Conditions: Brain Metastases Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a single arm phase II study of brigatinib alone for patients with brain metastases from anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), who have either not been treated previously with a tyrosine kinase inhibitor (TKI) targeting ALK or who have had prior exposure to crizotinib.

Detailed description:
In this single-arm phase II trial, patients with brain metastases from ALK+ NSCLC will be treated with brigatinib alone without upfront brain irradiation. Patients will have close monitoring with clinical follow up visits and brain magnetic resonance imaging (MRI) surveillance, which will maximize safety and allow for early treatment if disease progression is observed. If brigatinib alone can demonstrate high rates of CNS disease control, these data could support a strategy of upfront brigatinib alone for carefully selected patients with brain metastases from ALK+ NSCLC.

Arms:
arm 1: Including patients with brain metastases from ALK (anaplastic lymphoma kinase) positive NSCLC (non-small cell lung cancer), who are either neurologically asymptomatic or who have only mild neurologic symptoms (RTOG \[Radiation therapy Oncology Group\] acute neurologic morbidity score 0-2) from their brain metastases, who are TKI (tyrosine kinase inhibitor) naïve or who have had prior exposure to crizotinib, but who are naïve to brigatinib and other ALK TKIs including alectinib, lorlatinib, and ceritinib.

Interventions: intervention 1: Brigatinib
Intervention descriptions: intervention 1: At day 1, all patients will be started on brigatinib 90 mg daily for 7 days, before escalating to 180 mg daily thereafter as tolerated.

Protocol document:
Prot_SAP_000.pdf: 
 
 
1 of 58 
 
Brigatinib Before Brain Irradiation Trial (B3i Trial): A Phase II Trial of Brigatinib 
Alone for Brain Metastases from ALK+ Lung Cancer 
Protocol Number:  
19-2862 
Principal Investigator: 
 
 
Chad Rusthoven, MD 
Department of Radiation Oncology 
1665 Aurora Ct, Room 1032 
Mail Stop F706 
Aurora, CO 80045 
Phone: 720-848-5376 
Fax: 720-848-0113 
Coordinating 
Center 
and 
Lead 
Principal 
Investigator:  
University of Colorado 
Chad Rusthoven, MD 
Funded by:  
Takeda 
 
 
 
PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change 
Brief Rationale  
V.2 
03/02/2021 
Addition of risk to sun 
exposure. Clarification of study 
visit windows, SAE/AE 
reporting language, and follow 
up language. General protocol 
clarifications. 
Changes made due to brigatinib 
memo from Takeda. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
2 of 58 
Version 
Date 
Description of Change 
Brief Rationale  
V.3 
09/01/2021 
Changed PI, Clarified AE/SAE 
reporting language 
 
V.4 
9/14/2021 
Changed PI 
Temporary PI change due to PI going 
on leave. 
V.5 
TBD 
Changed PI 
PI has returned from leave. 
 
 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
3 of 58 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................................... 5 
LIST OF ABBREVIATIONS ............................................................................................................................ 6 
1 
PROTOCOL SUMMARY ......................................................................................................................... 8 
1.1 
Synopsis ....................................................................................................................................................... 8 
1.2 
Study Schema ........................................................................................................................................... 10 
1.3 
Schedule of Events ................................................................................................................................... 11 
2 
INTRODUCTION ..................................................................................................................................... 13 
2.1 
Study Rationale ......................................................................................................................................... 13 
2.2 
Background ................................................................................................................................................ 13 
2.3 
Risk/Benefit Assessment ......................................................................................................................... 15 
2.3.1 
Known Potential Risks ...................................................................................................................... 15 
2.3.2 
Known Potential Benefits ................................................................................................................. 15 
2.3.3 
Assessment of Potential Benefits ................................................................................................... 15 
3 
OBECTIVES AND ENDPOINTS ............................................................................................................ 16 
4 
STUDY DESIGN ...................................................................................................................................... 18 
4.1 
Overall Design ........................................................................................................................................... 18 
4.2 
Scientific Rationale for Study Design ..................................................................................................... 19 
4.3 
Justification for Dose ................................................................................................................................ 19 
4.4 
End of Study Definition ............................................................................................................................. 19 
5 
STUDY POPULATION ............................................................................................................................ 20 
5.1 
Inclusion Criteria........................................................................................................................................ 20 
5.2 
Exclusion Criteria ...................................................................................................................................... 22 
5.3 
Lifestyle Considerations ........................................................................................................................... 23 
5.4 
Screen Failures ......................................................................................................................................... 23 
5.5 
Strategies for Recruitment and Retention ............................................................................................. 23 
6 
STUDY INTERVENTION ........................................................................................................................ 24 
6.1 
Study Intervention(s) Administration ...................................................................................................... 24 
6.1.1 
Study Intervention Description ........................................................................................................ 24 
6.1.2 
Dosing and Administration ............................................................................................................... 24 
6.2 
Preparation/Handling/Storage/Accountability ....................................................................................... 32 
6.2.1 
Acquisition and Accountability ......................................................................................................... 32 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................................... 32 
6.2.3 
Product Storage and Stability .......................................................................................................... 33 
6.2.4 
Preparation ......................................................................................................................................... 33 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................................. 33 
6.4 
Study Intervention Compliance ............................................................................................................... 33 
6.5 
Prohibited Therapy .................................................................................................................................... 33 
6.6 
Concomitant Therapy ............................................................................................................................... 34 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................................... 35 
7.1 
Discontinuation of Study Intervention (Stopping Rules) ...................................................................... 35 
7.2 
Participant Discontinuation/Withdrawal from Study ............................................................................. 35 
7.3 
Lost to Follow-Up ...................................................................................................................................... 36 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 36 
8.1 
Efficacy Assessments .............................................................................................................................. 36 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
4 of 58 
8.1.1 
CNS Surveillance: ............................................................................................................................. 36 
8.1.2 
Extracranial surveillance .................................................................................................................. 38 
8.1.3 
Quality of life (QOL) assessments. ................................................................................................. 38 
8.2 
Safety and Other Assessments .............................................................................................................. 39 
8.3 
Adverse Events and Serious Adverse Events ...................................................................................... 39 
8.3.1 
Definition of Adverse Events (AE) .................................................................................................. 39 
8.3.2 
Definition of Serious Adverse Events (SAE) ................................................................................. 39 
8.3.3 
Classification of an Adverse Event ................................................................................................. 39 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 41 
8.3.5 
Adverse Event Reporting ................................................................................................................. 41 
8.3.6 
Serious Adverse Event Reporting .................................................................................................. 43 
8.3.7 
Product Complaints or Medication Errors (Including Overdose) ................................................ 43 
8.3.8 
Reporting of Pregnancy ................................................................................................................... 44 
8.4 
Unanticipated Problems ........................................................................................................................... 45 
8.4.1 
Definition of Unanticipated Problems (UAP) ................................................................................. 45 
8.4.2 
Reporting of Unanticipated Problems ............................................................................................ 46 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 46 
9.1 
Statistical Hypotheses .............................................................................................................................. 46 
9.2 
Sample Size Determination ..................................................................................................................... 47 
9.3 
Population for Analyses ........................................................................................................................... 47 
9.4 
Statistical Analyses ................................................................................................................................... 48 
9.4.1 
General Approach ............................................................................................................................. 48 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ................................................................................ 48 
9.4.3 
Analysis of the Secondary Endpoint(s) .......................................................................................... 48 
9.4.4 
Safety Analyses ................................................................................................................................. 49 
9.4.5 
Baseline Descriptive Statistics ........................................................................................................ 49 
9.4.6 
Planned Interim Analyses ................................................................................................................ 49 
9.4.7 
Tabulation of Individual Participant Data ....................................................................................... 50 
9.4.8 
Exploratory Analyses ........................................................................................................................ 50 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 50 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................................. 50 
10.1.1 
Informed Consent Process .............................................................................................................. 50 
10.1.2 
Confidentiality and Privacy .............................................................................................................. 51 
10.1.3 
Future Use of Stored Specimens or Data ..................................................................................... 52 
10.1.4 
Safety Oversight ................................................................................................................................ 53 
10.1.5 
Clinical Monitoring ............................................................................................................................. 54 
10.1.6 
Quality Assurance and Quality Control .......................................................................................... 54 
10.1.7 
Data Handling and Record Keeping ............................................................................................... 54 
10.1.8 
Protocol Deviations ........................................................................................................................... 55 
10.1.9 
Publication and Data Sharing Policy .............................................................................................. 56 
10.1.10 Conflict of Interest Policy ................................................................................................................. 56 
11 
REFERENCES .................................................................................................................................... 56 
 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
5 of 58 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The principal investigator (PI), Chad Rusthoven, MD is 
conducting the study and acting as the sponsor.  As the sponsor-investigator, both the legal/ethical 
obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United States 
(US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812), as applicable.  
 
 
The PI will assure that no changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB). All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments.  
 
 
 
Sponsor-Principal Investigator:    
 
 
 
 
 
  
 
 
 
 
 
 
                        Print/Type Name  
 
 
Signature:    _________________________________ 
 
 
 Date:   
 
 
 
  
 
Site Principal Investigator:   
 
 
 
 
 
 
 
 
  
 
           Print/Type Name  
 
 
Signature:    _________________________________ 
 
 
 Date:   
 
 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
6 of 58 
LIST OF ABBREVIATIONS 
ACRONYM 
DESCRIPTION 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
BM  
Brain metastases  
CBC  
Complete blood count  
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CMP 
Comprehensive metabolic panel 
CMP  
Clinical monitoring plan 
CNS  
Central nervous system  
CR 
Complete response 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P40 enzymes 
DCR 
Disease Control Rate 
DSMC 
Data and Safety Monitoring Committee 
ECOG-PS 
Eastern Cooperative Oncology Group – Performance Status 
EORTC 
European Organization for Research and Treatment of Cancer  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
HIV 
Human immunodeficiency virus 
IIT 
Investigator-Initiated Trial 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
MI 
Myocardial Infarction 
MRI 
Magnetic resonance imaging 
NCCN  
National Comprehensive Cancer Network  
NCCTG 
North Central Cancer Treatment Group 
NCI 
National Cancer Institute 
NSCLC  
Non-small cell lung cancer  
OHRP 
Office of Human Research Protection 
ORR 
Objective response rates 
PCI 
Percutaneous Coronary Intervention 
PD 
Progressive Disease 
PET/CT 
Positron emission tomography-computed tomography 
PI 
Principal Investigator 
PR 
Partial Response 
QLQ 
Quality of Life Questionnaire 
QOL  
Quality of life  
RANO 
Response Assessment in Neuro-Oncology Criteria 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
7 of 58 
ACRONYM 
DESCRIPTION 
RECIST  
Response Evaluation in Solid Tumors Criteria  
RT  
Radiation therapy  
RTOG 
Radiation therapy Oncology Group 
SAE 
Serious Adverse Event 
SD 
Stable disease 
SRS  
Stereotactic radiosurgery  
T2/FLAIR 
T2 Weighted fluid attenuated inversion recovery 
TKI 
Tyrosine kinase inhibitor 
UAP 
Unanticipated Problem 
UCCC 
University of Colorado Cancer Center 
UCD 
University of Colorado Denver 
WBRT 
Whole-brain radiotherapy 
 
 
 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
8 of 58 
1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol Title: 
Brigatinib Before Brain Irradiation Trial (B3i Trial): A Phase II Trial of 
Brigatinib Alone for Brain Metastases from ALK+ Lung Cancer 
Objectives: 
 
• Primary Objective: 
1. To evaluate if CNS control is acceptable with a strategy of 
brigatinib alone for patients with ALK+ lung cancer with brain 
metastases 
 
• Secondary Objectives:  
1. To evaluate time until progression with brigatinib alone 
2. To evaluate overall survival with a strategy of brigatinib alone 
3. To evaluate the best CNS objective response rates (ORR) with 
brigatinib alone 
4. To evaluate the time until the administration of WBRT with 
brigatinib alone 
5. To evaluate longitudinal changes in quality of life with brigatinib 
alone 
 
 
Endpoint: 
• Primary Endpoint: 
1. Disease Control Rate (DCR) of brain metastases at 3 months 
(13-week MRI ±7 days) where DCR is defined as complete 
response (CR), partial response (PR), or stable disease (SD) as 
defined by the RANO-BM criteria. 
 
• Secondary Endpoints: 
1a. Time until any CNS progressive disease (PD) by RANO-BM 
criteria and rates at follow up intervals (up to 24 months from Day 
1). 
1b. Time until any local PD (ie, in brain lesions identified at the 
time of enrollment) by RANO-BM criteria and rates at follow up 
intervals (up to 24 months from Day 1). 
1c. Time until any distant brain PD (ie, new brain lesions that were 
not present at the time of enrollment) by RANO-BM criteria and 
rates at follow up intervals (up to 24 months from Day 1). 
1d. Time until progression at any site using RANO-BM for 
intracranial disease and RECIST for extracranial disease and rates 
at follow up intervals (up to 24 months from Day 1). 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
9 of 58 
2a. Time until death from any cause and rates at follow up 
intervals (up to 24 months from Day 1). 
2b. Time until brain metastases-specific mortality, defined as 
intracranial progression as a component of cause of death and 
rates at follow up intervals (up to 24 months from Day 1). 
3. Cumulative rate of best responses individually for complete 
response (CR), partial response (PR), stable disease (SD), by 
RANO-BM criteria 
4. Time until the administration of whole brain-radiotherapy 
(WBRT) and rates at follow up intervals (up to 24 months from 
Day 1). 
5. Quality of life will be assessed using standardized QOL metrics 
(EORTC QLQ C30/BN 20) 
 
• Exploratory:  
1. Analysis of blood at baseline and at progression to correlate 
blood-based markers with clinical outcomes. 
2. To characterize corticosteroids administration before and after 
brigatinib initiation 
 
Population: 
• Sample size 
o Maximum number of participants that can be enrolled is 
35 (allow for screen failures)  
o Minimum number of participants to be enrolled 19 
(number of participants needed to answer scientific 
question/aims) 
• Gender Male and Female 
• Age Range 18-100 years 
• Demographic group: Patients with brain metastases from ALK+ 
lung cancer without prior treatment with brigatinib 
• General health status: ECOG ≤2 
• Geographic location: United States 
 
Phase: 
II 
Participating Sites: 
University of Colorado, Mayo Rochester, City of Hope Los Angeles 
Description of Study 
Intervention: 
Brigatinib, an oral tyrosine kinase inhibitor (TKI) targeting anaplastic 
lymphoma kinase (ALK) 
Study Duration: 
4 years 
Participant 
Duration:  
2 years 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
10 of 58 
1.2 
STUDY SCHEMA 
 
 
*Patients with prior exposure to brigatinib, alectinib, lorlatinib, and ceritinib are excluded.


PI: Chad Rusthoven, MD 
Protocol #:   19-2862 
Version Date:  29DEC2021 
11 of 58 
1.3 
SCHEDULE OF EVENTS 
 
Screen/ 
Enroll 
Year 1 
Year 2 
(Week) 
End of 
Treatment 
Survival 
Follow Up 
Day 
Week 
Procedures 
≤28 
days 
Day 1 
Day 
1 
Day 
8c 
3c 
13d 
26e 
39e 
52e 
65e 
78e 
91e 
104e 
Terminationj 
Every 6 
months for 
up to 2 years 
from Day 1f 
Informed Consent/Review Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Brain 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
QOL Assessmentsb 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinic Visit (complete physical exam) 
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 
 
Pregnancy Test (WOCBP only)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds (including corticosteroids 
agent and dose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Labs (CBC, CMP, CPK, Lipase, Amylase)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Research Blood for cfDNA 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
RECIST 1.1/RANO-BM  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Systemic Imaging (CT C/A±P or PET/CT) 
X, 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Brigatinib Administrationa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CNS 
Radiation 
for 
Brain 
Metastases 
Progression (as indicated per PI/Sub-I) 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
Vitals Collection (BP, spO2 and HR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and Disease Status, Current Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
3-month intervals are defined as 13 weeks (52 weeks per 12 months / 4) 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
12 of 58 
a All patients will be started on brigatinib 90 mg daily for 7 days, before escalating to 180 mg daily thereafter as tolerated 
b EORTC QLQ-C30 and BN20 brain-specific questionnaire  
c Day 8 and Week 3 procedures have a window of ± 4 days from Day 1 
d Week 13 procedures have a window of ± 7 days 
e All time points 26 weeks and onwards inclusive have a window of ± 14 days 
f For patients removed from study treatment prior to 24 months (Week 104), survival follow-up will be done every 6 months (±14 days from Termination Visit) for up to 24 months 
from Day 1, or until death or patient withdrawal of consent; this includes for patients who develop CNS progression while on study 
g Pregnancy Test (for WOCBP only) should also be performed prior to any radiation therapy subsequent to enrollment including radiation for brain or extracranial disease 
according to SOC. 
h Baseline neurologic symptoms should be scored per Cox, James D., et al "Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for 
research and treatment of cancer (EORTC)." International Journal of Radiation Oncology• Biology• Physics 31.5 (1995): 1341-1346. Only patients with neurologic symptoms from 
their brain metastases that are grade 0, 1, 2 are eligible for inclusion; patients with grade 3 and 4 neurologic symptoms are excluded (see section 5). Scale: Grade 0 (no 
neurologic symptoms), Grade 1 (Fully functional status (i.e., able to work) with minor neurological findings, no medication needed), Grade 2 (Neurological findings present 
sufficient to require home care/nursing assistance may be required/medications including steroids/antiseizure agents may be required), Grade 3 (Neurological findings requiring 
hospitalization for initial management), Grade 4 (Serious neurological impairment that includes paralysis, coma, or seizures > 3 per week despite medication/hospitalization 
required) 
iCNS salvage radiation therapy will be done in the event of brain metastases progression, per treating investigator 
jFor patients discontinuing study treatment prior to Week 104, termination visit assessments (other than CNS salvage therapy, if required) are to occur within 30 days of last 
dose of study drug. If patient continues on study treatment until Week 104, the study termination visit is to occur at Week 104 (month 24) and patients may transition to SOC 
brigatinib at that time, if still receiving clinical benefit. 
k Baseline systemic imaging (CT or PET/CT only) performed per standard of care within 6 weeks (42 days) of Day 1 will be permitted 


PI: Chad Rusthoven, MD 
Protocol #:   19-2862 
Version Date:  29DEC2021 
13 of 58 
 
2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Patients with metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase 
(ALK) mutations that can be targeted with oral tyrosine kinase inhibitors (TKIs) have an excellent 
prognosis compared to historic data on NSCLC patients without targetable mutations. Brain 
metastases (BM) are common in patients with ALK+ lung cancer and BM have historically been 
treated with radiation therapy either to the entire brain with whole-brain radiotherapy (WBRT) 
or focally with stereotactic radiosurgery (SRS). Radiation therapy (RT) is effective for the control 
of brain metastases, but can be associated with toxicity to cognitive function and quality of life. 
Newer generation of TKIs targeting ALK, including brigatinib, have demonstrated increased CNS 
penetration and activity in the treatment brain metastases. This raises the possibility of a new 
paradigm in the treatment of ALK+ NSCLC brain metastases involving brigatinib alone and 
reserving radiation therapy to the brain as a salvage therapy option for subsequent CNS 
progression. However, there have not been dedicated trials designed to prospectively evaluate a 
strategy of brigatinib alone for brain metastases.  
 
In this single-arm phase II trial, patients with ALK+ brain metastases who are either TKI naïve or 
have had prior crizotinib, but without prior treatment with brigatinib or other CNS-penetrant TKIs 
(e.g., alectinib, lorlatinib, and ceritinib), will be treated with brigatinib alone in the setting of close 
clinical follow up and brain magnetic resonance imaging (MRI) surveillance to maximize safety 
and allow for early intervention with radiation therapy in the event any CNS progression occurs. 
If brigatinib alone can offer high rates of CNS disease control in this setting, this data could 
contribute to a change in paradigm in the treatment of BM in ALK+ NSCLC that would allow more 
patients to delay or avoid the potential sequelae of CNS RT. 
2.2 
BACKGROUND 
Brain metastases (BM) are a significant problem for patients with non-small cell lung (NSCLC) 
driven by anaplastic lymphoma kinase (ALK) gene rearrangements. Up to 30-40% of ALK NSCLC 
patients will present with BM at diagnosis and over 70% will ultimately develop BM (Rusthoven 
2016). Crizotinib, a first-generation ALK inhibitor has demonstrated relatively poor CNS 
penetration and limited CNS activity (Costa 2015). As a result, historically, ALK+ NSCLC patients 
treated with crizotinib who developed BM were treated with early administration of CNS 
radiotherapy (RT) as the standard of care. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
14 of 58 
CNS RT is effective at treating BM but can significantly affect quality-of-life (QOL) and cognitive 
function. In the EORTC 22952-26001 trial, the use of WBRT was associated with inferior global 
QOL at 9 months and inferior cognition at 1 year compared to radiosurgery alone (Soffieti 2011). 
In the NCCTG-N0574, WBRT was associated with an objective decrease in cognition at 3 months, 
which persisted for 1 year in long term survivors (Brown 2016). 
Brigatinib is a next-generation TKI with FDA approval for the treatment of metastatic ALK NSCLC. 
Brigatinib has notably demonstrated promising central nervous system (CNS) activity in the 
treatment and prevention of BM. In a multicenter phase II trial, brigatinib provided an intracranial 
objective response of 67% in crizotinib-refractory patients with measurable BM at enrollment 
(Kim 2017). In a phase 3 trial comparing brigatinib to a crizotinib, the intracranial response rate 
for measurable BM at enrollment was 78% with brigatinib vs 29% with crizotinib (Camidge 2018). 
The observation of high intracranial ORRs with brigatinib raises the possibility of a new paradigm 
for the treatment of patients with ALK+ NSCLC brain metastases with drug alone and reserving 
CNS RT for patients who subsequently develop CNS progression. 
Prospective investigations of CNS RT de-intensification strategies are particularly important for 
ALK+ NSCLC, where patients are often younger at diagnosis and experience prolonged median 
survival of >4 years after the identification of brain metastases, which is more than long enough 
to manifest potential cognitive sequelae from CNS RT. For example, in a multi-institutional study 
of ALK+ NSCLC treated in the crizotinib era, the median OS was 49.5 months post BM; 50% 
required ≥2 courses of RT, 25% required ≥3 courses of RT, and 50% required WBRT (Johung 2016). 
Given the impressive CNS response rates with brigatinib in subgroup analyses of patients with 
brain metastases treated on prior prospective trials, there is now strong rationale and 
justification for prospective trials dedicated to the evaluation of a strategy of brigatinib alone, for 
patients with ALK+ NSCLC brain metastases, reserving CNS RT for CNS progression. In particular, 
clinicians considering brigatinib alone for ALK+ patients with BM will require prospective data 
demonstrating the safety and efficacy of brigatinib alone in this setting. Short-term outcomes, 
such as CNS disease control at 3 months, are important in order to demonstrate that a strategy 
of brigatinib will not result in harm or missed opportunities to offer effective salvage therapies. 
Here we propose a prospective phase II trial of brigatinib alone for patients with BM. If, as we 
hypothesize, brigatinib can offer high rates of CNS disease in this setting, this data could 
contribute to a change in paradigm in the treatment of BM in ALK+ NSCLC that would allow more 
patients to delay or avoid the potential sequelae of CNS RT. 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
15 of 58 
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
KNOWN POTENTIAL RISKS 
 
This study involves the treatment of patients with BM from ALK+ NSCLC with brigatinib alone and 
close clinical and MRI surveillance (delaying CNS RT until potential CNS progression, if that were 
to occur in the future). The primary risk is the potential for higher rates of CNS progression, which 
is the focus of the trial and the primary endpoint of the study. BM can cause neurologic 
symptoms, anxiety, require treatments, and may be potentially life threatening in some cases. 
For this reason, the study involves close clinical follow up and MRI surveillance, to allow early 
interventions if CNS progression were to occur in patients treated on the trial.  
 
Additional risks are related to the side effect profile of the drug brigatinib. Brigatinib is an FDA 
approved standard therapy in the first and subsequent lines for patients with metastatic ALK+ 
NSCLC according to the contemporary NCCN non-small cell lung cancer guidelines. The side effect 
profile of brigatinib is detailed in subsequent sections of the protocol. In patients who develop 
CNS progression and require CNS RT, the standard risks associated with CNS RT including fatigue, 
hair loss, headaches, nausea, and small risks of seizure, radiation necrosis, and focal neurologic 
deficits apply. It is important to note that CNS RT is considered the gold standard treatment for 
brain metastases, endorsed by the contemporary NCCN CNS tumor guidelines (v2.2019) and the 
above risks are considered standard side effects with radiation in this setting that are applicable 
to patients treated on or off protocol. 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
This study involves the treatment of patients who have BM with brigatinib alone (delaying CNS 
RT until potential CNS progression, if that were to occur in the future). The benefit patients in 
this arm may achieve is the effective treatment of their BM with a single modality (brigatinib 
alone) while avoiding or delaying the need for CNS RT. CNS RT can be associated with a negative 
impact on QOL and cognition, as well as logistical stress and anxiety.  
2.3.3 
ASSESSMENT OF POTENTIAL BENEFITS 
 
The risks to participants are reasonable in relation to the anticipated benefits to participants 
and/or society, and in relation to the importance of the knowledge that may reasonably be 
expected to result, thereby falling in favor of performing the study: 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
16 of 58 
• To Participant: Patients enrolling on this trial may benefit from a single-
modality approach (i.e., brigatinib alone without CNS radiation) for the 
treatment of their disease while avoiding the potential toxicities of CNS 
radiation 
• To Society: Investigations into treatment strategies that can potentially reduce 
toxicity and the number of modalities used to treat an illness are important to 
society and have the potential to reduce toxicities, dependency, and health 
care associated costs and to improve the quality of life for patients and care 
givers. 
• Justify the importance of the knowledge gained: If a treatment strategy of 
brigatinib alone for patients with ALK+ NSCLC brain metastases demonstrates 
acceptable CNS disease control, this study has the potential to improve patient 
QOL and to potentially reduce health care costs in this population. Conversely, 
if a treatment strategy of brigatinib alone results in unacceptable CNS disease 
control rates, this would affirm the historic standard of care of combining 
systemic therapy with CNS RT to treat brain metastases. 
3 
OBECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
To evaluate if CNS control is 
acceptable with a strategy of 
brigatinib alone for patients 
with ALK+ lung cancer brain 
metastases 
Disease Control Rate (DCR) of 
brain metastases at 3 months 
(13-week MRI ±7 days), where 
DCR is defined as complete 
response (CR), partial response 
(PR), or stable disease (SD) as 
defined by the RANO-BM 
criteria. 
It is critical to confirm the short-
term safety and efficacy of a 
treatment approach involving 
brigatinib alone without CNS RT  
Secondary 
1. To evaluate time until 
progression with brigatinib 
alone 
 
1a. Time until any CNS 
progressive disease (PD) by 
RANO-BM criteria and rates at 
follow up intervals (up to 24 
months from Day 1). 
1b. Time until any local PD (i.e., 
in brain lesions identified at the 
time of enrollment) by RANO-
BM criteria and rates at follow 
up intervals (up to 24 months 
from Day 1). 
It is important to evaluate the 
specific elements of disease 
control (including local and 
distant control, as well as CNS 
and extracranial control) with a 
strategy of brigatinib alone. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
17 of 58 
1c. Time until any distant brain 
PD (i.e., new brain lesions that 
were not present at the time of 
enrollment) by RANO-BM criteria 
and rates at follow up intervals 
(up to 24 months from Day 1). 
1d. Time until progression at any 
site using RANO-BM for 
intracranial disease and RECIST 
for extracranial disease and rates 
at follow up intervals (up to 24 
months from Day 1). 
2. To evaluate overall survival 
with a strategy of brigatinib 
alone 
2a. Time until death from any 
cause and rates at follow up 
intervals (up to 24 months from 
Day 1). 
2b. Time until brain metastases-
specific mortality, defined as 
intracranial progression as a 
component of cause of death 
and rates at follow up intervals 
(up to 24 months from Day 1). 
It is important to describe the 
overall survival with a strategy of 
brigatinib alone. 
3. To evaluate the best CNS 
objective response rates (ORR) 
with brigatinib alone 
3. Cumulative rate of best 
responses individually for 
complete response (CR), partial 
response (PR), stable disease 
(SD), by RANO-BM criteria 
It is important to describe the 
rates of responses in existing 
brain lesions with a strategy 
brigatinib alone. 
4. To evaluate the time until 
the administration of WBRT 
with brigatinib alone 
4. Time until the administration 
of whole brain-radiotherapy 
(WBRT) and rates at follow up 
intervals (up to 24 months from 
Day 1). 
It is important to characterize 
the time until WBRT with a 
strategy brigatinib alone, as 
WBRT is associated with known 
toxicities. 
5. To evaluate longitudinal 
changes in quality of life with 
brigatinib alone 
5. Quality of life will be assessed 
using standardized QOL metrics 
(EORTC QLQ C30/BN 20) 
It is important to characterize 
the longitudinal QOL achieved 
with a strategy of brigatinib 
alone. 
Exploratory 
1. Analysis of blood at baseline 
and at progression to correlate 
with clinical outcomes. 
 
1. Evaluation of cfDNA and/or 
other blood-based markers 
at baseline and progression 
to correlate with clinical 
outcomes including disease 
recurrence, survival, and 
quality of life 
Evaluations of cfDNA can offer 
important 
insights 
into 
prognostic 
and 
predictive 
biomarkers for patients with 
metastatic ALK+ NSCLC with 
brain metastases. 
2. To characterize 
corticosteroids 
2.   Quantification of the agent 
and dosage of corticosteroids at 
each study assessment 
It is important to quantify the 
effect 
of 
brigatinib 
on 
corticosteroid 
requirements 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
18 of 58 
administration before and 
after brigatinib initiation 
because corticosteroids can be 
associated with symptoms and 
negative effects on quality of life 
 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a single arm phase-II study including patients with ALK+ NSCLC and brain metastases, who 
are either neurologically asymptomatic or have only mild neurologic symptoms (RTOG acute 
neurologic morbidity score 0-2) from their brain metastases, who are TKI naïve or have had prior 
exposure to crizotinib, but who are naïve to brigatinib and other ALK TKIs including alectinib, 
lorlatinib, and ceritinib. At screening and enrollment, patients will have a history and physical 
exam, CTCAE symptoms assessment, and brief QOL questionnaires.  
At day 1, all patients will be started on brigatinib 90 mg daily for 7 days, before escalating to 180 
mg daily thereafter as tolerated. 
At day 8, patients will be seen for a scheduled clinic visit. Each clinic visit will include toxicity 
assessment and physical exam. Day 8 procedures have an allowable window of ±4 days. Brief 
QOL questionnaires will be administered at baseline (Day 1), at 3 weeks (Day 21), and at 3 months 
(week 13) and subsequent visits every 3 months.  
At 3 weeks (Day 21), patients will be seen for scheduled clinic visits and a scheduled surveillance 
brain MRI. Week 3 procedures have an allowable window of ± 4 days. Subsequently, patients will 
have scheduled clinic visits and surveillance brain MRIs at 3 months post enrollment (week 13) 
and at 3 month intervals for year 1 and 2 (ie, at week 26, 39, 52, 65, 78, 104). 
Patients who develop CNS progression during the study will be offered palliative radiation for 
their brain metastases and their disease status will be recorded as CNS progression event. 
Patients who experience disease progression per RECIST 1.1 or RANO BM may continue to be 
treated with brigatinib if, in the opinion of the treating investigator, they continue to experience 
clinical benefit. Note, this is an accepted treatment strategy per the contemporary NCCN NSCLC 
guidelines. In this case, patients will be removed from study treatment and will be followed for 
survival for up to 24 months from Day 1, but may continue to receive brigatinib per standard of 
care.  


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
19 of 58 
If patients do not experience disease progression, they will complete the study treatment at 24 
months. Patients continuing to benefit from brigatinib in the opinion of the treating physician 
may remain on the drug after 24 months per standard of care.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Brigatinib has demonstrated promising ORRs for patients with existing BM in subgroup analyses 
of prospective phase 2 and 3 trials, as well as prevention of new BM. In a multicenter phase II 
trial, brigatinib provided an intracranial objective response of 67% in crizotinib-refractory 
patients with measurable BM at enrollment (Kim 2017). In a phase 3 trial comparing brigatinib to 
a crizotinib, the intracranial response rate for measurable BM at enrollment was 78% with 
brigatinib vs 29% with crizotinib (Camidge 2018). However, these trials were not designed to 
evaluate the role brigatinib alone in patients with brain metastases and many of the patients 
included in these subset analyses received brain radiation therapy for the brain metastases. The 
current trial proposal is dedicated specifically to the evaluation of brigatinib alone in patients 
with brain metastases with a primary endpoint to evaluate whether this approach results in 
acceptable CNS control. 
4.3 
JUSTIFICATION FOR DOSE 
The dose selected is the standard FDA approved doses for brigatinib. All patients will be started 
on brigatinib 90 mg daily for 7 days, before escalating to 180 mg daily thereafter.  
4.4 
END OF STUDY DEFINITION 
Individuals will be followed for 2 years from Day 1, or until death or patient withdrawal of 
consent; this includes patients who develop CNS progression while on study. Participants are free 
to withdraw from participation in the study at any time upon request. Patients who continue to 
benefit from brigatinib in the opinion of the treating physician may stay on brigatinib beyond 2 
years per standard of care. The study will conclude when the final patient on study reaches 2 
years of follow up, or is removed from the study.  
 
 
 
 
 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
20 of 58 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all the following 
criteria: 
1. Provision to sign and date the consent form. 
2. Stated willingness to comply with all study procedures and be available for the duration 
of the study. 
3. Ability to take and retain oral medications. 
4. Be a male or female aged ≥18 years. 
5. Patients with ALK+ lung cancer with evidence of ≥1 previously untreated brain metastases 
on brain MRI. Prior therapy (radiation or surgery) for brain metastases is allowed, similar 
to other prospective trials of systemic therapy alone for BM (e.g., Tawbi et al, NEJM, 379.8 
(2018): 722-730). However, patients must have ≥1 previously untreated at the time of 
enrollment. 
6. Patients may be ALK TKI naïve OR have had prior crizotinib therapy.  
7. Patients may be included if they are asymptomatic from their brain metastases 
(RTOG/EORTC grade 0) or if they have mild symptoms from their brain metastases not to 
exceed RTOG/ EORTC grade 1 or 2  (Grade 1: Fully functional status (i.e. able to work) with 
minor neurological findings, no medication needed; Grade 2: Neurological findings 
present sufficient to require home care / nursing assistance may be required / 
medications including steroids/anti-seizure agents may be required) (Cox, James D., et al 
"Toxicity criteria of the radiation therapy oncology group (RTOG) and the European 
organization for research and treatment of cancer (EORTC)." International Journal of 
Radiation Oncology• Biology• Physics 31.5 (1995): 1341-1346). See table below for acute 
CNS symptom grading. 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
21 of 58 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
(excluded) 
Grade 4 
(excluded) 
No neurologic 
symptoms 
Fully 
functional 
status (i.e., 
able to work) 
with minor 
neurological 
findings, no 
medication 
needed 
Neurological findings 
present sufficient to 
require home care/ 
nursing assistance may 
be required/medications 
including steroids/ 
antiseizure agents may 
be required 
Neurological 
findings 
requiring 
hospitalization 
for initial 
management 
Serious 
neurological 
impairment that 
includes 
paralysis, coma, 
or seizures > 3 
per week 
despite 
medication/ 
hospitalization 
required 
 
8. Neurologically symptomatic patients must not require immediate surgical or radiation 
therapy for their symptoms, as decided by an investigator. 
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.  
10. Have adequate organ function, as determined by 
o ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable if liver 
metastases are present 
o Total serum bilirubin ≤1.5 × ULN (<3.0×ULN for patients with Gilbert syndrome) 
o Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the 
modification of diet in renal disease (MDRD) equation 
o Serum lipase/amylase ≤1.5 × ULN 
o Absolute neutrophil count (ANC) ≥1.5 × 109/L 
o Platelet count ≥75 × 109/L 
o Hemoglobin ≥9 g/dL 
11.  For females of childbearing potential, have a negative pregnancy test documented prior 
to initiating brigatinib. 
12. For female and male patients who are fertile, agree to use 2 effective methods of 
contraception with their sexual partners 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. Brigatinib may decrease effectiveness of hormonal 
contraceptives, therefore, women are recommended to use non-hormonal methods of 
contraception. Highly effective non-hormonal birth control for women of child bearing 
potential with male partners includes:                 
• Sexual abstinence (no sexual intercourse) 
• Intrauterine device (IUD) or intrauterine system (IUS) 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
22 of 58 
• Bilateral tubal ligation (both tubes tied) 
• Vasectomized partner 
13. 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 completely abstain from 
heterosexual intercourse. 
14. Patient is willing and able to comply with avoiding prolonged sun exposure while taking 
brigatinib, and for at least 5 days after discontinuation of treatment. 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Patients who have received prior brigatinib therapy or other CNS-penetrant ALK TKIs, 
including alectinib, lorlatinib, or ceritinib. 
2. RTOG/EORTC Acute CNS symptoms, grade 3 and 4 (Grade 3: Neurological findings 
requiring hospitalization for initial management; Grade 4: Serious neurological 
impairment that includes paralysis, coma, or seizures > 3 per week despite medication / 
hospitalization required). 
3. Be pregnant, planning a pregnancy, or breastfeeding. 
4. Have clinically significant, uncontrolled cardiovascular disease per investigator, 
specifically including, but not restricted to:  
a. Myocardial infarction (MI) within 6 months prior to the first dose of study drug  
b. Unstable angina within 6 months prior to first dose of study drug 
c. Clinically significant congestive heart failure (CHF) within 6 months prior to first 
dose of study drug  
d. History of clinically significant atrial or ventricular arrhythmia (including clinically 
significant bradyarrhythmia), as determined by the treating physician  
e. Cerebrovascular accident or transient ischemic attack within 6 months prior to first 
dose of study drug 
5. Have uncontrolled hypertension per the investigator. Patients with persistent 
hypertension of systolic ≥140 or diastolic ≥90 mm Hg should be under treatment on study 
entry to control blood pressure.  
6. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related 
pneumonitis, or radiation pneumonitis. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
23 of 58 
7. Have an ongoing or active infection, including, but not limited to, the requirement for 
intravenous (IV) antibiotics. 
8. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not 
required in the absence of history. 
9. Have a known or suspected hypersensitivity to brigatinib or its excipients. 
10. Additional systemic therapies for the treatment of lung cancer may not be taken 
concomitantly with brigatinib (eg, TKIs, immunotherapy, chemotherapy). No washout 
period is required for prior therapy. 
11. Have malabsorption syndrome or other GI illness that could affect oral absorption of 
brigatinib. 
12. Have any condition or illness that, in the opinion of the investigator, would compromise 
patient safety or interfere with the evaluation of brigatinib. 
13. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong 
cyp3a inducers, or moderate cyp3a inducers within 14 days before enrollment.    
14. Had major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures 
such as catheter placement or minimally invasive biopsies are allowed. 
15. Have been diagnosed with another primary malignancy other than NSCLC, except for  
adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively 
treated nonmetastatic prostate cancer; or patients with another primary malignancy who 
are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other 
primary malignancy. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Lifestyle considerations are similar to patients treated with metastatic ALK+ NSCLC in other 
settings. Patients should contact their physicians immediately if they develop new or worsening 
neurologic symptoms or side effects suspected to be related to brigatinib therapy.  
5.4 
SCREEN FAILURES 
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures. Once the investigator determines that screening 
will not continue for a patient, and the patient will not be enrolled in the study, the screen failure 
should be documented. Patients who screen fail may later be re-screened with prior sponsor-
investigator approval. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
24 of 58 
Patient and physician interest in enrollment is expected to be high given the strong clinical 
rationale to support a strategy of brigatinib alone with close clinical and MRI surveillance as a 
potential strategy to avoid the toxicity of CNS RT. We anticipate that retention rates will be high 
given that the follow-up requirements are similar to the standard of care with the exception of 
the 1-week clinic visit and 3-week clinic visit and brain MRI. These additional follow up 
requirements are considered appropriate to ensure the safety of the brigatinib alone approach. 
All other clinic visits and follow up MRIs are considered to be consistent with the standard-of-
care. 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
 
All patients will be started on brigatinib 90 mg daily for 7 days, before escalating to 180 mg daily 
thereafter. 
 
The clinical follow-up and imaging requirements are similar to the standard of care with the 
exception of the 1-week clinic visit and 3-week clinic visit and brain MRI. These additional follow-
up requirements are considered appropriate to ensure the safety of the brigatinib alone 
approach. 
 
Patients who develop CNS progression will be treated with standard of care CNS RT, as prescribed 
by a board-certified radiation oncologist. CNS RT may entail stereotactic radiosurgery (SRS), 
WBRT, or partial brain radiotherapy, as appropriate in the opinion of the radiation oncologist. 
For guidance on radiation techniques and doses, adherence to the NCCN CNS tumor guidelines 
for brain metastases section (www.ncccn.org) is recommended. 
 
6.1.2 
DOSING AND ADMINISTRATION 
 
The recommended dosing regimen for brigatinib is 90 mg orally once daily for the first 7 days. If 
90 mg is tolerated per investigator during the first 7 days, increase the dose to 180 mg orally once 
daily.  
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
25 of 58 
If brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume 
treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. 
Interruptions due to treatment related AEs should be managed as per section 6.1.2.2 and 6.1.2.3 
below. 
 
Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not 
crush or chew tablets. If a dose of brigatinib is missed or vomiting occurs after taking a dose, do 
not administer an additional dose and take the next dose of brigatinib at the scheduled time. 
6.1.2.1 
RECOMMENDED BRIGATINIB DOSE REDUCTION LEVELS 
Table 1: Recommended Brigatinib Dose Reduction Levels 
Starting Dose 
Dose Reduction Levels 
 
First 
Second 
Third 
Fourth 
Fifth 
90mg QD 
60mg QD 
Permanently 
discontinue 
Not applicable 
Not applicable 
Not 
applicable 
180mg QD 
120mg QD 
90mg QD 
60mg QD 
Permanently 
discontinue 
Not 
applicable 
 
6.1.2.2 DOSE MODIFICATIONS FOR PNEUMONITIS 
 
Pneumonitis and interstitial lung disease are known side effects of TKIs used in NSCLC, generally 
occurring later in the course of therapy. Crizotinib has been associated with severe, life-
threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 
255 (1.6%) patients. Other TKIs used in the treatment of NSCLC have similar adverse reactions. 
In the ALTA trial, brigatinib was associated with pneumonitis in 3.7% of patients in the 90 mg 
group (90 mg once daily) and 9.1% of patients in the 90 → 180 mg group (180 mg once daily with 
7-day lead-in at 90 mg once daily).  Adverse reactions consistent with possible ILD/pneumonitis 
occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of 
patients, with Grade 3 to 4 reactions occurring in 2.7%.  
 
Drug-related pneumonitis may be associated with signs and symptoms such as dyspnea, hypoxia, 
cough, hemoptysis, and fever as well as radiologic evidence of parenchymal or interstitial 
changes. The diagnosis of pneumonitis and determination of causal relationship to the drug is 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
26 of 58 
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 oxygen saturation, evaluation 
for infectious etiologies, and thoracentesis, bronchoscopy, or open lung biopsy should be 
considered to reach a diagnosis. If the causality is at least possibly related to the study drug, 
management of pneumonitis, including dose interruption and potential discontinuation, as 
presented in during first 7 days of treatment prior to escalation to 180 mg QD) and after 
escalation to 180 mg QD), is required. 
 
BRIGATINIB 
DOSE 
MODIFICATION 
RECOMMENDATIONS 
FOR 
TREATMENT-RELATED 
PNEUMONITIS OCCURRING PRIOR TO DOSE ESCALATION TO 180 MG QD (IE, FIRST 7 DAYS OF 
TREATMENT): 
 
Toxicity Grade 
(CTCAE v4.03) 
Recommended Action 
Grade 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.* 
Grade 2 
Withhold the dose until pneumonitis returns to Grade 0, then resume at 60 
mg and do not escalate.* 
If pneumonitis recurs, permanently discontinue treatment.* 
Grade 3 
Permanently discontinue treatment.* 
Grade 4 
Permanently discontinue treatment.* 
*Or in select cases per investigator discretion and discussion with Lead PI, consider continued 
use/shallower dose escalation as per Camidge et al, JTO 2019 
 
BRIGATINIB 
DOSE 
MODIFICATION 
RECOMMENDATIONS 
FOR 
TREATMENT-RELATED 
PNEUMONITIS OCCURRING AFTER DOSE ESCALATION TO 180 MG QD: 
 
Toxicity Grade (CTCAE 
v4.03) 
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 120 mg 
QD.* 
If pneumonitis recurs, permanently discontinue treatment.* 
Grade 3 
Permanently discontinue treatment.* 
Grade 4 
Permanently discontinue treatment.* 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
27 of 58 
*Or in select cases per investigator discretion and discussion with Lead PI, consider continued 
use/shallower dose escalation as per Camidge et al, JTO 2019 
 
 
6.1.2.3 DOSE MODIFICATION RECOMMENDATION TABLE FOR TREATMENT-RELATED 
ADVERSE EVENTS (EXCLUDING PNEUMONITIS)  
 
Table 2: Brigatinib Dose Modification Recommendations for Treatment-Related Adverse Events 
(excluding pneumonitis)  
Adverse Reaction 
Severity* 
Dose Modification 
Hypertension 
Grade 3 hypertension (SBP 
greater than or equal to 160 
mmHg or DBP greater than or 
equal to 100 mmHg, medical 
intervention indicated, more 
than one anti-hypertensive 
drug, or more intensive therapy 
than previously used indicated) 
• 
Withhold brigatinib until 
hypertension has recovered 
to Grade 1 or less (SBP less 
than 140 mmHg and DBP 
less than 90 mmHg), then 
resume brigatinib at same 
dose. 
• 
Recurrence: withhold 
brigatinib until recovery to 
Grade 1 or less, and resume 
at next lower dose (Table 1) 
or permanently discontinue 
treatment. 
Grade 4 hypertension (life-
threatening consequences, 
urgent intervention indicated) 
• 
Withhold brigatinib until 
recovery to Grade 1 or 
less(SBP less than 140 
mmHg and DBP less than 90 
mmHg), and resume at next 
lower dose (Table 1) or 
permanently discontinue 
treatment. 
• 
Recurrence of Grade 4 
hypertension: permanently 
discontinue brigatinib. 
Bradycardia (HR less than 60 
bpm)  
Symptomatic bradycardia 
• 
Withhold brigatinib until 
recovery to asymptomatic 
bradycardia or to a resting 
heart rate of 60 bpm or 
above. 
• 
If a concomitant medication 
known to cause bradycardia 
is identified and 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
28 of 58 
Adverse Reaction 
Severity* 
Dose Modification 
discontinued or dose-
adjusted, resume brigatinib 
at same dose upon recovery 
to asymptomatic 
bradycardia or to resting 
heart rate of 60 bpm or 
above. 
• 
If no concomitant 
medication known to cause 
bradycardia is identified, or 
if contributing concomitant 
medications are not 
discontinued or dose-
adjusted, resume brigatinib 
at next lower dose (Table 1) 
upon recovery to 
asymptomatic bradycardia 
or to resting heart rate of 60 
bpm or above. 
Bradycardia with life-
threatening consequences, 
urgent intervention indicated 
• 
Permanently discontinue 
brigatinib if no contributing 
concomitant medication is 
identified. 
• 
If contributing concomitant 
medication is identified and 
discontinued or dose-
adjusted, resume brigatinib 
at next lower dose (Table 1) 
upon recovery to 
asymptomatic bradycardia 
or to a resting heart rate of 
60 bpm or above, with 
frequent monitoring as 
clinically indicated.  
• 
Recurrence: permanently 
discontinue brigatinib. 
Visual Disturbance  
Grade 2 or 3 visual disturbance 
Withhold brigatinib until 
recovery to Grade 1 or baseline, 
then resume at the next lower 
dose (Table 1) 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
29 of 58 
Adverse Reaction 
Severity* 
Dose Modification 
Grade 4 visual disturbance 
Permanently discontinue 
brigatinib 
Creatine Phosphokinase (CPK) 
Elevation  
Grade 3 CPK elevation (greater 
than 5.0 × ULN) 
• 
Withhold brigatinib until 
recovery to Grade 1 or less 
(less than or equal to 2.5 × 
ULN) or to baseline, then 
resume brigatinib at same 
dose. 
• 
If Grade 3 elevation of CPK 
recurs, brigatinib should be 
withheld until recovery to 
Grade 1 or less (less than or 
equal to 2.5 × ULN) or to 
baseline, then resume at 
the next lower dose level 
per Table 1. 
Grade 4 CPK elevation (greater 
than 10.0 × ULN)  
• 
Withhold brigatinib until 
recovery to Grade 1 or less 
(less than or equal to 2.5 × 
ULN) or to baseline, then 
resume brigatinib at next 
lower dose (Table 1). 
• 
If Grade 4 elevation of CPK 
recurs, permanently 
discontinue brigatinib 
Lipase/Amylase Elevation 
Grade 3 lipase or amylase 
elevation (greater than 2.0 × 
ULN) 
• 
Withhold brigatinib until 
recovery to Grade 1 or less 
(less than or equal to 1.5 × 
ULN) or to baseline, then 
resume brigatinib at same 
dose. 
• 
If Grade 3 elevation of 
lipase and amylase reoccurs, 
brigatinib should be 
withheld until recovery to 
Grade 1 or less (less than or 
equal to 1.5 × ULN) or to 
baseline, then resume at 
the next lower dose level 
per Table 1. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
30 of 58 
Adverse Reaction 
Severity* 
Dose Modification 
Grade 4 lipase or amylase 
elevation (greater than 5.0 × 
ULN)  
• 
Withhold brigatinib until 
recovery to Grade 1 or less 
(less than or equal to 1.5 × 
ULN) or to baseline, then 
resume brigatinib at next 
lower dose (Table 1). 
• 
If Grade 4 elevation of 
lipase/amylase recurs, 
permanently discontinue 
brigatinib 
Hyperglycemia  
Grade 3 (greater than 250 
mg/mL or 13.9 mmol/L) or 
greater 
If adequate hyperglycemic 
control cannot be achieved with 
optimal medical management, 
withhold brigatinib until 
adequate hyperglycemic control 
is achieved and consider 
reduction to the next lower 
dose (Table 1) or permanently 
discontinue brigatinib.. 
Other  
Grade 3 
• 
Withhold brigatinib until 
recovery to baseline, then 
resume at same dose. 
• 
Recurrence: withhold 
brigatinib until recovery to 
baseline, then resume at 
next lower dose or 
discontinue brigatinib (Table 
1). 
Grade 4 
• 
First occurrence: either 
withhold brigatinib until 
recovery to baseline and 
resume at next lower dose 
(Table 1) or permanently 
discontinue. 
• 
Permanently discontinue 
brigatinib for recurrence. 
bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood 
pressure; ULN = upper limit of normal 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
31 of 58 
Adverse Reaction 
Severity* 
Dose Modification 
*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 
(NCI CTCAE v4). 
Asymptomatic lab abnormalities may be excluded pending discussion with the lead PI. Hypertension 
grading should be based on persistent blood pressure readings on optimal therapy, rather than 
specific drug use for the therapy 
 
6.1.2.4 MANAGEMENT OF ADDITIONAL SELECTED TREATMENT-RELATED ADVERSE 
EVENTS 
 
HYPERTENSION 
Blood pressure should be monitored and recorded at each visit. Hypertension detected by at 
least 2 blood pressure measurements should be graded according to NCI CTCAE, v4.03, which 
defines hypertension as a disorder characterized by a pathological increase in blood pressure: a 
repeated elevation in the blood pressure exceeding 140 mmHg for systolic and over 90 mmHg 
for diastolic. For patients who either develop hypertension or experience worsening 
hypertension during treatment with study drug, at the discretion of the investigator, 
antihypertensive medication should be initiated or optimized to achieve target blood pressure 
before interruption or dose reduction of the study drug. If hypertension is persistent despite 
adequate antihypertensive therapy—including titration of antihypertensive medication or 
introduction of additional antihypertensive medications—or if grade 4 hypertension develops, 
dose interruption and reduction is recommended according to the tables above.  
 
 
BRADYCARDIA 
Heart rate should be monitored and recorded at each visit. Brigatinib should be avoided in 
combination with other agents known to cause bradycardia (e.g., beta-blockers, 
nondihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. For 
symptomatic bradycardia, dose interruption and reduction is recommended according to the 
tables above. 
 
PHOTOSENSITIVITY 
Photosensitivity to sunlight has occurred in patients treated with brigatinib. Patients should be 
advised to avoid prolonged sun exposure and tanning beds while taking brigatinib, and for at 
least 5 days after discontinuation of treatment. When outdoors, patients should be advised to 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
32 of 58 
wear a hat and protective clothing, and to use a broad-spectrum UVA/UVB sunscreen and lip 
balm (SPF at least 30) to help protect against potential sunburn. For severe photosensitivity 
reactions (≥ Grade 3), brigatinib should be withheld until recovery to baseline. The dose should 
be modified accordingly. 
 
NAUSEA AND EMESIS 
Nausea should be treated with standard-of-care anti-emetics. Prophylactic anti-emetics may be 
used. 
 
DIARRHEA 
For grade 1 diarrhea, symptomatic care such as loperamide (Imodium®, McNEIL-PPC, Inc.) may 
be given, or no intervention may be undertaken, according to the investigator’s clinical judgment. 
For grade 2 diarrhea, administer loperamide at 4 mg, then 2 mg every 2 to 4 hours until the 
patient is symptom-free for 12 hours. No dose modification is necessary unless the patient does 
not tolerate brigatinib or the symptom recurs. For grade ≥3 despite loperamide, treatment will 
be withheld until recovery to grade ≤1. Secondary prophylaxis in patients who have experienced 
diarrhea with brigatinib treatment is allowed. Other medications and supportive care may be 
added according to the institution’s standard of care. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
Brigatinib tablets will be provided by, Takeda Pharmaceuticals. 
 
The appropriate study personnel will maintain records of study drug receipt and dispensing.  
 
Patients are to be instructed on proper storage, accountability, and administration of brigatinib. 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Brigatinib drug product is supplied as film-coated tablets containing 30 mg of brigatinib active 
pharmaceutical ingredient. Other ingredients are typical pharmaceutical excipients (lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silica, and magnesium 
stearate). The tablet coating is composed of typical pharmaceutical grade coating components 
(talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide). The drug product is 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
33 of 58 
manufactured under current Good Manufacturing Practice in accordance with approved 
procedures. Brigatinib will be supplied in white high-density polyethylene bottles with induction 
sealed caps or blister packs. Bottle or blister pack labels will bear the appropriate label text as 
required by governing regulatory agencies. At a minimum, such text will include product name, 
product strength, number of tablets, and lot number. 
6.2.3 
PRODUCT STORAGE AND STABILITY 
 
Brigatinib tablets should be stored in accordance with the storage instructions on the label. The 
recommended storage condition for brigatinib is under 30°C. Do not refrigerate or freeze. 
6.2.4 
PREPARATION 
 
The study pharmacist or designee at the site will be responsible for handling and dispensing 
brigatinib and completing associated documentary paperwork. Supplies are shipped to the 
investigative site at appropriate intervals, depending on patient accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor or an acceptable 
substitute used by the site. Each time study medication is dispensed for a patient, the following 
information must be recorded: the patient’s initials, the patient’s study number, drug product 
strength (e.g., 30 mg), quantity dispensed with the corresponding lot number, date of 
dispensation, and the initials of the person dispensing the drug. These logs are to be maintained 
by the study pharmacist in the pharmacy throughout the duration of the study and will be 
periodically verified by a representative of the sponsor. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is a prospective, unblinded single arm phase 2 trial. 
6.4 
STUDY INTERVENTION COMPLIANCE 
At clinic visits, patients will be asked by an investigator or coordinator about drug compliance 
and responses will be documented in the patient’s chart. Unused study drug will be returned to 
the Investigational Pharmacy upon completion of each treatment cycle.  
6.5 
PROHIBITED THERAPY 
At enrollment, additional systemic therapies for the treatment of lung cancer may not be taken 
concomitantly with brigatinib (eg, TKIs, immunotherapy, chemotherapy), but there will not be a 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
34 of 58 
required washout period for prior systemic therapies, with the exception of systemic treatment 
with strong cytochrome p-450 (cyp)3a inhibitors, strong cyp3a inducers, or moderate cyp3a 
inducers, which are not permitted within 14 days of study enrollment (refer to current brigatinib 
IB version for comprehensive list). 
 
Patients may be switched to regimens containing these therapies by the treating physician if 
brigatinib is discontinued due to progressive disease or brigatinib intolerance by the patient. 
Disease progression and the associated changes in therapy will be recorded, the patient will be 
removed from study treatment, and they will continue to be followed for survival (for up to 24 
months from Day 1). 
 
Use of alternative or herbal therapy while on study treatment is only allowed if no known 
interactions with the study medication exist and must be documented and approved by the 
sponsor. 
 
6.6 
CONCOMITANT THERAPY 
Corticosteroids for the treatment of cancer-related symptoms from brain metastases or 
extracranial disease are allowed. Prophylactic corticosteroids in the absence of symptoms are 
discouraged. Corticosteroid agent, dose, frequency, and duration recommendations are at the 
discretion of the treating physician.  
 
Medications taken and considered by the treating physician to be related to the patient’s cancer 
will be recorded in the eCRF from first dose of study drug through 30 days after the last dose. 
 
Brigatinib should be avoided in combination with other agents known to cause bradycardia 
(e.g., beta-blockers, nondihydropyridine calcium channel blockers, clonidine and digoxin) to the 
extent possible.  
 
 
Potential drug interactions: 
In vitro studies with human liver microsomes indicate that cytochrome P450 (CYP) 2C8 and 
CYP3A4 are involved in the human metabolism of brigatinib. Medications and dietary (grapefruit-
containing products) or herbal products (St John’s Wort) that are strong inhibitors or inducers of 
CYPs, in particular, CYP2C8 or CYP3A4, should be avoided. Brigatinib is not a reversible inhibitor 
of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, with IC50 values of >70 μM. Brigatinib is also 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
35 of 58 
not a metabolism-dependent or a time-dependent inhibitor of the CYPs tested. Hence, drug-drug 
interactions (DDIs) due to inhibition of CYPs by brigatinib are unlikely. 
 
The list of drugs that interact with CYP450 enzymes (notably, CYP2C8 and CYP3A4, 5, and 7) can 
be found online at http://medicine.iupui.edu/clinpharm/ddis/table.aspx [Accessed: 
October 6, 2019]. Drugs listed should be avoided if possible. Note: The website should be used 
as a guideline and is not necessarily comprehensive. It is the investigator’s responsibility to 
ensure that any drugs under consideration have not been newly identified as CYP inhibitors. 
 
For 
reference, 
FDA 
label 
information 
for 
brigatinib 
may 
also 
be 
found 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdf  
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION (STOPPING RULES) 
The Sponsor-Investigator has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
o The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 
o Patient enrollment is unsatisfactory. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
o Patient withdrawal of consent at any time 
o Any medical condition that the Sponsor-Investigator determines may jeopardize the 
patient’s safety if he or she continues in the study. 
o Sponsor-Investigator determines it is in the best interest of the patient. 
o Patient non-compliance with study procedures as determined by investigator 
o Lost to follow-up (see section 7.3). 
 
Patients must discontinue study treatment if they experience any of the following: 
o Intolerable toxicity as determined by the investigator. 
o Progression of disease requiring an alternate therapy, in the opinion of investigator 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
36 of 58 
o Pregnancy. 
o Patient withdrawal of consent or decision to discontinue participation. 
 
At the time of withdrawal, all study procedures outlined for the End of Treatment visit should be 
completed. Every effort should be made to obtain information on patients who withdraw from 
the study. The primary reason for withdrawal from the study or study drug discontinuation 
should be documented on the appropriate eCRF. 
 
7.3 
LOST TO FOLLOW-UP 
A subject will be considered lost to follow-up if he or she fails to return for ≥ 3 scheduled visits 
and is unable to be contacted by the study staff. 
 
The following actions must be taken if a subject fails to return to clinic for a required study visit: 
• Site will attempt to contact the subject and reschedule the missed visit and advise subject 
on importance of maintaining assigned visit schedule 
• Before a subject is deemed lost to follow-up, study staff will make three documented 
attempts to contact the subject.  Should the subject continue to be unreachable, he or 
she will be considered to have withdrawn from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
CNS SURVEILLANCE:  
 
Patients will have surveillance brain MRIs at week 3 (± 4 days), 3 months (13 weeks ±7 days), then 
every 3 months (±14 days). CNS disease status will be graded (complete response, partial 
response, stable disease, progressive disease) per the modified RANO-BM criteria (Lin, et al The 
lancet oncology 16.6 (2015): e270-e278). Per modified RANO-BM, brain lesions with a 
unidimensional diameter of ≥5mm are evaluable as measurable lesions.   
 
 
Complete Response 
Partial Response 
Stable Disease 
Progressive Disease 
Target lesion 
None 
≥30% decrease in 
sum longest 
distance relative to 
baseline 
<30% decrease 
relative to baseline 
but <20% increase 
in sum longest 
≥20% increase in 
sum longest 
distance relative to 
nadir* 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
37 of 58 
 
Complete Response 
Partial Response 
Stable Disease 
Progressive Disease 
distance relative to 
nadir 
Non-target lesions 
None 
Stable or improved 
Stable or improved 
Unequivocal 
progressive 
disease* 
New lesion (s)† 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decreased 
Stable or decreased 
Not applicable‡ 
Clinical status 
Stable or improved 
Stable or improved 
Stable or improved 
Worse* 
Requirements for 
response 
All 
All 
All 
Any 
* Progression occurs when this criterion is met. 
† A new lesion is one that was not present on prior scans and is visible in minimum two projections. If a new 
lesion is equivocal, for example because of its small size, continued therapy can be considered, and follow-up 
assessment will clarify if the new lesion is new disease. If repeat scans confirm there is definitely a new lesion, 
progression should be declared using the date of the initial scan showing the new lesion. For immunotherapy-
based approaches, new lesions alone to do not define progression. 
‡ Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 
 
 
TARGET LESIONS 
COMPLETE RESPONSE: 
Disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no 
use of corticosteroids, and patient is stable or improved clinically. 
 
PARTIAL RESPONSE: 
At least a 30% decrease in the sum longest diameter of CNS target lesions, taking as reference 
the baseline sum longest diameter sustained for at least 4 weeks; no new lesions; stable to 
decreased corticosteroid dose; stable or improved clinically. 
 
PROGRESSIVE DISEASE: 
At least a 20% increase in the sum longest diameter of CNS target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, at least one lesion must increase by an absolute value of 5 mm 
or more to be considered progression. 
 
STABLE DISEASE: 
Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum longest diameter while on study. 
 
NON-TARGET LESIONS 
Non-target lesions should be assessed qualitatively at each of the imaging time points specified 
in the protocol. 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
38 of 58 
COMPLETE RESPONSE: 
Requires all of the following: disappearance of all enhancing CNS non-target lesions, no new CNS 
lesions. 
 
NON-COMPLETE RESPONSE OR NON-PROGRESSIVE DISEASE: 
Persistence of one or more non-target CNS lesion or lesions. 
 
PROGRESSIVE DISEASE: 
Any of the following: unequivocal progression of existing enhancing non-target CNS lesions, new 
lesion(s) (except while on immunotherapy-based treatment), or unequivocal progression of 
existing tumor-related non-enhancing (T2/FLAIR) CNS lesions.  
8.1.2 
EXTRACRANIAL SURVEILLANCE 
 
Patients will have surveillance imaging of the body at 3 months (13 weeks ± 7 days) and then 
every 3 months (± 14 days) for 2 years or as required for standard of care by the investigator. At 
the discretion of the investigator, the patient may have a computed tomography (CT) scan of the 
chest/abdomen, with or without the pelvis OR a positron emission tomography–computed 
tomography (PET/CT) scan. Extracranial disease status will be graded per standard RECIST 1.1 
criteria (Eisenhauer et al. "New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1)." European journal of cancer 45.2 (2009): 228-247.) 
8.1.3 
QUALITY OF LIFE (QOL) ASSESSMENTS.  
 
QOL will be assessed using the EORTC QLQ-C30 and BN20 brain-specific questionnaire. The 
EORTC QLQ-C30 is one of the most frequently used questionnaires in cancer patients, and the 
BN20 is a supplemental questionnaire specifically developed for use with the QLQ-C30 in patients 
with brain cancer. Both tools have robust psychometric properties resulting from rigorous 
testing, development, and external validity, and have been used in numerous of oncology trials 
(Efficace 2002). Specific to PCI, the QLQ-C30 and BN20 have been used in the RTOG PCI trials 
(RTOG 0212 and 0214) (Gondi 2013), the EORTC 08993-22993 PCI trial (Slotman 2007), and the 
Intergroup PCI trial (Le Pechoux 2011). The questionnaires are translated and validated in over 
80 languages. Use of the questionnaires requires no monetary charge in the non-commercial 
setting. Together, the questionnaires typically take under 5 minutes to complete, and collection 
is planned at baseline and with each planned clinical surveillance visit (with the exception of Day 
8). 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
39 of 58 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Adverse events will be assessed at scheduled clinical follow up visits or any intervening time when 
new adverse events are reported by enrolled patients. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means untoward or unfavorable medical occurrence considered to be related to 
a study intervention or treatment in humans.  
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
Serious adverse event or serious suspected adverse reaction. An AE or suspected adverse 
reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization 
or prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious 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 this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 
SEVERITY OF EVENT 
 
The adverse event severity grading scale for the NCI CTCAE (v4.03) will be used for assessing 
adverse event severity. The following table will be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE (v4.03). 
Grade             Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
40 of 58 
Grade             Severity 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-
appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated  
5 
Death related to adverse event  
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. Note: Based 
on 
the 
most 
recent 
version 
of 
NCI 
CTCAE 
(v4.03), 
which 
can 
be 
found 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, 
using the toilet, and taking medications, as performed by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event. 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
 
Only adverse events directly related to study treatment or procedures will be recorded. All 
serious adverse events, both related and not related, will be reported per section 8.3.6. If 
there is any doubt as to whether a clinical observation is related or not related to the study 
treatment or procedures, the event should be reported as related. 
To help assess, the following guidelines will be used.  
• Related – The AE is known to occur with the study procedures, there is a reasonable 
possibility that a study procedure caused the AE, or there is a temporal relationship 
between the study procedure and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study procedures and the AE. 
• Not Related – There is not a reasonable possibility that the study procedure caused 
the event, there is no temporal relationship between the study procedure and event 
onset, or an alternate etiology has been established.  
8.3.3.3 
EXPECTEDNESS 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
41 of 58 
Expectedness will only be documented for SAEs. An SAE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent. 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor. All study intervention-related AEs including local and systemic reactions not meeting 
the criteria for SAEs will be captured on the appropriate CRF. Information to be collected includes 
event description, date of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and date of 
resolution/stabilization of the event. All study drug or intervention-related AEs and SAEs, as well 
as unrelated SAEs occurring while on study must be documented appropriately. All study 
intervention-related AEs and SAEs, as well as unrelated SAEs will be followed to adequate 
resolution per investigator (e.g., to grade 1 or baseline) during the study treatment period for up 
to 2 years from Day 1. After the study treatment period of 2 years from Day 1, AEs will be 
managed by the treating physicians per standard of care. 
 
Any medical condition that is present at the time the participant is screened up through the 
patient’s first dose of study treatment will be considered as baseline medical history and will not 
be reported as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Investigators will record all reportable events with start dates occurring any time after the first 
dose of study medication until 30 days after the last day of study treatment. SAEs will be followed 
until resolution or stabilization. At each study visit, the investigator will inquire about the 
occurrence of AE/ SAEs since the last visit.  
8.3.5 
ADVERSE EVENT REPORTING 
 
The investigator must record related non-serious adverse events and report to DSMC and IRB 
according to timetable for reporting specified in section 10.1.6.  
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
42 of 58 
Adverse Events may be spontaneously identified by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments or other 
clinical finding attributed as related to the study treatment or intervention is considered to be an 
AE.  When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.   
 
All Adverse Events which are serious must be reported per section 8.3.6 to Takeda 
Pharmacovigilance (or designee), sponsor-investigator, and the University of Colorado DSMC 
from the first dose of brigatinib up to and including 30 days after administration of the last dose 
of brigatinib.  In addition, new primary malignancies that occur during the follow-up periods must 
be reported, regardless of causality to study regimen, for a minimum of three years after the last 
dose of the investigational product, starting from the first dose of study drug. All new cases of 
primary malignancy must be reported to Takeda Pharmacovigilance (or designee). 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial and the attribution is determined to be 
related to the study intervention (e.g., surgery was performed earlier or later than planned).  All 
SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness (es). 
 
Since this is an investigator-initiated study, the principal investigator Chad Rusthoven, MD, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency and to the sponsor- investigator’s EC or IRB.    
 
Regardless of expectedness or causality, all events meeting SAE criteria must be reported in 
English to Takeda Pharmacovigilance or designee, to the sponsor-investigator, and to the 
University of Colorado DSMC (see additional SAE reporting instructions in section 8.3.6): 
Fatal and Life-Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
All other serious (non-fatal/non life threatening) events within 24 hours of the 
sponsor-investigator’s observation or awareness of the event 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
43 of 58 
E-mail: takedaoncocases@cognizant.com 
 
    
 
8.3.6 
 SERIOUS ADVERSE EVENT REPORTING 
 
The investigator must record all serious adverse events and report to DSMC and IRB according to 
timetable for reporting specified in section 10.1.4.  
 
 
All SAEs will be reported using the FDA 3500A Mandatory MedWatch report form. SAE form can 
be found at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
 
To submit an SAE, email as follows within 24 hours of becoming aware of the event: 
To:  
 
Chad.Rusthoven@cuanschutz.edu  
cpdm.iit@cuanschutz.edu 
DSMC@cuanschutz.edu 
takedaoncocases@cognizant.com 
Subject: 
19-2862 SAE Report Form 
 
Attach: 
SAE form completed and signed by the Investigator 
 
Follow-up of unresolved serious adverse events  
Any SAEs that are unresolved at the time of the initial report submission should be followed up 
by the investigator for as long as medically indicated, and an updated SAE report submitted at 
the time new information regarding the event becomes available.  
8.3.7 
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 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
44 of 58 
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.  
 
For Product Complaints or Medication Errors (Including Overdose), contact Takeda Pharmacovigilance  
Phone: 1-844-ONC-TKDA (1-844-662-8532) 
Email: MedInfoUS@takeda.com.  
 
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  
 
8.3.8 
REPORTING OF PREGNANCY 
 
While a pregnancy test will be performed on female participants of childbearing potential as part 
of the screening process to ensure no pregnant patients are enrolled, all participants of 
childbearing potential will be counseled to utilize appropriate contraception.  If a pregnancy does 
occur in a female patient on trial, the pregnancy will be reported as an SAE.  The outcome of all 
pregnancies of female study subjects (spontaneous miscarriage, elective termination, normal 
birth or congenital abnormality) must be followed up and documented even if the participant 
was discontinued from the study treatment.  Should pregnancy occur during a participant’s trial 
participation, the participant will be immediately discontinued from the study treatment and 
followed-up per trial protocol. 
 
If a pregnancy occurs, the following must be documented in the SAE report: 
• Relevant family history 
• Previous pregnancies (overall number, deliveries, spontaneous miscarriages, etc.) 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
45 of 58 
• Current pregnancy (last menstrual period, expected delivery date, any 
amniocentesis, chorionic villus sampling, in-vitro fertilization) 
• Outcome of pregnancy (i.e. full term, premature birth, spontaneous miscarriage, 
elective termination.  If premature birth, specify gestational age in weeks.  If 
elective abortion, specify any medical reason) 
• Details of birth (i.e. DOB, weight, sex, healthy baby, sick baby, congenital 
anomaly/birth defect, still birth, multiple births, sickness manifestations, etc.) 
• Any complications, infections, illness during pregnancy 
 
8.3.8.1 
 PROCEDURES FOR REPORTING DRUG EXPOSURE DURING PREGNANCY 
AND BIRTH EVENTS 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor-investigator must fax a completed MedWatch Form to the Takeda Pharmacovigilance 
or designee immediately (see Section 8.3).  The pregnancy must be followed for the final 
pregnancy outcome (i.e., delivery, still birth, miscarriage) and Takeda Pharmacovigilance or 
designee will request this information from the sponsor-investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s participation 
in this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form 
to the Takeda Pharmacovigilance or designee.  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
 
Pregnancy Reporting Form: 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UAP) 
 
The Office of Human Research Protection (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
46 of 58 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
This study will use the OHRP definition of UAP. 
8.4.2 
REPORTING OF UNANTICIPATED PROBLEMS 
 
Incidents or events that meet the OHRP criteria for UAPs require the creation and completion of 
a UAP report. It is the Site PI’s responsibility to report UAPs to their IRB. The Lead PI is responsible 
for reporting the UAP to the IRB and the UCCC DSMC. The UAP report will include the following 
information: 
• Protocol-identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents a UAP; 
• A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UAP. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
• Primary Efficacy Endpoint(s): 
Disease Control Rate (DCR) of brain metastases at 3 months (13-week MRI), where DCR is 
defined as complete response (CR), partial response (PR), or stable disease (SD) as defined 
by the RANO-BM criteria. The primary analysis will test the following hypotheses: 
 
H0:  p ≤ 0.60 
 
H1:  p ≥ 0.90 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
47 of 58 
where p represents the proportion of patients who meet the DCR criteria. 
 
• Secondary Efficacy Endpoint(s): 
1a. Time until any CNS progressive disease (PD) by RANO-BM criteria 
1b. Time until any local PD (ie, in brain lesions identified at the time of enrollment) by 
RANO-BM criteria 
1c. Time until any distant brain PD (ie, new brain lesions that were not present at the time 
of enrollment) by RANO-BM criteria 
1d. Time until progression at any site using RANO-BM for intracranial disease and RECIST 
for extracranial disease 
2a. Time until death from any cause 
2b. Time until brain metastases-specific mortality, defined as intracranial progression as 
a component of cause of death  
3. Cumulative rate of best responses for complete response (CR), partial response (PR), 
stable disease (SD), by RANO-BM criteria 
4. Time until the administration of whole brain-radiotherapy (WBRT) 
5. Quality of life will be assessed using standardized QOL metrics (EORTC QLQ C30/BN 20) 
 
• Exploratory Endpoint(s): 
1. Quantification of corticosteroid agent and dose at screening and at each clinical 
assessment 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
The goal of this single arm phase 2 trial is to demonstrate specifically the short-term safety and 
efficacy of a strategy of brigatinib alone for patients with asymptomatic or mildly symptomatic 
brain metastases. Using contemporary prospective data on brigatinib (Camidge, et al. 
"Exploratory Analysis of Brigatinib Activity in Patients with Anaplastic Lymphoma Kinase-Positive 
Non–Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials" Journal of Clinical 
Oncology (2018): JCO-2017), our alternate hypothesis (H1) is that brigatinib alone will result in a 
CNS disease control rate (DCR) of 90% at 3 months in this population. An upper 1-sided 1-sample 
exact binomial test with 19 analyzable patients will have 88.5% power to detect a difference 
between the null hypothesis (H0) of 60% or less DCR and H1, assuming a type-1 error rate of 0.025.   
Assuming a 20% dropout rate, it is expected that 23 patients would need to be enrolled to yield 
19 evaluable patients (i.e. completers). 
9.3 
POPULATION FOR ANALYSES 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
48 of 58 
This is a modified intent-to-treat analysis. Patients who enroll and initiate brigatinib and undergo 
the 3-month (13-week) brain MRI assessment will be analyzed for the study primary endpoint. 
Secondary endpoints related to safety, tolerability or duration of therapy/progression will be 
conducted on all who start brigatinib. 
9.4 
STATISTICAL ANALYSES 
9.4.1 
GENERAL APPROACH 
 
Standard statistical conventions will be used, such as statistical hypotheses will be tested 
controlling the type 1 error rate at 0.05 for 2-sided tests and at 0.025 for 1-sided tests, and p-
values less than 0.05 will be considered significant.  When confidence intervals are reported 95% 
confidence intervals will be used.  In addition to the formal statistical tests of the primary and 
secondary endpoints, descriptive summary statistics will be produced.  All analyses will be 
performed by a biostatistician in the University of Colorado Cancer Center Biostatistics Core.  The 
full analysis data set includes all patients who are enrolled onto the trial.  The safety data set 
includes all patients who receive at least one treatment of brigatinib.  SAS® software 9.4 M5 (SAS 
Institute Inc., Cary, NC, USA) or later will be used for the statistical analyses of the study.  
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy endpoint is 3-month Disease Control Rate (DCR) of brain metastases (based 
on the 13-week MRI), where DCR is defined as complete response (CR), partial response (PR), or 
stable disease (SD) as defined by the RECIST 1.1 criteria and brain metastases are defined per 
RANO-BM criteria.  A 1-sided 1-sample exact binomial test will be performed to test the null 
hypothesis (H0) that p ≤ 0.60, where p represents the proportion of patients who meet the DCR 
criteria.  With 19 evaluable patients, the test will have 88.5% power to detect an alternative 
hypothesis value of p ≥ 0.90 when the type 1 error rate is controlled at 0.025.  In addition to the 
hypothesis test, the proportion of patients meeting the 3-month DCR definition will be 
summarized using the sample proportion and a 95% exact confidence interval. 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints include several time-to-event endpoints:  4 measuring time-to-progression 
(time-to-CNS PD, time-to-local PD, time-to-distant brain PD, and time until PD at any site), 2 
measuring time-to-death (overall and metastases-specific mortality), as well as time-to-
administration of WBRT.  All time-to-event endpoints will be analyzed using Kaplan-Meier 
product-limit methods and summarized graphically using Kaplan-Meier survival plots.  In 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
49 of 58 
addition, secondary endpoints will be summarized descriptively, including the rates of events, 
progressive disease, and survival at the follow up intervals (up to24 months from Day 1).  
Cumulative rates of best CNS objective response with be described. For QOL, scores from the 
QLQ-C30 and BN20 will be normalized to 0-100 scales, changes from baseline of ≥10 points will 
be considered clinically meaningful, and cumulative changes at each assessment with be 
described and time-to-event outcomes for declines in QOL will be summarized graphically using 
Kaplan-Meier and cumulative incidence plots.  
 
9.4.4 
SAFETY ANALYSES  
 
Safety will be measured via the CTCAE Version 4.03 criteria and the rate and type of adverse event 
(AE) will be compared to historical controls and assessed for any increased risk.  Listings will be 
produced of all study-related AEs, which will be reviewed by the study PI.  Additionally, any serious 
adverse event (SAE) will be reported within 24 hours to the study PI who will investigate the 
attribution of the SAE to the experimental treatment and only continue the study if the 
experimental treatment is considered safe.  
 
9.4.5 
BASELINE DESCRIPTIVE STATISTICS 
 
Subject baseline characteristics will be summarized using descriptive statistics.  Quantitative 
variables will be summarized using both measures of the center and spread as well as quantiles 
of each variable’s distribution (e.g. Mean, SD, Minimum, Q1, Median, Q3, and Maximum).  
Qualitative variables will be summarized using counts and percentages.   
9.4.6 
PLANNED INTERIM ANALYSES 
 
This study is designed to enroll approximately 23 patients in order to yield 19 evaluable patients.  
Given this relatively small sample size, there are no planned interim analyses for efficacy or 
futility. After 19 evaluable patients have completed a 3-month brain MRI (allowing for analysis of 
the primary endpoint of DCR of brain metastases at 3 months), an initial analysis of the primary 
endpoint and short-term data on secondary endpoints may be performed. 
9.4.6.1 
SUB-GROUP ANALYSES 
 
Subgroup analyses will be conducted as necessary in order to inform the sensible design of 
follow-up studies to this trial.  The purpose of such subgroup analyses will be to investigate 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
50 of 58 
which subgroups demonstrated favorable response rates to the experimental treatment of 
brigatinib.  
9.4.7 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Listings will be created from all study data, grouped by domain (e.g. demographics, adverse 
events, lab values, outcome data, etc.).  
9.4.8 
EXPLORATORY ANALYSES 
 
Blood will be collected at baseline and at progression. For exploratory analyses, circulating free 
(cf) DNA levels and/or other blood-based markers will be correlated with measured study 
endpoints including overall survival, disease progression, and quality of life. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 
INFORMED CONSENT PROCESS 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product.  
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
  
Informed consent process will be initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of participation will be provided to the participants and their families.  
 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
51 of 58 
comprehension of the purposes, procedures, and potential risks of the study and of their rights 
as research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants will have the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study.  
 
The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 
CONFIDENTIALITY AND PRIVACY 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor-investigator(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor-investigator, representatives 
of the IRB or pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the University of Colorado Cancer. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by the University of Colorado 
Cancer Center research staff will be secured and password protected. At the end of the study, all 
study databases will be de-identified and archived at the University of Colorado Cancer Center. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
52 of 58 
 
 
10.1.3 
FUTURE USE OF STORED SPECIMENS OR DATA 
 
• Intended Use: Samples and data collected under this protocol may be used to study 
blood-based markers associated with clinical outcomes on brigatinib therapy. No 
germline genetic testing will be performed.  
• Storage: Access to stored samples will be limited using freezers stored in badge-
protected research areas. The freezer also has a lock to prevent tampering. Samples and 
data will be stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the samples and 
data. 
• Tracking: Data will be tracked using REDCap and OnCore.  
• Disposition at completion of the study: All stored samples will be sent to the Pathology 
Shared Resources. Study participants who request destruction of samples will be 
notified of compliance with such request and all supporting details will be maintained 
for tracking. 
 
Data collected for this study will be analyzed and stored at the University of Colorado Cancer 
Center. After the study is completed, the de-identified, archived data will be transmitted to and 
stored at the Pathology Shared Resource for use by other researchers including those outside of 
the study. Permission to transmit data to the Pathology Shared Resource will be included in the 
informed consent. 
 
With the participant’s approval and as approved by local IRBs, de-identified biological samples 
will be stored at the Pathology Shared Resource with the same goal as the sharing of data with 
the Pathology Shared Resource. These samples could be used for research into the causes of 
NSCLC, its complications and other conditions for which individuals with NSCLC are at increased 
risk, and to improve treatment. The Pathology Shared Resource will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each 
participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, and individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage will not be possible after the study is completed. 
 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
53 of 58 
When the study is completed, access to study data and/ or samples will be provided through the 
Pathology Shared Resource. 
 
10.1.4 
SAFETY OVERSIGHT 
 
The sponsor investigator will be responsible for monitoring the trial per the trial monitoring plan, 
in addition to overseeing the safety and efficacy of the trial including any specimens collected, 
executing the data and safety monitoring (DSM) plan, and complying with all reporting 
requirements to local and federal authorities. This oversight will be accomplished through 
additional oversight from the Data and Safety Monitoring Committee (DSMC) at the University 
of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for ensuring data quality 
and study participant safety for all clinical studies at the CU Cancer Center, which is the 
coordinating institution of this trial. A summary of the DSMC’s activities is as follows: 
 
• Conduct of internal audits  
• Ongoing review of all serious adverse events (SAEs) and unanticipated problems (UAPs) 
• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
 Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to the DSMC, IRB 
and the sponsor investigator per protocol. All SAEs and UAPs are to be reported to the DSMC 
within 7 (for fatal or life-threatening events) or 15 (non-life-threatening events) calendar days of 
the sponsor investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at 
regularly scheduled meetings. Data regarding number of subjects, significant toxicities, dose 
modifications, and treatment responses will be discussed and documented in the meeting’s 
minutes.  
 
The sponsor investigator is responsible for organizing and conducting regularly scheduled 
teleconferences with all participating sites. The sponsor investigator will also be responsible for 
including data from all the participating sites to include the minutes from these regularly 
scheduled teleconferences between the sponsor investigator and the sites within the overall 
trial’s DSM progress report.  
The sponsor investigator will provide a DSM progress report to the CU Cancer Center DSMC on a 
recurring basis (either every six or twelve months based on DSMC vote). The DSM report will 
include a protocol summary, current enrollment numbers, summary of toxicity data to include 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
54 of 58 
specific SAEs, UAPs and AEs, any dose modifications, all protocol deviations, and protocol 
amendments. The DSM report submitted to the DSMC will also include, if applicable, the results 
of any efficacy data analysis conducted. Results and recommendations from the review of this 
progress report by the DSMC will then be provided to the sponsor investigator in a DSMC review 
letter. The sponsor investigator is then responsible for ensuring this letter is submitted to the 
site’s IRB of record at the time of IRB continuing 
 
http://www.ucdenver.edu/academics/colleges/medicalschool/centers/cancercenter/clinicaltrials/
DSMC/Pages/DSMC.aspx 
10.1.5 
CLINICAL MONITORING 
 
Clinical site monitoring will be conducted to ensure that the rights and well-being of human 
participants are protected, that the reported trial data are accurate, complete, and verifiable, 
and that the conduct of the trial is in compliance with the currently approved protocol/ 
amendment(s), with GCP, and with applicable regulatory requirement(s).  
 
Monitoring for this study will be performed by a CU Cancer Center Clinical Monitor in accordance 
with the clinical monitoring plan (CMP), incorporated herein by reference. The CMP describes in 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
of detail monitoring will be performed, and the distribution of the monitoring reports. 
10.1.6 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality Control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/ resolution. 
 
Following written SOPs, the study monitor will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all trial-related sites, source data/ 
documents, and reports for the purpose of monitoring and auditing by the DSMC audit team, and 
inspection by local and regulatory authorities. 
10.1.7 
DATA HANDLING AND RECORD KEEPING 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
55 of 58 
10.1.7.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported.  
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained 
for recording data for each participant enrolled in the study. Data reported in the eCRF derived 
from source documents should be consistent with the source documents or the discrepancies 
should be explained and captured in a progress note and maintained in the participant’s official 
electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into REDCap. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
10.1.7.2 
STUDY RECORDS RETENTION 
 
Study documents should be retained for a minimum of 2 years after the last approval of an 
investigational marketing application and until there are no pending or contemplated 
marketing applications or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by local regulations or institutional policies. No records will 
be destroyed without the written consent of the sponsor, if applicable. It is the responsibility of 
the sponsor to inform the PI when these documents no longer need to be retained.  
10.1.8 
PROTOCOL DEVIATIONS 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or SOP 
requirements. The noncompliance may be either on the part of the participant, the 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
56 of 58 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. These practices are consistent with ICH E6, 
sections: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
• 5.1 Quality Assurance and Quality Control, section 5.1.1. 
• 5.20 Noncompliance, sections 5.20.1 and 5.20.2. 
It is the responsibility of the study team to use continuous vigilance to identify and report 
deviations. All deviations must be addressed in study source documents, and reported to DSMC 
and COMIRB. Protocol deviations must be sent to the local IRB per their guidelines. The site PI/ 
study staff is responsible for knowing and adhering to their IRB requirements. Further details 
about the handling of protocol deviations will be included in the -SOP and/or study procedures 
manual.  
10.1.9 
PUBLICATION AND DATA SHARING POLICY 
 
This study will ensure that the public has access to the published results of this research.  
 
As required, either for publication (the ICMJE or other publication policy), or according to U.S. 
regulations (Section 801 of the Food and Drug Administration Amendments Act of 2007) this 
clinical trial will be registered in a public trials registry including ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine, and the NCI CTRP Registry for cancer clinical 
trials. 
10.1.10 CONFLICT OF INTEREST POLICY 
 
Independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed.by the 
University of Colorado Denver’s (UCD) Office of Regulatory Compliance Conflict of Interest and 
Commitment Management (COIC) program. Persons with a perceived conflict of interest will 
have such conflicts managed in a way that is appropriate to their participation in the trial. Conflict 
of Interest management plans are project-specific and are reviewed at least annually. UCD has 
integrated the institutional conflict of interest management program with its existing program. 
 
 
11 
REFERENCES 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
57 of 58 
 
Rusthoven, Chad G., and Robert C. Doebele. "Management of brain metastases in ALK-positive 
non–small-cell lung cancer." Journal of Clinical Oncology 34.24 (2016): 2814-2819. 
Costa, Daniel B., et al. "Clinical experience with crizotinib in patients with advanced ALK-
rearranged non–small-cell lung cancer and brain metastases." Journal of Clinical Oncology 33.17 
(2015): 1881. 
Soffietti, Riccardo, et al. "A European Organisation for Research and Treatment of Cancer phase 
III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three 
brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life 
results." Journal of clinical oncology 31.1 (2012): 65-72. 
Brown, Paul D., et al. "Effect of radiosurgery alone vs radiosurgery with whole brain radiation 
therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical 
trial." Jama 316.4 (2016): 401-409. 
Kim, Dong-Wan, et al. "Brigatinib in patients with crizotinib-refractory anaplastic lymphoma 
kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial." Journal of 
Clinical Oncology 35.22 (2017): 2490-2498. 
Johung, Kimberly L., et al. "Extended survival and prognostic factors for patients with ALK-
rearranged non–small-cell lung cancer and brain metastasis." Journal of Clinical Oncology 34.2 
(2016): 123. 
National Comprehensive Cancer Network (NCCN) Central Nervous System Cancer Guidelines 
https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf 
National Comprehensive Cancer Network (NCCN) Non-Small Cell Lung Cancer Guidelines 
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdf  
Lin, Nancy U., et al. "Response assessment criteria for brain metastases: proposal from the 
RANO group." The lancet oncology 16.6 (2015): e270-e278. 
Eisenhauer et al. "New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1)." European journal of cancer 45.2 (2009): 228-247. 
Efficace, F., and A. Bottomley. "Health related quality of life assessment methodology and 
reported outcomes in randomised controlled trials of primary brain cancer patients." European 
Journal of Cancer 38.14 (2002): 1824-1831. 


PI: Chad Rusthoven, MD 
Protocol #: 19-2862 
Version Date: 29DEC2021 
58 of 58 
Gondi V, Paulus R, Bruner DW, Meyers CA, Gore EM, Wolfson A, Werner-Wasik M, Sun AY, Choy 
H, Movsas B. Decline in tested and self-reported cognitive functioning after prophylactic cranial 
irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group 
randomized trials 0212 and 0214. International Journal of Radiation Oncology* Biology* 
Physics. 2013 Jul 15;86(4):656-64. 
Le Péchoux, Cécile, et al. "Clinical neurological outcome and quality of life among patients with 
limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in 
the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01)." 
Annals of oncology 22.5 (2010): 1154-1163.