], respectively). Treatment-emergent AEs Grade ≥3 by PT 
(occurring in ≥2% of all patients) that occurred in a greater proportion (≥50% 
relative increase) of patients in Arm A than in Arm B were neoplasm progression 
(15.6% [17/109] vs 7.3% [8/110], respectively), lipase increased (4.6% [5/109] vs 
3.6% [4/110], respectively), and neutrophil count decreased (3.7% [4/109] vs  
1.8% [2/110], respectively); and a greater proportion (≥50% relative increase) of 
patients in Arm B than in Arm A were blood CPK increased (12.7% [14/110] vs 
4.6% [5/109], respectively). 
The most common treatment-related TEAE Grade ≥3 in Arm A was lipase 
increased and hypertension (3.7% [4/109] for each) and in Arm B was blood CPK 
increased (10.9% [12/110]). A greater proportion (≥50% relative increase) of 
patients in Arm B than in Arm A had blood CPK increased (10.9% [12/110] vs 
2.8% [3/109], respectively), pneumonitis (3.6% [4/110] vs 1.8% [2/109], 
respectively), and rash (3.6% [4/110] vs 0.9% [1/109], respectively). No treatment- 
related TEAEs Grade ≥3 occurring in ≥2% of all patients occurred in a greater 
proportion (≥50% relative increase) of patients in Arm A than in Arm B. 
 
Overall, 49.8% (109/219) of patients experienced a treatment-emergent AEs (TEAE) 
that led to dose interruption of any duration. A greater proportion of patients in Arm 
B than in Arm A had a TEAE that led to dose interruption (59.1% [65/110] vs 40.4% 
[44/109], respectively). The TEAEs occurring in ≥3% of patients overall by PT that 
led to dose interruption were blood CPK increased (5.5% [12/219]), pneumonitis 
(4.6% [10/219]), neoplasm progression (4.1% [9/219]), lipase increased (3.2% 
[7/219]) and vomiting (3.2% [7/219]). The most common TEAEs that led to dose 
interruption in Arm A were neoplasm progression, vomiting, and pyrexia; in Arm B, 
the most comment TEAEs that led to dose interruption were blood CPK increased, 
pneumonitis, rash, and lipase increased. 


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TEAEs that led to dose reduction occurred in 9.2% (10/109) of patients in Arm A 
and 30.0% (33/110) of patients in Arm B. The only TEAE leading to dose 
reduction that occurred in ≥2% of patients overall by PT was blood CPK increased 
(4.1% [9/219]), which occurred in 1.8% (2/109) of patients in Arm A and 6.4% 
(7/110) of patients in Arm B. 
 
TEAEs that led to discontinuation of brigatinib occurred in 7.3% (16/219) of 
patients overall, 3.7% (4/109) of patients in Arm A and 10.9% (12/110) of patients 
in Arm B. A greater proportion (≥50% relative increase) of patients in Arm B than 
in Arm A had a TEAE that led to brigatinib discontinuation (10.9% [12/110] vs 
3.7% [4/109], respectively). The most common TEAE (occurring in ≥2 patients 
overall) that led to brigatinib discontinuation by PT were pneumonitis (1.8% 
[4/219]), neoplasm progression (0.9% [2/219]), and pneumonia (0.9% [2/219]). 
 
Specific adverse events of clinical importance 
Early Onset Pulmonary Event (EOPE) 
As of a database extraction date of 21 February 2017, out of 219 treated patients, 4 
patient cases were determined to meet the criteria for definite EOPE, and 10 cases 
met the criteria for possible EOPE. In total, 14 of 219 (6.4%) patients overall had 
an event that was at least possibly an EOPE. All EOPEs occurred at a dose of 90 
mg QD, regardless of arm (ie, within the first 7 days of treatment in Arm B). No 
EOPEs were identified after escalation to 180 mg QD in Arm B. Median time of 
onset of EOPE was Day 2 (range: 1 to 9). Of the 14 patients who had an EOPE 
(Arm A: 5/109 [4.6%] and Arm B: 9/110 [8.2%]), all occurred while patients were 
receiving brigatinib 90 mg QD. 
 
Eleven EOPE patient cases included SAEs, and 3 EOPE patient cases included  
only nonserious events. Seven (3.2%) patients had events that were Grade 1 or 2 
only. Seven (3.2%) patients had events that were Grade ≥3, all of whom 
permanently discontinued brigatinib after the EOPE. There were 6 patients who 
had an EOPE with highest Grade of 3 or 4 (pneumonitis [n=4], radiation 
pneumonitis [n=1], pneumonia [n=1]). One patient (Patient 615-002) had a possible 
EOPE that was Grade 5. This patient developed pneumonia Grade 5 after taking 
brigatinib for 7 days (90 mg QD at event onset). At autopsy, microscopic 
examination revealed widespread dissemination of lung cancer, with spread to the 
paratracheal lymph nodes and left half of the chest, and lymphangitis 
carcinomatosis in the right lung. Additionally, histological changes in the right lung 
were compatible with diffuse alveolar damage, which indicated acute respiratory 
distress syndrome. Although the patient’s lung cancer and infection were 
considered to be underlying causes of death, a contribution of brigatinib  could not 
be ruled out, and this case was considered a possible EOPE given the association of 
events within 7 days of the start of brigatinib, as well as evidence for a 
pneumonitis-like process. 
 
In 7 of 14 (50.0%) patients experiencing EOPE, brigatinib was permanently 
discontinued after the EOPE (including the fatal case). All 7 patients who 
permanently discontinued had Grade ≥3 events. In 6 of 14 cases, brigatinib was 
interrupted and successfully resumed after resolution of the pulmonary event. In 1 


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of these 6 cases (Patient 588-001), brigatinib was continued during the event, with 
interruption for 1 day prior to escalating to 180 mg QD, and the events resolved. In 
1 of 14 patient cases (Patient 590-003), the brigatinib dose was reduced to 60 mg 
QD without an interruption and the event resolved. Events resolved with dose 
interruption or brigatinib discontinuation (drug withdrawn). Steroids and antibiotics 
were administered in 11 of 14 (78.6%) and 4 of 14 (28.6%) patient cases, 
respectively. There were 7 patients who successfully resumed brigatinib or 
continued administration through the pulmonary event; 2 of the patients had a 
confirmed PR and 5 of the patients had stable disease as best response. 
 
Later-Onset Pneumonitis Events 
Five patients each experienced a single later-onset pneumonitis event. Four of these 
occurred with the most recent dose being 180 mg QD, and 1 occurred at a dose of 
90 mg QD. In 3 cases, brigatinib was successfully restarted without recurrence of 
pneumonitis. In 1 case, the patient had already permanently discontinued due to 
progression of disease. In the last case, the patient permanently discontinued 
brigatinib due to the event 
 
Bradycardia 
Bradycardia TEAEs of any grade occurred in 5.5% (12/219) of patients overall 
(Arm A: 6.4% [7/109] and Arm B: 4.5% [5/110]). Sinus bradycardia and 
bradycardia TEAEs occurred in 3.7% (8/219) and 1.8% (4/219) of patients overall, 
respectively. None of the bradycardia events were Grade ≥3. There were no dose 
reductions or treatment discontinuations due to bradycardia. 
 
Hypertension 
Hypertension TEAEs of any grade occurred in 22.4% (49/219) of patients overall 
(CSR AP26113-13-201 Table 14.3.3.4). Hypertension TEAEs were reported in a 
greater proportion of patients in Arm B than in Arm A (27.3% [30/110] vs 17.4% 
[19/109], respectively). Grade 3 hypertension TEAEs occurred in 6.8% (15/219) of 
patients overall; 5.5% (6/109) and 8.2% (9/110) of patients in Arm A and Arm B, 
respectively (CSR AP26113-13-201 Table 14.7.2.2). No Grade 4 hypertension has 
been reported. One patient in Arm A had retinopathy hypertensive. One patient in 
each arm (0.9%) had a dose reduction due to hypertension. No patient discontinued 
brigatinib due to hypertension. 
 
Elevated Insulin/Hyperglycemia Events 
Elevated insulin/hyperglycemia TEAEs of any grade occurred in 5.5% (6/109) in 
Arm A and 11.8% (13/110) in Arm B. The elevated insulin/hyperglycemia events 
that occurred in >2 patients in either treatment arm by PT were hyperglycemia 
(3.7% [4/109] of patients in Arm A and 5.5% [6/110] of patients in Arm B) and 
diabetes mellitus (0.9% [1/109] of patients in Arm A and 4.5% [5/110] of patients 
in Arm B). Elevated insulin/hyperglycemia events Grade ≥3 occurred in only 1 
patient; this patient had a Grade 3 event of diabetes mellitus (which was also 
present in the previous 31 May 2016 data extraction) (Study AP26113-13-201 
Table 14.3.7.2.7). No patients have had dose reduction or treatment 
discontinuation due to increased insulin/hyperglycemia TEAEs. 
 


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Pancreatic Events 
Pancreatic TEAEs based on laboratory elevations (pancreatic enzyme elevations) of 
any grade occurred in 20.5% (45/219) of patients overall. No patients experienced 
clinical pancreatitis. A greater proportion of patients in Arm B than in Arm A had 
pancreatic events of any grade (24.5% [27/110] vs 16.5% [18/109], respectively). 
Pancreatic events Grade ≥3 occurred in 5.9% of patients overall (Arm A: 5.5%   
[6/109] and Arm B: 6.4% [7/110]) (Study AP26113-13-201 Table 14.3.7.5.6). 
Amylase increased led to dose reduction in 0.9% of patients overall (1 patient in  
each arm). Lipase increased led to dose reduction in 0.9% of patients (1/109) in  
Arm A and 1.8% of patients (2/110) in Arm B. No patients discontinued treatment 
due to TEAEs of lipase increased or amylase increased. 
 
Hepatic Events 
Hepatic TEAEs of any grade occurred in 21.9% (48/219) of patients overall, and 
occurred in 19.3% (21/109) of patients in Arm A and in 24.5% (27/110) of patients 
in Arm B. The most common hepatic events that occurred in >2 patients overall by 
PT were AST increased (15.1% [33/219] of patients overall; 10.1% [11/109] in Arm 
A and 20.0% [22/110] in Arm B) and ALT increased (12.8% [28/219] of patients 
overall;  10.1% [11/109] in Arm A and 15.5% [17/110] in Arm B). Grade 3 to 4 ALT 
increased TEAEs occurred in 3 patients (all in Arm B; 2.7%) and Grade 3 to 4 AST 
increased TEAEs occurred in 2 patients (both in Arm; 1.8%) (Study AP26113-13-
201 Table 14.3.7.3.8). One patient had a dose reduction due to a hepatic event. No 
patient discontinued treatment due to a hepatic event. There were no TEAEs of 
clinical hepatic failure, and no patients satisfied the laboratory criteria threshold for  
a possible Hy’s Law case. 
 
Vision Impairment Events 
Vision impairment events of any grade occurred in 15.1% (33/219) of patients 
overall (Arm A: 11.0% [12/109] and Arm B: 19.1% [21/110]). The most common 
vision impairment event by PT in patients overall was vision blurred (5.0% 
[11/219]), which occurred in in a higher number of patient in Arm B compared with 
Arm A (7.3% [8/110] and 2.8% [3/109], respectively). Two patients had Grade 3 
vision impairment events (macular oedema and cataract). Two patients have had a 
dose reduction due to vision impairment TEAEs (macular oedema, retinal oedema). 
No patients have discontinued treatment due to vision impairment TEAEs. 
 
1.4 
Rationale 
A significant population of ALK+ NSCLC patients exist that have progressed on or 
who were intolerant of next generation ALK inhibitor (e.g. ceritinib or alectinib). 
Brigatinib has demonstrated activity in patients who have progressed on crizotinib,  
but the activity of brigatinib in patients who have progressed on ceritinib, alectinib,  
or other next generation ALK inhibitors is unknown. Based on the preclinical data 
summarized in section 1.3, brigatinib has potent activity against known secondary 
ALK mutations suggesting it may retain activity as third-line treatment of ALK+ 
disease. 
 
Patients enrolled must have previously received a next generation ALK inhibitor 
other than brigatinib. Given that third-line treatment of ALK+ disease is analogous  
to a phase I population, we have chosen 20% as a clinically meaningful response  


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rate that would justify further study of brigatinib in previously treated ALK+  
disease. The recent data on brigatinib’s activity in the central nervous system (CNS) 
provides additional rationale for study of this drug in refractory disease. We have 
elected to use the dose regimen (90mg PO QD for 7 days followed by 180mg PO  
QD continuously) from the above ongoing randomized Phase II trial of brigatinib as 
second-line treatment for cohorts A and B. For cohort C we have chosen the dose of 
240 mg daily based on the phase I/II trial, and the fact all patients will have tolerated 
brigatinib at 180 mg daily. 
 
1.5 
Correlative Studies to Explore Mechanisms of Resistance 
The mechanisms of resistance to ALK inhibitors is an active area of investigation, 
and multiple mechanisms have been identified including ALK kinase domain 
mutations, ALK copy number gain, acquisition of oncogenic driver mutations and 
activation of the EGFR pathway. A substantial proportion of patients do not have  
an identifiable molecular mechanism of resistance. In a case series of 18 patients who 
underwent biopsy after experiencing disease progression on crizotinib, four patients 
had a mutation within the ALK tyrosine kinase domain and an additional patient had 
amplification of the ALK fusion gene.(Katayama et al. 2012)  Other mechanisms of 
resistance identified include amplification of KIT and increased auto- 
phosphorylation of EGFR suggesting activation of the EGFR pathway as a 
mechanism of resistance.  
 
A similar case series of 11 patients identified secondary mutations in the tyrosine 
kinase domain (n=4), ALK copy number gain (n=2; one patient also demonstrated 
an ALK resistance mutation), KRAS mutation (n=2; one without the evidence of the 
original ALK rearrangement), EGFR mutation without evidence of a persistent ALK 
rearrangement (n=1), and ALK rearrangement negative (n=1).(Doebele et al. 2012) 
ALK secondary resistance mutations are identified in approximately 30% of 
patients after crizotinib, and include 1151Tins, C1156Y, L1196M, S 1206Y and 
G1269A.(Gainor et al. 2016) Tumor specimens from patients who received 
crizotinib or next generation ALK inhibitors were analyzed.  In patients who 
received crizotinib ALK resistance mutations were identified in 20% of specimens, 
and ALK amplification (defined as ALK/centromere 2 ratio of > 2.0) was observed 
in 8% (none of which had an ALK resistance mutation). In contrast an ALK 
resistance mutation was observed in 54% of the specimens of patients with disease 
progression on ceritinib, and 53% of specimens of patients with disease progression 
on alectinib. Collectively, these data suggest the rate of ALK resistance mutations is 
higher after next-generation ALK inhibitors and the most common resistance 
mutation is the G1202R. 
 
No association between ALK resistance mechanism and ceritinib response was 
observed in the initial trial but the number of patients with a known mutation was 
small (n=19).(Shaw et al. 2014) Preclinical models suggest that different ALK 
inhibitors have differing degrees of activity depending on the resistance mutation. 
Ceritinib has activity against the L1196M, G1296A, I1171T and S1206Y, but not 
against the ALK secondary mutations C1156Y, 1151Tins, G1202R and 
F1174C.(Friboulet et al. 2014)  Patients treated with ceritinib have developed 
resistance mutations in G1202R or F1174. Patients previously treated with alectinib 
have been shown to develop V1180L and I1171T resistance mutations.22 Ceritinib 


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demonstrated activity against the V1180L and I1171T mutations, brigatinib 
demonstrated activity against the V1180L mutation but less activity against the 
I1171T, and ASP3026 was active against V1180L and inactive against the I1171T 
mutation.(Katayama et al. 2014) Thus, ALK tyrosine kinase inhibitors may have 
differing level of clinical activity depending on the resistance mutation. None of the 
previous studies are definitive, but they suggest that an understanding of the molecular 
mechanisms of resistance at the time of initiating a new ALK inhibitor will be 
important in assessing the clinical activity of an ALK inhibitor. 
 
In this study, pre-treatment tumor samples will undergo next generation sequencing 
to explore for an association between mutation presence or absence and type of 
mutation as well as other mechanisms of resistance and response to brigatinib. 
Tumor samples at progression will be used to identify resistance mutations after 
brigatinib. Participation in the biopsy at the time of progression on brigatinib is 
optional since biopsies may not be feasible, patients may not be candidates for 
further therapy, or patients may need to proceed to the next line of therapy in an 
expedited time frame. 
 
There is increasing interest in detecting oncogenic mutations in ctDNA obtained 
from peripheral blood samples.(Oxnard et al. 2014; Cui et al. 2017; Newman et al. 
2014; Wang et al. 2016) This will also be explored in the present study. The overall 
sensitivity, specificity, and accuracy of capture-based NGS of ctDNA was 54%, 
100%, and 72%, respectively. Of 13 ALK positive samples were identified by 
capture-based NGS among 24 samples with positive tumor samples for ALK. An 
additional study revealed a sensitivity and specificity was 79% and 100%, 
respectively. ALK rearrangements were successfully detected in 19 of 24 patients. 
Crizotinib resistance mutations were detected from a single patient. While the focus 
has been on the detection of ALK resistance mutations it is important to note the ALK 
resistance mutations are detected in approximately 50% of patients with progressive 
disease on next-generation ALK inhibitors and there is a need to identify other 
mechanisms of resistance. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Estimate ORR (rate of CR+PR) of brigatinib in patients with ALK+ NSCLC who 
have progressed on next generation ALK inhibitors 
 
2.2 
Secondary Objectives 
2.2.1 
Further characterize treatment-related adverse events associated with 
brigatinib including at different doses in patients with ALK+ NSCLC 
 
2.2.2 
Estimate duration of response in patients with ALK+ NSCLC 
treated with brigatinib who have progressed after prior ALK 
inhibition 
 
2.2.3 
Estimate PFS in patients with ALK+ NSCLC treated with brigatinib who 
have progressed after prior ALK inhibition 


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2.2.4 
Estimate intracranial and extra-cranial PFS in patients with ALK+ 
NSCLC treated with brigatinib who have progressed after prior ALK 
inhibition 
 
2.2.5 
Estimate OS in patients with ALK+ NSCLC treated with brigatinib 
who have progressed after prior ALK inhibition 
 
2.3 
Exploratory Objectives 
 
2.3.1 
Explore association between presence and/or type of mutation or 
mechanism of resistance at baseline and efficacy outcomes (ORR and PFS) 
 
2.3.2 
Identify resistance mutations or other mechanisms of resistance after 
brigatinib by evaluating tumor samples at time of progression 
 
2.3.3 
Explore whether ctDNA from peripheral blood samples can identify 
development of resistance mutations 
 
2.3.4 
Estimate intracranial ORR in patients with ALK+ NSCLC treated  
with brigatinib who have progressed after prior ALK inhibition who  
have measurable CNS disease at baseline 
 
2.4 
Primary Endpoint 
ORR as determined by RECIST 1.1 as assessed by the investigator 
 
2.5 
Secondary Endpoints 
 
2.5.1 
The treatment-related adverse events will be assessed using the 
NCI CTCAE version 4.0 as assessed by the investigator. 
 
2.5.2 
Duration of response is measured from the time measurement criteria are 
first met for CR/PR (whichever is first recorded) until the first date of 
progression 
 
2.5.3 
PFS with progression events as per RECIST 1.1 and as assessed by the 
investigator; PFS is defined from day 1 of treatment until progression 
of disease (either intracranial or extracranial) or death as a result of any 
cause 
 
2.5.4 
Intracranial PFS is defined from day 1 of treatment until intracranial 
progression of disease or death as a result of any cause; extracranial PFS 
is defined from day 1 of treatment until extracranial progression of 
disease or death as a result of any cause. Only patients with brain 
metastases at baseline will be included in this analysis 
 
2.5.5 
OS is defined from day 1 of treatment until death as a result of any cause 
 
2.5.6 
Intracranial ORR as determined by RECIST 1.1 as assessed by the 
investigator 


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3.0 
PATIENT ELIGIBILITY 
Patients must meet all of the following inclusion criteria to participate in this study: 
 
3.1 
Inclusion Criteria for all cohorts 
 
3.1.1 
Locally advanced or metastatic NSCLC that has been cytologically or 
histologically confirmed 
 
3.1.2 
ALK positive status based on Clinical Laboratory Improvement 
Amendments (CLIA) or test approved for use in Canada. Diagnostic 
test may be based on ctDNA testing or based in tumor testing 
 
3.1.3 
ECOG PS ≤2 
 
3.1.4 
Age of ≥ 18 years 
 
3.1.5 
Brain lesions may be used as target lesions if progressing, ≥10mm 
in longest diameter and if they were not previously treated with any 
of the following: 
• Whole brain radiation therapy (WBRT) within 3 months 
• Stereotactic radiosurgery (SRS) 
• Surgical resection 
 
3.1.6 
Availability of core biopsy of progressive lesion taken within 60 days 
prior to D1 of treatment under study therapy or willing to undergo 
tumor biopsy: NOTE:  All subjects must consent to provide tumor 
blocks or slides. 
• If archival tissue is not available and biopsies to obtain fresh tumor 
tissue cannot be performed with minimal risk to the subject, subjects 
may be permitted to enroll on the study with prior approval of the 
Study PI. 
• In the situation the patient undergoes biopsy within 60 days prior to D1 
and there is insufficient tumor tissue for the correlative science part of 
the protocol, the patient will be permitted to enroll on the study with 
prior approval of the study PI 
• In the situation the patient undergoes molecular testing or next-
generation sequencing as part of standard care there must be sufficient 
tumor sample available for participation in the study (i.e. a next 
generation sequencing report is not sufficient for enrollment) 
 
3.1.7 
Recovered from toxicities related to prior anticancer treatment to ≤Grade 2 
or baseline with the exception of alopecia 
 
3.1.8 
Have normal QT interval on ECG evaluation QT corrected Fridericia 
(QTcF) of  ≤ 450 ms in males or ≤ 470 ms in females 
 


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3.1.9 
Adequate organ function defined as: 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥75,000/µL 
Hemoglobin 
≥ 10g/dL 
AST /ALT 
≤ 2.5 x upper limit of normal (ULN); 
≤ 5 x ULN if liver metastasis 
Total serum bilirubin 
≤ 1.5 x ULN 
Serum creatinine 
≤ 1.5 x UNL 
Serum amylase 
≤ 1.5 x UNL 
 
3.1.10 At least 1 measurable lesion per RECIST version 1.1 
 
3.1.11 Female patients who: 
• Are postmenopausal for at least 1 year before the screening visit, OR 
• Are surgically sterile, OR 
• If they are of childbearing potential, agree to practice 2 effective 
methods of contraception, 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 completely abstain from heterosexual intercourse. 
(Oral and implantable contraceptives are not considered effective 
forms of contraception for study purposes. See Appendix C (auxiliary 
patient document)). 
• Women of child-bearing potential (WOCBP) must have a negative 
serum pregnancy test within 7 days of D1 of treatment. 
 
3.1.12 Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: 
• Agree to practice effective barrier contraception during the entire study 
treatment period and through 4 months after the last dose of study 
drug, or 
• Agree to completely abstain from heterosexual intercourse 
 
3.1.13 Ability to provide signed informed consent and willing and able to comply 
with all study requirements. 
 
3.2 
Inclusion criteria for cohort assignment 
3.2.1 
Cohort A: Progressive disease on any next generation ALK inhibitor 
except first line alectinib alone (eligible for study but assigned to cohort B) 
or brigatinib (any line). Patients who received previous therapy with 
lorlatinib will be assigned to cohort A. 
 
3.2.2 
Cohort B: Progressive disease on first-line therapy with alectinib, and no 
other ALK inhibitors 
 
3.2.3 
Cohort C: Previous treatment brigatinib at 180 mg daily for ≥4 weeks 
without > grade 2 drug-related toxicities and with radiographic evidence of 


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progressive disease and no intervening systemic therapies such as 
chemotherapy, immunotherapy or another ALK inhibitor (radiation therapy 
allowed as intervening therapy).  
 
3.2.4 
Patients who are treated on cohorts A and B will be allowed to enroll in 
cohort C if they meet the inclusion and exclusion criteria. Patients are 
required to undergo a biopsy before enrollment in cohort C. Patients who 
change cohorts from A or B to cohort C should not have  EOT assessments  
completed and do not discontinue brigatinib, and should complete a new 
registration form and will be given a new subject number 
 
3.3 
Exclusion Criteria for cohorts A, B, and C 
Patients meeting any of the following exclusion criteria will not be able to 
participate in this study: 
3.3.1 
History or the presence of pulmonary interstitial disease, drug-related or 
immune-related pneumonitis, or radiation pneumonitis requiring medical 
management within 6 months of trial enrollment 
 
3.3.2 
Prior treatment with brigatinib for cohorts A and B 
 
3.3.3 
History of or active significant gastrointestinal (GI) bleeding within 3 months 
 
3.3.4 
Malabsorption syndrome or other GI illness that could affect oral absorption 
of the study drug 
 
3.3.5 
Received cytotoxic chemotherapy, investigational agents or radiation within 
7 days prior to D1 of study treatment 
 
3.3.6 
Received prior ALK TKI therapy within 7 days prior to D1 of treatment 
under study drug. 7 day wash out period is required after prior ALK 
inhibitor treatment for cohorts A and B. Patients enrolling in cohort C should 
continue brigatinib and 7 day wash out is not required). 
 
3.3.7 
Have significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to: 
• Myocardial infarction (MI) within 6 months of trial enrollment 
• Unstable angina within 6 months of trial enrollment 
• Congestive heart failure (CHF) with 6 months prior to trial enrollment 
• Any history of ventricular arrhythmia 
• Cerebrovascular accident or transient ischemic attack within 6 months of 
D1 of study treatment 
• Clinically significant atrial arrhythmia (as determined by the investigator) 
or severe baseline bradycardia defined as resting heart rate < 60 beat per 
minute 
• Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 100 on 
3 separate clinic visits or past history of hypertensive urgency, emergency, 
or encephalopathy 


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3.3.8 
Another primary malignancy for which the patient is currently receiving therapy 
 
3.3.9 
Have been diagnosed with another primary malignancy within the past 3 years 
(except for adequately treated non-melanoma skin cancer, cervical cancer in 
situ, or prostate cancer, which are allowed within 3 years) 
 
3.3.10 Have symptomatic CNS metastases which require an increasing dose of 
corticosteroids within the last 2 weeks to remain asymptomatic. 
 
3.3.11 Have active infection requiring intravenous antibiotics 
 
3.3.12 Pregnant or breastfeeding 
 
3.3.13 Have any condition or illness that, in the opinion of the investigator, would 
compromise patient safety or interfere with evaluation of the study drug. 
 
 
4.0 
TREATMENT PLAN 
4.1 
Schema for cohorts A and B 
 
 
 
 
 
4.2 
Schema for cohort C 
 
 
 
 
 


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4.3 
Treatment Dosage and Administration 
4.3.1 Cohorts A and B 
Brigatinib will be administered at a dose of 90 mg (3 by 30 mg tablets) orally  
once a day (QD) for the first 7 days of cycle 1 followed by 180 mg (6 by 30 mg 
tablets) orally once a day continuously thereafter. NOTE: during cycle 1,  
patients will be seen on D8 to determine if dose escalation to 180mg is  
appropriate (see section 4.3.1 and 4.3.2. Should drug formulation change, 
equivalent doses in smaller numbers of capsules may be substituted to reduce 
patient pill burden in any cohort. 
 
A cycle of therapy will comprise 28 days of treatment, regardless of dose.  
Patients will be instructed to take the prescribed dose with water (recommended 
240 mL(8 oz)) at the same time each day, and without regard to food intake. 
Patients who forget to take their scheduled dose of study drug should be  
instructed not to make up the missed dose. Patients who vomit immediately after 
taking a dose should be instructed NOT to retake the dose. All doses should be 
recorded in the patient diary, with a notation made by the patient if any dose is 
missed, or if a dose is vomited. 
 
4.3.2 Cohort C 
Brigatinib will be administered at 240 mg daily (8 by 30 mg tablets). A cycle of 
therapy will comprise 28 days of treatment, regardless of dose. Patients will be 
instructed to take the prescribed dose with water [recommended 240 mL (8 oz)]  
at the same time each day, and without regard to food intake. Patients who forget  
to take their scheduled dose of study drug should be instructed not to make up  
the missed dose. Patients who vomit immediately after taking a dose should be 
instructed NOT to retake the dose. All doses should be recorded in the patient  
diary, with a notation made by the patient if any dose is missed, or if a dose is 
vomited. 
4.4 
Toxicities and Dosing Delays/Dose Modifications for cohorts A and B 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed periodically for the development of any AE 
according to the Time and Events table (Section 6.0). AE will be assessed 
according to the NCI CTCAE v4 for 30 days after dosing is completed. Of note, 
monitoring for signs of liver or vision dysfunction, monitoring serum levels of 
testosterone is recommended due to the safety profile of the ALK inhibitor 
crizotinib. 
 
Missed doses of brigatinib will be omitted and not made up. Unless otherwise noted  
in the tables below, treatment may be interrupted ≤ 2 weeks for any reason. If 
treatment is interrupted ≤ 2 weeks, subjects will proceed with treatment at the dose 
level recommended according to the tables below. In the event that brigatinib  
dosing is interrupted, the duration of cycle/treatment will not be extended. 
Therefore, if treatment is delayed on D1 of a cycle due to toxicity, and the patient  
does not begin therapy until D5 (for example), the start date of drug for that cycle  
remains D5, not D1 If treatment is delayed >2 weeks, then the patient should be  
discontinued from protocol mandated therapy and followed-up per protocol. 


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4.4.1 
Non-Hematologic Treatment-Related AEs during Brigatinib 90mg 
Daily 7 day lead-in other than Pneumonitis 
 
Grade1 
Dose Modification 
Criteria for Dose Escalation 
 
1 
Continue 90mg daily 
Escalate to 180 mg daily D8 as 
scheduled 
2 
(≤ 3 days) 
Continue 90mg daily 
If AE returns to ≤ Grade 1 or 
baseline at D8, escalate to 180mg 
daily on D8 
2 
(≥ 3 days despite 
optimal 
supportive care) 
Hold until event is ≤ Grade 1 or 
returned to baseline, then resume 
90mg daily 
If no recurrence of Grade 2 AE after 
90 mg daily for 7 days, escalate to 
120 mg daily. Do NOT escalate to 
180 mg daily. If recurrence of Grade 
2 after 90mg daily, do NOT escalate 
dose. 
3 
Hold until event is Grade ≤ 1 or 
has returned to baseline, then 
resume at 90mg daily 
Do NOT escalate dose 
4 
Hold until event is Grade ≤ 1 or 
has returned to baseline, then 
resume at 60 mg daily. 
Do NOT escalate dose 
1Per NCI CTCAE v4.0 
 
 
4.4.2 Hematologic Treatment-Related AEs during Brigatinib 90mg 
Daily 7 day lead-in 
 
Grade1 
Dose Modification 
Criteria for Dose Escalation 
1 or 2 
Continue 90mg daily 
Escalate to 180 mg daily D8 as 
scheduled 
3 or 4 
Hold until event is ≤ Grade 2 or returned 
to baseline, then resume 90mg daily 
Do NOT escalate dose 
1Per NCI CTCAE v4.0 
 
 
4.4.3 Non-Hematologic Treatment-Related AEs during Brigatinib 
180mg Daily other than Pneumonitis 
 
Grade1 
Dose Modification 
1 or 2 
Continue current dose 


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3 
• 
When the current dose is 180 mg QD: Hold until event is grade ≤ 1, 
or has returned to baseline. Resume at 180 mg QD or 120 mg QD at 
the discretion of the investigator 
• 
Upon recurrence at 180 mg QD: Hold until event is grade ≤ 1, or 
has returned to baseline and resume at 120 mg QD 
• 
When the current dose is 120 mg QD: Hold until event is ≤Grade 1, 
or has returned to baseline. Resume at 90 mg QD after recovery 
• 
When the current dose is 90 mg QD: Hold until event is ≤Grade 1, 
or has returned to baseline. Resume at 60 mg QD after recovery, or 
discontinue at the discretion of the Investigator. 
• 
When the current dose is 60 mg QD: Consider discontinuing 
treatment at the discretion of investigator 
4 
• 
When the current dose is 180 mg QD: Hold until event is grade ≤ 1, 
or has returned to baseline. Resume at 120 mg QD, or discontinue, 
at the discretion of the investigator 
 
• 
When the current dose is 120 mg QD, hold until event is grade ≤ 
2, or has returned to baseline. Resume at 90 mg QD after recovery 
• 
When the current dose is 90 mg QD: Hold until event is grade ≤ 1, 
or has returned to baseline. Resume at 60 mg QD after recovery, or 
discontinue at the discretion of the Investigator 
• 
When the current dose is 60 mg QD: Consider discontinuing 
treatment at the discretion of investigator 
1Per NCI CTCAE v4.0 
 
 
 
 
 
4.4.4 Hematologic Treatment-Related AEs during Brigatinib 180mg Daily 
 
Grade1 
Dose Modification 
1 or 2 
Continue at same dose 


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3 
• 
When the current dose is 180 mg QD: hold until event is grade ≤ 
2, or has returned to baseline. Resume at 180 mg or 120 mg QD at 
the discretion of the investigator 
• 
Upon recurrence at 180 mg QD: Hold until event is grade ≤ 2, or 
has returned to baseline. Resume at 120 mg QD 
• 
When the current dose is 120 mg QD: Hold until event is grade ≤ 
2, or has returned to baseline. Resume at 90 mg QD 
• 
When the current dose is 90 mg QD: Hold until event is grade ≤ 1, 
or has returned to baseline. Resume at 60 mg QD after recovery, 
or discontinue at the discretion of the investigator 
• 
When the current dose is 60 mg QD: Consider discontinuing 
treatment 
4 
• 
When the current dose is 180 mg QD: Hold until event is grade ≤ 
2, or has returned to baseline. Resume at 120 mg QD after 
recovery 
• 
When the current dose is 120 mg QD, hold until event is grade ≤ 
2, or has returned to baseline. Resume at 90 mg QD after recovery 
• 
When the current dose is 90 mg QD: Hold until event is ≤Grade 1, 
or has returned to baseline. Resume at 60 mg QD after recovery, 
or discontinue at the discretion of the Investigator 
• 
When the current dose is 60 mg QD Consider discontinuing 
treatment 
1Per NCI CTCAE v4.0 
 
4.4.5 Treatment-Related Pneumonitis during Brigatinib 90mg Daily 7 day lead-in 
 
Grade1 
Recommended Action 
1 
• 
Withhold the dose until pneumonitis returns to grade 0 (baseline), then 
resume at 90 mg and do not escalate. 
• 
If pneumonitis recurs, permanently discontinue treatment. 
2 
• 
Withhold dose until pneumonitis returns to grade 0, then resume at 60 
mg and do not escalate. 
• 
If pneumonitis recurs, permanently discontinue treatment. 
3 or 4 
Permanently discontinue treatment 
1Per NCI CTCAE v4.0 
 
 
 


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4.4.6 Treatment-Related Pneumonitis during Brigatinib 180mg Daily 
Grade1 
Recommended Action 
1 
• 
Withhold the dose until pneumonitis returns to grade 0 (baseline), then 
resume at same dose. 
• 
If pneumonitis recurs, permanently discontinue treatment. 
2 
• 
Withhold dose until pneumonitis returns to grade 0, then resume at 
120 mg QD. 
• 
If pneumonitis recurs, permanently discontinue treatment. 
3 or 4 
Permanently discontinue treatment 
1Per NCI CTCAE v4.0 
 
 
 
4.5 
Toxicities and dose modifications for cohort C 
 
Patients on cohort C will have tolerated brigatinib 180 mg daily and experienced 
disease progression. Patients will receive 240 mg daily. Since the purpose of this 
cohort is to investigate doses of brigatinib at dose greater than 180 mg daily and 
patients have experienced disease progression on that dose, dose reduction to 180 
mg daily will not be permitted. One cycle is 28 days. 
 
Dose level 
Brigatinib dose 
Schedule 
1 
240 mg 
Daily 
 
 
Brigatinib Dose Modification Recommendations for patients with for pneumonitis 
for cohort C 
 
Toxicity 
Grade per 
CTCAE v4.0 
Recommended Action 
Grade 1 
Withhold the dose until pneumonitis returns to grade 0 (baseline), then 
resume at the same dose. 
If pneumonitis recurs, permanently discontinue treatment. 
Grade 2 
Withhold the dose until pneumonitis returns to Grade 0. Resume at 240 
mg daily 
If pneumonitis recurs or remains grade ≥ 1, permanently discontinue 
treatment. 
Grade 3 
Permanently discontinue treatment. 
Grade 4 
Permanently discontinue treatment. 
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; QD=once 
daily 


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Brigatinib Dose Modification Recommendations for TRAEs (Excluding Pneumonitis) 
for cohort C 
 
Toxicity Grade 
per CTCAE v4.0 
Recommended Action* 
Hematologic Toxicity 
Grade 1 or Grade 2 
Continue at current dose 
Grade 3 
First grade AE: Hold until event is ≤ grade 1, or has returned to 
baseline 
If grade 3 AE for < 7 days then resume therapy at 240 mg daily. If 
second grade 3 hematologic toxicity occurs then discontinue 
brigatinib 
If grade 3 AE for ≥ 7 days then discontinue study therapy 
Grade 4 
Discontinue study therapy 
Nonhematologic Toxicity 
Grade 1 or Grade 2 
Manage the toxicity with supportive care while continuing at the 
same dose 
Grade 3 
First grade AE: Hold until event is ≤ grade 1, or has returned to 
baseline 
If grade 3 AE for < 7 days then resume therapy at 240 mg daily. If 
second grade 3 non-hematologic toxicity occurs then discontinue 
brigatinib 
If grade 3 AE for ≥ 7 days then discontinue study therapy 
Grade 4 
Discontinue study therapy 
Bradycardia (heart rate less than 60 bpm) 
Grade 1 
Continue at current dose 
Grade 2 or Grade 3 
Withhold until recovery to ≤ grade 1 or to heart rate 60 bpm or 
above 
Evaluate concomitant medications known to cause bradycardia, as 
well as antihypertensive medications 
If contributing concomitant medication is identified and 
discontinued, or its dose is adjusted, resume at previous dose upon 
recover to ≤ grade 1 or to heart rate 60 bpm or above 
If no contributing concomitant medication is identified, or if 
contributing concomitant medications are not discontinued then 
discontinue study therapy 
Grade 4 
Discontinue treatment if no contributing concomitant medication is 
identified 
 
 
 


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Toxicity Grade 
per CTCAE v4.0 
Recommended Action* 
* Apply these recommendations after either dose escalation was accomplished, or after 
dose reduction for grade 3 or grade 4 toxicity was implemented resulting in no dose 
escalation. 
Abbreviations: bpm=beats/minute; CTCAE=Common Terminology Criteria for Adverse 
Events; QD=once daily 
 
 
4.6 
Concomitant Medications/Juices/Herbal Supplements 
Patients may receive standard supportive care at the discretion of investigator (i.e. 
anti-emetics, bisphosphonates, narcotics for pain control, etc.). 
 
In vitro studies suggest that brigatinib, at the doses being evaluated clinically, is 
unlikely to inhibit CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. Thus, drug 
interactions (DDIs) due to inhibition of CYPs by brigatinib are highly unlikely. 
However, other medications that inhibit CYPs may cause DDIs because of their 
impact on brigatinib’s metabolism as outlined in section 1.3.9 and management is 
outlined in section 4.6.3. 
 
4.7 
Prohibited Palliative Radiotherapy 
Patients who require palliative radiotherapy for symptomatic or asymptomatic 
metastases will be considered as experiencing disease progression as per Section 
4.5 and will be followed up per protocol. 
 
Patients on cohort A or B who receive local ablative therapies such as radiation to 
sites of oligo-and/or isolated CNS progression should be considered for cohort C. 
 
4.8 
Prohibited Systemic Therapy 
Patients cannot receive systemic therapy (i.e. chemotherapy or targeted therapy) 
while on protocol therapy. 
 
4.9 
Prohibited Medications/Juices/Herbal Supplements 
See section 1.3.9 for rationale of why use of concomitant medications that fall into 
the following categories are prohibited: medications/juices/herbal supplements  
that are strong or moderate inducers or strong inhibitors of CYP3A4. Please refer 
to Appendix C (see as auxiliary patient document). 
 
4.10 
Duration of Therapy 
Patients should continue on protocol therapy until one of the following events: 
• Disease progression 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Pregnancy 
• Patient decides to withdraw from study treatment, OR 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 


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4.11 
Duration of Follow Up 
Long-term follow up will occur every 3 months from the last administration of 
protocol-directed therapy for up to 2 years or until death, whichever occurs first. 
Subsequent therapy and survival status will be documented. NOTE: follow-up 
may occur via review of medical records, on-site visits are not required. 
 
4.12 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.5 apply. The reason for discontinuation of protocol 
therapy will be documented on the eCRF. 
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
Treatment or withdraws consent”) the patient should be asked if she or he may 
still be contacted for further scheduled study assessments. The outcome of that 
discussion should be documented in both the medical records and in the eCRF. 
Excessive patient withdrawals from protocol therapy or from the study can 
render the study un-interpretable; therefore, unnecessary withdrawal of  
patients should be avoided. 
 
4.13 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. The investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as 
completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the patient’s study withdrawal should be made with an 
explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an adverse event, the principal specific 
event will be recorded on the eCRF. 
5.0 
DRUG INFORMATION 
5.1 
Investigational Agent Description and Management 
 
5.1.1 
Description and Characteristics of Drug 
Brigatinib is a novel, orally active, small molecule tyrosine kinase inhibitor 
(TKI). Brigatinib drug substance is isolated in crystalline form as a free base. 
Brigatinib has a melting point of 214°C (determined by differential scanning 
calorimetry [DSC]). The aqueous solubility of brigatinib is pH-dependent (e.g., at 
a pH of approximately 2.4, aqueous solubility is > 300 mg/mL, and at a pH of 
approximately 7.2, aqueous solubility is 11 mg/mL). Brigatinib does not contain 
any chiral centers. 
 
5.1.2 
Formulation 
Brigatinib drug product is supplied as film-coated tablets, which contain 
brigatinib active pharmaceutical ingredient (please refer to pharmacy manual). 
All strengths are dose-weight proportional and manufactured with a common-
blend including typical pharmaceutical excipients (lactose monohydrate, 


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microcrystalline cellulose, sodium starch glycolate, hydrophobic colloidal silica, 
magnesium stearate); tablet film-coating is comprised of typical pharmaceutical 
grade coating components (talc, polyethylene glycol, polyvinyl alcohol, titanium 
dioxide). 
 
The drug product is manufactured under Current Good Manufacturing Practice 
(cGMP) in accordance with approved procedures. 
 
5.1.3 
Supplier, Storage and Stability 
Brigatinib will be provided at no cost to the study patient by Takeda 
Pharmaceuticals Inc., the manufacturer of the drug. Takeda will ship the drug to 
the main study center. Brigatinib will be supplied in white high density 
polyethylene (HDPE) bottles with induction sealed caps. Bottle labels will bear 
the appropriate label text as required by governing regulatory agencies. At a 
minimum, such text will include product name, product strength, number of 
tablets, lot number, and use by dating. The recommended storage condition for 
brigatinib is under 30°C. It should not be refrigerated or frozen. 
 
5.1.4 
Handling and Disposal 
Brigatinib should be handled using standard precautions for the safe handling of 
antineoplastic agents. Latex gloves are recommended. It must be dispensed only 
from official study sites by authorized personnel according to local regulations, 
and stored in a secure area according to local regulations. It is the responsibility  
of the investigator to ensure that study drug is only dispensed to eligible study 
patients. 
 
The study pharmacist or designee at the site will be responsible for handling and 
dispensing study drug, and completing associated documentary paperwork. The 
site must use an appropriate dispensing log/accountability form. 
 
5.1.5 
Return and Retention of Study Drug 
All used bottles or blister packs of study drug must be returned to Takeda or 
destroyed in an appropriate manner according to the standard practice at each 
study center. Destruction of such supplies will be documented. During the study 
and at termination, patients must return all unused study drug supplies to their 
study site and the return of these unused study drug supplies must be recorded. 
Returned supplies must not be re-dispensed. 
 
5.1.6 
Management of Adverse Events of Note 
See section 6.1.2.1 of the Investigator’s Brochure for additional information on 
the safety of brigatinib. The study sponsor will be responsible for distributing the 
IB to all sites when a new version is released from Takeda. 
 
Pulmonary Symptoms 
Pulmonary events occurring within the first week of brigatinib treatment, 
including, but not limited to, dyspnea, hypoxia, dry cough, chest tightness, and 
presumptive lung infection (pneumonia) that may be accompanied by chest x-ray 
or CT findings of linear or ground-glass opacities should be monitored and 


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reported. In some patients, the symptoms resolved without drug interruption, dose 
modification, or specific intervention. This suggests that the pathogenesis and 
natural history of this condition may differ from later-onset pneumonitis, rarely 
observed with brigatinib, but described with other TKIs. Pulmonary events have 
been observed after a single dose of brigatinib in patients. It is possible that 
patients with pre-existing pulmonary interstitial disease, including lymphangitic 
involvement by tumor, may be at increased risk. Nonetheless, investigators must 
be aware that these pneumonitis-like symptoms may present within 24 hours of 
initial dosing. 
 
The management of these pulmonary events should include drug interruption, 
monitoring of oxygen saturation, and radiographic evaluation, and treatment with 
high-dose corticosteroids, supplemental oxygen therapy, and empiric antibiotics, 
as indicated. 
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 effect due to 
non-specific signs and symptoms as well as similar radiological appearance.  
Pneumonitis should be suspected when such signs and symptoms 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 O2 
saturation, and evaluation for infectious etiologies, and thoracentesis, 
bronchoscopy, or open lung biopsy should be considered to reach a diagnosis  
After dose interruption and symptom work-up, dose modification should be 
accomplished according to the recommendations in section 4.3.4 and 4.3.5 
(treatment-related pneumonitis). If the symptoms include documented hypoxia 
and/or radiologic evidence of interstitial or ground glass changes, or result in an 
SAE, the early onset condition should be treated according to section 4.3.4 and 
4.3.5 (treatment-related pneumonitis) 
Hypertension 
Brigatinib may result in elevations in BP (blood pressure, systolic or diastolic). 
During brigatinib treatment, BP should be regularly monitored and hypertension 
should be clinically managed. Brigatinib treatment might need to be temporarily 
interrupted if hypertension is not medically controlled. 
 
Bradycardia 
Treatment with brigatinib may result in bradycardia. An analysis of intensive ECG 
and PK data indicates a decrease in heart rate is associated with the timing of 
brigatinib maximum plasma concentrations (Cmax). During brigatinib treatment, 
heart rate should be monitored at each physician visit; especially in patients who 
have a medical history of bradycardia. 
 
 


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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
Assessment 
Screening 
1 
C1 
D11,2 
C1 
D8 2 
C2 
D11,2, 
14
C3 
D11,2 
C4 
D11,2, 
14 
C5 
D1 1,2 
C6 
D11,2 
C7 
D11,2 
C8 
D11,2, 
14 
C9 
D11,2 
C10 
D11,2, 
14 
C11 
D11,2 
C12 
D11,2 
EOT3 
FU4 
Informed consent12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Prior cancer 
therapy13  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam & 
vital signs5, 14 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differential6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistries7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Testosterone (males) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
Test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan 
chest/abdomen2 
X 
 
 
 
X2 
 
X2 
 
X2 
 
X2 
 
X2 
 
 
 
Brain MRI2 
X 
 
 
 
X2 
 
 
X2 
 
 
X2 
 
 
X2 
 
 
Peripheral blood 
sample9 
 
X9 
 
 
X9 
 
X9 
 
X9 
 
X9 
 
X9 
 
X9 
 
Tumor sample 
X10 
 
 
 
 
 
 
 
X10 
Adverse event 
assessment
5, 14
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Diary 
Provide11 Review Review Review Review Review Review Review Review Review Review Review Review Review 
Concomitant Meds 
Review 
Review Review Review Review Review Review Review Review Review Review Review Review Review Review 
Subsequent Therapy 
and Survival Status 
X 
Brigatinib 
 
See section 4.2 for brigatinib schedule and dose  


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Key to Footnotes 
 
1   Within 28 days prior to Day 1 of brigatinib unless otherwise noted. If screening (baseline) 
hematology and serum chemistries were performed within 7 days of D1 of cycle 1, these do 
not need to be repeated. 
 
2   Unless otherwise noted, a window of 2 days will be applied to all study visits; for every other 
cycle tumor imaging starting with D1 of cycle 3, imaging may take place within 7 days prior to 
the study visit to accommodate holiday, weekends, and transportation issues. CT scan should be 
of the chest and abdomen. The pelvis should only be performed if there is evidence on  
metastatic disease in the pelvis.  
 
Brain imaging MRI of the brain should be performed at baseline. In patients with known  
brain metastases MRI is performed every 3 cycles to assess for intracranial disease  
progression. Patients without brain metastases on screening MRI will undergo repeat  
brain imaging as clinically indicated or institutional standard (i.e. a specific interval is not 
mandated by the protocol). If patient cannot tolerate or has contraindication to brain  
MRI, a CT scan with and without contrast can be used. 
 
3   This visit should occur 30 days (+/- 3 days) after brigatinib treatment stops for whatever  
reason (adverse event, progression, or at discretion of the investigator). Patients who have  
an ongoing grade 4 AE or SAE at the time of discontinuation from treatment will be  
contacted every 2 weeks until the event is resolved, determined to be irreversible by the 
investigator, or until the patient begins an alternate form of treatment. For patients  
participating on cohorts A or B who are enrolled in cohort C this visit is omitted. 
 
4   Long-term follow up will occur every 3 months from the last administration of protocol- 
directed therapy for up to 2 years or until death, whichever occurs first. Subsequent therapy  
and survival status will be documented. NOTE: follow-up may occur via review of medical  
records, on-site visits are not required. 
 
5   Complete history at baseline only, thereafter focused history on symptoms/adverse  
event. Blood pressure and heart rate should be checked at each physician visit 
 
6   This includes CBC with differential and platelet count 
 
7   Serum chemistries include blood urea nitrogen (BUN), creatinine, bilirubin, ALT (SGPT),  
AST (SGOT), alkaline phosphatase, amylase, creatinine phosphokinase (CPK). Additional  
can be ordered if clinically indicated or at the discretion of the investigator but are not  
required by the protocol 
 
8   Within 7 days of D1 of treatment with brigatinib in women of child-bearing potential 
 
9   This blood sample will be used to explore whether resistance mutations can be detected in  
ctDNA; see laboratory manual for additional details. Sample is to be drawn on C1D1 and  
Day 1 of every odd cycle (3, 5, etc.) while patient is receiving treatment with brigatinib. 
 
10   Biopsy after progression on previous ALK inhibitor and within 60 days prior  
to D1 of treatment is mandatory (i.e., if tissue available from pre-study biopsy, this  


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tissue will be accessed for correlative studies, otherwise, patients must consent to  
tumor biopsy to meet eligibility criteria). All subjects must consent to provide tumor  
blocks or slides. Patients treated on cohorts A or B and enrolling in cohort C are required  
to undergo biopsy. 
 
Biopsy specimens and peripheral blood samples will be destroyed as per standard  
institutional procedures at the time study termination or may be stored for future research. 
Patients will be provided both options on the informed consent document. 
 
11   On C1D1 provide the patient diary for use. D1 of all subsequent cycles patient diary is  
to be collected from previous cycle, reviewed with the patient, and a new diary provided. 
 
12    Patients in cohort A and B are brigatinib treatment naïve and receiving brigatinib at a 
standard dose. Patients in cohort C will have progressed on brigatinib and will be 
receiving a higher than the standard dose brigatinib. Depending on the institutional  
practice and policies this may require patients on cohort C to sign a “post-progression”  
treatment informed consent document. 
 
13    Prior systemic therapy will be collected including number of prior ALK TKI’s and  
names, prior chemotherapy treatment. The sites of disease progression (CNS, extra-CNS or  
both) and if the patient received local therapy (e.g. radiation therapy, SBRT, etc.) to site of  
disease progression between disease progression and enrollment in study (i.e. disease  
progression in brain and lungs, brain metastases treated with SBRT and lungs metastases or 
primary not)  
 
14   Even day cycle visits not including Brain MRI imaging and are conducted (at treating 
physician’s discretion) as telemedicine visits will not include standard clinic assessments  
(i.e., symptoms/adverse event, blood pressure and heart rate). To maintain data integrity,  
these missed assessments are to be noted in the EDC as deviations (planned) and indicate  
that visit was conducted remotely. 
 
6.2 
Pre-Study Assessments 
The assessments required as part of screening can be completed in one or more  
visits, as long as the assessments are completed within the time frames listed in  
the Key to the Time and Events table. 
 
Clinical evaluation: complete history, comprehensive physical examination (to  
include height and weight), vital signs, ECOG performance status 
 
Laboratory studies: 
▪ Pregnancy Test: Serum pregnancy test is required for all women of 
childbearing potential within 7 days prior to D1 
▪ Hematology: CBC with differential 
▪ Serum Chemistries: blood urea nitrogen (BUN), creatinine, bilirubin,  
ALT (SGPT), AST (SGOT), alkaline phosphatase, amylase, creatinine 
phosphokinase (CPK) 
▪ Serum Testosterone: Limited to male patients  
 


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Cardiac studies: ECG 
 
Tumor measurement: Tumor imaging should remain consistent throughout study,  
and should always include CT scans of chest and abdomen. CT scan of the pelvis  
should only be done if there is known metastatic disease to the pelvis. Brain MRI  
should be done, and if the patient cannot tolerate or has contraindication to MRI a  
CT scan with and without contrast should be done. 
 
Concomitant medications: Documentation of all concomitant medications, and in 
particular any drugs that moderately or strongly inhibit or induce CYP3A4 and/or 
CYP2C8. NOTE: Patients will be instructed to bring their list of medications (all, 
including over the counter medications) to each study visit for review by their  
study team and for all visits to healthcare professionals (e.g., primary care  
physicians, consultants) while on study. 
 
Patient diary: Patients will be provided a diary at baseline and instructed to  
document all doses of study medication (referenced herein as Appendix B, see as 
independent IRB/REB approved (patient) document). 
 
Tissue acquisition: Tumor biopsy after progression on previous ALK inhibitor  
and within 60 days prior to study entry is mandatory i.e., if tissue available from  
pre-study biopsy, this tissue will be accessed for correlative studies, otherwise, 
patients must consent to tumor biopsy to meet eligibility criteria; see section 6.6  
and laboratory manual for additional details. If patients have undergone NGS  
testing, as part of standard of care, on tumor sample after experiencing disease 
progression on prior therapy and prior to starting study therapy we will collect  
redacted report. If not performed/unavailable, sites will note not performed/not  
available in the database.  
 
Prior cancer therapy: Prior systemic therapy will be collected including number  
of prior ALK TKI’s and names, prior chemotherapy treatment. The sites of  
disease progression (CNS, extra-CNS or both) and if the patient received local  
therapy (e.g. radiation therapy, SBRT, etc.) to site of disease progression  
between disease progression and enrollment in study (i.e. disease progression in 
brain and lungs, brain metastases treated with SBRT and lungs metastases or  
primary not) 
 
6.3 
Treatment Assessments 
 
6.3.1 
D1 each Cycle 
Tests and procedures in this Section 6.3.1 are to be conducted during each Day 1 cycle  
visit. Sections 6.3.3 and 6.3.4 include additional assessments to be conducted during  
each Day 1 at specific numbered cycle visit (e.g., odd cycles, each third cycle visit). 
 
Clinical evaluation: focused medical history on symptoms/adverse events,  
comprehensive physical examination (to include weight), vital signs, ECOG  
performance status 


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Laboratory studies: 
▪ Hematology: CBC with differential 
▪ Serum Chemistries: blood urea nitrogen (BUN), creatinine, bilirubin,  
ALT (SGPT), AST (SGOT), alkaline phosphatase, amylase, creatinine 
phosphokinase (CPK). 
▪ Blood sample: A blood sample for ctDNA will be requested (mandatory); 
see section 6.6 and the laboratory study for additional details. (Cycle 1 
Day 1 & Day 1 of every odd cycle- 3, 5, etc.). 
 
Patient diary: Collect, review with patient, and provide patient with new diary. 
(C1D1- provide patient with initial diary) 
Concomitant medications: Review any additions or deletions. 
 
AE: Adverse events will be assessed according to the NCI CTCAE v. 4.0. 
 
6.3.2 
D8 Cycle 1 
Clinical evaluation: focused medical history on symptoms/adverse events,  
Laboratory studies: 
▪ Hematology: CBC with differential 
▪ Serum Chemistries: blood urea nitrogen (BUN), creatinine, bilirubin, 
ALT (SGPT), AST (SGOT), alkaline phosphatase, amylase, creatinine 
phosphokinase (CPK) 
 
Patient diary: Review 
Concomitant medications: Review any additions or deletions. 
AE: Adverse events will be assessed according to the NCI CTCAE v. 4.0. 
 
6.3.3 
D1 Cycle 3 and every odd numbered cycle thereafter (Cycle 3, 5, 7, etc.) 
Tumor measurement: Tumor imaging should remain consistent throughout study, 
and should include CT scans of chest and abdomen. Pelvis should only be done if 
there is known metastatic disease in the pelvis.  
 
Laboratory studies: 
▪ Serum Testosterone: Male patients only 
Blood sample: A blood sample for ctDNA will be requested (mandatory); see 
section 6.6 and the laboratory study for additional details. 
 
6.3.4 
D1 Cycle 3 and every third cycle thereafter (Cycle 3, 6, 9, etc.) 
Brain metastases: Brain MRI or CT scan with or without contrast should be done 
every 3 cycles (3 months) for patients with known brain metastases to evaluated 
for CNS disease progression. 
6.3.5 
D1 Cycle 2 and each non-imaging even numbered cycle thereafter 
(Cycle 2, 4 or 8, etc.) 
The safety profile of the Study Drug is well-known at this point of this research 


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study and many patients may be demonstrating stable tolerance of the Study 
Drug. For these patients, at the treating physician’s discretion, even numbered 
cycle visits that do not include imaging procedures (i.e., CT scan, Brain MRI) 
may be conducted as telemedicine visits. When standard clinic assessments (i.e., 
symptoms/adverse event, blood pressure and heart rate) are not conducted, to 
maintain data integrity, these missed assessments are to be noted in the EDC as 
deviations (planned) and indicate that visit was conducted remotely. 
 
6.4 
EOT Visit 
This visit should occur 30 days (+/- 3 days) after brigatinib treatment stops for  
whatever reason (adverse event, progression, or at discretion of the investigator).  
Patients who have an ongoing grade 4 AE or SAE at the time of discontinuation  
from treatment will be contacted every 2 weeks until the event is resolved,  
determined to be irreversible by the investigator, or until the patient begins an  
alternate form of treatment. 
 
NOTE: The first EOT follow up visit is to be performed 30 days (+/- 3 days) after  
the date a participant receives the last dose of study drug. The date of the EOT visit  
will not match the date the last dose of study drug was administered and should be 
entered accordingly on the eCRF/EDC system.  
 
Clinical evaluation: focused medical history on symptoms/adverse events,  
comprehensive physical examination (to include weight), vital signs, ECOG  
performance status. 
 
Laboratory studies: 
▪ Hematology: CBC with differential 
▪ Serum Chemistries: blood urea nitrogen (BUN), creatinine, bilirubin, 
ALT (SGPT), AST (SGOT), alkaline phosphatase, amylase, creatinine 
phosphokinase (CPK) 
 
AE: Adverse events will be assessed according to the NCI CTCAE v. 4.0. All SAEs 
(see section 7.0) ongoing 30 days or more after last dose of study drug is administered 
should be followed at least every 4 weeks until they resolve to baseline (or CTCAE 
grade ≤1), stabilize, or are considered to be chronic/irreversible regardless of causality. 
See also section 7 for documentation of AEs/SARs, when applicable, for patients 
remaining in the study after transition from cohort A or B to cohort C. 
 
Concomitant medications: Review for any changes since previous visit. 
 
Tissue acquisition: At time of progression on study therapy, biopsy will be repeated 
in patients who consent to this optional biopsy; see section 6.6 and laboratory manual 
for additional details. 
 
Blood sample: A blood sample for ctDNA will be requested at time of progression on 
current therapy. Time of progression for cohort C means patient’s further progression 
(as indicated by CT scan) from their entry into cohort C); see section 6.6 and the 
laboratory study for additional details. 
 


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Cohort C: For patients enrolling in cohort C from cohorts A or B end of treatment 
is not required; however: 
• The EOT section of the eCRF form must still be completed; 
• To avoid repeating assessments, EOT (cohort A or B) and screening 
(cohort C) assessments (including CT scans, brain MRIs, etc.), 
reasonable efforts should be taken to perform these assessments as 
standard of care at EOT to be used for cohort C screening assessments;  
• Data relevant to each cohort’s participation in the study will be 
independent according to their cohort assignment and recorded on each 
applicable eCRF for (i.e., EOT for cohort A or B, screening for cohort C). 
• In the event of  active AE’s which continue past the subjects transition to 
cohort C, and continuing past the transition date, they are to be recorded 
under the new Subject number within the Medical History Log, to be 
updated upon change in AE. severity or status. 
 
 
6.5 
Post-Treatment/Follow-up Assessments 
Long-term follow up will occur every 3 months from the last administration of  
protocol-directed therapy for up to 2 years or until death, whichever occurs first. 
Subsequent therapy and survival status will be documented.  
Each cohort A, cohort B and cohort C participant’s follow-up data will be captured  
from their time of enrollment in the cohort (for up to 2 years, or until death, whichever 
occurs first).  
NOTE:  
• The first post-treatment follow-up is to be performed 30 days (+/- 3 days) 
after the date a participant receives the last dose of study drug.  
• The date of the EOT visit will not match the date the last dose of study 
drug was administered and should be entered accordingly on the 
eCRF/EDC system.  
• Follow-up may occur via review of medical records, and on-site visits are 
not required. To maintain the every 3 month follow-up schedule, these 
methods should be used for long-term follow up of cohort A or B 
participants, when their participation and treatment in the study continues 
as a cohort C participant. 
 
6.6 
Correlative Studies Procedures 
6.6.1 
Tumor Biopsies 
Tumor biopsy (core biopsy) after progression on previous ALK inhibitor and  
within 60 days prior to D1 of study treatment is mandatory i.e., if tissue available  
from pre-study biopsy, this tissue will be accessed for correlative studies, otherwise, 
patients must consent to tumor biopsy to meet eligibility criteria. All subjects must 
consent to provide tumor blocks or slides. If archival tissue is not available and biopsies 
to obtain fresh tumor tissue cannot be performed with minimal risk to the subject, 


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subjects may be permitted to enroll on the study with prior approval of the Study PI. 
Patients who undergo biopsies and subsequently found to have insufficient will be 
permitted to enroll on the study with prior approval of the study PI. Patients who have 
standard of care next-generation sequencing performed are able to enroll on the study, 
but must have sufficient tumor tissue to participate in the study (i.e. next generation 
sequencing cannot be substituted for providing tumor sample). 
 
Core biopsies may be performed by clinical personnel trained in this procedure for 
standard of care collections. The number of passes made through the tumor per biopsy 
will be determined by the treating physician and the physician performing the biopsy 
procedure with primary consideration being safety. The tissue collected will be divided 
into aliquots (depending on size of collection, up to 4 aliquots per collection) to enable 
enough tissue for planned correlative studies. Additional details regarding processing, 
storing and handling tissue will be provided in a separate laboratory manual. 
 
Biological samples collected for the study will be shipped to and stored in the research 
laboratories at the University of Colorado until the completion of the study. With patient 
consent, any remaining tumor tissue after protocol specific studies are complete will be 
stored for future research concerning lung cancer. 
 
6.6.2 
Blood Sample for ctDNA 
Blood samples from enrolled patients will be evaluated via next generation sequencing 
for circulating tumor DNA (no germline studies will be performed). If possible, blood 
sample at progression should be performed while patient is still taking brigatinib; if 
drug is discontinued, the blood sample should be performed within 2 days of 
discontinuation. 
 
6.6.3 
Risks of Correlative Study Procedures-Biopsy 
Liver (core needle biopsy): 
Likely: local discomfort and minor bleeding 
Less likely: moderate or major bleeding, need for blood transfusion, hospitalization 
due to bleeding or other complications, infection, bowel perforation or damage to 
adjacent organs 
 
Lung (core needle biopsy in all patients): 
Likely: local discomfort and minor bleeding 
Less likely: pneumothorax, hemothorax, intraparenchymal hemorrhage, 
hemoptysis, bronchopleural fistula, air embolism, and vascular injury 
 
In order to minimize the risk of a biopsy, only qualified personnel will perform 
these procedures. Prior to the procedure, the physician performing the procedure 
will discuss the risks with each study participant, answer any questions, and obtain 
separate procedure consent. For biopsies of lesions that are not superficial and 
clearly palpable, imaging studies such as CT scan will be used to guide the biopsy 
in order to minimize the risk of damage to adjacent structures. After liver biopsies, 
patients will be observed for approximately 4 hours (range 4-6 hours) after the 
procedure, or per institutional standard guidelines. Less than the goal quantity of 
tissue is acceptable for each type of biopsy, and will be left to the clinical judgment 
of the physician performing the procedure. 


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6.6.4 
Risks of Correlative Study Procedures-Anesthesia 
Local Anesthesia 
All biopsy procedures require local anesthesia using lidocaine, xylocaine, or  
related compounds. There is a small risk of an allergic reaction associated with  
these drugs. In order to minimize the risk of local anesthesia, only qualified 
personnel will perform the biopsy procedure. Patients will be queried if they have 
had previous allergic reactions to local anesthetics. 
 
Intravenous Conscious Sedation 
Certain biopsy procedures may require IVCS. IVCS is a minimally depressed level of 
consciousness that retains the patient’s ability to maintain a patent airway 
independently and continuously and respond appropriately to physical stimulation and 
verbal commands. The medications used to induce conscious sedation include the 
benzodiazepine midazolam and the opioid agonist fentanyl, as per standard of care. 
IVCS is performed once over a 30-60 minute period, and may require administration 
of multiple doses of each agent over this time-frame. 
Rarely, IVCS will last longer than 60 minutes. 
 
Midazolam: 
See http://www.drugs.com/pro/midazolam-injection.html for complete prescribing 
information on midazolam, including complete information on risks associated with its 
use. 
 
The risks of midazolam include respiratory depression and respiratory arrest, especially 
when used for sedation in non-critical settings. Respiratory arrest could require 
intubation. In very rare cases, when this was not recognized promptly and treated 
effectively, death or hypoxic encephalopathy has resulted. Other serious 
cardiorespiratory adverse events have occurred after administration of midazolam, 
including airway obstruction, oxygen desaturation, apnea, and cardiac arrest, rarely 
resulting in death or permanent neurologic injury. There have also been rare reports of 
hypotensive episodes requiring treatment, particularly in patients with hemodynamic 
instability. Agitation, involuntary movements, hyperactivity and combativeness have 
been reported in adults patients treated with midazolam. 
 
Concomitant use of midazolam with other respiratory depressants like fentanyl may 
increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may 
contribute to profound and/or prolonged drug effect. Prolonged sedation may also be seen 
midazolam is administered concomitantly with drugs known to inhibit the P450 3A4 
enzyme system such as cimetidine, erythromycin, diltiazem, verapamil, ketoconazole 
and itraconazole. 
 
Adverse effects reported after intravenous administration of a single dose when used as a 
sedative include the following (percentage is percentage of adult patients with adverse 
events): hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), 
“oversedation” (1.6%), headache (1.5%), and drowsiness (1.2%). In addition, the 
following local effects at the site of the injection have been reported: tenderness (5.6%), 
pain during injection (5.0%), redness (2.6%), induration (1.7%), and phlebitis (0.4%). 


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Additional rare (<1.0%) adverse events occurring when midazolam is used as a sedative 
include: 
 
• Respiratory (laryngospasm, bronchospasm, dyspnea, hyperventilation,  
wheezing, shallow respirations, airway obstruction, tachypnea); 
• Cardiovascular (bigeminy, premature ventricular contractions, vasovagal episode, 
bradycardia, tachycardia, nodal rhythm); 
• Gastrointestinal (acid taste, excessive salivation, retching); 
• CNS/Neuromuscular (retrograde amnesia, euphoria, hallucination, confusion, 
argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence 
delirium or agitation, prolonged emergence from anesthesia, dreaming during 
emergence, sleep disturbance, insomnia, nightmares, athetoid movements, 
seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, 
paresthesia); 
• Special Senses (blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic 
movements of eyelids, visual disturbance, difficulty focusing eyes, ears 
blocked, loss of balance, light-headedness); 
• Integumentary (hive-like elevation at injection site, swelling or feeling of 
burning, warmth or coldness at injection site); 
• Hypersensitivity (allergic reactions including anaphylactoid reactions, hives, 
rash, pruritus); 
• Miscellaneous (yawning, lethargy, chills, weakness, toothache, faint feeling, 
hematoma). 
 
Fentanyl 
See http://www.drugs.com/pro/fentanyl-injection.html for complete prescribing 
information on fentanyl (Duragesic®), including complete information on risks 
associated with its use. 
 
Fentanyl may cause muscle rigidity, particularly involving the muscles of 
respiration. Skeletal muscle movements in the extremities, neck and external eye 
have also been reported with fentanyl; rarely, these have been strong enough to 
pose patient management problems. Fentanyl may also produce euphoria, miosis, 
bradycardia and bronchoconstriction, as seen with other narcotic analgesics. The 
most common serious adverse reactions reported with fentanyl include respiratory 
depression, apnea, rigidity, and bradycardia. If these remain untreated, respiratory 
arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions 
that have been reported are hypertension, hypotension, dizziness, blurred vision, 
nausea, emesis, laryngospasm and diaphoresis. 
 
The risks of IVCS also include inhibition of the gag reflex and concomitant risk of 
aspiration and allergic reactions to the sedative or analgesic medications. The 
chances of serious risks from IVCS are small but real; for example, in a 
prospective study of 14,149 patients undergoing IVCS during upper 
gastrointestinal endoscopies, the rate of immediate cardiopulmonary events was 2 
in 1000. The 30-day mortality was 1 per 2,000 cases. In this study, there was a 
strong association between lack of monitoring and use of high-dose 
benzodiazepines with adverse outcomes. There was also an association between  
the use of local anesthetic sprays to the oropharynx and the development of 


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pneumonia (Waring JP, B.T., Hirota WK, et al Gastrointestinal Endoscopy). 
 
In order to minimize the risk of IVCS, only qualified personnel (M.D. and R.N) 
will be responsible for conscious sedation. A minimum of two individuals will be 
involved in the care of patients undergoing conscious sedation—the physician 
performing the biopsy procedure, and the individual (R.N.) who monitors the 
patients and his/her response to both the sedation and the procedure, and who is 
capable of assisting with any supportive or resuscitative measures. The room 
where the procedure utilizing IVCS takes place in the interventional radiology 
suite will have adequate equipment to provide supplemental oxygen, monitor vital 
signs, and maintain an airway should this be necessary. An emergency cart will 
also be immediately accessible to the room where the procedure is to take place, 
and emergency support services will be available on page. Patients will be 
screened and evaluated for their fitness to undergo conscious sedation by a trained 
physician. Patients with active cardiac disease are excluded from this study. No 
local anesthetic spray to the oropharynx will be necessary, given that endoscopy is 
not a planned procedure. Following the procedure, patients will be observed 
closely in the recovery room according to standard institutional guidelines. 
 
6.6.5 
Risks of Correlative Study Procedures-Blood Draws and IV Insertion 
Risks of Blood Draws and I.V. Insertion 
Blood draws may be associated with slight discomfort from the needle-stick, 
localized erythema, bleeding/bruising, or soreness around the area where the 
needle is inserted. Insertion of an intravenous catheter (I.V.) has similar risks, in 
addition to a small risk of infection at the site where the needle is inserted. 
 
In order to minimize the risk of blood draws and I.V. insertion, only trained 
personnel will perform these procedures, according to standard institutional 
guidelines. 
 
6.6.6 
Risks of Study Procedures-Imaging Studies 
Risks of Imaging Studies 
CT scans will expose study participants to controlled amounts of radiation. The 
total dose of radiation from these tests is not anticipated to cause any adverse 
effects. There is also a risk of an allergic reaction to the intravenous contrast dye 
used during CT imaging, as well as a risk of experiencing feelings of anxiety or 
claustrophobia while undergoing a CT scan. There are no anticipated risks with 
the use of ultrasound. 
 
In order to minimize these risks, patients will be queried, as per standard 
institutional practice, regarding their history of reactions to intravenous contrast 
dye. If a patient has had such a reaction, she/he will be premedicated, or dye will  
not be used, as per standard institutional practice. If a patient has previously 
experienced anxiety or claustrophobia while undergoing a CT scan, she/he will be 
encouraged to discuss this with her primary oncologist. Anxiolytics may be 
considered by the patient’s primary oncologist as indicated. 
 
 


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6.7 
Assessment of Safety 
Any patient who receives treatment on this protocol should be evaluable for 
toxicity. The criteria used to assess safety (typically the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Please refer back to the Time and Events table for the schedule of AE assessment. 
6.8 
Assessment of Efficacy 
Patients will be assessed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee, version 1.1for objective response and disease  
progression.27 See section 8.3. 
 
6.8.1 
Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
See the international criteria proposed by the Response Evaluation Criteria in  
Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247)  
for additional details on RECIST1.1. 
 
Measurable disease will be defined as the presence of at least one measurable lesion 
that can be accurately measured in at least one dimension with the longest diameter a 
minimum size of: 
• >10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non- measurable). 
• 20 mm by chest x-ray. 
• >10 mm by MRI scan (MRI scan slice thickness no greater than 5 mm) 
 
For malignant lymph nodes to be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
All other lesions, including small lesions (longest diameter <10mm or pathological 
lymph nodes with ≥10 to <15 mm short axis) as well as truly non- measurable lesions, 
will be considered non-measurable. Lesions considered truly non-measurable include: 
leptomeningeal disease; ascites; pleural/pericardial effusion; inflammatory breast 
disease; lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. The 
same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. Clinical lesions 
will only be considered measurable when they are superficial and ≥10 mm diameter as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation 


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by color photography including a ruler to estimate the size of the lesions is 
recommended. 
 
6.8.2 
Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
If lymph nodes are to be included in the sum, only the short axis is added into the 
sum. The baseline sum diameters will be used as reference to further characterize 
the objective tumor response of the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as “present” or “absent”, or in 
rare cases “unequivocal progression”. 
 
6.8.3 
Evaluation of Target Lesions using RECIST 1.1 Criteria 
NOTE: In addition to the information below, also see section 4.3.2 in the international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee, version 1.1 for special notes on the assessment of target lesions.25 
 
Complete response (CR) −Disappearance of all target lesions. Any pathological lymph 
node (LN) (whether target or non-target) must have decreased in short axis to <10mm. 
 
Partial response (PR) −At least a 30% decrease in the sum of the LD of the target lesions 
taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the target 
lesions taking as reference the smallest sum LD recorded since the treatment started 
including baseline if that is the smallest on study. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5mm. The 
appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD) −Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
 
6.8.4 
Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and normalization 
of tumor marker levels. All LN must be non-pathological in size (<10mm short axis). 


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Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one or 
more non-target lesion(s) or/and maintenance of tumor marker level above the normal 
limits. 
 
Progressive disease (PD) −Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
6.8.5 
Evaluation of Best Overall Response using RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment provided the confirmation criteria are met. To be 
assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed ≥ 4 weeks after the criteria for response are 
first met. If a CR/PR cannot be confirmed the original "response" should be 
considered stable disease. The best overall response will be defined according to the 
following table: 
 
Overall 
Response First 
Time Point 
Overall Response 
Subsequent Time 
Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
NE 
NE2 
NE2 
 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
2 NE=inevaluable 
 
 
7.0 
ADVERSE EVENTS  
7.1 
Intentionally blank. 
7.2 
Definitions  
7.2.1 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including 


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an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not related to the medicinal product. 
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered AEs 
and should not be recorded as an AE. Disease progression should not be recorded 
as an AE, unless it is attributable by the investigator to the study therapy. 
 
7.2.2 
Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions. Other 
factors to consider in considering drug as the cause of the AE: 
 
• Single occurrence of an uncommon event known to be strongly associated  
• with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon  
• rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is  
• reasonable possibility that the drug caused the event. 
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group  
• than in the concurrent or historical control group. 
 
7.2.3 
Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure (IB) 
for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). Unexpected also refers to AEs or SARs that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
7.2.4 
Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 


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• Death; 
• Is life-threatening (places the subject at immediate risk of death from  
• the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of  
• existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial  
• disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life- 
• threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical  
• judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in 
the definition. For reporting purposes, also consider the occurrences of 
pregnancy as an event which must be reported as an important medical 
event. 
 
* Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered  
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
 
7.3 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30-day follow-up period after treatment is 
discontinued. 
 
Collected information should be recorded in the Case Report Forms (CRF) for that 
patient. Please include a description of the event, its severity or adverse event grade, 
onset and resolved dates (if applicable), and the relationship to the study drug. 
Documentation should occur at least monthly. 
 
For patients with two Subject Identification Numbers (SI#), resulting as participants 
in Cohort A or Cohort B, and then Cohort C (upon disease progression), each AE 
should be recorded as applicable to their cohort participation including the following: 
• An original AE under their SI#1 should be completed (followed and recorded 
to resolution) under that cohort. 
• AEs for Cohort C should be applicable to their participation under Cohort C: 
a. AEs from SI#1 should be recorded once resolved under SI# 1. 
b. AE history from the patient’s SI#1 to be included as medical history 
for the patient under their SI# 2. 
c. Original AEs under SI#1 that increase in severity to be recorded as a 
new AE under the patient’s SI#2 (as cohort C). 
 


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7.4 
SAEs or Serious SARs 
 
7.4.1 
Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout). 
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30-day follow-up period after treatment is discontinued. 
 
7.4.2 
Documentation and Notification 
All SAEs or Serious SARs must be recorded as an SAE within the study 
electronic data capture system and the printed SAE eCRF must be submitted to 
Criterium Project Manager & Duke Principal Investigator via email at 
ARIAT002SAE@criteriuminc.com within 24 hours of learning of its occurrence. 
 
7.4.3 
Reporting 
Institutional Review Board (IRB) / Research Ethics  Reporting (REB) 
Reporting Requirements: 
Sites using a local IRB/REB of record, are required to submit adverse events per 
their local IRB/REB policy. 
 
Reporting of Pregnancy 
Pregnancy 
It is not known what effects brigatinib has on human pregnancy or development of  
the embryo or fetus. Therefore, female patients participating in this study should  
avoid becoming pregnant, and male patients should avoid impregnating a female 
partner. Non-sterilized female patients of reproductive age group and male patients 
should use effective methods of contraception through defined periods during and  
after study treatment as specified below. 
 
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 2 effective methods of 
contraception from the time of signing of the informed consent form through 
4 months after the last dose of study drug, or agree to completely abstain 
from heterosexual intercourse. 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 
1 of the following: 
• Practice effective barrier contraception during the entire study treatment period 
and through 4 months after the last dose of study drug, or  


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• completely abstain from heterosexual intercourse. 
 
If a subject becomes pregnant during the study, or within 30 days of the subject’s 
last dose of study drug, the investigator is to stop dosing with study drug 
immediately. A pregnancy is not considered to be an AE or SAE; however, it must 
be reported to Takeda at Toll-Free Fax #: 1-800-963-6290, E-mail: 
takedaoncocases@cognizant.com  using the Pregnancy Report Form within the  
same timelines as an SAE. This applies to female subjects as well as female  
partners of male subjects. A pregnancy should be followed through to outcome, 
whenever possible. Once the outcome of the pregnancy is known, the Pregnancy 
Outcome Report Form should be completed and reported to the IND Office and 
Takeda. 
 
It is not known whether brigatinib passes into the breast milk. Mothers should not 
breastfeed while receiving study drug. 
 
In cases of pregnancy or suspected pregnancy, the patient is to be discontinued 
immediately (within 24 hours) from the study and the female subject should be 
referred to an obstetrician- gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
 
In addition to reporting to Takeda, pregnancy, suspected pregnancy, positive 
pregnancy test and pregnancy outcome must be reported to the Criterium Project 
Manager & Duke Principal Investigator immediately via email:  
ARIAT002SAE@criteriuminc.com 
If the pregnancy results in spontaneous abortion or stillbirth, the event should be 
reported as an SAE. If there are any abnormal outcomes that meet the serious 
criteria, it must be reported as an SAE. Please follow the SAE reporting 
instructions in Section 7.3.2. 
 
Pregnancy outcomes must be collected for the female partners of any males  
who took study drug in this study. Consent to report information regarding 
 these pregnancy outcomes should be obtained from the female partner. 
 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusing of any 
dose of study treatment that exceeds the dose described in the protocol. Overdoses 
are not considered AEs; however, all overdoses should be recorded on an Overdose 
Report Form and submitted to Criterium Project Manager and Duke Principal 
Investigator within 24 hours. An overdose should be reported even if it does not 
result in an AE. Overdoses do not need to be recorded on the eCRF; dosing 
information is recorded on the dose administration eCRF. 
 
Email for submitting an Overdose Report Form to Criterium Project Manager and 
Duke PI: ARIAT002SAE@criteriuminc.com. 
 


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Takeda Reporting Requirements: 
The sponsor or designee is responsible for emailing pregnancy and overdose reports  
to Takeda at takedaoncocases@cognizant.com as soon as they are aware. 
FDA Expedited Reporting requirements for studies conducted under an IND: 
If an investigator deems that an event is a Suspected Unexpected Serious Adverse 
Reaction (SUSAR), de-identified supporting documentation defining the event and 
causality within 24 hrs. of knowledge of the event should be emailed to the  
Criterium Project Manager and Duke Principal Investigator at:  
ARIAT002SAE@criteriuminc.com. 
 
Once the Duke Principal Investigator determines an event is a SUSAR, the  
MedWatch 3500A form will be created by Criterium Project Manager or designee  
and submitted to the FDA. 
 
The MedWatch 3500a form can be accessed at:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.  
(Please be sure and access form 3500a, and not form 3500). ATOMIC, as the  
Sponsor of the study, will make the final determination regarding FDA submission). 
 
Criterium Project Manager or designee is responsible for emailing expedited reports to 
Takeda Pharmaceuticals, Inc. at takedaoncocases@cognizant.com immediately but no 
later than 24 hours after the FDA submission. 
 
Criterium Project Manager or designee will also be responsible for informing each  
site of all serious and unexpected SARs reported to the FDA via email as soon as 
possible. 
 
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 contact Takeda Pharmacovigilance or designee (see below) and report 
the event. Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a Takeda 
Quality representative. 
 
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. While 
overdoses and underdoses constitute medication errors, doses missed inadvertently  
by a patient do not. Investigators must record all medication errors (including 
overdose) on the appropriate CRF form. Individuals who identify a potential 
medication error situation should immediately contact Takeda (see below) and report 
the event. 
 


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Product complaints in and of themselves are not AEs. If a product complaint results  
in an SAE, an SAE form should be completed and sent to Takeda Pharmacovigilance 
 
7.5 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in  
this trial with annual reporting to the ATOMIC Data and Safety Monitoring  
Committee (DSMC). 
 
Additional safety meetings/teleconferences will be held at a frequency dependent 
on study accrual, and in consultation with the study biostatistician. These meetings 
will include the investigators as well as protocol nurses, clinical research  
associates, regulatory associates, data managers, biostatisticians, and any other 
relevant personnel the principal investigators may deem appropriate. At these 
meetings, the research team will discuss all issues relevant to study progress, 
including enrollment, safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data. 
 
The Data and Safety Monitoring Committee (DSMC) will be constituted by 
ATOMIC and will review the study on an annual basis. The Duke PI, with 
Criterium Project Manager’s support, will be responsible for submitting the 
following information for review: 1) safety and accrual data including the number 
of patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report. 
Findings of the DSMC review will be disseminated by memo to the participating 
sites. 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
The statistical design for this protocol involves a single arm phase II trial to 
investigate the clinical activity of brigatinib in three patient populations (Cohorts 
A, B, and C). Each cohort will be assessed separately. A Simon two-stage design  
is used to determine the primary endpoint of objective response rate (ORR). 
(Eisenhauer et al. 2009) Secondary endpoints include duration of response, PFS, 
intracranial PFS, extracranial PFS, OS and safety. We will also explore for any 
association between presence and/or type of mutation at baseline and efficacy 
outcomes (ORR and PFS). Resistance mutations will also be identified using a 
tumor sample from progression as well as ctDNA from peripheral blood samples. 
For Product Complaints or Medication Errors (Including Overdose), contact Takeda 
Pharmacovigilance 
Email: GlobalOncologyMedInfo@takeda.com 
Fax: 1-800-881-6092, Hours Mon – Fri, 9 a.m. – 7 p.m. ET 


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8.2 
Sample Size and Accrual 
With the number of sites being increased, the study is expected to complete  
accrual (40 patients in each of the 3 cohorts) in about 2 years from amendment 
approval. The primary endpoint is objective tumor response of brigatinib via 
RECIST1.1. A true response rate of 20% would be considered active and worthy  
of further investigation, and a response rate of 5% will be considered inactive and 
not worthy of further investigation. 
 
A two-stage design will be used for this study. (Simon 1989)  Twenty patients will 
be initially entered in Stage I of the study for each cohort, assuming all twenty are 
eligible.  If there are at least 2 responses among the 20 eligible patients, an 
additional 20 patients will be entered into that cohort. If there are fewer than 2 
responses among the first twenty patients in a cohort, then the cohort will be 
stopped early for futility. If at least 5 responses are observed among the 40 eligible 
patients in a cohort, then the treatment will be considered promising for that  
cohort population. 
 
Table below gives the characteristics of this design as a function of the true 
response rate. 
 
If the true response rate of a cohort is 20%, for example, then the probability of 
stopping that cohort early for futility is 7% and the overall probability of rejecting 
the treatment for that cohort after the second stage is 11%. This is comparable to a 
power of 89%. If the true response rate of a cohort is 10%, the probability of 
stopping that cohort early is 39% and the overall probability of rejecting the 
treatment for that cohort after the second stage is 67%. 
 
PROBABILTY OF RESPONSE 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
Probability of stopping 
early (<2 responses) 
0.74 
0.39 
0.18 
0.07 
0.02 
0.008 
Probability >1 
responses during stage 
1 (and rejecting the 
treatment) 
0.22 
0.28 
0.14 
0.04 
0.01 
0.002 
Overall probability of 
rejecting the treatment 
0.96 
0.67 
0.32 
0.11 
0.03 
0.009 
 
8.3 
Data Analysis Plans 
All analyses for the three cohorts will be separated. A modified intent-to-treat 
approach will be followed in all data summaries using all available data in the 
analyses. Consequently, no special adjustments to the data are intended for dealing 
with missing values or patients who withdraw prior to completing study. Patients 
who sign informed consent for the study but who voluntarily withdraw prior to 
treatment or never initiate treatment due to the development of inter-current illness 
or death will not be included in the analysis. Patients who sign inform consent and 


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subsequently have a change in their functional status, laboratory values, or other 
eligibility criteria prior to initiating treatment, which makes them ineligible will  
not be included in the analysis. All patients who enroll and start study therapy will 
be included in the analysis. 
 
Patients who are not able to get radiographic assessment due to decline in 
performance status, symptomatic progression, and any other reason will be 
considered non-responders and will be considered as having disease progression  
at the time they discontinue protocol therapy. 
 
The primary endpoint is objective response rate (ORR); the secondary endpoints 
are duration of response, PFS, intracranial PFS, extra-cranial PFS, OS and the 
evaluation of the AE using NCI CTCAE version 4.0. For the primary analysis on 
ORR, the ORR and its 95% CI will be estimated using the statistical method taking 
into account the 2-stage design.28 Mean and median of duration of response and 
their 95% CIs will be estimated. Time to event endpoints, including PFS and OS, 
will be summarized using the method of Kaplan and Meier. PFS is the time from 
Day 1 treatment to disease progression or death, whichever comes first. OS is the 
time from Day 1 treatment to death of all causes. Patients without relevant events 
at last follow up will be treated as censored. Median PFS and median OS will be 
provided as well as their 95%CI. The association of survival endpoints with 
baseline covariates will be evaluated using Cox regression models. Treatment- 
related adverse events will be summarized by type, grade, and attribution. 
 
The association between presence and/or type of mutation or mechanism of 
resistance at baseline and efficacy outcomes will be explored using logistic 
regression (ORR) and Cox regression model (PFS). The frequency/rate of 
 resistance mutations after brigatinib will be estimated using tumor samples 
collected at time of progression. The association between cfDNA from peripheral 
blood samples and resistance mutations will be evaluated using Wilcoxon rank  
sum test. 
 
All demographic and analytic data will be summarized by descriptive statistics. 
Categorical data will be summarized using frequency tables while summary 
statistics such as means, medians, standard deviation, range, etc. will be provided 
for continuous data. 
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) / Research Ethics Board (REB)  
Approval and Consent 
It is expected that the IRB/REB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB/REB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply  
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 


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Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent  
form. Each consent form must include all the relevant elements currently required  
by applicable regulations (i.e., FDA, Health Canada, and local or state regulations). 
Once this essential information has been provided to the patient and the investigator  
is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an 
IRB/REB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
 
 
Patients in cohort C will have progressed on brigatinib and will be receiving a 
higher than the standard dose brigatinib. Depending on the institutional practice 
and policies this may require patients on cohort C to sign a “post- progression” 
treatment informed consent document. 
 
9.2 
Required Documentation 
Before a site can be open to enrollment, the following documentation must be on 
file with Criterium, Inc. 
• A copy of the official IRB/REB approval letter for the protocol and 
informed consent 
• IRB/REB membership list 
• IRB FWA documentation and GCP compliance statement, or REB 
equivalent, as applicable 
• CVs and medical licensure for the principal investigator and any sub- 
investigators who are listed on the 1572. 
• Current GCP certificates for site PI and all sub-investigators on the 1572 
• Form FDA 1572 appropriately filled out and signed with appropriate 
Financial Disclosures for PI and all sub-investigators on the1572 
• Laboratory certificates (e.g., CLIA (and CAP if applicable)) and 
associated lab normal values 
• Executed clinical research contract 
• Protocol signature page of IRB/REB approved protocol 
• Investigator Brochure acknowledgement of receipt 
9.3 
Enrollment Procedures 
All patients must be approved by the Duke Principal Investigator or designee before 
enrollment to study. Site is to email completed eligibility checklist, signed informed 
consents with all but first initial of first and last name of patient censored and all de-
identified source documents used to confirm eligibility to: 
ARIAT002PM@criteriuminc.com 
Enrollment confirmations will be sent via email. Date of enrollment will be defined 
as the date of the confirmation e-mail in the EDC.  


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9.4 
Data Management and Monitoring/Auditing 
Data for each cohort (A, B and C) participant data will be captured from their time 
of enrollment in the cohort for up to 2 years, or until death, whichever occurs first. 
 
Data will be collected through a web-based electronic data capture system. All 
study institutions will be given a password to directly enter their own data into the 
study electronic case report forms (eCRFs). Criterium, Inc. will coordinate and 
manage data for quality control assurance and integrity. 
 
All data will be collected and entered by site research coordinators or other 
designees from participating institutions. The investigators at each site will be 
required to submit de-identified source documentation to Criterium, Inc for routine 
data monitoring upon request. 
 
On site monitoring visits will be performed by ATOMIC representative according 
to the Monitoring Plan.  During these visits, information recorded in the eCRFs 
will be verified against source documents. Data will be reviewed for safety 
information, legibility, completeness, and accuracy. 
 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
 
9.5.1 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior Duke Principal 
Investigator or their respective institution’s IRB/IEC/REB approval/favorable 
opinion. 
 
For investigators relying on their own institution’s IRB/REB, as soon as possible 
after the modification has been made, the implemented deviation or change and the 
reasons for it should be submitted to: 
• To Duke Principal Investigator for agreement 
• The institution’s IRB/REB for review and approval. (Once 
IRB/REB’s response is received, this should be forwarded to the 
Criterium Project Manager). 
 
9.5.2 
Other Protocol Deviations/Violations 
A protocol deviation is any unplanned variance from an IRB/REB approved protocol 
that: 
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected 
• Did not result from willful or knowing misconduct on the part of the  
investigator(s). 


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An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria: 
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of  the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
If a deviation or violation occurs, please follow the guidelines below:  
For Institutions Relying on Their Own IRB/REB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB/REB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in the electronic data capture system.  
 
The protocol was amended in 2020 adding the ability, in limited situations and at 
treating physician’s discretion, for some Day 1 even cycles to be conducted as 
telemedicine visits. Some standard in clinic assessments (i.e., symptoms/adverse 
event, blood pressure and heart rate) will not be conducted with these remote visits. 
To maintain data integrity, these missed assessments are to be noted in the EDC as 
protocol deviations (planned) and indicate the visit was conducted remotely. For 
purposes of regulatory reporting, these are not considered Protocol Deviations and 
will not require reporting to your IRB/REB, or the Duke Principal Investigator or 
designee to determine safety.  
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB/REB per institutional policies and reported to the Criterium Project Manager 
within 5 days. 
 
Duke Principal Investigator or designee will determine if the violation affects the 
safety of the patient and integrity of the data. Once your institution’s IRB/REB 
response is received, please forward to the Criterium Project Manager within 5 
business days of receipt via email. 
 
9.5.3 
Termination rules 
The Duke principal investigator and the study sponsor have the right to terminate 
this clinical study at any time. The Duke principal investigator and study sponsor, 
as appropriate, will be involved in any decisions regarding terminating the study, 
temporarily suspending enrollment, or stopping ongoing treatment with study 
treatment. 
 
Reasons for terminating the clinical study or a study site’s participation include, 
but are not limited to, the following: 


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• The incidence or severity of an adverse reaction related to treatment in this 
study or other studies indicates a potential health hazard to patients 
• Patient enrollment is unsatisfactory 
• Data recording is significantly inaccurate or incomplete 
• Study site personnel are noncompliant with study procedures 
• Pattern of noncompliance is observed 
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator at Duke. It should also be noted that 
when an amendment to the protocol substantially alters the study design or the 
potential risk to the patient, a revised consent form might be required. 
 
The written amendment, and if required the amended consent form, must be sent to 
your site IRB/REB for approval prior to implementation. 
 
All sites must submit their informed consent revisions to the Criterium Project 
Manager or designee for review and approval prior to submission to their IRB/REB. 
 
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB/REB correspondence 
and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study 
investigator. In the case of a study with a drug seeking regulatory approval and 
marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization 
(ICH) region. In Canada the Principal Investigator will retain the study records in a 
secure and confidential location for 25 years as required by Canadian law. In all 
other cases, study documents should be kept on file until three years after the 
completion and final study report of this investigational study. 
 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 


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The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the eCRFs. Periodically, 
data monitoring will be conducted and the Principal Investigator or designee must 
provide de-identified source upon request to permit remote verification of proper 
entry of data. At the completion of the study, all eCRFs  will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy 
of the data. 
 
 
10.0 APPENDICES 
 
Appendix A: ECOG Performance Status 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g. light housework, office work). 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Death 
 
 
Appendix B: Model Patient Diary for Brigatinib (see as auxiliary patient document) 
Appendix C: Prohibited Drugs, Juices and Herbal Supplements, and Medications to be used 
with Caution (see as auxiliary patient document) 
 
 


Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
Page 80 of 82 
 
11.0  REFERENCES  
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T. Mitsudomi, N. Yamamoto, T. Asakawa, R. Asabe, T. Tanaka, and T. Tamura. 2017. 'Alectinib 
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Drug Substance: brigatinib  
                        ATOMIC Protocol Number: ARI-AT-002 
Version 7.0 April 20, 2020 
CONFIDENTIAL 
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H. J. M. Groen, M. J. Hochmair, N. B. Leighl, S. N. Gettinger, C. J. Langer, L. G. Paz-Ares 
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W. A. Franklin, S. L. Aronson, P. F. Su, Y. Shyr, D. R. Camidge, L. V. Sequist, B. S. Glisson, F. 
R. Khuri, E. B. Garon, W. Pao, C. Rudin, J. Schiller, E. B. Haura, M. Socinski, K. Shirai, H. 
Chen, G. Giaccone, M. Ladanyi, K. Kugler, J. D. Minna, and P. A. Bunn. 2014. 'Using 
multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs', JAMA, 311: 
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Lin, J. J., G. J. Riely, and A. T. Shaw. 2017. 'Targeting ALK: Precision Medicine Takes on Drug 
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Lindeman, N. I., P. T. Cagle, D. L. Aisner, M. E. Arcila, M. B. Beasley, E. H. Bernicker, C. Colasacco, S. 
Dacic, F. R. Hirsch, K. Kerr, D. J. Kwiatkowski, M. Ladanyi, J. A. Nowak, L. Sholl, R. Temple-
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and Y. Yatabe. 2018. 'Updated Molecular Testing Guideline for the Selection of Lung Cancer 
Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of 
American Pathologists, the International Association for the Study of Lung Cancer, and the 
Association for Molecular Pathology', J Thorac Oncol, 13: 323-58. 
Newman, A. M., S. V. Bratman, J. To, J. F. Wynne, N. C. Eclov, L. A. Modlin, C. L. Liu, J. W. Neal, H. 
A. Wakelee, R. E. Merritt, J. B. Shrager, B. W. Loo, Jr., A. A. Alizadeh, and M. Diehn. 2014. 'An 
ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage', Nat 
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Oxnard, G. R., C. P. Paweletz, Y. Kuang, S. L. Mach, A. O'Connell, M. M. Messineo, J. J. Luke, M. 
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response and resistance in EGFR-mutant lung cancer using quantitative next-generation 
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Dziadziuszko, R. Rosell, A. Zeaiter, E. Mitry, S. Golding, B. Balas, J. Noe, P. N. Morcos, T. 
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Shaw, A. T., D. W. Kim, R. Mehra, D. S. Tan, E. Felip, L. Q. Chow, D. R. Camidge, J. Vansteenkiste, S. 
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ICF_001.pdf: 
Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 1 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
CONCISE SUMMARY
The purpose of this study is to test and evaluate the safety and effectiveness of an investigational drug 
called brigatinib (AP26113) in subjects with advanced lung cancer (called non-small cell lung cancer or 
NSCLC) with ALK rearrangement, who have previously received at least one line of treatment with an 
anti-cancer drug, and whose cancer has gotten worse.
You will be prescribed brigatinib to take orally once a day for the duration of the study. Blood samples 
and possibility a small piece of tissue may be required. You will also have other tests, exams and 
procedures for study purposes and your standard of care. If you enroll, you may continue to take 
brigatinib, as long as it’s working, otherwise your participation will last approximately 2 years.
There are risks to this study that are described in this document. Some risks include diarrhea, headache, 
nausea and/or vomiting, being tired or weak, and radiation risks from CT scans. 
If you are interested in learning more about this study, please continue reading below. 
You are being asked to take part in this research study because you have advanced lung cancer. 
Research studies are voluntary and include only people who choose to take part.  Please read this 
consent form carefully and take your time making your decision. As your study doctor or study staff 
discusses this consent form with you, please ask him/her to explain any words or information that you 
do not clearly understand.  We encourage you to talk with your family and friends before you decide to 
take part in this research study.  The nature of the study, risks, inconveniences, discomforts, and other 
important information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Thomas Stinchcombe will conduct the study and it is funded by Takeda Pharmaceuticals.  The 
sponsor of this study is the Academic Thoracic Oncology Medical Investigators Consortium 
(ATOMIC).  The study is being conducted by investigators affiliated with ATOMIC and Dr. 
Stinchcombe is the lead investigator for the study. Duke University will be paid by this group to perform 
this research and these funds may reimburse part of Dr. Stinchcombe’s salary. Dr. Stinchcombe serves 
on an advisory board for Takeda Oncology.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Stinchcombe will be your doctor for the study and will be in contact 
with your regular health care provider throughout the time that you are in the study and afterwards, if 
needed.
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 2 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to test an investigational drug called brigatinib (AP26113) in subjects with 
advanced lung cancer (called non-small cell lung cancer or NSCLC) with ALK rearrangement. 
An ALK mutation is an abnormality or mutation in a gene called ALK (anaplastic lymphoma kinase) 
that can occur in cancer cells such as lung cancer cells. This mutation is actually a gene rearrangement 
(a fusion of 2 genes) that is causing your cancer cells to grow and spread. This type of lung cancer is not 
very common, and people who get it are normally younger and are not smokers. Doctors do not know 
definitively what causes this disease, but they are searching for new and better treatments that would 
slow the cancer down and help people who have it feel better. 
Brigatinib has been approved by the FDA for patients with metastatic non-small cell lung cancer 
(NSCLC) and alterations in the ALK gene whose cancer has progressed during their initial therapy.
The uses of Brigatinib in this study have not been approved by the FDA, therefore Brigatinib is 
considered an investigational drug. The word “investigational” means the study drug is still being tested 
in research studies and is not approved by the U.S. Food and Drug Administration (FDA).
The purpose of this study is to evaluate the safety and effectiveness of brigatinib in subjects with 
advanced lung cancer (NSCLC), with an ALK gene rearrangement, whose cancer got worse after or 
while taking a drug called an ALK inhibitor. ALK inhibitor drugs specifically target the abnormal ALK 
protein. Examples of these drugs are ceritinib (ZykadiaR) and alectinib (AlecensaR). Brigatinib also 
targets the ALK protein and has undergone some preliminary testing in subjects with lung cancer with 
ALK rearrangement. Because it also targets different mutations, it may help subjects who have 
progressed on or failed to respond to other ALK inhibitor drugs. 
ARE THERE ANY REASONS YOU SHOULD NOT BE IN THIS STUDY?
You should not be in this study if you have received (or are receiving) chemotherapy, radiation therapy, 
or other investigational drugs within 7 days of the first dose of brigatinib. You should also not be in this 
study if you are a pregnant or breast-feeding female or are unwilling to take contraceptive drugs to 
prevent pregnancy during the study; have any history or presence of any lung disease; have drug-related 
or radiation pneumonitis (lung inflammation); have had any active significant gastrointestinal bleeding 
within the past 3 months or any active infection requiring intravenous antibiotics; or are unable to 
swallow study medication. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 120 people will take part in this study at approximately 11 different hospitals and 
medical facilities, and approximately 14 people will take part at Duke.
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 3 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form. 
Some tests and procedures will be necessary to confirm that you meet the eligibility requirements to 
participate in this study.  
Tests and Procedures 
After you have signed the consent form, we will schedule you for a screening visit to conduct the tests 
and procedures necessary to see if you are eligible to participate.
If you have recently had some of the tests or procedures that are required during the screening visit, you 
may not need these tests or procedures repeated. The study doctor and members of the study team will 
talk to you about what tests will be necessary. Additionally, all of these tests and procedures may not 
occur on the same day but are required prior to determining whether or not you can be in the study.  
The following tests and procedures will occur during this visit and will be used to confirm that you are 
eligible for the study: 
•
Physical Examination along with height and weight and a complete medical history
•
Vital signs (blood pressure, heart rate, temperature, respirations)
•
Review of  how well you perform daily tasks
•
Routine blood laboratory tests – approximately 2 tablespoons of blood (CBC, platelet count, and 
serum chemistries) 
•
Serum pregnancy test for women of childbearing potential (7 days prior to receiving study drug). 
•
Testosterone level if male 
•
Electrocardiogram (ECG) to see how well your heart is functioning
•
CT Scan (Computed Tomography) of your chest, abdomen and pelvis to look at the extent of 
your cancer 
•
MRI (Magnetic Resonance Imaging) of your brain to see if your cancer may have spread to this 
area. 
•
Tumor sample (from a previous biopsy when you were taking an ALK inhibitor drug).  If no 
previous tumor sample is available, you will need to have a new biopsy performed in order to participate 
in this study, unless it cannot be performed with minimal risk (no deep tissue biopsies would be 
performed, such as lung biopsies). 
•
Review of all medications (including any herbal or nutritional supplements) you may be taking.  
Please bring all medications, vitamins, and supplements that you are taking to this visit for review.
If after all screening tests and procedures your study doctor determines that you are eligible for 
participation in the study, you will come to the clinic for your first visit.  This is considered Cycle 1 Day 
1.   A cycle consists of 28 days.  You will be given a medication diary to record each use of your study 
medication. The study team will collect and review this diary during your clinic visits.  You must also 
bring your empty bottle or remaining pills with you to each visit.  
During this study, you will be placed in Cohort A or Cohort B depending on what other treatment you 
have received for your cancer.  Subjects in both Cohorts A and B  will receive the study medication, 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 4 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
brigatinib, at a dose of 90 mg.  It is to be taken by mouth once a day for the first 7 days of Cycle 1 
followed by 180 mg by mouth once a day, continuously, thereafter.
OR
If you were previously treated with brigatinib, prior to this study, and your cancer has gotten worse, or if 
your cancer has gotten worse while you have been on this study but you are tolerating the current dose 
well, you may be eligible for Cohort C.  Cohort C subjects will receive brigatinib at a dose of 240mg to 
be taken by mouth daily. 
Subjects  who are currently in Cohorts A and B and have disease progression, will be asked to read and 
sign a separate consent addendum, called “beyond progression” if interested in continuing in the study.
Your doctor and your dosing diary will tell you your dose and the number of tablets per dose.
Study  Regimen Procedures
All Cycles, Day 1 (Every 28 days) plus or minus 2 days
The following tests and procedure will be done during each cycle visit every 28 days as follows: 
•
Physical examination and weight
•
Measure vital signs (blood pressure, heart rate, temperature, respirations) 
•
Review how well you perform your daily tasks and activities
•
Review any signs and symptoms you may be experiencing
•
Routine blood laboratory tests – approximately 2 tablespoons of blood (CBC, platelet count, and 
serum chemistries) 
•
Research  Blood Sample for ctDNA -  to see how the study drug may work in someone who has 
previously taken drugs called ALK inhibitors (Cycle 1, Day 1 and Day 1 of every odd cycle- 3, 5, etc.). 
Your genes are made up of DNA. DNA is short for deoxyribonucleic acid. A gene, or DNA, contains 
information that determines in part the traits, such as eye color, height, or disease risk, that are passed on 
from parent to child. ctDNA is DNA from your tumor that can be detected in your blood sample. About 
2 tablespoons of blood will be collected each time.
•
Review all medications you may be taking
•
Receive study drug brigatinib and new diary
•
Review & collect medication diary 
•
Collect empty medication bottle or remaining pills
Cycle 1, Day 8   plus or minus 2 days
•
Measure vital signs (blood pressure and heart rate)
•
Review any signs and symptoms you may be experiencing
•
Routine blood laboratory tests – approximately 2 tablespoons of blood (CBC, platelet count, and 
serum chemistries) 
•
Review all medications you may be taking
•
Review your medication diary
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 5 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
If your study doctor feels it is appropriate, after 7 days, and on day 8 of Cycle 1, the study doctor will 
increase your dose of brigatinib to 180mg. 
If you were treated with brigatinib, prior to this study, your dose will not change on Cycle 1 Day 8, if 
you are tolerating your current dose well.
In addition to the tests and procedures done during each cycle visit, the following additional tests will 
occur on odd numbered cycles (1,3,5,7 and so forth) as outlined below:
Cycles 3, 5 and Every Odd Numbered Cycle thereafter on Day 1,  plus or minus 2 days
•
Research  Blood Sample for ctDNA -  to see how the study medication may work in someone 
who has previously taken drugs called ALK inhibitors 
•
Testosterone level if male 
•
MRI (Magnetic Resonance Imaging) of your brain to see if your cancer may have spread to this 
area.  This will be done if you have known brain metastases or if it is needed for your care (clinically 
indicated). 
•
CT Scan (Computed Tomography) of your chest and abdomen  to look at the extent of your 
cancer. A CT scan of the pelvis will be done as well if there is evidence that the disease has spread to 
that region. 
After the study drug has been stopped for any reason, we will ask you to come back in 30 days for a 
final visit, where you will have the following tests and/or procedures:
Visit at End of Study Drug Regimen (30 days, plus or minus 3 days)
•
Physical examination and weight
•
Measure vital signs (blood pressure, heart rate, temperature, respirations) 
•
Review how well you perform your daily tasks and activities
•
Review any signs and symptoms you may be experiencing
•
Routine blood laboratory tests – approximately 2 tablespoons of blood (CBC, platelet count, and 
serum chemistries) 
•
Research  Blood Sample for ctDNA -  to see how the study medication may work in someone 
who has previously taken drugs called ALK 
•
Optional biopsy to obtain tumor sample: 
Optional Tumor Biopsy at Progression:
You will be asked if you are willing to undergo a biopsy to provide new samples of tumor tissue at the 
end of study if your tumor(s) has progressed. A biopsy would only be done if you have tumor in an 
accessible area (such as on the skin or a superficial lymph node). No biopsies that would entail 
significant risk would be done (for example, deep tissue biopsies such as lung biopsies). The site of the 
biopsy will not be the same in every subject and it will depend on where you have superficial tumor 
located. Your doctor will discuss the location of the biopsies, the procedure, and the risks with you in 
detail. 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 6 of 18                                                  Subject*Initials:______________
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THIS BIOPSY IS COMPLETELY OPTIONAL AND YOU CAN STILL PARTICIPATE IN THIS 
STUDY IF YOU DO NOT AGREE TO THE BIOPSY.  This sample of your tumor will help researchers 
identify if there are any mutations causing resistance.  You can change your mind at any time and 
withdraw your consent to the biopsy.
A biopsy of tumor tissue may be taken by cutting out the entire tumor nodule or by taking a biopsy with 
a hollow needle (called a core biopsy). In some cases, a smaller needle procedure (called a fine needle 
aspirate) may be enough.  
If you have a biopsy for your routine care (not for research), you also have the option to provide a tumor 
tissue sample. 
Please initial and date your choice below:
______Yes, I will provide a biopsy and understand that I can change my mind and withdraw my 
consent:
______No, I decline to provide the biopsy:
After you have completed this study, you will come to clinic for your long-term standard of care follow-
up every 3 months for up to two 2 years.  This may be able to be done by review of your medical 
records.   This can be discussed with your study doctor.
USE OF TISSUE FOR FUTURE RESEARCH
Biological samples collected for the study will be shipped and stored in the research laboratories at the 
University of Colorado until the completion of the study. If there is tumor tissue remaining after study 
specific tests are completed, you are being asked to give permission for the remaining tissue to be stored 
and used for future research on lung cancer. 
If you do not wish to allow your samples to be used for future research, you should initial “no” in the 
boxes below. You are not required to agree to the use of your samples for future research. If you choose 
to provide your samples, they will be used to conduct research tests that may help the study sponsor find 
out if certain types of cancer respond better to treatment than others and may improve future treatment 
options for patients with lung cancer. Because the field of science is always advancing, we cannot 
predict all the tests that will be done. If you agree to provide your samples, they will be kept indefinitely.
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 7 of 18                                                  Subject*Initials:______________
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Some data about your disease will be linked to the samples. These data may be used by researchers,
including your diagnosis, disease history, prior treatments, age, gender, and race.  Your data will be de-
identified so that researchers will not know who you are.
It is unlikely that what is learned from these future research studies will have a direct benefit to you.
Because all information and samples will be coded, it will not be possible to share any test results with
you or your study doctors. There are no plans to provide financial compensation to you.
Please place your initials next to “Yes” or “No” for the question below:
My tumor sample(s) may be stored, used and disclosed for future research as described above.
_____ Yes _____ No
Initials        Initials
HOW LONG WILL I BE IN THIS STUDY?
This study involves an initial screening visit (which might last 4-8 hours) to determine if you are eligible 
to be in the study.  If after screening you are eligible for participation and are enrolled in the study, you 
will come to clinic for approximately 7 clinic visits that may last 2-4 hours to be followed for safety 
monitoring and to see if the study drug is working.  If the study drug is working, you may continue for 
as long as you receive benefit or until you decide to stop the study.  After you have stopped taking study 
drug, you will be asked to do a final visit for safety.  Follow up will consist of coming to clinic every 3 
months for routine standard of care visits for up to 2 years or until you choose to stop the study 
completely.   This may be able to be done by review of your medical records.   This can be discussed 
with your study doctor at your end of the study regimen visit.
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
WHAT ARE THE POSSIBLE REASONS THAT I CAN BE REMOVED FROM THE STUDY 
OR THE STUDY MIGHT END?
•
Your disease progresses while on study
•
You experience a deterioration of your condition
•
Requirement for other anti-tumor therapy
•
Non-compliance to taking the study drug in accordance with instructions provided
•
Pregnancy
•
Death
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 8 of 18                                                  Subject*Initials:______________
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•
Lost to follow up
•
Any other reason that, in the opinion of your physician, justifies your removal
•
Sponsor terminates the study for any reason
WHAT ARE THE RISKS OF THE STUDY?
We cannot know the side effects of brigatinib ahead of time. Some of the side effects could be serious or 
even cause death in rare circumstances, and allergic reactions could happen in some people.
Brigatinib may interfere with other drugs that you are taking, or vice versa. You should tell your Study 
Doctor about any changes in your health that develop while you are in this study.
During the study you may have discomforts and risks from brigatinib or from the study procedures. 
Discomforts and risks may vary from person to person. Although we do not know when all the 
discomforts and/or risks may happen, all patients participating in the study will be carefully watched for 
side effects.
It is possible you may experience no discomfort, some, or many discomforts. It is also possible there is 
risk of a rare or previously unknown side effect that may be mild or severe and can be life-threatening or 
fatal. You must tell your Study Doctor any side effects that you experience. Please notify your Study 
Doctor of any visual changes experienced during the treatment course. Your Study Doctor may give you 
treatment to ease the undesirable effects. Your Study Doctor may also stop the study treatment if you 
have a severe reaction to brigatinib. You will be monitored closely for all side effects.
The following list of side effects (all grades) which may be associated with brigatinib have been seen 
with the use of brigatinib.
Very common (reported in more than 10% of patients) included:
•
Low levels of red blood cell count (which can cause you to feel tired)
•
Low levels of a type of white blood cells, including white blood cells called neutrophils and 
lymphocytes (which could increase the risk of infection)
•
Activated partial thromboplastin time (APTT) increased (mean a lack of or low level of one of 
the blood clotting factors or another substance needed to clot blood)
•
High blood sugar levels
•
White blood cell count decreased
•
Decreased appetite
•
Low levels of sodium in the blood
•
Low levels of potassium in the blood
•
Low levels of magnesium in the blood
•
Low levels of phosphate in the blood
•
Headache
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 9 of 18                                                  Subject*Initials:______________
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•
Peripheral neuropathy, a condition in which nerves outside the brain and spinal cord (peripheral 
nerves) have been damaged which can result in symptoms such as numbness, tingling, prickling 
sensation, or pain
•
Dizziness
•
Visual Disturbance
•
High Blood Pressure
•
Cough
•
Shortness of breath
•
Pneumonitis (inflammation of the lung) or Interstitial lung disease (ILD), diseases that affect the 
lungs 
•
Nausea
•
Diarrhea
•
Vomiting
•
Constipation
•
Abdominal pain
•
Increased liver enzymes (Aspartate aminotransferase (AST) increased or Alanine
•
(ALT) increased) which can suggest damage to the liver
•
Increased lipase level (an enzyme measured in the blood that reflects function of the pancreas; 
elevations in lipase may indicate inflammation of the pancreas)
•
Increased amylase level (an enzyme measured in the blood that reflects function of the pancreas; 
elevations in amylase may indicate inflammation of the pancreas)
•
Increased alkaline phosphatase level, an enzyme in the blood produced by the liver and other 
organs
•
Rash includes dermatitis acneiform (appearance similar to acne), erythema (redness of the skin), 
exfoliative rash (redness and peeling of the skin), rash erythematous (redness of the skin or 
mucous membranes, caused by increased blood flow in superficial blood vessels), rash macular 
or rash maculo- papular (a type of rash characterized by a flat, red area on your skin that is 
covered with small connected bumps)
•
Itchy skin
•
Increased creatine phosphokinase level (an enzyme measured in the blood, elevations may 
indicate injury or stress to muscle tissue, the heart, or the brain)
•
Muscle pain
•
Muscle spasms, an involuntary contraction of a muscle, which usually resolve quickly but are 
often painful
•
Joint Pain
•
Fatigue or tiredness
•
Edema (buildup of fluid in the body which causes the affected tissue to become swollen)
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 10 of 18                                                  Subject*Initials:______________
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Common (reported in 1-10% of patients) included:
•
Decreased platelet count (a decrease in platelets, a component of blood whose function is to stop 
bleeding by clumping and clotting blood vessel injuries)
•
Unable to obtain an adequate amount or quality of sleep
•
Distortion of the sense of taste
•
Electrocardiogram QT prolonged (a change in ECG, a study of the electrical system of the heart 
that may indicate an increased risk of serious abnormalities in the heart’s rhythm)
•
Slow heart rate
•
Noticeably rapid, strong, or irregular heartbeats
•
Dry mouth
•
Stomatitis (inflammation of the lining of any of the structures in the mouth, including cheeks, 
gums, tongue, lips, throat and roof or floor of the mouth)
•
Indigestion or upset stomach
•
Dry skin
•
Musculoskeletal chest pain
•
Pain in extremity
•
Fever
•
Non-cardiac chest pain
Because brigatinib shares some features with other drugs already being investigated for non-small cell 
lung cancer and other cancers, it is possible that it will cause similar side effects to those drugs. These 
include visual disturbances, testosterone level decrease, inflammation of lung tissue which can be fatal, 
and liver dysfunction which can be fatal.  Symptoms of liver dysfunction can include weakness, fatigue, 
anorexia, nausea, vomiting, abdominal pain, yellowing of the skin, dark urine, generalized itching, and 
can cause many complications including excessive bleeding. 
Brigatinib may cause side effects that we cannot know about ahead of time, some of which could be 
serious or even cause death in rare circumstances.
You will be monitored closely for these side effects.  If you develop symptoms, your doctors will give 
you the care that you need.  You must tell the study doctor about any new health problems that develop 
while you are in the study.
Reproductive Risks
It is not known what effects brigatinib has on human pregnancy or development of the embryo or fetus. 
Therefore, female patients participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner. 
For Women
If you are a woman who could possibly become pregnant (you have not completed menopause, or you 
have not had a hysterectomy and/or both tubes and/or both ovaries removed), and you have a partner 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 11 of 18                                                  Subject*Initials:______________
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who is able to father children, a blood pregnancy test (using 1 teaspoon of blood drawn from a vein by 
needle stick) will be performed and it must be negative before you can continue in this study.   In 
women 40 years old and older, blood pregnancy tests can sometimes give a false positive or 
indeterminate result, and additional testing may be required to confirm your eligibility.  
You and your partner must agree to either abstain completely from vaginal intercourse for the time you 
sign this consent form until 4 months after the last dose of study drug, or agree to use a highly effective 
method of contraception for the same length of time.  Brigatinib may decrease effectiveness of hormonal 
contraceptives, so birth control pills, implants, injections, patches, or vaginal rings are not allowed in 
this study.  Highly effective methods that are allowed include (a) partner vasectomy, (b) bilateral tubal 
ligation, or (c) intrauterine devices IUDs).   If you and your partner are not currently using one of these 
methods, your study doctor will discuss options with you, given your medical condition, your personal 
preferences, and the level of effectiveness required by this study. 
 
Women should abstain from egg donation, from the time of screening to at least 4 months after the last 
dose of study drug. 
Because no method of birth control is 100% effective, you should notify your study doctor immediately 
if you think there is any chance you could be pregnant.   If pregnancy is confirmed, the study doctor will 
stop your study drugs but continue to follow you during the pregnancy to better understand the potential 
effects of brigatanib on developing pregnancies. 
 
For Men
The effects of brigatanib on developing pregnancies that began while the father was taking the drug are 
not known.  In addition, brigatanib may be transmitted in semen to a partner during sexual activity.   If 
you have a partner who could possibly become pregnant (she has not completed menopause, or she has 
not had a hysterectomy and/or both tubes and/or both ovaries removed), you must agree to either abstain 
completely from vaginal intercourse from the time you sign this consent form until 4 months after the 
last dose of study drug, or agree to use a condom every time you have intercourse, even if you have had 
a vasectomy (because a vasectomy does not prevent transmission of drug in semen).   If your partner is 
currently pregnant, becomes pregnant, or is breastfeeding, you should use a condom for all types of 
intercourse.  You should inform your partner of the potential for harm to an unborn child.  She should 
know that if pregnancy occurs, you will need to report it to the study doctor, and she should promptly 
notify her doctor.  She will be asked for permission to follow the pregnancy to better understand the 
potential effects of brigatanib on developing pregnancies. 
 
Men should not donate sperm from the time of screening until 4 months after the last dose of study drug 
No human data on the effect brigatinib on fertility are available. Based on reproductive studies in male 
animals, brigatinib may cause reduced fertility in males. The clinical relevance of these findings to 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 12 of 18                                                  Subject*Initials:______________
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human fertility is unknown.   If you are concerned about future fertility, your study doctor will discuss 
options for fertility preservation with you. 
Risks of Radiation: 
You may have a number of CT scans and MRI scans that are part of the regular care for your condition, 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk of the research. However, if you have concerns about the overall radiation exposure or MRI 
safety issues, you should discuss them with your physician. 
A possible health problem seen with radiation exposure is the development of cancer later in life. This 
extra cancer risk is higher at younger ages and for girls and women. The extra lifetime risk of dying of a 
fatal cancer due to the radiation exposure from this research may range from about one in 2,000 to about 
one in 1,000. At such low radiation exposures, scientists disagree about the amount of risk. These 
estimates are very uncertain, and there may be no extra risk at all. 
We can compare this possible extra cancer risk to other risks (over a lifetime) that everyone is subject to 
in everyday life. For example, the chances of a person dying of cancer with no extra radiation exposure 
are about one in 4. The chances of dying in a car crash are about one in 82, and the chances of being 
killed by a car while crossing the street are about one in 730.
MRI: 
MRI uses a magnet and radio waves to make images (pictures) of the inside of the head and/or body. 
There have been no ill effects reported from exposure to the magnetism or radio waves used for these 
studies; however, it is possible that harmful effects could be recognized in the future. A known risk is 
that the magnet could attract certain kinds of metal that may cause injury to you. We will ask you about 
metal within your body (this includes certain dyes used in tattoos and body piercings). If there is any 
question about potentially hazardous metal within the body, you will not be able to have an MRI study. 
We will also keep the MR room locked so that no one carrying metal objects enters the room while you 
are having this scan performed. In addition, the MR scanner makes a loud buzzing noise that could 
affect hearing ability. You will be provided with earplugs and assistance in their use in order to protect 
your hearing. You will be able to communicate with the scanner technologist using an intercom and/or 
signaling device. The technologist will try to help you feel as comfortable as possible in the scanner. 
You can ask to stop the scan and be removed from the scanner at any time by using the intercom or 
signaling device
Risks of Tumor Biopsies: 
The biopsy site will depend on where you have superficial tumor located (in the skin or in a lymph 
node). Your study doctor will discuss this and the specific risks of the biopsy with you at the time of the 
procedure. 
A biopsy of the skin or lymph node is generally a non-hazardous procedure, but as with any procedure, 
there are risks and discomforts. For example, you may feel some amount of pain or discomfort during 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 13 of 18                                                  Subject*Initials:______________
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the biopsy, including slight stinging pain when a local anesthetic is injected by needle to numb the area, 
pressure and dull pain where a biopsy needle or punch is inserted,  discomfort from lying still for an 
extended time, and/or  soreness at the biopsy site. Possible hazards may include: 1) reaction to the 
anesthetic (numbing medicine), 2) excessive bleeding at the needle injection site or from the surgical 
incision, 3) redness, bruising and swelling, 4) infection and 5) excessive scarring.
While the local numbing medicine xylocaine is almost entirely free from allergic properties (such as 
causing hives), an allergic reaction is possible, and you will not be given xylocaine if you have a history 
of such a reaction. The xylocaine will be given by a small injection into the skin at the site of the biopsy. 
To speed healing, one or two stiches (also known as sutures) will be placed, which will be removed 5-7 
days later. During the healing process, you will be asked to keep the biopsy site clean and dry, and to 
apply antibiotic ointment. Infection rarely occurs and is largely prevented by the use of an aseptic (or 
sterile) biopsy technique and proper wound care. If infection does occur, you will be instructed to keep 
the wound clean and to apply warm, wet compresses for 15 minutes, three times a day, until the 
infection subsides. If the infection persists, antibiotics may be prescribed.
Any complications arising from the biopsy may be treated with observation, additional medications, or 
in some cases, additional surgery.  The study doctor will discuss the specific risks of the biopsy with you 
at the time of the procedure.  
Risks of Drawing Blood: 
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising.  
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely.
Drug and Food Interactions: 
Other medications may be harmful to take with brigatinib. Brigatinib may interfere with other drugs you 
need or other drugs you take may interfere with brigatinib. For your safety, you must tell the study 
doctor or nurse about all the prescribed medical foods and drugs, herbal products, over-the-counter 
(OTC) drugs, vitamins, natural remedies, and alcohol that you are taking before you start the study and 
before starting to take any of these products while you are on the study. Talk to your study doctor if you 
take any herbal medications (St. John‘s Wort, Blue Cohash, Estroven, etc.) and grapefruit-containing 
products.  These medications may interact with brigatinib.
You may not receive any other anticancer medication while on this study.  
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
Research studies are designed to obtain new knowledge.  If you agree to take part in this study, there 
may be direct medical benefit to you. It is possible that your tumor could shrink temporarily, but that 
cannot be guaranteed. We hope that in the future the information learned from this study will benefit 
other people with your condition.  
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 14 of 18                                                  Subject*Initials:______________
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WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
Instead of being in this study, you have the following alternatives: standard of care treatment for your 
type of lung cancer, palliative care (treatment of your symptoms only), or no treatment. Please talk to 
your doctor about these and perhaps other options (other investigational approaches).
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to ATOMIC and its affiliates. In addition, your records may be reviewed in order to meet 
federal or state regulations. Reviewers may include representatives from the Food and Drug 
Administration, representatives and affiliates of ATOMIC, the Duke University Health System 
Institutional Review Board, the Duke Cancer Institute, the National Cancer Institute, the Duke Office of 
Audit, Risk and Compliance (OARC), and others as appropriate. If any of these groups review your 
research record, they may also need to review your entire medical record.
As part of this study, you will be asked to have certain tests, x-rays, and/or procedures performed. Some 
of these tests, x-rays and/or procedures would have been done as part of your regular care. The study 
doctor will use these test results both to treat you and to complete this research.  These test results will 
be recorded in your medical record and will be reported to  representatives and affiliates of ATOMIC. 
Results of tests and studies done solely for this research study and not as part of your regular care will 
not be included in your medical record.
Study information, your study number, and samples collected as part of this study will be included in 
secure electronic trial systems. These systems may be managed and monitored by companies who work 
with the Sponsor.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 15 of 18                                                  Subject*Initials:______________
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designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
The study results will be retained in your research record forever.  Any research information in your 
medical record will also be kept indefinitely.
This information may be further disclosed by the sponsor of this study, ATOMIC.  If disclosed by the 
sponsor, the information is no longer covered by the federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by the federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal,  your name or other personal information will not be revealed.
Genetic Information Nondiscrimination Act (GINA):
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal 
for health insurance companies, group health plans, and most employers to discriminate against you 
based on your genetic information. This law generally will protect you in the following ways:
•
Health insurance companies and group health plans may not request your genetic information 
that we get from this research.
•
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums.
•
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment.
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell 
life insurance, disability insurance, or long-term care insurance.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 16 of 18                                                  Subject*Initials:______________
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study with Dr. Stinchcombe.  At your request, a Financial Counselor in the clinic may provide you with 
an estimate of costs for routine services.
The study sponsor, ATOMIC, has agreed to pay for services and procedures that are done solely for 
research purposes.  Please talk with the PI/study team about the specific services and procedures that the 
sponsor will pay for, and the ones for which you or your insurance will be responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
ATOMIC  will provide the study drug/biologic free of charge to you. If you decide to withdraw from the 
study before it ends, your study doctor may request that you return for a checkup before you stop your 
study drug if he  thinks that stopping it suddenly may harm you and may ask you to complete the tests 
that would ordinarily occur when a person completes the study.
Please ask the research staff if you would like to know more about which tests and studies are being 
done solely for research purposes.
WHAT ABOUT COMPENSATION?
You will not be paid for taking part in this research study. 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury.
If you are injured as a direct result of the Study Drug or any properly performed procedures required by 
the Protocol, the study sponsor, Academic Thoracic Oncology Medical Investigators Consortium, will 
reimburse you or the provider of services for the reasonable and necessary costs of diagnosis and 
treatment you receive for your injuries provided all aspects of the study protocol have been followed 
correctly and the injuries are not the result of the natural progression of your underlying or pre-existing 
conditions or events, unless made worse by your participation in the study.
For questions about the study or research-related injury, contact Dr. Thomas Stinchcombe at (919) 681-
6509 during regular business hours and at (919) 970-2829 after hours and on weekends and holidays.
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 17 of 18                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  All data that have already been 
collected for study purposes, and any new information about an adverse event related to the study, will 
be sent to the study sponsor.
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  Deciding not 
to be in the study or leaving the study before it is done will not affect your relationship with the 
researcher, your health care provider, or institution.
If you do decide to withdraw, we ask that you contact Dr. Stinchcombe in writing and let him know that 
you are withdrawing from the study.  His mailing address is:
Dr. Thomas Stinchcombe
Duke University Medical Center
Morris Building, DUMC, PO Box 3198
30 Medicine Circle
Durham, North Carolina 27710
In addition, you must return all unused study drug to Dr. Stinchcombe or his staff.
Dr. Stinchcombe may ask you to complete the tests that would ordinarily occur when a person 
completes the study.
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at anytime without your consent.  If this occurs, you 
will be notified and your study doctor will discuss other options with you.
For withdrawal of samples: If you want to withdraw your samples from storage, you must contact your 
study doctor, Dr. Thomas Stinchcombe, in writing and let him know you are withdrawing your 
permission for your samples to be stored. His mailing address is stated above. 
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021


Consent to Participate in a Research Study
ATOMIC ARI-AT-002: Phase 2 Trial of Brigatinib after Treatment with
Next-Generation ALK inhibitors in Refractory ALK Rearranged NSCLC
Page 18 of 18
                                                  *
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Thomas Stinchcombe at (919) 681-6509 during regular 
business hours and at (919) 970-2829 after hours and on weekends and holidays.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me.  I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
___________     ____________
Signature of Subject
Date
   Time
__________________________________________
Printed Signature of Subject
   
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
__________________________________________
Printed Signature of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00074492
IRB REFERENCE DATE: 01/14/2020
IRB EXPIRATION DATE: 01/19/2021