Clinical trial NCT02737501
Conditions: Non-small Cell Lung Cancer Lung Cancer Advanced Malignancies Carcinoma
Keywords: Non-small cell lung cancer Non-small cell lung carcinoma Epithelial lung cancer Squamous cell carcinoma Large cell carcinoma Adenocarcinoma Carcinoma Anaplastic Lymphoma Kinase (ALK) Advanced Cancers Brigatinib AP26113
Sponsor: Ariad Pharmaceuticals
Start date: 2016-05-26; Completion date: 2021-01-29
Enrollment: 275 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic non-small cell lung cancer (NSCLC) participants naive to ALK inhibitors, as evidenced by progression-free survival (PFS).

Detailed description:
The purpose of this phase III, randomized, open-label, comparative, multicenter, international study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC participants who have not previously been treated with an ALK inhibitor. Participants will be stratified by the presence of CNS metastases at baseline and prior chemotherapy used for locally advanced or metastatic disease. Participants will be randomized in a 1:1 ratio to receive either brigatinib, 90 mg orally once daily (QD) for 7 days, then a 180 mg orally QD, or crizotinib, 250 mg orally twice daily (BID). Participants will receive treatment until disease progression, intolerable toxicity, consent withdrawal, or death. Crossover from crizotinib to brigatinib is also permitted.

The total estimated duration of the study is at least 4.5 years, including 1.5 years to accrue participants, with at least 3 years for treatment and follow-up.

Arms: arm 1: Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). arm 2: Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). arm 3: Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Interventions: intervention 1: Brigatinib intervention 2: Crizotinib
Intervention descriptions: intervention 1: Brigatinib tablets intervention 2: Crizotinib tablets

Protocol documents:
Prot_000.pdf: 



Title: A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) versus Crizotinib in 
Patients with ALK-positive Advanced Lung Cancer
NCT Number: NCT02737501
Protocol Approve Date: 12 May 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


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CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3 Multicenter Open-label Study of Brigatinib 
(AP26113) versus Crizotinib in Patients with ALK-positive 
Advanced Lung Cancer 
Protocol Number:
AP26113-13-301
Study Phase:
Phase 3
Product Name:
Brigatinib
IND Reference Number:
IND 110,935
EudraCT Number:
2015-003447-19
Sponsor:
ARIAD Pharmaceuticals, Inc.
a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Protocol Issue Date:
12 May 2020
Version Number:
Version 4.0
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Original Protocol
Version 1.0
22 October 2015
Amendment 01
Version 2.0
21 September 2016
Amendment 02
Version 3.0
17 May 2018
Amendment 03
Version 4.0
12 May 2020
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Protocol Amendment 03 Summary of Changes and Rationale
1.1
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Amendment Number 03
Protocol Version Number 4.0
Amendment Date
12 May 2020
Global
Protocol Amendment Summary and Rationale:
This table describes the changes in reference to the protocol incorporating Amendment 02. The primary reasons for 
this amendment are to:

update the “final statistical analysis” and “End-of Study” due to achievement of the primary efficacy 
endpoint at the pre-planned interim analysis.  The study will close at approximately 3 years after the last 
patient was enrolled because the primary endpoint of blinded Independent Review Committee (BIRC) 
assessed progression-free survival (PFS) met the prespecified critical value at the first interim analysis and 
was confirmed at the second interim analysis.

incorporate administrative changes resulting from the change of sponsor representatives.

Provide clarification for some of the protocol language.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not affecting the conduct 
of the study are included for clarification and administrative purposes only.
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Description of Each Change and Rationale 
Sections Affected by Change
Description 
Rationale 
Location
1. Updated Sponsor representatives 
and contact information 
Administrative
Section 2  Signatory Page 
Section 3  Contact Information 
2. Added the approximate duration 
of patient participation is 4 years
The study will close at 
approximately 3 years after the last 
patient was enrolled because the 
primary endpoint of blinded 
Independent Review Committee
(BIRC) assessed progression-free 
survival (PFS) met the prespecified 
critical value at the first interim 
analysis and was confirmed at the 
second interim analysis.
Section 4  Protocol Synopsis
Section 11.8.1  Approximate 
Duration of Patient Participation
3. Updated the approximate 
duration of the study to 4.5 years
See Item 3 above.
Section 4  Protocol Synopsis
Section 11.8.2  Approximate 
Duration of Study
4. Added that the primary analysis 
of the primary endpoint will be 
performed at the End-of-Study if the 
study ended before 198 events PFS 
events were observed.
Added because the endpoint was 
met at the first interim analysis 
(before 198 events PFS events were 
observed) and was confirmed at the 
second interim analysis.
Section 4  Protocol Synopsis
Section 15.5.2  Primary Efficacy 
Endpoint Analyses
5. Added that analysis of the final 
assessment of overall survival (OS) 
will also be performed at the end of 
the study.
Added because the primary 
endpoint was met at the first interim 
analysis and was confirmed at the 
second interim analysis.
Section 15.5.2  Primary Efficacy 
Endpoint Analyses
6. Added that patients may 
crossover in Arm B (crizotinib) to 
brigatinib with “either” BIRC “or 
“investigator” assessed 
progression.
For logistical purposes. 
Section 11.1Study Procedure 
Description
Section 13.1.2  Continuation of 
Treatment after Disease Progression
7. Added language for 
Acknowledgement of Receipt 
(AOR) when an SAE is submitted 
to Takeda or designee by facsimile.
Sponsor initiated a new process for 
SAE reporting for information sent 
via fax.
Section 14.2.2  Reporting Serious 
Adverse Events
8. Minor editorial revisions 
Administrative
Throughout the protocol
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2
SIGNATURE PAGES
Representatives from Sponsor
2.1
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible sponsor medical officer and other signatories can be found on 
the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
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Investigator Signature
2.2
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this protocol as outlined therein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by the sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure they are 
fully informed about the study drug and the study. I understand that the study may be terminated 
or enrollment suspended at any time by the sponsor, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients.
I agree to conduct this study in full accordance with all applicable regulations.
Investigator’s Signature 
Date (dd-mmm-yyyy)
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3
CONTACT INFORMATION
Sponsor
ARIAD Pharmaceuticals, Inc.
a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
40 Landsdowne Street
Cambridge, MA 02139 
USA
Telephone: +1 (617) 679-7000
Sponsor Medical Monitor:
PPD
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4
PROTOCOL SYNOPSIS
Sponsor
ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceuticals 
International Co.
35 Landsdowne Street
Cambridge, MA 02139-4234
Study Treatment
Brigatinib (AP26113)
Protocol Title
A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) versus Crizotinib in 
Patients with ALK-positive Advanced Lung Cancer 
Development Phase
Phase 3
Summary and Study 
Rationale
Activating gene rearrangements in anaplastic lymphoma kinase (ALK) have been 
identified as driver mutations in approximately 2% to 7% of patients with non-small 
cell lung cancer (NSCLC) (Kwak et al, 2010; Wong et al, 2009). Crizotinib 
(XALKORI® USPI, Pfizer, Inc.) has demonstrated clinical efficacy in ALK+ NSCLC. 
Results from a phase 1 study and a phase 2 single-arm study of crizotinib 
demonstrated objective response rates (ORRs) of 61% and 50%, respectively 
(XALKORI® USPI, Pfizer, Inc.). These 2 studies served as the basis for accelerated 
approval of crizotinib for treatment of ALK+ advanced NSCLC in the United States 
(US) in 2011 and conditional marketing authorization in the European Union (EU) in 
2012. The efficacy of crizotinib in ALK+ NSCLC patients has also been investigated 
in a randomized active-control study against chemotherapy (pemetrexed or docetaxel) 
(XALKORI® USPI, Pfizer, Inc.). A statistically significant improvement in 
progression-free survival (PFS) was observed in patients treated with crizotinib 
compared with patients treated with chemotherapy (hazard ratio, 0.49; 95% CI: 0.37 
to 0.64; p<0.001). A median PFS of 7.7 months was seen with crizotinib versus 
3.0 months with chemotherapy. Regular approval for crizotinib was granted by the 
US Food and Drug Administration (FDA), on the basis of this study, in 2013. In a 
separate randomized active-control study of crizotinib against pemetrexed-platinum 
doublet chemotherapy in patients with advanced previously untreated non-squamous 
ALK+ NSCLC, median PFS was 10.9 months in the crizotinib arm and 7.0 months in 
the chemotherapy arm (hazard ratio for progression or death with crizotinib, 0.45; 
95% CI: 0.35 to 0.60; p<0.001) (Solomon et al, 2014). Currently, two tests are FDA-
approved for detection of ALK+ NSCLC: the Vysis® ALK Break-Apart fluorescence 
in situ hybridization (FISH) Probe Kit (Abbott Molecular, Inc.) and the Ventana ALK 
(D5F3) CDx Assay (Ventana Medical Systems, Inc.), an immunohistochemistry 
(IHC) assay. 
Although crizotinib is an effective treatment for ALK+ NSCLC, almost half (39% and 
52%, respectively) of ALK+ NSCLC patients in the two trials that supported its 
accelerated approval failed to achieve a response. For those patients who did respond, 
the benefit was relatively short with a median duration of response of 11 months 
(XALKORI® USPI, Pfizer, Inc.). In many patients, loss of response to crizotinib 
manifests as systemic progression, but in some patients the disease progresses only 
within the brain, possibly as a result of low central nervous system (CNS) penetration 
of crizotinib (Camidge et al, 2012; Costa et al, 2011).
The underlying reason for failure to achieve a response to crizotinib (primary 
resistance) is difficult to identify, but suboptimal potency of the agent against the 
targeted oncogene could be a contributing factor. The mechanisms underlying loss of 
response (secondary or acquired resistance) to crizotinib are becoming more clear 
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(Camidge et al, 2012). Emerging data suggest that an important acquired resistance 
mechanism is the emergence of point mutations in the kinase domain of ALK 
(Katayama et al, 2012). Mutations that confer resistance to crizotinib (such as the 
gatekeeper mutant L1196M, as well as L1152R, G1269A, S1206Y, F1174L, 
D1203N, C1156Y, T1151Tins, and G1202R mutations) may act by reducing the 
binding affinity of crizotinib to ALK (Bang, 2012).
In some patients, loss of response to crizotinib may also have a pharmacologic basis, 
with inadequate drug exposure resulting from dose modifications, or changes in drug 
metabolism or transport over time. In all of these scenarios, a rational approach to 
overcoming resistance is the use of a more potent ALK inhibitor with a broader 
therapeutic window that suppresses the emergence of resistance mutations in ALK 
and that can also achieve deep and prolonged target inhibition both systemically and 
in the CNS (for patients with brain metastases).
Brigatinib is a novel, synthetic, orally-active ALK tyrosine kinase inhibitor (TKI) 
discovered and developed at ARIAD Pharmaceuticals, Inc. Brigatinib has 
demonstrated potent in-vitro inhibitory activity against activated ALK (approximately 
10-fold more potent than crizotinib) and pan-inhibitory activity against all 17 ALK 
resistance mutants identified to date, including the L1196M gatekeeper mutation and 
the G1202R mutation.
The phase 1/2 clinical study of brigatinib (Study AP26113-11-101) consists of a 
phase 1 dose escalation portion in multiple tumor types, followed by a phase 2 
expansion portion with defined clinical cohorts. Daily doses from 30 mg to 300 mg 
were investigated in 137 patients, including 79 ALK+ NSCLC patients, of which 71 
(90%) had previously been treated with crizotinib. Three regimens were evaluated in 
phase 2: 90 mg QD, 90 mg QD for 7 days followed by escalation to 180 mg QD (90 
mg QD→180 mg QD), and 180 mg QD. 
As of 17 February 2015, the median time on treatment for all patients and ALK+ 
NSCLC patients was 7.4 months and 12.6 months, respectively. Median dose 
intensity for patients receiving the phase 2 doses explored in this study—90 mg QD 
(n=18), 90 mg QD→180 mg QD (n=32), and 180 mg QD (n=44)—was 90 mg/day, 
177 mg/day, and 177 mg/day, respectively. For the 90 mg QD, 90 mg QD→180 mg 
QD, and 180 mg QD cohorts, 0%, 25%, and 14% of patients had dose reductions due 
to AEs and 17%, 25%, and 43% of patients had dose interruptions (≥3 days), 
respectively. A total of 13 patients (9.5%) discontinued treatment due to an AE. 
The most commonly reported treatment emergent adverse events (TEAEs) in ≥15% of 
patients who received the 90 mg QD→180 mg QD (n=32) regimen were diarrhea 
(44%), fatigue (44%), nausea (41%), headache (28%), cough (28%), arthralgia (28%), 
amylase increased (25%), lipase increased (25%), constipation (22%), back pain 
(22%), hypertension (22%), aspartate aminotransferase increased (19%), decreased 
appetite (16%), alanine aminotransferase increased (16%), insomnia (16%), 
peripheral sensory neuropathy (16%), and joint swelling (16%). Grade 3 or greater 
TEAEs reported in 2 or more patients (>5%) who received the 90 mg QD→180 mg 
QD (n=32) regimen included: increased lipase (9%), hypertension (9%), pericardial 
effusion malignant (9%), dyspnea (6%), and alanine aminotransferase increased (6%). 
During dose escalation and initial phase 2 expansion, patients were observed to 
experience pulmonary AEs such as dyspnea, hypoxia, pneumonia, and pneumonitis 
within the first 7 days of treatment at starting doses of 180 mg QD and higher. Many 
of these early pulmonary AEs occurred within 24 to 48 hours after initiating 
treatment. Based on these safety observations, 2 additional regimens were tested in 
the phase 2 portion (90 mg QD and 90 mg QD→180 mg QD). In the study overall, 
there were 13/137 (9%) patients with these early onset pulmonary events within the 
first 7 days of treatment: 2/2 (100%) patients at 300 mg QD, 2/10 (20%) patients at 
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240 mg QD, 6/44 (14%) patients at 180 mg QD, 1/11 (9%) patients at 120 mg QD, 
and 2/50 (4%) patients at starting at 90 mg QD (including 90 mg QD and 90 mg 
QD→180 mg QD). The addition of a 90 mg QD 7 day lead in to therapy with 180 mg 
QD appears to lessen the incidence of early onset pulmonary events. Of 32 patients 
started at 90 mg for 7 days and then escalated to 180 mg, none (0%) experienced 
these early onset pulmonary symptoms within the first 7 days at 90 mg or after 
escalation to 180 mg. 
In evaluable ALK+ NSCLC patients treated with prior crizotinib, a 71% (50/70) 
overall response rate (ORR) was observed, including 4 complete responses (CRs). 
The ORR for the cohort that received 90 mg QD→180 mg QD was 81% (22/27 
evaluable). An ORR of 100% was observed for crizotinib naïve patients (8/8), 
including 3 CRs. Median PFS was 13.4 months for patients treated with prior 
crizotinib. Median PFS was not reached for the crizotinib-naive patients, with a 
median time on treatment of 62 weeks (max: 134 weeks, ongoing) and 6/8 patients 
ongoing without progression. 
To evaluate the potential for brigatinib anti tumor activity in the CNS, a blinded 
independent radiological review of intracranial response was performed in ALK+ 
NSCLC patients with intracranial CNS metastases at baseline. In patients with 
measurable metastases, 53% (8/15) had an intracranial response; in those with only 
nonmeasurable metastases, 35.5% (11/31) had an intracranial response. Among 
patients who had no prior brain radiotherapy (n=21), intracranial ORR was 5/9 
(55.6%) for patients with measurable lesions and 7/12 (58.3%) for those with only 
nonmeasurable lesions. For patients with a follow up scan (n=46), median intracranial 
PFS was 15.6 months.
Based on the findings of Study AP26113-11-101, a pivotal 2-arm, open-label, phase 2 
study of brigatinib in ALK+ NSCLC patients whose disease has progressed on 
therapy with crizotinib was designed (AP26113-13-201, “ALTA”). This study 
randomizes patients in a 1:1 fashion to one of two brigatinib regimen: 90 mg QD and 
90 mg QD→180 mg QD. The study is currently enrolling patients with a target 
accrual of 218 patients.
In summary, brigatinib was generally tolerated and has an acceptable safety profile 
for the stage of development up to regimens including 90 mg→180 mg QD. 
Brigatinib exhibited substantial anticancer activity in patients with ALK+ NSCLC, 
including patients who were crizotinib-naïve. Brigatinib is active in ALK+ brain 
metastases with frequent responses of clinically meaningful duration. There is strong 
rationale to evaluate brigatinib in the treatment of TKI-naïve ALK+ NSCLC.
Study Design
This is a phase 3, randomized, open-label, comparative, multicenter, international 
study in which ALK+ NSCLC patients who have not previously received an 
ALK-targeted TKI will be randomized in a 1:1 fashion to receive brigatinib (Arm A) 
or crizotinib (Arm B). Patients will be stratified by the presence of intracranial CNS 
metastases at baseline (Yes versus No) and prior chemotherapy use for locally 
advanced or metastatic disease (Yes versus No). For the purposes of stratification, 
prior chemotherapy is defined as completion of ≥1 full cycle of chemotherapy in the 
locally advanced or metastatic setting.
Patients will be treated until they experience progressive disease (PD) assessed by the 
blinded Independent Review Committee (BIRC), intolerable toxicity, or another 
discontinuation criterion is met. Continuation of brigatinib beyond progression is 
permitted, at the investigator’s discretion, if there is evidence of continued clinical 
benefit. Crossover in Arm B (crizotinib) to brigatinib is also permitted, at the 
investigator’s discretion with the sponsor’s medical monitor approval, for patients 
who have experienced objective progression assessed by the BIRC.
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Study Objectives
The primary objective of the study is to compare the efficacy of brigatinib to that of 
crizotinib in ALK+ locally advanced or metastatic NSCLC patients naive to ALK 
inhibitors, as evidenced by PFS.
The secondary objectives of the study are:
1.
To compare the efficacy of brigatinib to that of crizotinib, as evidenced by 
confirmed ORR, time to/duration of response, disease control rate (DCR), 
and Overall Survival (OS)
2.
To compare the efficacy in the CNS of brigatinib to that of crizotinib, as 
evidenced by intracranial response and intracranial PFS in those patients 
with intracranial CNS metastases at baseline
3.
To assess the safety and tolerability of brigatinib in comparison with 
crizotinib 
4.
To determine pharmacokinetic (PK) parameters of brigatinib through 
population PK modeling
5.
To assess patient-reported symptoms and health-related quality of life 
(HRQoL) with the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (v3.0) and its 
lung cancer module, QLQ-LC13 (v3.0) in patients treated with brigatinib 
compared to those treated with crizotinib
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Study Endpoints
Primary Endpoint:
PFS, as assessed by the BIRC, per RECIST v1.1 (Eisenhauer et al, 2009)
Secondary Endpoints:
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
5.
Duration of response, as assessed by the BIRC
6.
Time to response, as assessed by the BIRC
7.
Disease control rate, as assessed by the BIRC
8.
Safety and tolerability
9.
Change from baseline scores in global health status/quality of life (QOL) 
assessed with the EORTC QLQ-C30 (v3.0), and time-to-deterioration in 
dyspnea assessed with the EORTC QLQ-LC13 (v3.0)
Inclusion Criteria
All patients must meet all of the following eligibility criteria for study entry:
1.
Have histologically or cytologically confirmed stage IIIB (locally advanced 
or recurrent and not a candidate for definitive multimodality therapy) or 
stage IV NSCLC. 
2.
Must meet one of the following two criteria:
a.
Have documentation of ALK rearrangement by a positive result from 
the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) 
Probe Kit or the Ventana ALK (D5F3) CDx Assay. The test must have 
been performed according to the product’s instructions for use (IFU). 
b.
Have documented ALK rearrangement by a different test and adequate 
tissue available for central laboratory testing by an FDA-approved test. 
Confirmation of central test positivity is not required prior to 
randomization.
3.
Have sufficient tumor tissue available for central analysis (see the Study 
Reference Manual for minimum requirements)
4.
Have at least 1 measurable (i.e., target) lesion per RECIST v1.1 (see 
Appendix C).
5.
Recovered from toxicities related to prior anticancer therapy to NCI CTCAE 
v 4.0 grade ≤1. Note: treatment-related alopecia or peripheral neuropathy 
that are grade >1 are allowed if deemed irreversible.
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6.
Are a male or female patient ≥18 years old. 
7.
Have adequate organ function, as determined by:
a.
ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable 
if liver metastases are present
b.
Total serum bilirubin ≤1.5 × ULN (<3.0×ULN for patients with Gilbert 
syndrome)
c.
Serum creatinine ≤1.5 × ULN
d.
Serum lipase/amylase ≤1.5 × ULN
e.
Absolute neutrophil count (ANC) ≥1.5 × 109/L 
f.
Platelet count ≥75 × 109/L
g.
Hemoglobin ≥10 g/dL
8.
Have Eastern Cooperative Oncology Group (ECOG) performance status <2 
(see Appendix B).
9.
Have normal QT interval on screening ECG evaluation, defined as QT 
interval corrected (Fridericia) (QTcF) of ≤450 milliseconds (msec) in males 
or ≤470 msec in females. 
10. For female patients of childbearing potential, have a negative pregnancy test 
documented prior to randomization.
11. For female and male patients who are fertile, agree to use a highly effective 
form of contraception with their sexual partners during the dosing period and 
for a period of at least 4 months after the end of treatment with brigatinib and 
at least 3 months after the end of treatment with crizotinib (Section 14.3.1). 
12. Provide signed and dated informed consent indicating that the patient has 
been informed of all pertinent aspects of the study, including the potential 
risks, and is willingly participating.
13. Have the willingness and ability to comply with scheduled visit and study 
procedures.
Exclusion Criteria
Patients meeting any of the criteria below are ineligible for the study:
1.
Previously received an investigational antineoplastic agent for NSCLC.
2.
Previously received any prior TKI, including ALK-targeted TKIs.
3.
Previously received more than 1 regimen of systemic anticancer therapy for 
locally advanced or metastatic disease. 
Note: a systemic anticancer therapy regimen will be counted if it is 
administered over at least 1 cycle. A new antineoplastic agent used as 
maintenance therapy will be counted as a new regimen. Neo-adjuvant or 
adjuvant systemic anticancer therapy will be counted as a prior regimen if 
completion of (neo) adjuvant therapy occurred <12 months prior to 
randomization. 
4.
Received chemotherapy or radiation within 14 days of first dose of study 
drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation 
therapy (SBRT). 
5.
Received anti-neoplastic monoclonal antibodies within 30 days of the first 
dose of study drug.
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6.
Had major surgery within 30 days of the first dose of study drug, minor 
surgical procedures such as catheter placement or minimally invasive 
biopsies are allowed. 
7.
Have been diagnosed with another primary malignancy other than NSCLC, 
except for adequately treated non-melanoma skin cancer or cervical cancer in 
situ; definitively treated non-metastatic prostate cancer; or patients with 
another primary malignancy who are definitively relapse-free with at least 
3 years elapsed since the diagnosis of the other primary malignancy. 
8.
Have symptomatic CNS metastases (parenchymal or leptomeningeal) at 
screening or asymptomatic disease requiring an increasing dose of 
corticosteroids to control symptoms within 7 days prior to randomization. 
Note: If a patient has worsening neurological symptoms or signs due to CNS 
metastasis, the patient needs to complete local therapy and be neurologically 
stable (with no requirement for an increasing dose of corticosteroids or use 
of anticonvulsants) for 7 days prior to randomization.
9.
Have current spinal cord compression (symptomatic or asymptomatic and 
detected by radiographic imaging). Patients with leptomeningeal disease and 
without cord compression are allowed.
10. Be pregnant, planning a pregnancy, or breastfeeding 
11. Have significant, uncontrolled, or active cardiovascular disease, 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.
Congestive heart failure (CHF) within 6 months prior to first dose of 
study drug
d.
History of clinically significant atrial arrhythmia (including clinically 
significant bradyarrhythmia), as determined by the treating physician
e.
Any history of ventricular arrhythmia
f.
Cerebrovascular accident or transient ischemic attack within 6 months 
prior to first dose of study drug
12. Have uncontrolled hypertension. Patients with hypertension should be under 
treatment on study entry to control blood pressure.
13. Have a history or the presence at baseline of pulmonary interstitial disease, 
drug-related pneumonitis, or radiation pneumonitis. 
14. Have an ongoing or active infection, including, but not limited to, the 
requirement for intravenous (IV) antibiotics.
15. Have a known history of human immunodeficiency virus (HIV) infection. 
Testing is not required in the absence of history.
16. Have a known or suspected hypersensitivity to brigatinib or its excipients.
17. Have a known or suspected hypersensitivity to crizotinib or its excipients.
18. Have malabsorption syndrome or other gastrointestinal (GI) illness or 
condition that could affect oral absorption of the study drug. 
19. Have any condition or illness that, in the opinion of the investigator, would 
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compromise patient safety or interfere with the evaluation of the study drug.
Approximate Number of 
Patients
Approximately 270 patients total (135 in Arm A, 135 in Arm B)
Approximate Duration of 
Patient Participation
Patients will continue to be treated with brigatinib (Arm A) or crizotinib (Arm B) 
until they experience disease progression assessed by the BIRC or intolerable toxicity. 
Treatment with brigatinib may be continued after progression, at the discretion of the 
investigator, if there is still evidence of clinical benefit. At the discretion of the 
investigator with the sponsor’s medical monitor approval, patients who experience 
disease progression assessed by the BIRC while on crizotinib therapy may crossover 
to treatment with brigatinib. All patients who crossover to brigatinib from crizotinib 
must have a washout period of at least 10 days between treatments. On average, a 
patient is expected to participate in this study for approximately 4 years.
Approximate Duration of 
Study
The total estimated duration of the study is approximately 4.5 years, including 
1.5 years to accrue patients, with at least 3 years for treatment and follow-up of the 
last patient. Since the study met the statistical significance at the first interim analysis 
and the primary endpoint was consistent at the second interim analysis, the study will 
be closed approximately 3 years after the last patient enrolled. 
Approximate Number of 
Study Centers
Approximately 150 centers
Study Drug 
Administration and 
Modification
Patients will be randomized to receive brigatinib or crizotinib in a 1:1 fashion. 
Patients will be stratified by the presence of intracranial CNS metastases at baseline 
(Yes versus No) and prior chemotherapy use for locally advanced or metastatic 
disease (Yes versus No). For the purposes of stratification, prior chemotherapy is 
defined as completion of ≥1 full cycle of chemotherapy in the locally advanced or 
metastatic setting.
Arm A (brigatinib):
Brigatinib will be administered orally at a dose of 90 mg QD for 7 days, then 180 mg 
QD, continuously, with or without food. Patients will take the prescribed dose with 
water (recommended 240 mL).
Arm B (crizotinib):
Crizotinib will be administered as 250 mg orally BID, with or without food. Patients 
will take the prescribed dose with water (recommended 240 mL).
Dose Modifications
Dose interruptions or reductions should be implemented for patients who experience 
treatment-related AEs, based on the clinical judgment of the investigator. Criteria for 
dose modifications of brigatinib for drug-related toxicity are described in the protocol. 
The European Medicines Agency (EMA) Summary of Product Characteristics 
(SmPC) for crizotinib (XALKORI® SmPC, Pfizer, Inc.) will be used as a guideline 
for dose modification of patients in the crizotinib arm and is detailed in the protocol.
Concomitant Treatment
Palliative therapy and supportive care are permitted during the study for management 
of symptoms and underlying medical conditions that may develop during the study. 
Patients with CNS lesions requiring local radiotherapy such as SRS are allowed to 
continue brigatinib after appropriate interruption, as determined by the investigator 
with sponsor agreement; however, for analysis purposes, these patients will be 
considered to have progressive disease (PD).
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The following concurrent medications or procedures are prohibited for the duration of 
the study:
1.
Any other systemic anticancer therapy, including, but not limited to: 
chemotherapeutic agents, immunotherapy, biological response modifiers 
(excluding growth factors), radiotherapy, and/or systemic hormonal therapy 
(with the exception of local therapies, such as SRS, used for palliative or 
symptomatic control of existing lesions, with appropriate treatment 
interruption at the discretion of the investigator). Use of any other 
investigational drug or device;
2.
Medications that are known to be associated with the development of 
Torsades de Pointes (see Appendix E). Medications that prolong the QT 
interval, but are not known to be associated with Torsades de Pointes, should 
be avoided but are not prohibited;
3.
Extensive surgery requiring inpatient care (patients may have an interruption 
in therapy for 14 days should emergency surgery be required).
Brigatinib
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 (see Appendix D).
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 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.
Crizotinib
Crizotinib is predominantly metabolized by CYP3A4/5. Coadministration of 
crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations. 
Avoid concomitant use of strong CYP3A inhibitors, including, but not limited to, 
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. 
Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of 
crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors.
Crizotinib inhibits CYP3A both in vitro and in vivo. Coadministration of crizotinib 
with strong CYP3A inducers decreases crizotinib plasma concentrations. Avoid 
concomitant use of strong CYP3A inducers, including, but not limited to, 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort.
Avoid concomitant use of CYP3A substrates with narrow therapeutic range, 
including, but not limited, to alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking crizotinib. 
If concomitant use of these CYP3A substrates with narrow therapeutic range is 
required in patients taking crizotinib, dose reductions of the CYP3A substrates may 
be required due to adverse reactions.
Efficacy Evaluation
Tumor response assessments will be performed every 8 weeks and evaluated per 
RECIST v1.1 by the BIRC and the investigator until BIRC-assessed disease 
progression. Tumor response (CR or partial response [PR]) should be confirmed 
≥4 weeks after initial response. For patients in Arm A who continue brigatinib beyond 
disease progression, tumor assessments will continue to be performed every 8 weeks. 
Crossover in Arm B (crizotinib) to brigatinib treatment (Crossover Phase) is 
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permitted, at the investigator’s discretion, for patients who have experienced objective 
progression assessed by the BIRC. For these patients, the tumor response assessment 
with BIRC-assessed progression will be re-evaluated per RECIST v1.1 criteria as a 
new baseline for the Crossover Phase. Tumor response assessments will be performed 
every 8 weeks and evaluated per RECIST v1.1 by the BIRC and the investigator until 
BIRC-assessed disease progression.
OS will be followed for approximately 3 years after the last patient has been 
randomized. 
Safety Evaluation
Safety assessments will include physical and laboratory examinations, vital signs, and 
electrocardiograms (ECGs). Adverse events (AEs) will be graded according to the 
NCI CTCAE v4.0. 
Pharmacokinetic 
Evaluations
Sparse plasma brigatinib concentration data obtained from this study will be included 
in integrated population PK analyses, along with data from study AP26113-11-101 
and study AP26113-13-201, with the objective of further characterizing the plasma 
PK of brigatinib in the intended patient population, and to assess exposure-response 
(for efficacy) and exposure-safety relationships in patients receiving brigatinib.
Exploratory Biomarker 
Evaluations in Tissue and 
Blood
Patient-Reported 
Symptoms and Quality of 
Life Assessments
Patient-reported symptoms and HRQoL will be collected by administering the 
EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13 (v3.0) questionnaires, which have 
been studied extensively, are validated, and are suitable for use in global clinical 
studies. The questionnaires will be administered to patients in their local language.
Statistical Methods
The primary analysis of the primary endpoint will be performed using a 2-sided 
stratified log-rank test (stratification factors: presence of intracranial CNS metastases 
at baseline [yes versus no], and prior chemotherapy use for locally advanced or 
metastatic disease [yes versus no]) to compare the BIRC-assessed PFS of patients 
randomized to brigatinib with the BIRC-assessed PFS of patients randomized to 
crizotinib. The overall (2-sided) Type I error rate will be controlled at 0.05. The 
primary analysis will be based on the intent-to-treat (ITT) population. PFS will be 
estimated for each treatment arm using the Kaplan-Meier method (Kaplan and Meier, 
1958). Additionally, hazard ratios will be estimated using the Cox regression model 
with the stratification factors as covariates.
Two interim analyses are planned after approximately 50% and 75% of the total 
expected events (progression or death) have been observed. An O’Brien-Fleming 
Lan-DeMets (DeMets and Lan, 1994) alpha spending function will be used to control 
the overall alpha level at 0.05 2-sided.
The first interim analysis will be performed after the first 99 events have been 
observed. The primary endpoint of PFS will be tested at a 2-sided alpha level of 
0.0042. A second interim analysis will be performed after 149 events and the primary 
endpoint will be tested at a 2-sided alpha level of 0.0194. The primary analysis of the 
primary endpoint will be performed after 198 events have been observed or at End-of-
Study, whichever comes first, and will be tested at a 2-sided alpha level of 0.043. If 
CCI
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the efficacy boundary is surpassed at an interim analysis, patients will remain on 
assigned treatments unless a survival advantage is noted. 
Further details of statistical analyses including the data handling rules will be 
provided in the Statistical Analysis Plan (SAP).
Rationale for Number of 
Patients
For the purposes of this sample size calculation, the median PFS for crizotinib is 
estimated as 10 months. Approximately 270 patients will be randomized in a 
1:1 fashion to receive brigatinib or crizotinib. A total of 198 events (progression or 
death among the randomized patients) will provide 90% power to detect a 6-month 
improvement in PFS (hazard ratio=0.625). This power projection is based on a 
2-sided log-rank test and is controlled at the 2-sided 0.043 level, adjusting for the 
proposed interim analysis plan. The number of events is fixed, but the enrollment 
number may change based on an assessment of the overall event rate pooled across 
treatment groups (prior to the close of enrollment).
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5
TABLE OF CONTENTS
1
DISCLOSURE STATEMENT .................................................................................2
Protocol Amendment 03 Summary of Changes and Rationale ...............................2
1.1
2
SIGNATURE PAGES...............................................................................................4
Representatives from Sponsor..................................................................................4
2.1
Investigator Signature ..............................................................................................5
2.2
3
CONTACT INFORMATION ..................................................................................6
4
PROTOCOL SYNOPSIS..........................................................................................7
5
TABLE OF CONTENTS........................................................................................18
6
DEFINITIONS OF TERMS...................................................................................25
7
INTRODUCTION...................................................................................................27
Background.............................................................................................................27
7.1
Nonclinical Summary..............................................................................................28
7.2
7.2.1
Nonclinical Activity Against ALK..........................................................................28
7.2.2
Nonclinical Activity Against Other Targets...........................................................28
Brigatinib Clinical Summary .................................................................................28
7.3
7.3.1
Phase 1/2 Trial: Study AP26113-11-101.................................................................29
7.3.2
Study AP26113-13-201 (ALTA)..............................................................................30
Rationale for the Phase 3 Study of Brigatinib in ALK-inhibitor-naive ALK+ 
7.4
NSCLC ....................................................................................................................31
Rationale for Proposed Phase 3 Dose.....................................................................32
7.5
8
STUDY OBJECTIVES...........................................................................................32
Primary Objective...................................................................................................32
8.1
Secondary Objectives..............................................................................................32
8.2
Exploratory Objectives...........................................................................................33
8.3
9
INVESTIGATIONAL PLAN .................................................................................33
Overall Study Design and Plan...............................................................................33
9.1
9.1.1
Primary Endpoint ...................................................................................................34
9.1.2
Secondary Endpoints ..............................................................................................34
9.1.3
Exploratory Endpoints ...........................................................................................34
Randomization ........................................................................................................34
9.2
10
SELECTION OF STUDY POPULATION ............................................................35
Inclusion Criteria....................................................................................................35
10.1
Exclusion Criteria ...................................................................................................36
10.2
11
STUDY PROCEDURES.........................................................................................37
Study Procedure Descriptions ................................................................................38
11.1
Screening Period .....................................................................................................48
11.2
Screen Failures........................................................................................................48
11.3
Treatment Through 30 Days after Last Dose of Study Drug ................................48
11.4
End-of-Treatment or Early Termination...............................................................48
11.5
30 Days After Last Dose..........................................................................................48
11.6
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Follow-up Period Procedures .................................................................................49
11.7
Study Duration........................................................................................................49
11.8
11.8.1
Approximate Duration of Patient Participation ....................................................49
11.8.2
Approximate Duration of Study.............................................................................49
Patient Discontinuation...........................................................................................49
11.9
Study or Site Termination ......................................................................................51
11.10
Sample Collection, Storage, and Shipping .............................................................51
11.11
12
EFFICACY AND SAFETY ASSESSMENTS .......................................................51
Efficacy Assessments...............................................................................................51
12.1
Safety Assessments..................................................................................................52
12.2
Pharmacokinetic Assessments ................................................................................52
12.3
Exploratory Biomarker Evaluations in Tissue and Blood.....................................52
12.4
Patient Reported Symptoms and Quality of Life Assessments .............................52
12.5
13
STUDY TREATMENTS ........................................................................................53
Study Drug ..............................................................................................................53
13.1
13.1.1
Treatment Administration......................................................................................53
13.1.2
Continuation of Treatment after Disease Progression ..........................................53
13.1.3
Management and Dose Modification Recommendations for Treatment-
Related Adverse Events ..........................................................................................54
13.1.4
Re-introducing Brigatinib after Dose Interruption ...............................................65
13.1.5
Re-Escalation after Dose Modification...................................................................65
Prior and Concomitant Treatment(s)/Therapy .....................................................65
13.2
Prohibited Treatment(s)/Therapy ..........................................................................65
13.3
Potential Drug Interactions ....................................................................................66
13.4
Treatment Compliance ...........................................................................................67
13.5
Treatment Supply ...................................................................................................67
13.6
13.6.1
Formulation, Packaging and Labeling...................................................................67
13.6.2
Preparation and Dispensing ...................................................................................68
13.6.3
Treatment Storage and Accountability..................................................................68
14
ADVERSE EVENT REPORTING ........................................................................68
Adverse Events........................................................................................................68
14.1
14.1.1
Adverse Event Definition........................................................................................68
14.1.2
Performing Adverse Events Assessments...............................................................69
14.1.3
Reporting Period.....................................................................................................70
14.1.4
Adverse Event Severity...........................................................................................70
14.1.5
Causality..................................................................................................................70
14.1.6
Expectedness ...........................................................................................................72
Serious Adverse Events...........................................................................................72
14.2
14.2.1
Serious Adverse Event Definition...........................................................................72
14.2.2
Reporting Serious Adverse Events .........................................................................73
14.2.3
Information to be Provided by the Investigator for a Serious Adverse Event......74
14.2.4
Follow-up Information on a Serious Adverse Event..............................................74
14.2.5
Expedited Reporting of Suspected Unexpected and Serious Adverse 
Reactions (SUSARs)................................................................................................74
Other Safety Issues .................................................................................................75
14.3
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14.3.1
Pregnancy and Breastfeeding .................................................................................75
14.3.2
Overdose..................................................................................................................76
15
PLANNED STATISTICAL METHODS ...............................................................76
General Considerations ..........................................................................................76
15.1
Analysis Populations ...............................................................................................76
15.2
Study Endpoints......................................................................................................76
15.3
15.3.1
Primary Endpoint ...................................................................................................76
15.3.2
Secondary Endpoints ..............................................................................................77
15.3.3
Exploratory Endpoints ...........................................................................................77
Determination of Sample Size ................................................................................77
15.4
Efficacy Analysis.....................................................................................................77
15.5
15.5.1
Definitions of Efficacy Endpoints...........................................................................77
15.5.2
Primary Efficacy Endpoint Analyses .....................................................................78
15.5.3
Secondary Efficacy Endpoint Analyses..................................................................79
15.5.4
Exploratory Efficacy Endpoint Analyses ...............................................................80
15.5.5
Data Handling Rules for Efficacy Endpoint Analyses...........................................80
Safety Analysis ........................................................................................................81
15.6
15.6.1
Pharmacokinetic Analysis ......................................................................................81
15.6.2
QTcF Analysis.........................................................................................................81
HRQoL Data Analysis ............................................................................................81
15.7
Correlation Analyses of Tumor and Plasma Biomarkers with Efficacy and 
15.8
Safety.......................................................................................................................82
Protocol Deviations/Violations ...............................................................................82
15.9
16
QUALITY CONTROL AND QUALITY ASSURANCE ......................................82
Investigators and Study Administrative Structure................................................83
16.1
Study Monitoring....................................................................................................83
16.2
17
ETHICAL CONDUCT OF THE STUDY..............................................................83
Institutional Review Board or Ethics Committee Approval .................................84
17.1
Patient Information and Consent...........................................................................84
17.2
Patient Confidentiality............................................................................................84
17.3
Study Committees...................................................................................................85
17.4
17.4.1
Data Monitoring Committee...................................................................................85
17.4.2
Blinded Independent Review Committee...............................................................85
17.4.3
Steering Committee.................................................................................................85
18
DATA HANDLING AND RECORD KEEPING...................................................85
Case Report Forms and Study Records .................................................................85
18.1
Access to Source Documentation............................................................................85
18.2
Retention of Data ....................................................................................................86
18.3
Termination of Study..............................................................................................86
18.4
19
FINANCING AND INSURANCE..........................................................................86
20
PUBLICATION AND DISCLOSURE POLICY ...................................................87
21
REFERENCES .......................................................................................................89
22
APPENDICES.........................................................................................................91
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TABLE OF TABLES
Table 1
Treatment Emergent Adverse Events (All Grades) Occurring in ≥10% of 
Patients in Study AP26113-13-201 .........................................................................31
Table 2
Treatment Emergent Adverse Events ≥ Grade 3 in 2 or More Patients in 
Study AP26113-13-201............................................................................................31
Table 3
Schedule of Events - Randomized Phase................................................................46
Table 4
Schedule of Events – Brigatinib Crossover Phase (Arm B Only)..........................47
Table 5
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events (Excluding Pneumonitis) Prior to Dose Escalation to 180 mg 
QD (i.e., First 7 Days of Treatment).......................................................................56
Table 6
Brigatinib Dose Modification Recommendations for Treatment-Related 
Pneumonitis Occurring Prior to Dose Escalation to 180 mg QD (i.e., First 
7 Days of Treatment) ..............................................................................................57
Table 7
Brigatinib Dose Modification Recommendations for Treatment-Related 
Pneumonitis Occurring After Dose Escalation to 180 mg QD ..............................58
Table 8
Dose Modification Recommendations for Treatment-Related Adverse Events 
(Excluding Pneumonitis) after Dose Escalation to 180 mg QD* ...........................59
Table 9
Crizotinib Dose Modification Recommendations for Treatment-Related 
Adverse Events........................................................................................................64
Table 10 Assumptions and Considerations for OS Endpoint...............................................80
LIST OF APPENDICES
APPENDIX A NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) ...............................92
APPENDIX B EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS..........................................................................93
APPENDIX C RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1)...............................................................................94
APPENDIX D DRUGS THAT INTERACT WITH CYP450 ENZYMES...........................97
APPENDIX E DRUGS WITH A RISK OF TORSADES DE POINTES.............................98
APPENDIX F PROTOCOL HISTORY .............................................................................102
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LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARIAD
ARIAD Pharmaceuticals, Inc.
AST
aspartate aminotransferase
BAL
bronchoalveolar lavage
BID
twice daily
BIRC
blinded Independent Review Committee 
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CK
creatine kinase
CNS
central nervous system
CR
complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events (version 4.0)
CYP
cytochrome P450
DCR
disease control rate
DDI
drug-drug interaction
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EEA
European Economic Area
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EML4
echinoderm microtubule-associated protein-like 4 
EORTC
European Organisation for Research and Treatment of Cancer
EU
European Union
FDA
Food and Drug Administration (United States)
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
GI
gastrointestinal
HIV
human immunodeficiency virus
HRQoL
health-related quality-of-life
IC50
50% maximum inhibitory concentration
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
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Abbreviation
Term
IEC
Independent Ethics Committee
IFU
instructions for use
IGF-1R
insulin-like growth factor 1 receptor
IHC
immunohistochemistry
IRB
Institutional Review Board
IRC
independent review committee
ITT
intent-to-treat
IV
intravenous
KM
Kaplan-Meier
LD
longest diameter
LD50
oral lethal dose
LDH
lactate dehydrogenase
LLT
lowest level term
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labor, and Welfare (Japan)
MI
myocardial infarction
MRI
magnetic resonance imaging
msec
millisecond
NCI
National Cancer Institute (of the United States)
NE
non-evaluable
NSCLC
non-small cell lung cancer
OCT
optical coherence tomography
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PR
partial response
PRO
patient-reported outcome
QD
once-daily
QLQ
Quality of Life Questionnaire
QOL
quality of life
QT
QT interval; a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle
QTc
heart rate-corrected QT interval (calculated)
QTcF
QT interval corrected (Fridericia)
RECIST
Response Evaluation Criteria in Solid Tumors (version 1.1)
SAE
serious adverse event
SAP
statistical analysis plan
SBRT
stereotactic body radiation therapy 
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
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Abbreviation
Term
SLD
sum of longest diameter
SmPC
Summary of Product Characteristics (EMA)
SOC
System Organ Class
SRS
stereotactic radiosurgery
SUSAR
suspected unexpected and serious adverse reaction
TEAE
treatment emergent adverse event
TKI
tyrosine kinase inhibitor
TRAE
treatment-related adverse event
UE
unable to evaluate
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
WBRT
whole brain radiation therapy
β-HCG
beta-human chorionic gonadotropin
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6
DEFINITIONS OF TERMS
Term
Definition
30 Days After Last 
Dose
At 30 days after last dose of study drug, a patient completes all 
post-treatment discontinuation assessments. 
Clinically 
Significant
A clinical observation or laboratory result that leads to a new intervention 
or change in therapy is defined in the context of this study as clinically 
significant.
Cycle
For the purposes of this study, a cycle consists of 28 days and is equivalent 
to a month in the measurement of study endpoints.
End-of-Treatment
The end-of-treatment occurs at the last dose of study drug or when the 
investigator and patient decide that the patient will receive no further study 
drug, whichever occurs later.
End-of-Study
End-of-study (completion) date is when all patients have completed all 
study visits or have otherwise discontinued from the study.
Enrolled Patient
An enrolled patient is a patient who has signed the informed consent form, 
completed all screening evaluations, and has been randomized to a 
treatment group.
Ethics Committee
Throughout this document, the term Ethics Committee (EC) refers to all 
appropriate properly constituted committees or boards recognized by the 
appropriate regulatory agencies for approving clinical studies. These 
include independent EC and Institutional Review Boards.
Evaluable for 
Efficacy
Any eligible patient who receives study drug is considered evaluable for 
efficacy analyses.
Evaluable for 
Safety
Any patient who receives study drug is considered evaluable for safety
analyses.
Follow-up Period
The follow-up period for survival begins at the end of treatment and 
continues until patient contact discontinues.
Institutional 
Review Board
Throughout this document, the term Institutional Review Board (IRB) 
refers to all appropriate properly constituted committees or boards 
recognized by the appropriate regulatory agencies for approving clinical 
studies. These include independent ECs and IRBs.
Patient
Throughout this document, the term patient refers to a patient in this 
clinical research study.
QTcF
QT corrected (Fridericia) Calculation Formula: QTcF=QT/(RR)1/3, where 
RR=the interval from the onset of one QRS complex to the onset of the 
next QRS complex, measured in seconds.
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Term
Definition
Regulation
Throughout this document, the term regulation refers to all appropriate 
regulations, laws, and guidelines. This study will be conducted according 
to all appropriate regulations. The regulations may be international, 
national, or local and may include but not be limited to the Code of 
Federal Regulations (United States); Ministry of Health, Labor, and 
Welfare (MHLW): Ethical Guidelines for Clinical Research (Japan); 
MHLW: Good Clinical Practice Guidelines (Japan); Japan 
Pharmaceuticals Affairs Law; the International Conference on 
Harmonisation Guideline for Good Clinical Practice; and the World 
Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Patients.
Regulatory Agency
Throughout this document, the term regulatory agency refers to all 
applicable health and regulatory agencies. These may be international, 
national, or local and may include but not be limited to MHLW (Japan), 
Pharmaceuticals and Medical Devices Agency (PMDA), European 
Medicines Agency (EMA), and the United States Food and Drug 
Administration (FDA).
Screening Period
The screening period for a patient begins when the informed consent form 
is signed and continues until randomization has taken place.
Sponsor
Throughout this document, the term sponsor refers to all applicable 
departments within ARIAD Pharmaceuticals, Inc., a wholly owned 
subsidiary of Takeda Pharmaceuticals or its designee.
Study Reference 
Manual
In the context of this study, Study Reference Manual is a general term for 
the information provided to sites on technical aspects of the study. 
Study Drug
For the purposes of this protocol, study drug refers to brigatinib and 
crizotinib.
Study Start Date
The study start date is the date that the first patient signs the informed 
consent form.
Suspected Adverse 
Reaction
A suspected adverse reaction is any adverse event (defined in 
Section 14.1.1) for which there is a reasonable possibility that the drug 
caused the adverse event. For the purposes of regulatory reporting, 
"reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Treatment Period
The treatment period is from time of first dose until 30 days past last dose.
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7
INTRODUCTION
Background
7.1
Activating gene rearrangements in anaplastic lymphoma kinase (ALK) have been identified as 
driver mutations in approximately 2% to 7% of patients with non-small cell lung cancer 
(NSCLC) (Kwak et al, 2010; Wong et al, 2009). Crizotinib (XALKORI® USPI, Pfizer, Inc.) has 
demonstrated clinical efficacy in ALK+ NSCLC. Results from a phase 1 study and a phase 2 
single-arm study of crizotinib demonstrated objective response rates (ORRs) of 61% and 50%, 
respectively (XALKORI® USPI, Pfizer, Inc.). These 2 studies served as the basis for accelerated 
approval of crizotinib for treatment of ALK+ advanced NSCLC in the United States (US) in 
2011 and conditional marketing authorization in the European Union (EU) in 2012. The efficacy 
of crizotinib in ALK+ NSCLC patients has also been investigated in a randomized active-control 
study against chemotherapy (pemetrexed or docetaxel) (XALKORI® USPI, Pfizer, Inc.). A 
statistically significant improvement in progression-free survival (PFS) was observed in patients 
treated with crizotinib compared with patients treated with chemotherapy (hazard ratio, 0.49;
95% CI: 0.37 to 0.64; p<0.001). A median PFS of 7.7 months was seen with crizotinib versus 
3.0 months with chemotherapy. Regular approval for crizotinib was granted by the US Food and 
Drug Administration (FDA), on the basis of this study, in 2013. In a separate randomized 
active-control study of crizotinib against pemetrexed-platinum doublet chemotherapy in patients 
with advanced previously untreated non-squamous ALK+ NSCLC, median PFS was 
10.9 months in the crizotinib arm and 7.0 months in the chemotherapy arm (hazard ratio for 
progression or death with crizotinib, 0.45; 95% CI: 0.35 to 0.60; p<0.001) (Solomon et al, 2014). 
Currently, two tests are FDA-approved for detection of ALK+ NSCLC: the Vysis® ALK Break-
Apart fluorescence in situ hybridization (FISH) Probe Kit (Abbott Molecular, Inc.) and the 
Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Inc.), an immunohistochemistry 
(IHC) assay. 
Although crizotinib is an effective treatment for ALK+ NSCLC, almost half (39% and 52%, 
respectively) of ALK+ NSCLC patients in the two trials that supported its accelerated approval 
failed to achieve a response. For those patients who did respond, the benefit was relatively short 
with a median duration of response of 11 months (XALKORI® USPI, Pfizer, Inc.). In many 
patients, loss of response to crizotinib manifests as systemic progression, but in some patients the 
disease progresses only within the brain, possibly as a result of low central nervous system 
(CNS) penetration of crizotinib (Camidge et al, 2012; Costa et al, 2011).
The underlying reason for failure to achieve a response to crizotinib (primary resistance) is 
difficult to identify, but suboptimal potency of the agent against the targeted oncogene could be a 
contributing factor. The mechanisms underlying loss of response (secondary or acquired 
resistance) to crizotinib are becoming more clear (Camidge et al, 2012). Emerging data suggest 
that an important acquired resistance mechanism is the emergence of point mutations in the 
kinase domain of ALK (Katayama et al, 2012). Mutations that confer resistance to crizotinib 
(such as the gatekeeper mutant L1196M, as well as L1152R, G1269A, S1206Y, F1174L, 
D1203N, C1156Y, T1151Tins, and G1202R mutations) may act by reducing the binding affinity 
of crizotinib to ALK (Bang, 2012).
In some patients, loss of response to crizotinib may also have a pharmacologic basis, with 
inadequate drug exposure resulting from dose modifications, or changes in drug metabolism or 
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transport over time. In all of these scenarios, a rational approach to overcoming resistance is the 
use of a more potent ALK inhibitor with a broader therapeutic window that suppresses the 
emergence of resistance mutations in ALK and that can also achieve deep and prolonged target 
inhibition both systemically and in the CNS (for patients with brain metastases).
Nonclinical Summary
7.2
7.2.1
Nonclinical Activity Against ALK
Brigatinib is a novel, synthetic, orally-active ALK tyrosine kinase inhibitor (TKI) discovered and 
developed at ARIAD Pharmaceuticals, Inc. In nonclinical studies, brigatinib has been shown to:

Inhibit growth of ALK+ human tumor-derived cell lines with potency and selectivity 
approximately 10-fold greater than that of crizotinib

Potently inhibit all 17 ALK secondary mutations identified to date that confer resistance 
to crizotinib or the second generation ALK inhibitors, ceritinib, and alectinib. Mean 
brigatinib concentrations in patients dosed at 90 or 180 mg daily, corrected for the 
functional effects of protein binding, were found to exceed the IC50 values for native 
echinoderm microtubule-associated protein-like 4 (EML4)-ALK and 16 resistance 
mutants by at least 2-fold. The only exception was the G1202R mutant, whose IC50 was 
substantially exceeded by brigatinib levels achieved at 180 mg but not 90 mg daily 
dosing.

Suppress the emergence of any resistant ALK mutant in an in vitro mutagenesis assay, at 
concentrations that can be achieved clinically

Induce regressions or inhibit growth of tumor xenografts driven by native ALK or mutant 
variants that confer clinical resistance

Prolong survival of mice in an ALK-dependent orthotopic brain tumor model 
Refer to the Investigator’s Brochure for a more comprehensive presentation of the nonclinical 
data.
7.2.2
Nonclinical Activity Against Other Targets
In vitro kinase assays have revealed that brigatinib has potent inhibitory activity against kinases 
including activated epidermal growth factor receptor (EGFR) mutants commonly observed in 
NSCLC (e.g. exon 19 deletion, L858R, and activated EGFR mutants containing the T790M 
gatekeeper mutation), ROS1, CHK2, and insulin-like growth factor 1 receptor (IGF-1R).
Brigatinib Clinical Summary
7.3
Two company-sponsored clinical studies with brigatinib are being conducted in patients:

A phase 1/2 study of the safety, tolerability, pharmacokinetics (PK) and preliminary 
antitumor activity of brigatinib in advanced malignancies, including ALK+ NSCLC 
(study AP26113-11-101)

A pivotal phase 2 study in patients with advanced or metastatic ALK+ NSCLC whose 
disease has progressed on therapy with crizotinib (study AP26113-13-201; ALTA)
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7.3.1
Phase 1/2 Trial: Study AP26113-11-101
The phase 1/2 clinical study of brigatinib (Study AP26113-11-101) consists of a phase 1 dose 
escalation portion in multiple tumor types, followed by a phase 2 expansion portion with defined 
clinical cohorts. Daily doses from 30 mg to 300 mg were investigated in 137 patients, including 
79 ALK+ NSCLC patients, of which 71 (90%) had previously been treated with crizotinib. Three 
regimens were evaluated in phase 2: 90 mg QD, 90 mg QD for 7 days followed by escalation to 
180 mg QD (90 mg QD→180 mg QD), and 180 mg QD. 
As of 17 February 2015, the median time on treatment for all patients and ALK+ NSCLC 
patients was 7.4 months and 12.6 months, respectively. Median dose intensity for patients 
receiving the phase 2 doses explored in this study—90 mg QD (n=18), 90 mg QD→180 mg QD 
(n=32), and 180 mg QD (n=44)—was 90 mg/day, 177 mg/day, and 177 mg/day, respectively. 
For the 90 mg QD, 90 mg QD→180 mg QD, and 180 mg QD cohorts, 0%, 25%, and 14% of 
patients had dose reductions due to AEs and 17%, 25%, and 43% of patients had dose 
interruptions (≥3 days), respectively. A total of 13 patients (9.5%) discontinued treatment due to 
an AE.
The most commonly reported treatment-emergent adverse events (TEAEs) in ≥15% of patients 
who received the 90 mg QD→180 mg QD (n=32) regimen were diarrhea (44%), fatigue (44%), 
nausea (41%), headache (28%), cough (28%), arthralgia (28%), amylase increased (25%), lipase 
increased (25%), constipation (22%), back pain (22%), hypertension (22%), aspartate 
aminotransferase increased (19%), decreased appetite (16%), alanine aminotransferase increased 
(16%), insomnia (16%), peripheral sensory neuropathy (16%), and joint swelling (16%). Grade 3 
or greater TEAEs reported in 2 or more patients (>5%) who received the 90 mg QD→180 mg 
QD (n=32) regimen included: increased lipase (9%), hypertension (9%), pericardial effusion 
malignant (9%), dyspnea (6%), and alanine aminotransferase increased (6%). 
During dose escalation and initial phase 2 expansion, patients were observed to experience 
pulmonary AEs such as dyspnea, hypoxia, pneumonia, and pneumonitis within the first 7 days of 
treatment at starting doses of 180 mg QD and higher. Many of these early pulmonary AEs 
occurred within 24 to 48 hours after initiating treatment. Based on these safety observations, 
2 additional regimens were tested in the phase 2 portion (90 mg QD and 90 mg QD→180 mg 
QD). In the study overall, there were 13/137 (9%) patients with these early onset pulmonary 
events within the first 7 days of treatment: 2/2 (100%) patients at 300 mg QD, 
2/10 (20%) patients at 240 mg QD, 6/44 (14%) patients at 180 mg QD, 1/11 (9%) patients at 
120 mg QD, and 2/50 (4%) patients at starting at 90 mg QD (including 90 mg QD and 90 mg 
QD→180 mg QD). The addition of a 90 mg QD 7-day lead-in to therapy with 180 mg QD 
appears to lessen the incidence of early onset pulmonary events. Of 32 patients started at 90 mg 
for 7 days and then escalated to 180 mg, none (0%) experienced these early onset pulmonary 
symptoms within the first 7 days at 90 mg or after escalation to 180 mg. 
In evaluable ALK+ NSCLC patients treated with prior crizotinib, a 71% (50/70) overall response 
rate (ORR) was observed, including 4 complete responses (CRs). The ORR for the cohort that 
received 90 mg QD→180 mg QD was 81% (22/27 evaluable). An ORR of 100% was observed 
for crizotinib-naïve patients (8/8), including 3 CRs. Median PFS was 13.4 months for patients 
treated with prior crizotinib. Median PFS was not reached for the crizotinib-naive patients, with a 
median time on treatment of 62 weeks (max: 134 weeks, ongoing) and 6/8 patients ongoing 
without progression. 
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To evaluate the potential for brigatinib anti-tumor activity in the CNS, a blinded independent 
radiological review of intracranial response was performed in ALK+ NSCLC patients with 
intracranial CNS metastases at baseline. In patients with measurable metastases, 53% (8/15) had 
an intracranial response; in those with only nonmeasurable metastases, 35.5% (11/31) had an
intracranial response. Among patients who had no prior brain radiotherapy (n=21), intracranial 
ORR was 5/9 (56%) for patients with measurable lesions and 7/12 (58.3%) for those with only 
nonmeasurable lesions. For patients with a follow-up scan (n=46), median intracranial PFS was 
15.6 months. 
7.3.2
Study AP26113-13-201 (ALTA)
A pivotal phase 2 study of patients with advanced or metastatic ALK+ NSCLC whose disease 
has progressed on therapy with crizotinib (Study AP26113-13-201; ALTA) is ongoing. This 
study randomizes patients in a 1: 1 fashion between 2 brigatinib treatment regimens: 90 mg QD 
(Arm A) and 90 mg QD→180 mg QD (Arm B). A total of 218 patients are planned to be 
enrolled.
As of 15 June 2015, 69 and 71 patients in Arm A and Arm B, respectively, were included an 
interim analysis of the safety population. Median duration of treatment was 89 days (range: 3 to 
249 days) in Arm A and 88 days (range: 2 to 356 day) in Arm B. TEAEs occurring in ≥10% of 
patients in either arm are summarized in Table 1, with the most commonly reported events 
(≥15% overall) including diarrhea, cough, nausea, fatigue, dyspnea and headache. TEAEs 
≥grade 3 in 2 or more patients are summarized in Table 2, with the most commonly reported 
grade 3 to grade 5 events (≥3% overall) including neoplasm progression, pneumonia and 
hypertension. Across both arms, 8/140 (5.7%) patients experienced a pulmonary SAE without a 
conclusive alternative etiology (e.g. tumor progression, infectious) with symptoms starting 
within the first 7 days of treatment at 90 mg QD (pneumonitis, n=4; pneumonia, n=3; atypical 
pneumonia; n=1). No events have been observed to date in Arm B upon escalation to 180 mg 
QD.
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Table 1
Treatment Emergent Adverse Events (All Grades) Occurring in ≥10% of 
Patients in Study AP26113-13-201 
Preferred Term
Patients With Adverse Events by Arm and Overall, n (%)
Arm A (90 mg), N=69
Arm B (90 mg 180mg), N=71 
Total, N=140
Patients with at least 1 adverse event
61 (88.4)
59 (83.1)
120 (85.7)
Diarrhoea
13 (18.8)
15 (21.1)
28 (20.0)
Cough
12 (17.4)
15 (21.1)
27 (19.3)
Nausea
12 (17.4)
14 (19.7)
26 (18.6)
Fatigue
10 (14.5)
14 (19.7)
24 (17.1)
Dyspnoea
13 (18.8)
8 (11.3)
21 (15.0)
Headache
8 (11.6)
13 (18.3)
21 (15.0)
Vomiting
12 (17.4)
7 (9.9)
19 (13.6)
Amylase increased
5 (7.2)
9 (12.7)
14 (10.0)
Blood creatine phosphokinase increased
5 (7.2)
8 (11.3)
13 (9.3)
Decreased appetite
7 (10.1)
6 (8.5)
13 (9.3)
Hypertension
4 (5.8)
9 (12.7)
13 (9.3)
Pyrexia
9 (13.0)
2 (2.8)
11 (7.9)
Muscle spasms
1 (1.4)
8 (11.3)
9 (6.4)
Source: AP26113-13-201 Table 5.1, Table 5.2, Table 5.3. Data extraction date: 15 June 2015. 
Note: Adverse events are coded using Medical Dictionary for Regulatory Activities (MedDRA 18.0).
Table 2
Treatment Emergent Adverse Events ≥ Grade 3 in 2 or More Patients in 
Study AP26113-13-201
Preferred Term
Patients With Adverse Events by Arm and Overall, n (%)
Arm A (90 mg), N=69
Arm B (90180mg), N=71 
Total, N=140
Grade 3-4
Grade 5
Grade 3-4
Grade 5
Grade 3-4
Grade 5
Patients with at least 1 adverse event
10 (14.5)
7 (10.1)
17 (23.9)
3 (4.2)
27 (19.3)
10 (7.1)
Neoplasm progression
0
4 (5.8)
0
2 (2.8)
0
5 (3.6)
Pneumonia
2 (2.9)
1 (1.4)
1 (1.4)
1 (1.4)
3 (2.1)
2 (1.4)
Hypertension
1 (1.4)
0
4 (5.6)
0
5 (3.6)
0
Dyspnoea
3 (4.3)
0
1 (1.4)
0
4 (2.9)
0
Blood creatine phosphokinase increased
1 (1.4)
0
3 (4.2)
0
4 (2.9)
0
Lipase increased
2 (2.9)
0
1 (1.4)
0
3 (2.1)
0
Rash
1 (1.4)
0
2 (2.8)
0
3 (2.1)
0
Rash pruritic
1 (1.4)
0
1 (1.4)
0
2 (1.4)
0
Pneumonitis
0
0
2 (2.8)
0
2 (1.4)
0
Source: AP26113-13-201 Table 5.1, Table 5.2, Table 5.3. Data extraction date: 15 June 2015. 
Note: Adverse events are coded using Medical Dictionary for Regulatory Activities (MedDRA 18.0).
Refer to the Investigator’s Brochure for a more comprehensive summary of the safety and 
efficacy data from brigatinib clinical studies.
Rationale for the Phase 3 Study of Brigatinib in ALK-inhibitor-naive ALK+ 
7.4
NSCLC
There continues to be a need to explore new treatment options for patients with ALK+ NSCLC 
who are naïve to treatment with an ALK-targeted TKI. Although crizotinib is an effective 
treatment for ALK+ NSCLC, almost half of ALK+ NSCLC patients in the pivotal trials that 
supported its accelerated approval failed to achieve a response. PFS was relatively short in the 
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2 randomized phase 3 trials, with a median duration of 7.7 to 10.9 months. Chemotherapy is also 
used although it is not specifically approved for use in ALK+ NSCLC patients, with median PFS 
duration of 7.0 months with first line platinum doublet chemotherapy. New therapies are needed 
to improve response rates, provide greater durability of response, and to overcome potential 
mechanisms of resistance to ALK-targeted therapy, including the emergence of secondary 
resistance mutations in ALK and progression in the CNS. 
Based on the promising activity profile of brigatinib in vitro and in vivo and the clinical activity 
demonstrated in the phase 1/2 study (Study AP26113-11-101) and Phase 2 study (Study 
AP26113-13-201, ALTA), this phase 3 study will evaluate brigatinib in an ALK+ NSCLC 
patient population not previously treated with an ALK inhibitor. 
Rationale for Proposed Phase 3 Dose
7.5
Brigatinib has an acceptable safety profile at starting doses of 90 mg QD (including dose 
escalation to 180 mg QD after 1 week). The 7-day run-in period at 90 mg QD prior to escalation 
to 180 mg QD reduced the frequency of pulmonary toxicity observed with a starting dose of 
180 mg, and pulmonary toxicity has not been seen upon escalation to 180 mg. Taken together, 
the preliminary safety data from study AP26113-13-201 and longer follow up safety data in 
study AP26113-11-101 show that the AE profile of the 90 mg QD→180 mg QD is similar 
qualitatively and quantitatively to that of 90 mg QD. Mean plasma concentrations in patients 
dosed at 90 or 180 mg QD in study AP26113-11-101 were found to exceed the IC50 values for 
native EML4-ALK and all 17 resistance mutants tested by at least 2-fold, with the exception of 
the G1202R mutant, whose IC50 was substantially exceeded by brigatinib levels achieved at 
180 mg QD but not 90 mg QD dosing. This suggests that the higher 180 mg QD dose may 
prevent the emergence of a broader array of ALK resistance mutations than 90 mg QD. 
Importantly, with likely higher CNS exposure, the 180 mg QD dose may also provide increased 
activity against brain metastases. In order to optimize PFS and control CNS disease there is 
strong rationale to use the highest safe dose of brigatinib (90 mg QD for 7 days followed by 
180 mg QD). 
8
STUDY OBJECTIVES
Primary Objective
8.1
The primary objective of the study is to compare the efficacy of brigatinib to that of crizotinib in 
ALK+ locally advanced or metastatic NSCLC patients naive to ALK inhibitors, as evidenced by 
PFS.
Secondary Objectives
8.2
The secondary objectives of the study are:
1.
To compare the efficacy of brigatinib to that of crizotinib, as evidenced by confirmed 
ORR, time to/duration of response, disease control rate (DCR), and Overall Survival 
(OS)
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2.
To compare the efficacy in the CNS of brigatinib to that of crizotinib, as evidenced by 
intracranial response and intracranial PFS in those patients with intracranial CNS 
metastases at baseline
3.
To assess the safety and tolerability of brigatinib in comparison with crizotinib 
4.
To determine PK parameters of brigatinib through population PK modeling
5.
To assess patient-reported symptoms and health-related quality of life (HRQoL) with 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire (QLQ)-C30 (v3.0) and its lung cancer module, QLQ-LC13 (v3.0) 
in patients treated with brigatinib compared to those treated with crizotinib
Exploratory Objectives
8.3
9
INVESTIGATIONAL PLAN
Overall Study Design and Plan
9.1
This is a phase 3, randomized, open-label, comparative, multicenter, international study in which 
ALK+ NSCLC patients who have not previously received an ALK-targeted TKI will be 
randomized in a 1:1 fashion to receive brigatinib (Arm A) or crizotinib (Arm B). 
Patients will be stratified by the presence of CNS metastases at baseline (Yes versus No) and 
prior chemotherapy used for locally advanced or metastatic disease (Yes versus No). For the 
purposes of stratification, prior chemotherapy is defined as completion of ≥1 full cycle of 
chemotherapy in the locally advanced or metastatic setting. An estimated 270 patients (135 in 
Arm A, 135 in Arm B) will be enrolled at approximately 150 centers.
Patients will be treated until they experience progressive disease (PD) assessed by the blinded 
Independent Review Committee (BIRC), intolerable toxicity, or another discontinuation criterion 
is met. Continuation of brigatinib beyond progression is permitted, at the investigator’s 
discretion, if there is evidence of continued clinical benefit. Crossover from Arm B (crizotinib) 
to brigatinib is also permitted, at the investigator’s discretion with the sponsor’s medical monitor 
approval, for patients who have experienced objective progression assessed by the BIRC. 
Throughout the study, AEs will be assessed and categorized by the US National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0 (see Appendix A). 
Patients will be evaluated according to the Schedule of Events in Section 11.1. Patients will be 
supplied study drug until they discontinue from the study.
CCI
Property of Takeda: For Non-Commercial Use Only and
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9.1.1
Primary Endpoint
PFS, as assessed by the BIRC, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
(Eisenhauer et al, 2009). 
9.1.2
Secondary Endpoints
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR, as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
5.
Duration of response, as assessed by the BIRC
6.
Time to response, as assessed by the BIRC
7.
Disease control rate, as assessed by the BIRC 
8.
Safety and tolerability
9.
Change from baseline scores in global health status/quality of life (QOL) assessed 
with the EORTC QLQ-C30 (v3.0), and time-to-deterioration in dyspnea assessed with 
the EORTC QLQ-LC13 (v3.0)
9.1.3
Exploratory Endpoints
Randomization
9.2
Patients will be randomized in a 1:1 ratio to receive either brigatinib 90 mg once daily (QD) 
orally for 7 days followed by 180 mg QD orally continuously (Arm A) or crizotinib 250 mg 
twice daily (BID) orally (Arm B). Patients will be stratified by the following 2 factors, each 
having 2 levels:
1.
Intracranial CNS metastases at baseline (yes versus no) 
2.
Prior chemotherapy use for locally advanced or metastatic disease (yes versus no). For 
the purposes of stratification, prior chemotherapy is defined as completion of ≥1 full 
cycle of chemotherapy in the locally advanced or metastatic setting.
Specific instructions for randomization will be supplied in the Study Reference Manual. 
Randomization procedures should be performed following completion of eligibility assessments 
and prior to the initiation of treatment. This study is unblinded; patients, investigators, and the 
sponsor will know the identity of each patient’s study drug.
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10
SELECTION OF STUDY POPULATION
All patients must take part in the informed consent process. This process is described in 
Section 17.2. Screening tests and procedures used to establish eligibility are outlined in 
Section 11.1. Documentation from the screening period is required for each inclusion and 
exclusion criterion.
Inclusion Criteria
10.1
All patients must meet all of the following eligibility criteria for study entry:
1.
Have histologically or cytologically confirmed stage IIIB (locally advanced or 
recurrent and not a candidate for definitive multimodality therapy) or stage IV 
NSCLC. 
2.
Must meet one of the following two criteria:
a.
Have documentation of ALK rearrangement by a positive result from the Vysis®
ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the 
Ventana ALK (D5F3) CDx Assay. The test must have been performed according 
to the product’s instructions for use (IFU). 
b.
Have documented ALK rearrangement by a different test and adequate tissue 
available for central laboratory testing by an FDA-approved test. Confirmation of 
central test positivity is not required prior to randomization.
3.
Have sufficient tumor tissue available for central analysis (see the Study Reference 
Manual for minimum requirements) 
4.
Have at least 1 measurable (i.e., target) lesion per RECIST v1.1 (see Appendix C).
5.
Recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 
grade ≤1. Note: treatment-related alopecia or peripheral neuropathy that are grade >1 
are allowed if deemed irreversible.
6.
Are a male or female patient ≥18 years old. 
7.
Have adequate organ function, as determined by:
a.
ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable if liver 
metastases are present
b.
Total serum bilirubin ≤1.5 × ULN (<3.0×ULN for patients with Gilbert 
syndrome)
c.
Serum creatinine ≤1.5 × ULN
d.
Serum lipase/amylase ≤1.5 × ULN
e.
Absolute neutrophil count (ANC) ≥1.5 × 109/L 
f.
Platelet count ≥75 × 109/L
g.
Hemoglobin ≥10 g/dL
8.
Have Eastern Cooperative Oncology Group (ECOG) performance status <2 (see 
Appendix B).
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9.
Have normal QT interval on screening ECG evaluation, defined as QT interval 
corrected (Fridericia) (QTcF) of ≤450 milliseconds (msec) in males or ≤470 msec in 
females. 
10.
For female patients of childbearing potential, have a negative pregnancy test 
documented prior to randomization.
11.
For female and male patients who are fertile, agree to use a highly effective form of 
contraception with their sexual partners during the dosing period and for a period of at 
least 4 months after the end of treatment with brigatinib and at least 3 months after the 
end of treatment with crizotinib (Section 14.3.1). 
12.
Provide signed and dated informed consent indicating that the patient has been 
informed of all pertinent aspects of the study, including the potential risks, and is 
willingly participating.
13.
Have the willingness and ability to comply with scheduled visit and study procedures.
Exclusion Criteria
10.2
Patients meeting any of the criteria below are ineligible for the study:
1.
Previously received an investigational antineoplastic agent for NSCLC.
2.
Previously received any prior TKI, including ALK-targeted TKIs.
3.
Previously received more than 1 regimen of systemic anticancer therapy for locally 
advanced or metastatic disease.
Note: a systemic anticancer therapy regimen will be counted if it is administered over 
at least 1 cycle. A new antineoplastic agent used as maintenance therapy will be 
counted as a new regimen. Neo-adjuvant or adjuvant systemic anticancer therapy will 
be counted as a prior regimen if completion of (neo) adjuvant therapy occurred <12 
months prior to randomization. 
4.
Received chemotherapy or radiation within 14 days of first dose of study drug, except 
stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT). 
5.
Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of 
study drug.
6.
Had major surgery within 30 days of the first dose of study drug, minor surgical 
procedures such as catheter placement or minimally invasive biopsies are allowed. 
7.
Have been diagnosed with another primary malignancy other than NSCLC, except for 
adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively 
treated non-metastatic prostate cancer; or patients with another primary malignancy 
who are definitively relapse-free with at least 3 years elapsed since the diagnosis of 
the other primary malignancy. 
8.
Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or 
asymptomatic disease requiring an increasing dose of corticosteroids to control 
symptoms within 7 days prior to randomization. 
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Note: If a patient has worsening neurological symptoms or signs due to CNS 
metastasis, the patient needs to complete local therapy and be neurologically stable 
(with no requirement for an increasing dose of corticosteroids or use of 
anticonvulsants) for 7 days prior to randomization.
9.
Have current spinal cord compression (symptomatic or asymptomatic and detected by 
radiographic imaging). Patients with leptomeningeal disease and without cord 
compression are allowed.
10.
Be pregnant, planning a pregnancy, or breastfeeding 
11.
Have significant, uncontrolled, or active cardiovascular disease, 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.
Congestive heart failure (CHF) within 6 months prior to first dose of study drug
d.
History of clinically significant atrial arrhythmia (including clinically significant 
bradyarrhythmia), as determined by the treating physician
e.
Any history of ventricular arrhythmia
f.
Cerebrovascular accident or transient ischemic attack within 6 months prior to 
first dose of study drug
12.
Have uncontrolled hypertension. Patients with hypertension should be under treatment 
on study entry to control blood pressure.
13.
Have a history or the presence at baseline of pulmonary interstitial disease, 
drug-related pneumonitis, or radiation pneumonitis. 
14.
Have an ongoing or active infection, including, but not limited to, the requirement for 
intravenous (IV) antibiotics.
15.
Have a known history of human immunodeficiency virus (HIV) infection. Testing is 
not required in the absence of history.
16.
Have a known or suspected hypersensitivity to brigatinib or its excipients.
17.
Have a known or suspected hypersensitivity to crizotinib or its excipients.
18.
Have malabsorption syndrome or other gastrointestinal (GI) illness or condition that 
could affect oral absorption of the study drug. 
19.
Have any condition or illness that, in the opinion of the investigator, would 
compromise patient safety or interfere with evaluation of the study drug.
11
STUDY PROCEDURES
The screening period begins when the informed consent form is signed, and continues until 
randomization. The follow-up period begins at the end of treatment and continues until patient 
contact discontinues. 
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Study Procedure Descriptions
11.1
The study procedures to be performed at screening and throughout the Randomized Phase of the 
study are listed in Table 3 (Schedule of Events), which is meant to provide a convenient display 
of the timing and scope of required assessments expected at each visit, but does not provide a 
comprehensive description of each assessment. A complete list of all study-related assessments 
as well as a detailed description of what is expected in the assessment is included below. 
Investigators must be familiar with the details of this section and use it in conjunction with the 
table to adequately carry out the required study assessments. All study assessments should occur 
within ±3 days of the scheduled study visit unless otherwise noted in the Schedule of Events 
descriptions or table. A cycle is defined as 28 days. 
Crossover in Arm B (crizotinib) to brigatinib is permitted, at the investigator’s discretion with 
the sponsor’s medical monitor approval, for patients who have experienced objective progression 
documented by BIRC or the investigator. Patients who crossover from crizotinib to brigatinib 
treatment (Crossover Phase) will adhere to the Schedule of Events listed in Table 4. All 
assessments for the Crossover Phase will be performed as described below for the Randomized 
Phase, except as noted.
The following list describes the footnotes for Table 3 and Table 4.
1.
Screening
Patients with known locally advanced or metastatic ALK+ NSCLC and no history of prior 
ALK-targeted TKI treatment can be considered for screening. Screening assessments must 
be performed no more than 14 days prior to Day 1, with the exception of tumor imaging 
assessment, where the allowable window is 21 days prior to first dose of study drug 
(Cycle 1, Day 1). However, whenever feasible, baseline imaging should be performed as 
close as possible to Cycle 1, Day 1. 
Screening physical examination, ECOG Performance Status assessments, and clinical 
laboratory assessments (hematology, chemistry, testosterone [male patients], insulin, and 
pregnancy test) do not need to be repeated on Cycle 1, Day 1 if they were performed for 
screening within 7 days prior to Cycle 1, Day 1 AND, in the opinion of the investigator, 
there is no reason to believe they have substantially changed. The pregnancy test may be 
repeated at any time during the study if the patient or the investigator has cause to believe 
that the patient may be pregnant. If screening laboratory assessments need to be repeated 
on Cycle 1, Day 1, they should be obtained before starting treatment. 
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2.
Informed Consent
Informed consent, documented by a signed and dated consent form, must be obtained prior 
to any screening activities that are not otherwise considered part of normal patient care. 
Informed consent can be signed prior to the 14-day screening period window.
3.
Randomization
Specific instructions for randomization will be supplied in the Study Reference Manual. 
Randomization procedures should be performed following completion of all eligibility 
assessments and determination of patient eligibility and prior to the initiation of assigned 
treatment. 
4.
Demographics
Demographic information will be obtained at screening and consists of the patient’s age, 
sex, race, and ethnicity (as allowed by local law and regulations).
5.
Medical/Surgical History
A complete medical history will be taken at screening. Information to be documented 
includes relevant past illnesses, including other cancers, smoking history, ongoing medical 
conditions, and surgical procedures (not related to the primary diagnosis).
6.
Diagnosis and Cancer History
The initial cancer diagnosis and the current cancer stage at the time of screening, along 
with tumor histology and all sites of disease, should be recorded. Any previously identified 
mutations other than ALK, and the dates of identification, must be recorded.
7.
Prior Cancer Therapy
Prior cancer therapy history will be taken at screening and includes cancer-related surgical 
procedures, radiation, and systemic therapies. Surgical procedures include curative and 
palliative, as well as diagnostic procedures (e.g., biopsy). Radiation will include both 
definitive and palliative treatment. Systemic therapy should include all regimens given, 
type of regimen (e.g., neo-adjuvant, adjuvant, for advanced or metastatic disease), number 
of cycles administered for each regimen, each drug name in a regimen, the start and stop 
dates of each drug, the best response to the regimen, and the reason for discontinuation. 
Experimental or investigational therapy history must also be recorded. 
8.
ALK Mutation Status
Regarding current and past ALK mutation history, any previously identified mutations, and 
the dates of identification, must be recorded at screening. This includes ALK 
rearrangements by FISH, ALK abnormalities by other methods including 
immunohistochemistry (IHC), and ALK point mutations. 
Patients entering the study must either have a history of a positive Vysis® ALK 
Break-Apart FISH Probe Kit test or Ventana ALK (D5F3) CDx Assay, or must have 
history of ALK-positivity by another test and submit tissue samples for central laboratory 
analysis using an FDA-approved test. Specifications regarding handling and processing of 
tissue for this test are described under Item 21 below (Tumor Tissue Samples) and in the 
Study Reference Manual. 
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9.
Physical Examination
A complete physical examination must be performed at screening, the extent of which 
should be consistent with medical history and the patient’s underlying disease. Subsequent 
physical examinations may be directed to relevant findings. Of note, due to adverse 
reactions reported during treatment with crizotinib and brigatinib, investigators are 
cautioned to monitor patients for signs of vision dysfunction. For new or worsening severe 
vision disorders, ophthalmological evaluation consisting of best corrected visual acuity, 
retinal photographs, visual fields, optical coherence tomography (OCT) and other 
evaluations should be performed. The End-of-Treatment physical examination should be a 
complete physical examination. The physical examination 30 days after last dose may be 
directed to any relevant findings.
10.
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and blood pressure (when patient is 
seated). In addition, the screening assessment must include height and weight. Vital signs 
should be repeated on Cycle 1, Day 1, prior to first dose, regardless of the time from 
screening. Vital signs will also be assessed per the Schedule of Events throughout the 
study.
11.
ECOG Performance Status
The patient’s performance status must be assessed using the ECOG performance scale 
during screening ECOG performance status will also be assessed per the Schedule of 
Events throughout the study. The ECOG performance scale is provided in Appendix B.
12.
Hematology
Hematology laboratory measurements include complete blood count (CBC) with 5-part 
differential and platelet count. Cycle 1, Day 1 hematology blood draws should be 
performed prior to the first dose of study drug. Hematology laboratory measurements will 
be assessed per the Schedule of Events throughout the study.
13.
Chemistry
Serum chemistry laboratory assessments include: sodium, potassium, chloride, bicarbonate 
(or total carbon dioxide), blood urea nitrogen (BUN, or urea), albumin and total protein, 
creatinine, bilirubin (at least total and direct or total and indirect), ALT (SGPT), AST 
(SGOT), alkaline phosphatase, magnesium, phosphorous, calcium, lactate dehydrogenase 
(LDH), creatine kinase (CK), uric acid, amylase, lipase, and glucose. Cycle 1, Day 1 serum 
chemistry blood draws should be performed prior to the first dose of study drug. Chemistry 
laboratory measurements will also be assessed per the Schedule of Events throughout the 
study. 
14.
Insulin
Serum insulin and glucose should be measured concurrently. Cycle 1, Day 1 insulin blood 
draws should be performed prior to the first dose of study drug. Insulin will also be 
assessed per the Schedule of Events throughout the study. 
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15.
Testosterone Level (males only)
In male patients, serum testosterone should be measured at screening and throughout the 
study per the Schedule of Events. 
16.
Electrocardiogram 
All ECGs must be 12-lead ECGs and will be assessed per the Schedule of Events 
throughout the study. 
Additional ECGs may be performed at the investigator’s discretion to ensure patient safety. 
In particular, ECG monitoring should be performed during the study if a patient has, during 
the study, been prescribed medication that can prolong the QT interval or medication that 
can potentially alter the QT interval (other than medications explicitly prohibited).
For consistency, the Fridericia correction (QTcF = QT interval/(RR)1/3 interval) method 
must be used for all calculations of heart rate-corrected QT (calculated) (QTc) intervals. 
17.
Adverse Events
Adverse events (AEs) are to be recorded continuously throughout the entire study until at 
least 30 days after the last dose of study drug and graded per NCI CTCAE v4.0 (See 
Appendix A). It is expected that new and updated AEs and concomitant medications 
reported within the treatment period, ongoing AEs thought to be at least possibly 
study-drug related, and all ongoing SAEs should be followed at least every 4 weeks until 
they resolve to baseline (or to NCI CTCAE v4.0 grade ≤1), stabilize, or are considered to 
be chronic/irreversible.
18.
Concomitant Medications
Concomitant treatments for all ongoing medical history conditions or AEs, as well as 
prophylactic treatments and supplements, must be reported from the date the informed 
consent is signed until at least 30 Days After Last Dose, and for all concomitant treatments 
related to serious or study drug-related toxicities until the medication is no longer taken or 
until patient contact discontinues.
19.
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test, and either 
urine or serum can be used. Women who are not of childbearing potential (status 
post-hysterectomy, status post-bilateral oophorectomy, or post-menopausal [defined as 
amenorrhea for at least 12 months]) and men do not need to have the test performed. The 
test must be known to be negative prior to the study drug administration and be performed 
within 7 days prior to first study drug administration (Cycle 1, Day 1). Women of 
childbearing potential at study start must also complete the pregnancy test once every 
12 weeks thereafter and at the End-of-Treatment. Additional pregnancy testing should be 
performed if recommended or required per local guidelines or regulations.
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20.
Disease Assessment CT/MRI, Brain MRI
At screening, disease assessment must include imaging of the chest and abdomen 
(including adrenal glands), using appropriate radiological procedures (computed 
tomography [CT] scans or magnetic resonance imaging [MRI] with contrast, unless contrast 
media is contraindicated). Contrast-enhanced MRI of the brain (such as gadolinium) is 
required at screening for all patients. All radiographic images (e.g., CT scan, MRI) 
performed during the study will be submitted to the imaging core laboratory for central 
review. Patients must have at least 1 measurable lesion per RECIST v1.1. Previously 
irradiated lesions may not be used for target lesions, unless there is unambiguous 
radiological progression after radiotherapy. Brain lesions may be used as target lesions 
provided they are ≥10 mm and have not been: 1) previously treated with whole brain 
radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic 
radiosurgery (SRS) or surgical resection.
Disease assessment by CT and MRI scans will be performed at screening and at 8-week 
intervals thereafter (on Day 28 [±3 days] of every even-numbered cycle), through Cycle 14 
after the initial dose of study drug, and every 3 cycles thereafter until End-of-Treatment. 
Imaging of chest, abdomen and brain will occur at each assessment for all patients. More 
frequent imaging is recommended at any time if clinically indicated; confirmation of CR or 
PR should be performed at least 4 weeks after initial response. Imaging assessment will 
also be performed at End-of-Treatment if more than 4 weeks have passed since the last 
imaging assessment. The same imaging modality at the same institution should be used at 
each assessment, if possible. 
A patient randomized to Arm B (crizotinib) with objective disease progression assessed by 
the BIRC may crossover to brigatinib treatment, at the investigator’s discretion with the 
sponsor’s medical monitor approval (see Section 13.1.2). The disease assessment which 
documents progression will serve as the new baseline for the crossover portion of the 
study. The investigator will reevaluate the patient for target and non-target lesions, 
according to RECIST criteria, based on the disease assessment scans showing the initial 
progression. A crossover patient need not repeat imaging assessments before Crossover 
Cycle 1, Day 1, unless the disease assessment is incomplete, or occurred >21 days prior to 
Crossover Cycle 1, Day 1 (in which case, disease assessments must be repeated and will 
serve as the new baseline). If the disease assessment is incomplete, the site will obtain any 
missing radiographic imaging (e.g., MRI of the brain) prior to initiation of treatment with 
brigatinib. Disease assessment by CT and MRI scans will be performed at 8-week intervals 
thereafter (on Day 28 [±3 days] of every even-numbered cycle), through Cycle 14 after the 
initial dose of brigatinib, and every 3 cycles thereafter until End-of-Treatment. Imaging 
assessment will also be performed at End-of-Treatment if more than 4 weeks have passed 
since the last imaging assessment. The same imaging modality at the same institution 
should be used at each assessment, if possible.
For patients who discontinue the study drug due to a reason other than progressive disease, 
additional tumor assessment should be documented, if available, until disease progression 
or start of another systemic anti-cancer therapy. For patients who continue brigatinib 
beyond BIRC-assessed progressive disease at the investigator’s discretion, imaging will 
continue with a similar assessment schedule. If the patient experiences symptomatic 
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deterioration, it is strongly recommended that additional imaging studies be performed to 
confirm progressive disease.
21.
Tumor Tissue Samples
Mandatory Tumor Tissue From All Patients at Screening:
Formalin-fixed paraffin-embedded (FFPE) tumor tissue that was acquired prior to 
randomization must be provided for exploratory molecular genetic analysis. This tissue can 
be from the primary tumor or from a biopsied metastasis. A pathologist should assess the 
tissue sample to ensure adequate tumor tissue is available based on the minimum 
requirements described in the Study Reference Manual. 
For patients who do not have a prior positive result from the Vysis® ALK Break-Apart 
FISH Probe Kit or Ventana ALK (D5F3) CDx Assay, this sample will be used for central 
testing by an FDA-approved test and exploratory biomarker studies. For patients with a 
prior positive result for one of the FDA-approved tests, this sample will be used for 
exploratory biomarker studies. 
Optional Tumor Tissue at Time of Disease Progression:
For patients who consent, a biopsy will be performed at the time of progression on 
brigatinib (for patients in Arm A) or crizotinib (for patients in Arm B) and at the time of 
subsequent progression on brigatinib (for patients in Arm B after crossover to brigatinib). 
FFPE tumor tissue should be sent to the central laboratory. This tumor tissue will be used 
for exploratory molecular genetic analysis.
22.
23.
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24.
Quality of Life Assessments
The EORTC QLQ-C30 and EORTC QLC-LC13 questionnaires will be administered at 
baseline, per the Schedule of Events throughout the study, and at the 30 days after last dose 
visit. The questionnaires should be administered to patients when they arrive for their 
scheduled visits, prior to any clinical measurements, assessments, evaluations, or 
procedures being performed.
25.
End-of-Treatment Randomized Phase (Arms A and B)/Crossover Phase (Arm B Only)
The End-of-Treatment visit should be performed within 2 weeks (14 days) of the patient’s 
last dose of study drug or the patient/investigator decision to discontinue study drug—
whichever occurs later. Physical examinations, laboratory tests (hematology, chemistry, 
and insulin), and ECG may be omitted if they had been previously performed within 
2 weeks since the last assessments and if, in the investigator’s judgment, significant change 
is unlikely.
Patients in Arm B (crizotinib) who crossover to brigatinib should complete the assessments 
for the End-of-Treatment visit for crizotinib. These assessments will serve as baseline 
assessments for the Crossover Phase. After a minimum 10-day washout period, and a 
maximum of 28 days, the patient will start brigatinib treatment on Crossover Cycle 1, 
Day 1, and will follow the schedule of events for the crossover phase as described in Table 
4. For these patients, End-of-Treatment assessments must also be performed within 2 
weeks (14 days) of the patient’s last dose of brigatinib or the patient/investigator decision 
to discontinue study drug—whichever occurs later.
26.
30 Days After Last Dose
The 30 Days After Last Dose assessments must be performed 30 days (±7 days) after the 
last dose of study drug. Physical examinations and laboratory tests (hematology, chemistry, 
and insulin), and ECG can be omitted if the visit occurs within 10 days of the 
End-of-Treatment assessment and there have been no clinically significant findings. Any 
new systemic anticancer therapies that the patient has begun receiving since the end of 
treatment should be reported at this visit. For both the End-of-Treatment and 30 Days After 
Last Dose assessments, information may be collected from tests performed for the study or 
as part of the patient’s routine medical care.
Patients in Arm B (crizotinib) who crossover to brigatinib will not be required to have a 
30 Days After Last Dose visit after discontinuing crizotinib. A 30 Day After Last Dose 
visit will be required when brigatinib is discontinued.
27.
Follow-up
Patients will be followed throughout the study, as per Table 3 and Table 4. The follow-up 
assessments (i.e., contacting the patient for survival and subsequent anticancer therapy) 
must be performed every 12 weeks (±14 days) after the End-of-Treatment for the last study 
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drug administered (e.g., after End-of-Treatment with brigatinib for patients who crossover 
in Arm B). The allowable window for follow-up assessments is 14 days. All new systemic 
anticancer therapies should be reported. Follow-up will continue for approximately 3 years 
after the last patient is randomized into the study. 
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Confidential and Proprietary
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Table 3
Schedule of Events - Randomized Phase
Screening 
Period
During Treatment and Through 30 Days After Last Dose
Follow-
up 
Period
Assessment
Screening1
Cycle 1 
Cycle 2
Every 4 
weeks 
Every 
8 or 12 
weeks
End-of-
Treatment25
30 Days 
After Last 
Dose26
Follow-
up27
Day (D)
D-14 to D0
D1
D8
D15
D1
D15
Informed Consent2
X
Randomization3
X
Demographics4/Medical/Surgical History5
X
Diagnosis and Cancer History6/ Prior Cancer 
Therapy7
X
ALK Mutation Status8
X
Tissue for central ALK FISH Testing21
X
Physical Examination9
X
X1
X*
X
X
X
X
X
Vital Signs10
X
X
X
X
X
X
X
X
ECOG Performance Status11
X
X1
X
X
X
X
Hematology12
X
X1
X
X
X
X
X
Chemistry13
X
X1
X
X
X**
X
X
X
Insulin14
X
X
X
X
X
X
X
Testosterone Level (males only)15
X
X1
X
X
X
X
Pregnancy Test19
X
X19
X (every 12 
weeks)19
X19
Electrocardiogram (ECG)16
X
X
X
X
X
X
Brigatinib (Arm A only)
ONCE-DAILY ORAL DOSE
Crizotinib (Arm B only)
TWICE-DAILY ORAL DOSE
Adverse Events17
THROUGHOUT STUDY
Concomitant Treatments18
THROUGHOUT STUDY
Disease Assessment 20
X
X
X
Tissue Sample At Disease Progression21
X
Quality of Life Assessments24
X
X
X
X
X
X
Subsequent Anticancer Therapy/Survival
X
*Assessment for early pulmonary symptoms must be performed during the visit on Day 8. 
**Only AST, ALT and Total Bilirubin are required on Cycle 2, Day 15. 
For footnotes, see Section 11.1.
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Table 4
Schedule of Events – Brigatinib Crossover Phase (Arm B Only)
Crizotinib 
Washout
During Treatment and Through 30 Days After Last Dose
Follow-
up 
Period
Assessment
10-28 Days After 
Last Crizotinib 
Dose
Cycle 1 Crossover 
C1D1
Every 4 
Weeks
Every 8 or 
12 Weeks
End-of-
Treatment25
30 Days 
After Last 
Dose26
Follow-u
p27
Day (D)
D1
D8
D15
Physical Examination9
X
X*
X
X
X
X
Vital Signs10
X
X
X
X
X
X
ECOG Performance Status11
X
X
X
X
Hematology12
X
X
X
X
X
Chemistry13
X
X
X
X
X
Insulin14
X
X
X
X
X
Testosterone Level (males only)15
X
X
X
X
Pregnancy Test19
X19
X (every 
12 
weeks)19
X19
Electrocardiogram (ECG)16
X
X
X
X
Brigatinib
ONCE-DAILY ORAL DOSE
Adverse Events17
THROUGHOUT STUDY
Concomitant Treatments18
THROUGHOUT STUDY
Disease Assessment 20
X
X
Tissue Sample Upon Disease Progression
X
Quality of Life Assessments24
X
X
X
X
Subsequent Anticancer Therapy/Survival
X
*Assessment for early pulmonary symptoms must be performed during the visit on Day 8. 
For footnotes, see Section 11.1.
Note: All assessments for the Crossover Phase will be performed as described for the Randomization Phase, except as noted.
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Screening Period 
11.2
The screening period begins when the informed consent form is signed, and continues until 
randomization. See Section 11.1 for further details.
Screen Failures
11.3
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 on the Eligibility Criteria eCRF within 5 days. For all screen failures, the 
investigator is to maintain a screening log that documents the patient initials and reason(s) for 
screen failure. A copy of the log should be retained in the investigator’s study files. Patients who 
screen fail may later be re-screened with prior sponsor approval. 
Treatment Through 30 Days after Last Dose of Study Drug
11.4
This period begins when the patient receives the first dose of study drug.
Assessments required during this period for the Randomized Phase and the Crossover Phase are 
shown in Table 3 and Table 4, respectively. A detailed description of procedures and timing is 
provided in Section 11.1.
Note: clinical laboratory assessments do not need to be repeated on Cycle 1, Day 1 if they were 
performed for screening within 7 days prior to Cycle 1, Day 1.
End-of-Treatment or Early Termination 
11.5
End-of-Treatment is defined as the point when or the patient and investigator decide to end study 
drug (which may be after a dose interruption). Assessments required at Randomized Phase 
End-of-Treatment are shown in Table 3. A detailed description of procedures and timing is 
provided in Section 11.1.
Patients in Arm B (crizotinib) who crossover to brigatinib should complete the assessments for 
the End-of-Treatment visit for crizotinib. These assessments will serve as baseline assessments 
for the Crossover Phase. After a minimum 10-day washout period, the patient will start brigatinib 
treatment on Crossover Cycle 1, Day 1, and will follow the schedule of events for the crossover 
phase as described in Table 4. 
30 Days After Last Dose
11.6
Assessments required at 30 Days After Last Dose for the Randomized Phase and the Crossover 
Phase are shown in Table 3 and Table 4, respectively. A detailed description of procedures and 
timing is provided in Section 11.1. 
Patients in Arm B (crizotinib) who crossover to brigatinib will not be required to have a 30 Days 
After Last Dose visit for crizotinib.
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Follow-up Period Procedures
11.7
The follow-up period for a patient begins after End-of-Treatment (i.e., when all study drug has 
been discontinued) and continues until patient contact ceases (for approximately 3 years after the 
last patient has enrolled). 
Assessments required for the Follow-up Period for the Randomized Phase and the Crossover 
Phase are shown in Table 3 and Table 4, respectively. A detailed description of procedures and 
timing is provided in Section 11.1. 
Study Duration
11.8
11.8.1
Approximate Duration of Patient Participation
Patients will continue to be dosed with brigatinib (Arm A) or crizotinib (Arm B) until they 
experience BIRC-assessed disease progression or intolerable toxicity. Treatment with brigatinib 
may be continued after progression, at the discretion of the investigator, if there is still evidence 
of clinical benefit. At the discretion of the investigator with the sponsor’s medical monitor 
approval, patients who experience BIRC-assessed disease progression on crizotinib may 
crossover to treatment with brigatinib (see Section 13.1.2 for details on treatment continuation 
after progression). On average, a patient is expected to participate in this study for approximately 
4 years.
11.8.2
Approximate Duration of Study
The total estimated duration of the study is approximately 4.5 years, including 1.5 years to 
accrue patients, with approximately 3 years for treatment and follow-up of the last patient. Since 
the study met the statistical significance at the first interim analysis and the primary endpoint 
was consistent at the second interim analysis, the study will be closed approximately 3 years 
after the last patient enrolled. Patients will be allowed to receive brigatinib beyond the 3-year 
treatment period until they experience disease progression, they discontinue treatment for other 
reasons, or the study is closed. 
Patient Discontinuation
11.9
Patients in the Randomized Phase will be discontinued from further study drug administration 
(brigatinib or crizotinib) in the event of any of the following:

Intolerable toxicity as determined by the investigator

Progression of disease requiring an alternate therapy, in the opinion of investigator 
Note: Treatment of patients in Arm A with brigatinib may be continued, despite BIRC-
assessed progression by RECIST v1.1, at the discretion of the investigator, if there is still 
evidence of clinical benefit. In this clinical trial, patients in Arm B may not continue 
treatment with crizotinib beyond BIRC-assessed progression. Crossover of patients in 
Arm B to treatment with brigatinib may occur at the time of BIRC-assessed progression 
on crizotinib, at the discretion of the investigator with the sponsor’s medical monitor 
approval.
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
Progression of disease as assessed by the BIRC for patients in Arm B for which crossover 
is not being considered

Entry into another therapeutic clinical study or start of new anticancer therapy

Significant deviation from the protocol or eligibility criteria, in the opinion of the 
sponsor’s medical monitor or investigator

Noncompliance with study or follow-up procedures

Pregnancy

Patient withdrawal of consent or decision to discontinue participation

Termination of the study by the sponsor

Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
Patients in the Crossover Phase will be discontinued from further brigatinib administration in the 
event of any of the following:

Intolerable toxicity as determined by the investigator

Progression of disease requiring an alternate therapy, in the opinion of investigator 
Note: Treatment of patients with brigatinib may be continued, despite progression by 
RECIST v1.1, at the discretion of the investigator, if there is still evidence of clinical 
benefit. 

Entry into another therapeutic clinical study or start of new anticancer therapy

Significant deviation from the protocol or eligibility criteria, in the opinion of the 
sponsor’s medical monitor or investigator

Noncompliance with study or follow-up procedures

Pregnancy

Patient withdrawal of consent or decision to discontinue participation

Termination of the study by the sponsor

Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
In the event that a patient is withdrawn from the study, every effort must be made by the 
investigator to document and report the reasons for withdrawal as thoroughly as possible. The 
reason(s) for withdrawal must be clearly reported on the appropriate page of the patient’s 
electronic case report form (eCRF). An eCRF must be completed for any patient randomized and 
an End-of-Treatment reason must be recorded for any patient who is randomized, regardless of 
whether they receive study drug.
If a patient is discontinued from treatment for any reason, every effort must be made to perform 
all End-of-Treatment and 30 Days After Last Dose assessments per the schedule of events (Table 
3 or Table 4). In the event that the patient fails to return for the necessary visit(s), an effort must 
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be made to contact the patient to determine the reason, and this information should be recorded 
in the appropriate source record and reported as a deviation.
All patients who permanently discontinue from study drug will be followed-up for survival and 
collection of new systemic anti-neoplastic therapies administered every 12 weeks after End-of-
Treatment until patient contact ceases (for approximately 3 years after the last patient has been 
randomized). 
Study or Site Termination
11.10
If the sponsor, investigator, medical monitor, or regulatory agencies discover conditions during 
the study that indicate that the study or site should be terminated, this action may be taken after 
appropriate consultation between the sponsor and the investigator (in the case of site 
termination). Conditions that may warrant termination of the study include, but are not limited 
to:
●
The discovery of a serious, unexpected, or unacceptable risk to subjects enrolled in the 
study
●
The decision on the part of the sponsor to suspend or discontinue testing, evaluation, or
development of the study drug
●
Duration of the study extends greater than 3 years after the last patient is randomized
●
Submission of knowingly false information from the research facility to the sponsor, 
medical monitor, or regulatory authorities
●
Insufficient adherence to protocol requirements
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the guidelines for Good Clinical Practice (GCP), International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
Sample Collection, Storage, and Shipping
11.11
All samples must be collected by appropriately trained individuals. Use of Universal Precautions 
is recommended when collecting any biological specimen. Plasma samples must be stored at or 
below -20ºC until shipment. Specific instructions regarding the handling and shipment of these 
specimens will be provided in the Study Reference Manual. 
12
EFFICACY AND SAFETY ASSESSMENTS
Efficacy Assessments
12.1
Tumor response assessments will be performed every 8 weeks and evaluated per RECIST v1.1 
(see Appendix C) by the BIRC and the investigator until BIRC-assessed disease progression. 
Tumor response (CR or PR) should be confirmed ≥4 weeks after initial response. For patients 
who discontinue the study treatment due to a reason other than BIRC-assessed progressive 
disease, additional tumor assessment should be documented, if available, until disease 
progression or start of another systemic anti-cancer therapy. For patients in Arm A who continue 
brigatinib beyond disease progression, tumor assessments will continue to be performed every 8 
weeks. For patients in Arm B who crossover to brigatinib after BIRC-assessed progression on 
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crizotinib, the tumor response assessment with BIRC-assessed progression will be re-evaluated 
per RECIST v1.1 criteria as a new baseline for the Crossover Phase unless >21 days prior to 
Crossover C1D1, which will require a new disease assessment prior to starting brigatinib. Tumor 
response assessments will be performed every 8 weeks and evaluated per RECIST v1.1 by the 
BIRC and the investigator until BIRC-assessed disease progression. For patients who discontinue 
the study drug due to a reason other than BIRC-assessed progressive disease, additional tumor 
assessment should be documented, if available, until disease progression or start of another 
systemic anti-cancer therapy.
OS will be followed for approximately 3 years after the last patient has been randomized. 
Safety Assessments
12.2
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs. 
AEs will be graded according to the NCI CTCAE, v4.0 (see Appendix A and the Study 
Reference Manual). Safety assessments and their timing are outlined in Section 11.1.
Pharmacokinetic Assessments
12.3
Sparse plasma brigatinib concentration data obtained from this study will be included in 
integrated population PK analyses, along with data from study AP26113-11-101 and 
study AP26113-13-201, with the objective of further characterizing the plasma PK of brigatinib 
in the intended patient population, and to assess exposure-response (for efficacy) and exposure-
safety relationships in patients receiving brigatinib. 
Plasma PK samples may also be used for exploratory biomarker evaluations.
Exploratory Biomarker Evaluations in Tissue and Blood
12.4
Patient Reported Symptoms and Quality of Life Assessments 
12.5
Patient-reported symptoms and HRQoL will be collected by administering the EORTC 
QLQ-C30 (v3.0) and the lung cancer-specific module (the QLQ-LC13, v3.0) questionnaires, 
which have been studied extensively, are validated, and are suitable for use in global clinical 
studies. The questionnaires will be administered to patients in their local language, if available.
On the study days they are administered, the questionnaires should be completed by patients 
prior to any testing or discussion with the physician.
The EORTC QLQ-C30 is a cancer-specific questionnaire initially tested in lung cancer patients 
(Aaronson et al, 1993). The EORTC QLQ-C30 will be scored for 5 functional scales (physical, 
CCI
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role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and 
nausea/vomiting); and a global health status/QoL scale. Six single-item scales also are included 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 
The LC13 module was constructed in parallel with the core QLQ-C30. It comprises 13 questions 
assessing lung cancer associated symptoms (cough, hemoptysis, dyspnea, and site specific pain), 
treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and 
use of pain medication (Aaronson et al, 1996; Bergman et al, 1994). It is scored as a set of single 
items.
Note: Signs and symptoms assessed with the patient-reported outcome (PRO) questionnaires will 
not be considered AEs unless entered as such into the eCRF. 
13
STUDY TREATMENTS
Study Drug
13.1
Brigatinib is an investigational drug that will be administered only to eligible enrolled patients at 
qualified centers (e.g., listed on the FDA Form 1572).
13.1.1
Treatment Administration
Patients will be randomized 1:1 to receive brigatinib (Arm A) or crizotinib (Arm B). 
In Arm A, brigatinib will be administered orally at a dose of 90 mg QD for 7 days followed by 
180 mg QD continuously, with or without food. Patients will take the prescribed dose with water 
(recommended 240 mL). 
In Arm B, crizotinib orally will be administered as 250 mg BID, with or without food. Patients 
will take the prescribed dose with water (recommended 240 mL).
Patients who forget to take their scheduled dose of study drug should be instructed not to make 
up the missed dose. A missed dose is defined as a dose not taken within 6 hours of the intended 
scheduled administration. Missed doses should be recorded in an appropriate source record (e.g., 
clinic chart), patient diary card, and study drug administration eCRF.
Study drug administration will continue until the patient dies, meets another reason for treatment 
discontinuation, or the trial ends. 
13.1.2
Continuation of Treatment after Disease Progression
Patients in the Randomized Phase will continue to be dosed with brigatinib (Arm A) or crizotinib 
(Arm B) until they experience BIRC-assessed disease progression or intolerable toxicity or are 
discontinued for other reasons. In certain circumstances, at the discretion of the treating 
investigator, brigatinib may be continued after progressive disease has been identified.
Continued Therapy at the Time of Disease Progression in Arm A
Patients in Arm A who experience BIRC-assessed disease progression may continue to be 
treated with brigatinib if, in the opinion of the treating investigator, they continue to experience 
clinical benefit. Patients in Arm B may not continue treatment with crizotinib on study after 
BIRC-assessed disease progression.
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Crossover from Arm B (Crizotinib) to Brigatinib Treatment After Disease Progression 
Crossover to brigatinib is permitted, at the investigator’s discretion with the sponsor’s medical 
monitor approval, for patients treated with crizotinib in Arm B who experience objective disease 
progression assessed by the BIRC or investigator. Instructions for receiving notification of 
disease progression assessed by the BIRC can be found in the Study Reference Manual.
All patients who crossover to brigatinib from crizotinib must have a washout period of at least 
10 days between treatments. Brigatinib will be administered at a dose of 90 mg QD for 7 days 
followed by 180 mg QD continuously, with or without food. Patients will take the prescribed 
dose with water (recommended 240 mL). Brigatinib treatment will start on Crossover Cycle 1, 
Day 1, as shown in Table 4. A cycle of therapy in the Crossover Phase will comprise 28 days of 
treatment. 
13.1.3
Management and Dose Modification Recommendations for Treatment-Related 
Adverse Events
The following sections provide recommended dose modification guidelines for treatment-related 
AEs observed with brigatinib and crizotinib administration. 
Dose interruptions or reductions should be implemented for patients who experience 
treatment-related AEs, upon clinical judgment of the investigator. Study drug administration may 
be delayed for up to 28 days to allow for improvement or resolution of the event. If an AE does 
not resolve to grade 1 or less after dose interruption for more than 28 days, the sponsor’s medical 
monitor must be contacted. 
Comprehensive assessments of any study drug-related AEs (i.e., adverse drug reactions) 
experienced by the patient will be performed throughout the course of the study. The severity of 
the event, as well as clinical judgment, will be utilized to determine appropriate management of 
the patient for any AE experienced while participating in this study.
Any medication, including those administered for therapy of symptoms considered associated 
with study drug administration, should be reported on the appropriate concomitant medication 
page of the patient’s eCRF.
13.1.3.1
Management and Dose Modification Recommendations for Treatment-Related 
Adverse Events in Patients Receiving Brigatinib (Arm A or Crossover Patients)
13.1.3.1.1 Adverse Events within the First 7 Days of Treatment with Brigatinib, Prior to Dose 
Escalation 
Criteria for dose modification of general treatment-related adverse events (excluding 
pneumonitis) in the first 7 days of treatment prior to dose escalation are provided in Table 5. 
Criteria for dose modification of general treatment-related adverse events (excluding 
pneumonitis) after dose escalation are provided in Section 13.1.3.1.3. 
In study AP26113-11-101, pulmonary events occurring within the first 7 days of treatment with 
brigatinib, consistent in some cases with pneumonitis, were observed shortly after treatment 
initiation in 4% of patients who had received brigatinib at a starting dose of 90 mg QD 
(including patients who escalated to 180 mg QD after 7 days). No such events were observed in 
the 7 days after escalation to 180 mg QD. Events included the acute onset of symptoms of 
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dyspnea, cough, chest tightness, and fever. Pulmonary symptoms have been observed after a 
single dose of brigatinib in some patients. The pulmonary symptoms are associated in more 
severe cases with hypoxia and chest CT findings of ground glass opacities consistent with 
pneumonitis, and in these cases constituted SAEs. These events have been managed with 
treatment interruption and medical management as clinically indicated (e.g., steroids, 
antibiotics). Most events resolved with interruption or discontinuation of brigatinib. Three fatal 
pulmonary events (including hypoxia, pneumonia, and adult respiratory distress syndrome) 
starting within the first 7 days of treatment were observed in study AP26113-11-101. Upon 
resumption of dosing, some patients had events recur while others did not have recurrence with 
continued dosing. As such, investigators and patients must be aware that pneumonitis-like events 
may present as early as 24 to 48 hours of initial dosing. 
Pulmonary events occurring within the first 7 days of treatment, including, but not limited to, 
dyspnea, hypoxia, dry cough, chest tightness, and presumptive lung infection (pneumonia) 
should be monitored and reported. To reiterate, some events occur after a single dose of 
brigatinib, and physicians should be aware of this possibility and discuss it with patients. Newly 
developed or worsening of pulmonary symptoms in the first week of study drug administration 
specifically with hypoxia and ground glass opacity on radiographic imaging indicative of 
interstitial lung disease or pneumonitis could suggest a relationship to brigatinib. Other 
etiologies, including pulmonary embolism and infectious pneumonia, should be ruled out if 
possible. If no evidence of other etiology is identified, a causal relationship to brigatinib should 
be considered. 
The management of new or worsening pulmonary symptoms within the first 7 days of brigatinib 
treatment should include drug interruption, monitoring of oxygen saturation, radiographic 
evaluation of the chest, and appropriate work up for infectious or other etiology, with high dose 
corticosteroids, supplemental oxygen therapy, and empiric antibiotics as indicated. After drug 
interruption and workup of symptoms, dose modification should be accomplished according to 
the recommendations in Table 5. If the work up reveals documented hypoxia and/or radiologic 
evidence of interstitial or ground glass changes, or result in an SAE, the pulmonary events 
should be treated according to Table 6 in Section 13.1.3.1.2 (Pneumonitis).
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Table 5
Brigatinib Dose Modification Recommendations for Treatment-Related Adverse 
Events (Excluding Pneumonitis) Prior to Dose Escalation to 180 mg QD (i.e., First 7 Days 
of Treatment)
Toxicity Grade per 
CTCAE v4.0
Recommended Action
Criteria for Dose 
Escalation 
Hematologic Toxicity
Grade 1 or Grade 2
Continue at 90 mg QD
Escalate to 180 mg QD on 
Day 8, as scheduled
Grade 3
Hold until event is ≤ grade 2, or has returned to baseline, then 
resume at 90 mg QD
No dose escalation
Grade 4
Hold until event is ≤ grade 2, or has returned to baseline, then 
resume at 90 mg QD
No dose escalation
Nonhematologic Toxicity
Grade 1
Manage the toxicity with supportive care while continuing at 90 
mg QD
Escalate to 180 mg QD on 
Day 8, as scheduled
Grade 2 (≤3 days)
Manage the toxicity with supportive care while continuing at 90 
mg QD 
If the event is controlled to 
no worse than grade 1 at Day 
8, escalate to 180 mg QD, as 
scheduled
Grade 2 (for >3 days, 
despite optimal 
supportive care) 
Hold until event is ≤ grade 1, or has returned to baseline, then 
resume at 90 mg QD 
If no recurrence of grade 2 
after 90 mg QD for 7 days, 
escalate to 120 mg QD. Do 
not escalate to 180 mg QD.
If recurrence of grade 2 after 
90 mg QD, no escalation
Grade 3
Hold until event is ≤ grade 1, or has returned to baseline, then 
resume at 90 mg QD
No dose escalation
Grade 4 
Hold until event is ≤ grade 1, or has returned to baseline, then 
resume at 60 mg QD
No dose escalation
Bradycardia (heart rate less than 60 beats per minute [bpm])
Grade 1 
Continue at 90 mg QD
Escalate to 180 mg QD on 
Day 8, as scheduled
Grade 2 or Grade 3
Withhold until recovery to ≤ grade 1 or to heart rate 60 bpm or 
above
Evaluate concomitant medications known to cause bradycardia, 
as well as anti-hypertensive medications
If contributing concomitant medication is identified and 
discontinued, or its dose is adjusted, resume at 90 mg QD upon 
recovery to ≤ grade 1 or to heart rate 60 bpm or above
If no contributing concomitant medication is identified, or if 
contributing concomitant medications are not discontinued or 
dose modified, resume at 60 mg QD upon recovery to ≤ grade 1 
or to heart rate 60 bpm or above.
No dose escalation
Grade 4
Discontinue treatment if no contributing concomitant medication 
is identified
If contributing concomitant medication is identified and 
discontinued, or its dose is adjusted, resume at 60 mg QD upon 
recovery to ≤ grade 1 or to heart rate 60 bpm or above with 
frequent monitoring.
No dose escalation
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13.1.3.1.2 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 (XALKORI® USPI, Pfizer, Inc.). Other TKIs used in the treatment of 
NSCLC have similar adverse reactions. 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 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 Table 6 (during first 7 days of treatment prior to escalation to 180 mg QD) and
Table 7 (after escalation to 180 mg QD), is required. 
Table 6
Brigatinib Dose Modification Recommendations for Treatment-Related 
Pneumonitis Occurring Prior to Dose Escalation to 180 mg QD (i.e., First 7 Days of 
Treatment)
Toxicity Grade 
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.
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Table 7
Brigatinib Dose Modification Recommendations for Treatment-Related 
Pneumonitis Occurring After Dose Escalation to 180 mg QD 
Toxicity Grade 
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.
13.1.3.1.3 Dose Modification Recommendations for Treatment-Related Adverse Events 
(Excluding Pneumonitis) After Dose Escalation to 180 mg QD
Criteria for dose modification of general treatment-related adverse events (excluding 
pneumonitis) after dose escalation are provided in Table 8.
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Table 8
Dose Modification Recommendations for Treatment-Related Adverse Events 
(Excluding Pneumonitis) after Dose Escalation to 180 mg QD* 
Toxicity Grade per 
CTCAE v4.0
Recommended Action
Hematologic Toxicity
Grade 1 or Grade 2
Continue at current dose
Grade 3
When the current dose is 180 mg QD:
Hold until event is ≤ grade 2, or has returned to baseline
Resume at 180 mg or 120 mg QD at the discretion of the investigator
Upon recurrence at 180 mg QD:
Hold until event is ≤ grade 2, or has returned to baseline
Resume at 120 mg QD
When the current dose is 120 mg QD:
Hold until event is ≤ grade 2, or has returned to baseline
Resume at 90 mg QD
When the current dose is 90 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 60 mg QD after recovery, or discontinue at the discretion of the investigator
When the current dose is 60 mg QD:
Consider discontinuing treatment
Grade 4
When the current dose is 180 mg QD:
Hold until event is ≤ grade 2, or has returned to baseline
Resume at 120 mg QD after recovery 
When the current dose is 120 mg QD: 
Hold until event is ≤ grade 2, or has returned to baseline
Resume at 90 mg QD after recovery 
When the current dose is 90 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 60 mg QD after recovery, or discontinue at the discretion of the investigator
When the current dose is 60 mg QD:
Consider discontinuing treatment 
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Toxicity Grade per 
CTCAE v4.0
Recommended Action
Nonhematologic Toxicity
Grade 1 or Grade 2
Manage the toxicity with supportive care while continuing at the same dose 
Grade 3
When the current dose is 180 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 180 mg QD or 120 mg QD at the discretion of the investigator 
Upon recurrence at 180 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 120 mg QD 
When the current dose is 120 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 90 mg QD after recovery 
When the current dose is 90 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 60 mg QD after recovery, or discontinue at the discretion of the investigator 
When the current dose is 60 mg QD:
Consider discontinuing treatment
Grade 4
When the current dose is 180 mg QD: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 120 mg QD, or discontinue, at the discretion of the investigator
When the current dose is 120 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 90 mg QD, or discontinue, at the discretion of the investigator
When the current dose is 90 mg QD:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 60 mg QD after recovery, or discontinue at the discretion of the investigator
When the current dose is 60 mg QD:
Consider discontinuing treatment
Bradycardia (heart rate less than 60 beats per minute [bpm])
Grade 1
Continue at current dose
Grade 2 or Grade 3
Withhold until recovery to ≤ grade 1 or to heart rate 60 bpm or above
Evaluate concomitant medications known to cause bradycardia, as well as anti-
hypertensive medications
If contributing concomitant medication is identified and discontinued, or its dose is 
adjusted, resume at previous dose upon recover to ≤ grade 1 or to heart rate 60 bpm or 
above
If no contributing concomitant medication is identified, or if contributing concomitant 
medications are not discontinued or dose modified, resume at reduced dose upon 
recovery to ≤ grade 1 or to heart rate 60 bpm or above:
When the current dose is 180 mg QD, resume at 120 mg QD 
When the current dose is 120 mg QD, resume at 90 mg QD
When the current dose is 90 mg QD, resume at 60 mg QD
When the current dose is 60 mg QD, discontinue treatment
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Toxicity Grade per 
CTCAE v4.0
Recommended Action
Grade 4
Discontinue treatment if no contributing concomitant medication is identified
If contributing concomitant medication is identified and discontinued, or its dose is 
adjusted, resume at reduced dose upon recovery to ≤ grade 1 or to heart rate 60 bpm or 
above with frequent monitoring:
When the current dose is 180 mg QD, resume at 120 mg QD 
When the current dose is 120 mg QD, resume at 90 mg QD
When the current dose is 90 mg QD, resume at 60 mg QD
When the current dose is 60 mg QD, discontinue treatment
*
Apply these recommendations either after dose escalation was accomplished, or after dose reduction for 
grade 3 or grade 4 toxicity was implemented resulting in no dose escalation.
13.1.3.1.4 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, v4.0, 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, aggressive 
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 Dose Modification Guidelines for 
general nonhematologic AEs in Table 5 and Table 8.
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, non-
dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. For 
symptomatic bradycardia, dose interruption and reduction is recommended according to Table 5
and Table 8.
Nausea and Emesis
Nausea should be treated with standard-of-care anti-emetics. Prophylactic ant-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, 
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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. 
Visual Disturbance
In patients with new onset or worsening severe (grade ≥3) visual disturbance, ophthalmological 
evaluation should be performed. Visual disturbance should be managed as described in Table 5
and Table 8 (under Nonhematologic Toxicity).
13.1.3.2
Management and Dose Modification Recommendations for Treatment-Related 
Adverse Events in Patients Receiving Crizotinib (Arm B)
13.1.3.2.1 Management of Selected Adverse Events
Hepatotoxicity
Drug-induced hepatotoxicity with fatal outcome has occurred in patients treated with crizotinib. 
These cases have occurred during crizotinib treatment in less than 1% of patients in clinical 
trials. Concurrent elevations in ALT greater than 3×ULN and total bilirubin greater than 2×ULN 
without elevated alkaline phosphatase have been observed in less than 1% patients in clinical 
trials. Grade 3 and 4 elevations in liver function tests were generally reversible upon dosing 
interruption. When hepatotoxicity occurs, crizotinib should be temporarily suspended, dose 
reduced, or permanently discontinued as described in Table 9.
Interstitial Lung Disease
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients 
treated with crizotinib. These cases generally occurred within 2 months after the initiation of
treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. 
Other potential causes of ILD/pneumonitis should be excluded, and crizotinib should be 
discontinued in patients diagnosed with drug-related ILD/pneumonitis.
QT Prolongation
QTc prolongation can occur in patients treated with crizotinib. Crizotinib should be avoided in 
patients with congenital long QT syndrome. Crizotinib should be discontinued in patients who 
develop QTc greater than 500 msec or greater than or equal to 60 msec change from baseline 
with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious 
arrhythmia. Crizotinib should be withheld in patients who develop QTc greater than 500 msec on 
at least 2 separate ECGs until recovery to a QTc less than or equal to 480 msec, then resumed at 
a reduced dose as described in Table 9.
Bradycardia
Symptomatic bradycardia can occur in patients treated with crizotinib. Crizotinib should be 
avoided in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-
dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. Heart 
rate and blood pressure should be monitored regularly. Symptomatic bradycardia should be 
managed as described in Table 9.
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Visual Loss
Grade 4 visual field defect with vision loss has been reported in less than 1% of patients in 
clinical trials of crizotinib. In patients with new onset or worsening severe (Grade ≥ 3) visual 
disturbance, ophthalmological evaluation should be performed. Visual loss should be managed 
as described in Table 9.
13.1.3.2.2 Dose Modification Recommendations for Treatment-Related Adverse Events in 
Patients Receiving Crizotinib (Arm B)
Guidelines for dose modification of crizotinib treatment-related AEs are outlined in Table 9 and 
are based on the European Medicines Agency (EMA) Summary of Product Characteristics 
(SmPC) for crizotinib (XALKORI® SmPC, Pfizer, Inc.). Unless otherwise noted, reduce dose as 
below, if one or more dose reductions are necessary due to adverse reactions of grade 3 or 4 
severity, as defined by NCI CTCAE v4.0.

First dose reduction: crizotinib 200 mg BID

Second dose reduction: crizotinib 250 mg QD

Permanently discontinue if unable to tolerate crizotinib 250 mg QD
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Table 9
Crizotinib Dose Modification Recommendations for Treatment-Related Adverse 
Events 
Toxicity Grade per CTCAE v4.0
Recommended Action
Hematologic Toxicities 
except lymphopenia (unless associated with clinical events e.g., opportunistic infections)
Grade 1or Grade 2
Manage the toxicity with supportive care while continuing at the same dose 
Grade 3
Withhold until recovery to ≤grade 2, then resume at the same dose schedule
Grade 4
Withhold until recovery to ≤grade 2, then resume at 200 mg BIDb
Non-Hematologic Toxicities
Grade 3 or 4 ALT or AST 
elevation with ≤ Grade 1 total 
bilirubin
Withhold until recovery to ≤ Grade 1 or baseline, then resume at 250 mg QD 
and escalate to 200 mg BID if clinically toleratedc
Grade 2, 3, or 4 ALT or AST 
elevation with concurrent Grade 2, 
3 or 4 total bilirubin elevation (in 
the absence of cholestasis or 
haemolysis)
Permanently discontinue
Any grade drug-related interstitial 
lung disease/pneumonitis
Withhold if ILD/pneumonitis is suspected, and permanently discontinue if 
treatment-related ILD/pneumonitis is diagnosed
Grade 3 QTc prolongation
Withhold until recovery to ≤ Grade 1, check and if necessary correct 
electrolytes, then resume at 200 mg twice dailyc
Grade 4 QTc prolongation
Permanently discontinue
Grade 2, 3 Bradycardiad
Withhold until recovery to ≤ Grade 1 or to a heart rate of 60 bpm or above
Evaluate concomitant medications known to cause bradycardia, as well as 
anti-hypertensive medications
If contributing concomitant medication is identified and discontinued, or its 
dose is adjusted, resume at previous dose upon recovery to ≤ Grade 1 or to a 
heart rate of 60 bpm or above
If no contributing concomitant medication is identified, or if contributing 
concomitant medications are not discontinued or dose modified, resume at 
reduced dose upon recovery to ≤ Grade 1 or to a heart rate of 60 bpm or 
above
Grade 4 Bradycardiad
Permanently discontinue if no contributing concomitant medication is 
identified 
If contributing concomitant medication is identified and discontinued, or its 
dose is adjusted, resume at 250 mg once daily upon recovery to ≤ Grade 1 or 
to a heart rate of 60 bpm or above, with frequent monitoring
Grade 4 Ocular Disorder (Visual 
Loss)
Discontinue during evaluation of severe vision loss
aExcept lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
bIn case of recurrence, dosing should be withheld until recovery to ≤ Grade 2, then dosing should be resumed at 250 
mg once daily. Crizotinib must be permanently discontinued in case of further Grade 4 recurrence.
cCrizotinib must be permanently discontinued in case of further ≥ Grade 3 recurrence.
dHeart rate less than 60 beats per minute (bpm).
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13.1.4
Re-introducing Brigatinib after Dose Interruption
If brigatinib treatment interruption lasts ≥14 days, and prior dose was >90 mg QD, patients 
should resume treatment at 90 mg QD for 7 days, before escalating dose back to 120 mg QD or 
180 mg QD. The dose should not be escalated higher than the prior dose level before treatment 
interruption.
13.1.5
Re-Escalation after Dose Modification
Re-escalation after dose modification for adverse events is discouraged. However, if in the 
opinion of the treating investigator re-escalation is warranted, this must be undertaken after 
consultation with the sponsor. To be a candidate for re-escalation, the AE that led to dose 
modification must not have recurred, and no other AEs of grade 3 or 4 must have been observed 
during the preceding 28 days. 
Prior and Concomitant Treatment(s)/Therapy
13.2
History of prior cancer therapy will be recorded at screening, and concomitant cancer therapy 
will be recorded during the study on the appropriate eCRF for each patient.
Reasonable efforts will be made to collect information on all prior cancer therapy received by the 
patient (e.g., surgeries, chemotherapy, radiotherapy, immunotherapy, biologics). The information 
must be obtained from the patient’s medical chart and recorded on the appropriate eCRF.
Palliative therapy and supportive care are permitted during the study for management of 
symptoms and underlying medical conditions that may develop during the study. Once a patient 
has begun treatment, a condition may arise that requires the initiation of a new concomitant 
treatment. Patients with CNS lesions requiring local radiotherapy such as SRS are allowed to 
continue study drug after appropriate interruption, as determined by the investigator with sponsor 
agreement; however, for analysis purposes, these patients will be considered to have PD. 
Concomitant medications for all ongoing medical history conditions or AEs must be reported 
from the date the informed consent is signed until at least the 30 Days After Last Dose 
assessments, and for all concomitant medications related to serious or study drug-related 
toxicities until the medication is no longer taken or until patient contact discontinues. 
Prohibited Treatment(s)/Therapy
13.3
The following concurrent medications or procedures are prohibited for the duration of the study: 
1.
Any other systemic anticancer therapy including, but not limited to: chemotherapeutic 
agents, immunotherapy, biological response modifiers (excluding growth factors), 
radiotherapy, and/or systemic hormonal therapy (with the exception of local 
therapies, such as SRS, used for palliative or symptomatic control of existing lesions, 
with appropriate treatment interruption at the discretion of the investigator). Use of 
any other investigational drug or device;
2.
Medications that are known to be associated with the development of Torsades de 
Pointes (see Appendix E). Medications that prolong the QT interval, but are not 
known to be associated with Torsades de Pointes, should be avoided, but are not 
prohibited;
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3.
Extensive surgery requiring in-patient care (patients may have an interruption in 
therapy for 14 days should emergency surgery be required).
If a patient’s clinical condition requires treatment with one of the prohibited classes of 
medications specified above, the clinical details of the situation should be discussed with the 
sponsor’s medical monitor at the earliest possible time to determine whether it is safe for the 
patient to continue treatment. 
Potential Drug Interactions
13.4
Brigatinib
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 (see Appendix D).
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 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.
Crizotinib (XALKORI® USPI, Pfizer, Inc.) 
Crizotinib is predominantly metabolized by CYP3A4/5. Coadministration of crizotinib with 
strong CYP3A inhibitors increases crizotinib plasma concentrations. Avoid concomitant use of 
strong CYP3A inhibitors, including, but not limited to, atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase 
plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A 
inhibitors.
Crizotinib inhibits CYP3A both in vitro and in vivo. Coadministration of crizotinib with strong 
CYP3A inducers decreases crizotinib plasma concentrations. Avoid concomitant use of strong 
CYP3A inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, and St. John's Wort.
Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including, but not 
limited, to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, and tacrolimus in patients taking crizotinib. If concomitant use of these 
CYP3A substrates with narrow therapeutic range is required in patients taking crizotinib, dose 
reductions of the CYP3A substrates may be required due to adverse reactions.
In vitro studies in human hepatocytes have indicated that crizotinib may induce pregnane X 
receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g., CYP3A4, 
CYP2B6, CYP2C8, CYP2C9, UGT1A1). Caution should be exercised in administering 
crizotinib in combination with medicinal products that are predominantly metabolized by these 
enzymes. The effectiveness of concomitant administration of oral contraceptives may be 
reduced.
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Treatment Compliance
13.5
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded. Complete instructions will be provided with the Study Reference Manual. 
Patients who forget to take their dose should not make up the missed dose. A missed dose is 
defined as a dose not taken within 6 hours of the intended scheduled administration. Any missing 
doses must be recorded in an appropriate source record (e.g., clinic chart), patient diary card, and 
study drug administration eCRF. Training of patients should be documented in the appropriate 
source record (e.g., clinic chart). When possible, patients should take the study drug under 
observation during scheduled study visits to the clinic. The investigator is responsible for 
ensuring that the patient diary card(s) are retained and noted in source documentation. 
Treatment Supply
13.6
Upon receipt of clinical study materials and/or study drug, the investigator or designee must 
verify that the shipment was received as stated on the clinical supply shipment form enclosed 
within each shipment. The form is then to be returned to the clinical supply distributor as 
instructed on the form. If there are any discrepancies with the shipment, the sponsor should be 
contacted immediately (contact information is listed on the clinical supply shipment form). A 
copy of this form must be retained in the site files. 
13.6.1
Formulation, Packaging and Labeling
Brigatinib
Brigatinib drug product is supplied as film-coated tablets, containing 30 mg, 90 mg, or 180 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 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. 
Crizotinib (XALKORI® USPI, Pfizer, Inc.)
Crizotinib drug product is supplied as gelatin capsules containing either 200 mg or 250 mg of 
crizotinib active pharmaceutical ingredient. Other inactive ingredients include colloidal silicone 
dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch 
glycolate and magnesium stearate. The gelatin capsule is composed of gelatin, titanium oxide, 
and red iron oxide. 
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. 
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13.6.2
Preparation and Dispensing
The study pharmacist or designee at the site will be responsible for handling and dispensing 
brigatinib and crizotinib 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. 
13.6.3
Treatment Storage and Accountability
The recommended storage condition for brigatinib is under 30°C. Do not refrigerate or freeze. 
The recommended storage condition for crizotinib is room temperature 20º to 25º C; excursions 
permitted between 15º and 30º C.
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are reconciled and noted in source documentation.
All used bottles or blister packs of study drug must be returned to the study sponsor or destroyed 
in an appropriate manner according to the standard practice at each study center. Destruction of 
such supplies will be documented, and a representative of the sponsor will verify disposition 
records.
During the study and at termination, patients must return all unused study drug supplies and the 
return of these unused study drug supplies must be recorded. Returned supplies must not be 
re-dispensed.
No other utilization of brigatinib or crizotinib intended for use in this study is authorized by the 
sponsor. The principal investigator or his/her designee will be responsible for the appropriate 
handling and disposition of residual study drug. Each site is responsible for proper and careful 
destruction of study drug returned by patients.
Periodically, throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug. At the completion of the study, a final study drug 
accountability review will be conducted. Any discrepancies must be investigated and all unused 
study drug must be destroyed on site per the standard operating procedures of the investigative 
site. 
14
ADVERSE EVENT REPORTING
Adverse Events
14.1
14.1.1
Adverse Event Definition
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can be any unfavorable and unintended sign (including 
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an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product whether or not considered related to the medicinal product. Any worsening of 
a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs 
after the first dose of study drug) is also an AE.
Adverse Events include:
●
Abnormal test findings, according to the following criteria:
o
Test results associated with accompanying symptoms that are considered 
clinically significant in the opinion of the investigator.
o
Test results that require additional diagnostic testing (other than merely repeating 
an abnormal test) or medical/surgical intervention.
o
Test results that lead to a change in study drug dosing or discontinuation from the 
study, significant additional concomitant drug treatment, or other therapy.
o
Test results considered to be an AE by the investigator or sponsor.
●
Changes in physical examination findings
●
Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, or apparently unrelated illnesses, and
●
Hypersensitivity
Additionally, AEs may include signs or symptoms resulting from:
●
Drug overdose (events occurring from a medication error or overdose of a product or 
products whether accidental or intentional)
●
Drug withdrawal
●
Drug abuse
●
Drug misuse
●
Drug interactions
●
Drug dependency
●
Exposure during breastfeeding
●
Exposure in utero
14.1.2
Performing Adverse Events Assessments
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to the investigational product(s), will be reported, as described in the following sections. 
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious AE 
(SAE; see Section 14.2.1) requiring immediate notification to ARIAD Pharmaceuticals, Inc. 
(ARIAD) or its designated representative.
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14.1.3
Reporting Period
All AEs (serious and non-serious) should be recorded on the AE eCRF for all patients beginning 
at the time of signing the informed consent form and concluding 30 days following the last dose 
of the assigned study drug in the study or the investigator/patient decision to discontinue 
treatment, whichever occurs later. 
Once a patient is deemed a screen failure, AE collection is no longer required (see Section 11.3).
Any ongoing AEs (serious and non-serious) after the reporting period should be followed until 
they resolve to baseline, stabilize, or are considered to be chronic/irreversible. 
New SAEs after reporting period: There is no requirement to monitor subjects for SAEs after end 
of study. Investigators in the European Economic Area (EEA) are obligated to report SAEs that 
they become aware of to the sponsor even after the reporting period (reference European 
Commission CT-3 Section 4.4). Investigators outside the jurisdiction of the EEA are encouraged 
to report SAEs after the reporting period.
14.1.4
Adverse Event Severity
The severity of AEs will be assessed according to the CTCAE v4.0 (see Appendix A and the 
Study Reference Manual). If the AE is not defined in the CTCAE, the investigator will determine 
the severity of the AE based on the following definitions:

Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity;

Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest;

Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy;

Life-Threatening (grade 4): The patient is at immediate risk of death;

Death (grade 5): The patient dies as a direct result of the complication or condition 
induced by the AE.
14.1.5
Causality
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious). An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the study drug (i.e., brigatinib or crizotinib) caused or contributed to 
the AE. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form 
and report such an assessment in accordance with the SAE reporting requirements. 
The investigator will use medical consideration and use the following categories of causality to 
determine the relatedness of an AE with the study drug based on the following definitions. Not 
all criteria in each category of relatedness must be present. 
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Definitely Not Related (not drug related)

The patient did not receive study drug
OR

The temporal sequence of the AE onset relative to the administration of the study drug is 
not reasonable
OR

There is another obvious cause of the AE
Probably Not Related (not drug related)

There is evidence of exposure to study drug

There is another more likely cause of the AE

Dechallenge (if performed) is negative or ambiguous

Rechallenge (if performed) is negative or ambiguous
Possibly Related (drug related)

There is evidence of exposure to study drug

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable

The AE could have been due to another equally likely cause

Dechallenge (if performed) is positive
Probably Related (drug related)

There is evidence of exposure to study drug

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable

The AE is more likely explained by the study drug than by another cause
Definitely Related (drug related)

There is evidence of exposure to study drug

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable

Dechallenge is positive

Rechallenge (if feasible) is positive

The AE shows a pattern consistent with previous knowledge of the test drug or a test drug 
class
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14.1.6
Expectedness
The expectedness of an SAE is assessed by the sponsor in the overall classification of SAEs for 
regulatory reportability. The Investigator Brochure section “Summary of Data and Guidance for 
the Investigator” will be used as the reference for determination of expectedness and risk 
assessment for brigatinib. The current SmPC for Xalkori (crizotinib) will be used as the 
reference safety information for determination of expectedness for crizotinib.
Serious Adverse Events 
14.2
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2A, will be followed. 
14.2.1
Serious Adverse Event Definition
The investigator or the sponsor may determine the seriousness of an AE based on the following:
An AE is considered an SAE if at least one of the following conditions applies:

Death: An AE that results in death is any patient death within 30 days of the last dose of 
study drug administration. The cause of death or AE that resulted in a fatal outcome is the 
SAE.

Life-threatening AE: An AE that places the patient, in the view of the investigator or the 
sponsor, at immediate risk of death from the event as it occurred (i.e., this does not 
include an event that had it occurred in a more severe form might have caused death)

Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions: Any substantial disruption of a person’s ability to conduct 
normal life functions

Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization 
refers to admission of a patient into a hospital for any length of time.

A congenital anomaly/birth defect: A fixed, permanent impairment established at or 
before birth

Cancer: Occurrence or diagnosis of a new cancer during the study is considered an SAE; 
a new cancer is a cancer that is histopathologically different than the cancer under study 
in the study (i.e., does not include metastatic or progressive disease)

Important medical event: Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event. An important medical event 
may not result in death, be life-threatening, or require hospitalization. However, if it is 
determined that the event may jeopardize the patient and/or may require intervention to 
prevent one of the other outcomes listed in the definition above, the important medical 
events should be reported as serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization; or the development of drug dependency 
or drug abuse.
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14.2.1.1
Progression of the Malignancy Under Study (including signs and symptoms of 
progression)
Worsening of signs and symptoms of the malignancy under study should be reported as AEs in 
the appropriate section of the eCRF. Disease progression assessed by measurement of malignant 
lesions on radiographs or other methods should not be reported as an AE. 
14.2.1.2
Hospitalizations
Adverse events (reported from clinical studies) that require hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
health care facility meets these criteria. Adverse events that require emergency room care that do 
not result in hospital admission are not SAEs unless assessed by the investigator to be an 
important medical event. Hospitalization does not include the following:

Hospice facilities

Respite care

Skilled nursing facilities

Nursing homes

Routine emergency room admissions, and

Same day surgeries (as outpatient/same day/ambulatory procedure)
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in 
itself an SAE. Examples include:

Social admission (e.g., patient has no place to sleep)

Protocol-specified admission during a clinical study (e.g., for a procedure required by the 
study protocol)

Optional admission not associated with a precipitating AE (e.g., for elective cosmetic 
surgery that was planned prior to study enrollment [appropriate documentation is 
required for these cases])

Hospitalization or prolongation of hospitalization for scheduled therapy of the target 
malignancy of the study is not considered an SAE
14.2.2
Reporting Serious Adverse Events
Regardless of causality, SAEs must be reported (see Section 14.2.4 for the period of observation) 
by the investigator to the Takeda Global Pharmacovigilance department or designee within 
24 hours of becoming aware of the event. This will be done by transmitting an electronic data 
capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a 
facsimile of the completed Takeda paper-based SAE form will be sent. In case of fax, site 
personnel need to confirm successful transmission of all pages and include an e-mail address on 
the fax cover sheet so that an acknowledgment of receipt can be returned via e-mail within 1 
business day. A sample of the paper-based SAE form and processing directions are in the Study 
Manual. Information in the SAE report or form must be consistent with the data provided on the 
eCRF.
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14.2.3
Information to be Provided by the Investigator for a Serious Adverse Event
The sponsor or designee will require all of the following information about the patient and the 
event:

Investigator identification

Patient identification code (e.g., sex, age, or date of birth)

Information on study drug (e.g., start/stop date, dose and frequency of study drug 
administered)

Description of event
In addition to the above information, the sponsor will require the investigator’s assessment of the 
following:

Severity of the SAE 

Relationship of the SAE to the study drug

Outcome of the SAE 
14.2.4
Follow-up Information on a Serious Adverse Event
The investigator may be asked to provide additional information for any event submitted, which 
may include a discharge summary or extracts from the medical record. Information provided 
about the event must be consistent with information recorded on the electronic study case report 
forms (eCRF) where safety data may also be recorded (e.g., AE CRF). The investigator is 
responsible for management of the patients through the course of the event. There should be 
routine follow-up through and including a minimum 30 days after the last administration of study 
drug or the investigator/patient decision to discontinue treatment, whichever occurs later, in all 
patients in order to monitor for the occurrence of SAEs. If an SAE continues after the 30-day 
evaluation period, then the patient must be followed until the event resolves or stabilizes without 
further involvement expected. The sponsor’s medical monitor may specify a longer period of 
time if required to assure the safety of the patient.
14.2.5
Expedited Reporting of Suspected Unexpected and Serious Adverse Reactions 
(SUSARs)
ARIAD, as study sponsor, is responsible for reporting suspected, unexpected and serious adverse 
reactions (SUSARs) involving the study drug to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, ARIAD, or authorized designee, will be responsible for the submission of 
safety letters to central independent ECs (IECs).
The sponsor will notify investigators of all reportable SAEs. This notification will be in the form 
of an expedited safety report. Upon receiving such notices, the investigator must review and 
retain the notice with other study-related documentation.
The investigator and IRB/EC will determine whether the informed consent requires revision. The 
investigator should also comply with the IRB/EC procedures for reporting any other safety 
information. 
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Suspected serious adverse reactions and other significant safety issues reported from the 
investigational product development program will be reported by the sponsor or its designated 
representative, either as expedited safety reports and/or in aggregate reports, to the relevant 
competent health authorities in all concerned countries.
Other Safety Issues
14.3
14.3.1
Pregnancy and Breastfeeding
Female patients of childbearing potential and fertile male patients will be informed as to the 
potential risk of conception while participating in this study and will be advised that they must 
use highly effective contraception listed below (i.e., results in a low failure rate when used 
consistently and correctly) during the dosing period and for a period of at least 4 months after the 
end of treatment with brigatinib and at least 3 months after the end of treatment with crizotinib. 
Highly effective methods include: 

intrauterine device (IUD)

bilateral tubal occlusion

vasectomised partner

sexual abstinence
Adequate contraception during and after treatment with crizotinib and brigatinib should be used 
as oral contraceptives may be ineffective. A pregnancy test will be performed on each pre-
menopausal female patient of childbearing potential immediately prior to the first dose of study 
drug, once every three cycles while on treatment, and again at treatment discontinuation during 
the End-of-Treatment visit. A negative pregnancy test must be documented prior to 
administration of study drug.
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately. The investigator must immediately notify the sponsor medical 
monitor of this event and record the pregnancy on the Pregnancy Form. Initial information 
regarding a pregnancy must be immediately forwarded to ARIAD Pharmacovigilance and Risk 
Management or its designated representative.
The investigator must immediately report follow-up information to the sponsor regarding the 
course of the pregnancy, including perinatal and neonatal outcome, regardless of whether the 
patient has discontinued participation in the study. If the pregnancy results in the birth of a child, 
additional follow-up information may be requested. If the pregnancy results in spontaneous 
abortion or stillbirth, the event should be reported as an SAE.
Pregnancy outcomes also must be collected for the female partners of any male patients who 
took study drug in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner.
It is not known whether brigatinib passes into the breast milk. Mothers should not breastfeed 
while receiving study drug.
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14.3.2
Overdose
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
drug that exceeds the dose described in the protocol. 
All overdoses should be recorded on the Overdose Form and forwarded to ARIAD 
Pharmacovigilance and Risk Management, or its designated representative, within 24 hours. An 
overdose should be reported even if it does not result in an AE. If an overdose results in an AE, 
the AE should be reported on the AE eCRF. The dose administered should be documented on the 
Study Drug Administration eCRF. 
15
PLANNED STATISTICAL METHODS
General Considerations
15.1
Descriptive statistics (such as means, medians, standard deviations, and ranges for continuous 
data and percentages for categorical data) will be used to summarize patient characteristics, study 
drug administration/compliance, and safety parameters. Data will also be displayed graphically, 
where appropriate. For the purposes of this protocol and all analyses, unless otherwise specified, 
a month is defined as 28 days, the same length as a cycle of treatment for both brigatinib and 
crizotinib.
Analysis Populations
15.2
Intent–to-Treat (ITT) Population: The ITT population includes all patients randomized to each 
regimen regardless of whether they are ALK+ by the Vysis® ALK Break Apart fluorescence in 
situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay, or a local test other 
than FISH and IHC, or whether they receive study drug or adhere to the assigned dose. The 
primary analyses of efficacy will be based on the ITT population.
Treated population: The treated population for each regimen includes all patients receiving at 
least one dose of study drug. 
Safety will be analyzed using the treated population.
Per-protocol population: The per-protocol population will exclude all patients in the treated 
population who do not meet key entry criteria, have no measurable disease at baseline, or have 
no adequate post-baseline response assessment unless the reason is death or early discontinuation 
due to disease progression. Additional analyses may also be performed excluding patients who 
were not confirmed as ALK+ (locally or centrally) by an FDA approved test.
Further criteria for the per-protocol population and the sensitivity analyses of the primary 
endpoint and selected secondary efficacy endpoints using this population will be detailed in the 
statistical analysis plan (SAP). 
Study Endpoints
15.3
15.3.1
Primary Endpoint
The primary endpoint is PFS, as assessed by the BIRC, per RECIST v1.1.
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15.3.2
Secondary Endpoints
Secondary endpoints of the study include:
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR, as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
5.
Duration of response, as assessed by the BIRC
6.
Time to response, as assessed by the BIRC
7.
Disease control rate, as assessed by the BIRC
8.
Safety and tolerability
9.
Change from baseline scores in global health status/QOL assessed with the EORTC 
QLQ-C30 (v3.0), and time-to-deterioration in dyspnea assessed with the EORTC 
QLQ-LC13 (v3.0)
15.3.3
Exploratory Endpoints
Determination of Sample Size
15.4
For the purposes of this sample size calculation, the median PFS for crizotinib is estimated as 
10 months (Solomon et al, 2014). Approximately 270 patients will be randomized in a 
1:1 fashion to receive brigatinib or crizotinib. A total of 198 events (progression or death among 
the randomized patients) will provide 90% power to detect a clinically meaningful 6-month 
improvement in PFS (hazard ratio=0.625). This power projection is based on a 2-sided log-rank 
test and is controlled at the 2-sided 0.043 level, adjusting for the proposed interim analysis plan. 
The number of events is fixed, but the enrollment number may change based on an assessment of 
the overall event rate pooled across treatment groups (prior to the close of enrollment).
Efficacy Analysis
15.5
15.5.1
Definitions of Efficacy Endpoints
The primary endpoint, PFS assessed by BIRC, is defined as the time interval from the date of 
randomization until the first date at which disease progression is objectively documented, or 
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death due to any cause, whichever occurs first, in the ITT population. It will be censored for 
patients without documented disease progression.
Secondary efficacy endpoints for this study are defined as follows (unless otherwise stated, 
secondary efficacy endpoints of response will use BIRC assessments with sensitivity analyses 
performed using the investigator assessments):

Confirmed ORR is defined as the proportion of the patients who are confirmed to have 
achieved CR or PR using RECIST v1.1 in the ITT population. 

Confirmed intracranial ORR is defined as the proportion of the patients who have 
achieved CR or PR in the CNS per RECIST v1.1 in randomized patients with intracranial 
CNS metastases at baseline. 

Intracranial PFS is defined as the time interval from the date of randomization until the 
first date at which CNS disease progression is objectively documented, or death due to 
any cause, whichever occurs first. Intracranial PFS will be assessed in patients with and 
without intracranial CNS metastases at baseline. It will be censored at the last disease 
assessment for patients without documented CNS disease progression.

Time to response is defined as the time interval from the date randomization until the 
initial observation of CR or PR. 

Duration of response is defined as the time interval from the date that the criteria are first 
met for CR/PR (whichever is first recorded) until the first date that PD is objectively 
documented. 

Disease control rate is defined as the proportion of randomized patients who have 
achieved CR, PR, or SD (in the case of SD, criteria for SD must have been met at least 
once after randomization at a minimum interval of 6 weeks) after randomization. 

OS is defined as the time interval from the date of randomization until death due to any 
cause in the ITT population. It will be censored on the date of last contact for those 
patients who are alive.
Censoring for time-to-event efficacy endpoints will be detailed in the SAP. 
15.5.2
Primary Efficacy Endpoint Analyses
The primary analysis of the primary endpoint will be performed using a 2-sided stratified 
log-rank test (stratification factors: presence of intracranial CNS metastases at baseline [Yes 
versus No], and prior chemotherapy for locally advanced or metastatic disease [Yes versus No])
to compare the BIRC-assessed PFS of patients randomized to brigatinib with the BIRC-assessed 
PFS of patients randomized to crizotinib. The overall (2-sided) Type I error rate will be 
controlled at 0.05. The primary analysis will be based on the ITT population. PFS will be 
estimated for each treatment arm using the Kaplan-Meier method (Kaplan and Meier, 1958). 
Additionally, hazard ratios will be estimated using the Cox regression model with the 
stratification factors as covariates.
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Sensitivity analyses of the primary endpoint of PFS will also be performed in the following 
populations:

Per-protocol population, as assessed by the BIRC

FDA approved ALK test population, as assessed by the BIRC

ITT population (all patients randomized to a treatment arm), as assessed by the 
investigator. 
Subgroup analyses will be performed by baseline potential prognostic factors.
Two interim analyses are planned after approximately 50% and 75% of the total expected events 
(progression or death) have been observed. An O’Brien-Fleming Lan-DeMets (DeMets and Lan, 
1994) alpha spending function will be used to control the overall alpha level at 0.05 2-sided.
The first interim analysis will be performed after the first 99 events have been observed. The 
primary endpoint of PFS will be tested at a 2-sided alpha level of 0.0042. A second interim 
analysis will be performed after 149 events and the primary endpoint will be tested at a 2-sided 
alpha level of 0.0194. The primary analysis of the primary endpoint will be performed after 
198 events have been observed or at End-of-Study, whichever comes first, and will be tested at a 
2-sided alpha level of 0.043. Analyses of OS will also be performed at the time of the interim 
analysis and at End-of-Study, if the primary endpoint is met. If the efficacy boundary is 
surpassed at an interim analysis, patients will remain on assigned treatments unless a survival 
advantage is noted.
15.5.3
Secondary Efficacy Endpoint Analyses
Confirmed ORR will be analyzed with the Mantel-Haenszel test (using the stratification factors) 
on the ITT population to compare the proportion of patients achieving objective response 
between the 2 treatment arms. 
Confirmed intracranial ORR will be analyzed with the Mantel-Haenszel test (using the 
stratification factors) on the subset of subjects with intracranial CNS metastases at baseline, to 
compare the proportion of patients achieving intracranial objective response between the 
2 treatment arms. 
Intracranial PFS will be based on the population of patients with intracranial CNS metastases at 
baseline and analyzed using a 2-sided stratified log-rank test. Intracranial PFS will be estimated 
using the Kaplan-Meier method. 
Time- to-response and duration of response will be performed on the subset of patients who 
achieve objective response, using the Kaplan-Meier method. 
Disease control rate will be analyzed with the Mantel-Hanzel test (using the stratification factors) 
on the ITT population to compare the proportion of patients achieving objective response and 
CR, PR, or stable disease ≥6 weeks, between the 2 treatment arms. 
The primary analysis of the secondary endpoint of OS will be performed using a 2-sided 
stratified log-rank test on the ITT population. OS will be estimated using the Kaplan-Meier 
method. Additional sensitivity analyses to characterize the impact of patients in Arm B who 
crossover to brigatinib will be performed and documented in the SAP.
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For the secondary efficacy endpoints, subgroup analyses will be performed by baseline potential 
prognostic factors. 
The primary analysis of all secondary efficacy endpoints will be performed at the time of the 
primary analysis of the primary endpoint.
Assuming a median OS of 30 months in the crizotinib arm, 150 events will provide 
approximately 20% power to demonstrate a 20% improvement (median OS of 36 months in the 
brigatinib arm), and approximately 14% power to demonstrate a 15% improvement (median OS 
of 34.5 months in the brigatinib arm). The table below shows the approximate 95% confidence 
intervals for the hazard ratio for each scenario under the design assumptions.
Table 10 Assumptions and Considerations for OS Endpoint
Effect Size 
Number of OS 
Events
Power
Approx. 95% CI for HR 
after Specified Number 
of Events
1.20 (30 vs. 36 months)
150
20%
(0.87, 1.65)
1.15 (30 vs. 34.5 months)
157
14%
(0.84, 1.58)
Key secondary endpoints will be tested using a closed testing procedure to control the overall 
type error rate at 0.05. Analysis of a key secondary endpoint will be considered significant if the
test for that endpoint and comparisons of all other secondary endpoints with a smaller rank are 
significant at the two-sided 0.05 significance level.
Rank-ordering of key secondary endpoints:
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR, as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
15.5.4
Exploratory Efficacy Endpoint Analyses
15.5.5
Data Handling Rules for Efficacy Endpoint Analyses
A patient will be considered as not evaluable for response at a protocol-specified time point if no 
imaging/measurement is done or only a subset of lesion measurements are made, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) would 
not change the assigned time point response (i.e., if new lesions are documented). A patient will 
be considered to have a response if the criteria for response have been met at the 
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protocol-specified time points immediately before and after the time point of inevaluable 
response.
All patients will be assigned to one of the following best response categories: CR, PR, SD, PD, 
death prior to first disease assessment, or unknown (including no measurable disease at baseline, 
inevaluable post-baseline response, and no exposure to study drug after randomization). All 
patients whose best response is not CR or PR will be considered as non-responders in the 
calculation of ORR. Detailed data handling rules for efficacy outcomes as well as sensitivity 
analyses will be provided in the SAP. 
Safety Analysis
15.6
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs.
Adverse events will be graded according to the NCI CTCAE v4.0. 
All patients who receive at least 1 dose of study drug will be evaluated for safety. For each 
treatment arm, the incidence rates of treatment-emergent adverse events (TEAEs), 
treatment-related adverse events (TRAEs), and serious treatment-emergent adverse events 
(SAEs) will be described by Medical Dictionary for Regulatory Activities (MedDRA) System 
Organ Class (SOC) and Preferred Term. The frequency of occurrence of overall toxicity, 
categorized by the maximum toxicity grades (severity), will also be described. Listings of 
laboratory test results and CTCAE grades will be generated, and descriptive statistics 
summarizing the changes in laboratory tests over time will be presented. 
Exposure to study drug over time will be summarized with time on treatment, total amount of 
administrated treatment, dose intensity and relative dose intensity.
15.6.1
Pharmacokinetic Analysis
Summary statistics for steady-state trough (pre-dose) levels will be computed. PK data will be 
used in an exposure-response analysis for safety and efficacy. Details will be provided in the 
SAP.
15.6.2
QTcF Analysis
Descriptive statistics of maximum QTcF and change from baseline will be calculated following 
the ICH-E14 guidelines: the proportion of treated patients with at least 1 on-drug QTcF value 
>450 msec, >480 msec, and >500 msec; and the proportion of treated patients with a maximum 
change in QTcF from baseline >30 msec and >60 msec. 
HRQoL Data Analysis
15.7
The main PRO endpoints of interest will be the Global Health Status/QoL Scale, based upon 
Question 29 and Question 30, and the Dyspnea Scale, based on the QLQ-LC13 Questions 3-5. 
The QLQ-C30 will be scored according to the EORTC QLQ-C30 (V3) Scoring Manual 
(Fayers et al, 2001) including transformation of responses into scores for analysis and the 
handling of missing data. The EORTC QLQ-C30 (V3) Scoring Manual also includes instructions 
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for scoring the QLQ-LC13. Analysis of the Global Health Status/QoL Scale over time may be 
performed using mixed effects models that include randomized treatment group and the 
stratification factors used in randomization. Worsening on the Dyspnea Scale for a patient will 
be defined as a 50% decline from the baseline score. Time to worsening on the Dyspnea Scale 
will be analyzed using the same methods as for the primary analysis of PFS.
Protocol Deviations/Violations
15.9
To be protocol-compliant, a patient must not have any major protocol deviations during the study 
period. Major protocol deviations will be identified prior to database lock and will be listed in 
the clinical study report. 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it will be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
16
QUALITY CONTROL AND QUALITY ASSURANCE
The sponsor performs quality control and assurance checks on all clinical studies that it sponsors. 
Before enrolling any patients into this study, the sponsor personnel or its designee and the 
investigator will review the protocol, the Investigator’s Brochure, the eCRFs and instructions for 
their completion, the procedure for obtaining informed consent, and the procedure for reporting 
AEs. A qualified representative of the sponsor will monitor the conduct of the study by visiting 
the site and by contacting the site by telephone. During the visits, information recorded in the 
eCRFs will be verified against source documents. The sponsor’s medical monitor will review the 
data for safety information. The sponsor’s clinical data associates or designees will review the 
data for completeness and logical consistency. Additionally, the sponsor’s clinical data 
associates will use automated validation programs to help identify missing data, selected 
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protocol violations, out-of-range data, and other data inconsistencies. Requests for data 
clarification or correction will be added to the electronic database and reviewed by the 
investigational site for resolution. The sponsor may visit the investigational site and perform a 
quality check of the eCRFs against source documents. 
Investigators and Study Administrative Structure
16.1
The investigator must provide the sponsor with the following documents BEFORE enrolling any 
patients:

An executed Clinical Trial Agreement,

Completed and signed FDA Form 1572 or appropriate statement of investigator,

Disclosure of financial interests in ARIAD or ARIAD products (as defined in 21 Code of 
Federal Regulations [CFR] part 54),

Principal investigator’s Curriculum Vitae,

IRB/EC approval of the protocol, and

IRB/EC approved informed consent form.
If any investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records may be transferred to another person (sponsor, IRB/EC, or 
other investigators) who accepts the responsibility. The sponsor must be notified in writing and 
must agree to the change. An updated FDA Form 1572 will be filed with the sponsor for any 
changes in study personnel reported in the current FDA Form 1572, and a disclosure of any 
financial interests in ARIAD or ARIAD products (as defined in 21 CFR part 54) will be required 
of any individual assuming the investigator’s responsibilities. 
Study Monitoring
16.2
This study will be monitored by representatives of the sponsor. Site visits are made before the 
study begins, at regular intervals during the study, and at the study closeout. Communication by 
telephone, mail, and e-mail may be used, as needed, to supplement site visits. The investigator 
and study personnel will cooperate with the sponsor, provide all appropriate documentation, and 
be available to discuss the study. The purpose of the site visits is to verify:

Adherence to the protocol (the investigator should document and explain any deviation 
from the approved protocol).

The completeness and accuracy of the eCRFs and the dispensing and inventory record 
(adequate time and space for these visits should be allocated by the investigator).

Compliance with regulations (the verification will require comparison of the source 
documents to the eCRFs).
17
ETHICAL CONDUCT OF THE STUDY
This study will be conducted in accordance with the ethical standards that have their origin in the 
Declaration of Helsinki and that are consistent with ICH and GCP guidelines, the EMA guidance 
on “Ethical Considerations for Clinical Trials on Medicinal Products,” and other applicable 
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regulatory requirements. Any significant change in the study protocol will require an 
amendment, which will be submitted to competent authorities and IRB/IEC for review and 
approval per applicable guidance and regulations.
Nothing in this protocol or the regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations. In addition, the investigator 
should be aware that some regulations require that he/she permit regulatory agencies to conduct 
inspections and review records pertaining to this clinical investigation. 
Institutional Review Board or Ethics Committee Approval
17.1
The protocol and the informed consent document must have the initial and at least annual or 
bi-annual (when required) approval of an IRB/IEC. The signed IRB/IEC approval letter must 
identify the documents approved (i.e., list the investigator’s name, the protocol number and title, 
the date of the protocol and informed consent document, and the date of approval of the protocol 
and the informed consent document). Any advertisements used to recruit patients should also be 
reviewed by the IRB/IEC. The sponsor will not ship clinical supplies until a signed approval 
letter from the IRB/ IEC has been received and a Clinical Trial Agreement has been signed by 
the sponsor and the clinical site. 
Patient Information and Consent
17.2
Regulatory agencies have issued regulations to provide protection for human patients in clinical 
investigations and to describe the general requirements for informed consent.
A copy of the proposed informed consent document should be submitted to the sponsor for 
review and comment before submission to the IRB/IEC. The study should not begin until the 
document has been reviewed by the sponsor and must not begin until the document has been 
approved by the IRB/ IEC. In some instances, the study must not begin until the document has 
been approved by a regulatory agency. The informed consent document shall contain all of the 
elements of the informed consent specified in the regulations. Some regulations may require the 
disclosure of additional information to the patient and/or inclusion of additional information in 
an informed consent document. 
Patient Confidentiality
17.3
All unpublished information that the sponsor gives to the investigator, and all information 
generated in connection with the study, shall be kept confidential and shall not be disclosed to a 
third party without the prior written consent of the sponsor or published prior to the sponsor’s 
review in accordance with the terms of the Clinical Trial Agreement. When the sponsor 
generates reports for presentations to regulatory agencies, one or more of the investigators who 
have contributed significantly to the study will be asked to endorse the final report. The 
endorsement is required by some regulatory agencies. The investigator shall not make a patent 
application based on the results of this study and shall not assist any third party in making such 
an application without the written authorization of the sponsor. 
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Study Committees
17.4
17.4.1
Data Monitoring Committee
An independent Data Monitoring Committee (DMC), consisting of 3 to 5 members not 
associated with the conduct of the study, will be established for this study. The committee will 
perform data review quarterly and meet at least twice yearly until the final analysis has been 
performed. Ad-hoc DMC meetings may also be held if a significant issue should arise. 
The DMC will be responsible for evaluating the results of safety analyses and will make 
recommendations to the sponsor. Efficacy data can also be requested, if needed, to evaluate 
risk/benefit before making a recommendation; however, the trial will not be stopped early for 
positive efficacy. The DMC will operate under the DMC charter, which specifies the data to be 
included in each review, rules related to study modification, and protection of the integrity of the 
data. At each meeting, the DMC will make recommendations to either continue the study 
unchanged, to modify the study, or to discontinue the study. The DMC will communicate the 
recommendations to the sponsor. The final decision to act on the DMC recommendations will be 
made by the sponsor.
17.4.2
Blinded Independent Review Committee
A central blinded Independent Review Committee (BIRC) will evaluate all images collected 
during the study for the primary endpoint of PFS as well as several secondary endpoints. A 
BIRC charter defines the procedures used by the committee.
17.4.3
Steering Committee
A steering committee will be constituted with initiation of the study. Its purpose is to function in 
an advisory capacity to: 1) provide input on study conduct and progress; 2) ensure scientific and 
ethical integrity of the study; and 3) provide ongoing oversight of safety and efficacy in this 
open-label study. The steering committee will include clinicians expert in the clinical care and 
investigation of the targeted patient population, and will also include sponsor representatives. In 
addition to general study oversight, it will provide input on operational aspects of the study. The 
committee may make recommendations for the sponsor’s consideration based on periodic 
review.
18
DATA HANDLING AND RECORD KEEPING
Case Report Forms and Study Records
18.1
Study-specific eCRFs will be made available to the investigative site. Study data, contained in 
source documentation, will be entered into the eCRFs for all patients screened in the study. All 
pertinent data records are to be submitted to the sponsor during and/or at completion or 
termination of the study. 
Access to Source Documentation
18.2
The investigator agrees that qualified representatives of the sponsor and regulatory agencies will 
have the right, both during and after this study, to conduct inspections and to audit and review 
medical records pertinent to the clinical study as permitted by the regulations. Patients will not 
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be identified by name in any reports stemming from the study, and confidentiality of information 
in medical records will be preserved. The confidentiality of the patient will be maintained unless 
disclosure is required by regulations. Accordingly, the following statement (or similar statement) 
that permits the release of the patient’s medical records will be included in the informed consent 
document:
Representatives of regulatory agencies, IRB/IEC, the sponsor, and the patient’s 
personal physician may review the patient medical records and all information 
related to this study as permitted by law. Patient identity will remain confidential 
unless disclosure is required by law.
Retention of Data
18.3
Study documents (including correspondence related to this clinical study, patient records, source 
documents, eCRFs, study drug inventory records, and IRB/IEC and sponsor correspondence 
pertaining to the study, original patient, laboratory, and study drug inventory records relating to 
the study) should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications in 
an ICH region (that is at least 15 years or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product). Study documents should be retained for 
a longer period if required by applicable regulatory requirements or by agreement with the 
sponsor. Thereafter, records will not be destroyed without giving the sponsor prior written notice 
and the opportunity to further store such records, at the sponsor’s cost and expense. 
Termination of Study
18.4
The sponsor may terminate the study at a study site or in its totality at any time for any of the 
following reasons:

Failure to enroll patients

Protocol violations

Inaccurate or incomplete data

Unsafe or unethical practices

Questionable safety of the study drug

Suspected lack of efficacy of the study drug; or

Administrative decision
In the event of the termination of the Study, by either the sponsor or an investigator:

The investigator will return all study drugs and related study materials to the sponsor.

A written statement describing why the study was terminated prematurely will be 
provided by either the sponsor or the investigator.
19
FINANCING AND INSURANCE 
A clinical study agreement will be signed by the investigator (and/or, as appropriate, the hospital 
administrative representative) and the sponsor prior to the start of the study, outlining overall 
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sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included patient, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory, 
and other protocol-required services are being paid directly or indirectly. Prior to the start of the 
study, investigators and sub-investigators will release sufficient and accurate information that 
permits the sponsor or sponsor-designated agent to determine that an investigator has no personal 
or professional financial incentive regarding the future approval or non-approval of the study 
drug that his/her research might be biased by such financial incentives. The financial information 
is exclusive of agreements directly related to fees associated with the study being conducted. All 
information provided will be regarded as strictly confidential and will only be disclosed to the 
respective regulatory authority. 
20
PUBLICATION AND DISCLOSURE POLICY
The investigator must notify the IRB/IEC of the conclusion of the clinical study. This report 
should be made within 3 months of the completion or termination of the study. The final report 
sent to the IRB/IEC should also be sent to the sponsor and, along with the completed eCRFs, 
constitutes the final summary to the sponsor, thereby fulfilling the investigator’s regulatory 
responsibility. 
Section 801 of the FDA Amendments Act mandates the registration with ClinicalTrials.gov of 
certain clinical studies of drugs (including biological products) and medical devices subject to 
FDA regulations for any disease or condition. The International Committee of Medical Journal 
Editors (ICMJE) requires study registration as a condition for publication of research results 
generated by a clinical study (http://www.icmje.org [Accessed: 13 January 2014]). In addition, 
the EMA requires that clinical studies conducted in the European Union and other countries 
under their regulatory authority be registered (https://www.clinicaltrialsregister.eu/ [Accessed: 
13 January 2014]). 
The institution and principal investigator acknowledge that the study is multicenter study, and, as 
such, agree that they will not publish a publication, abstract, poster or other disclosures 
(“Publication”) before a combined paper that identifies all the sites that participated in the study 
(“Multi-Center Publication”) is published. If the Multicenter Publication has not been completed 
within one (1) year from the date of the completion, termination, or abandonment of the 
multicenter study, the institution may publish or present its individual results in accordance with 
the provisions stated below. 
In order to balance the institution’s right to publish with ARIAD’s proprietary interests, the 
institution will submit to ARIAD material intended for publication, abstracts, posters, and other 
disclosures (“Proposed Disclosures”) at least 45 days prior to submitting for publication or other 
disclosure to allow for expeditious review by ARIAD. If ARIAD believes that any Proposed 
Disclosure contains any information relating to any patentable invention, the disclosure of such
Proposed Disclosure shall be delayed for up to sixty (60) days from the date ARIAD receives the 
Proposed Disclosure to permit ARIAD to file patent applications. If ARIAD believes that any 
Proposed Disclosure contains Confidential Information, ARIAD shall have the right to require 
that the institution delete any reference to Confidential Information, excluding the results of the 
study or other Permitted Research (as defined in Section 11). If the institution and principal 
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investigator choose not to publish, ARIAD reserves the right to publish the results of the study, 
and, if appropriate, to include its medical staff in the author list of such publication in accordance 
with academic publication standards. 
Subject to applicable copyright law, if an institution and/or principal investigator publishes 
results of the study, institution and/or principal investigator hereby grants ARIAD an irrevocable, 
royalty-free license to make and distribute copies of such publication under any copyright 
privileges that the institution and/or principal investigator may have. 
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21
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Aaronson NK, Cull A, Ahmedzai, S, et al. The European Organization for Research and 
Treatment of Cancer (EORTC) modular approach to quality of life assessment in oncology: an 
update. In: Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd edition (B. Spilker, 
ed). Lippincott - Raven Publishers, Philadelphia, 1996;179-189.
Bang YJ. Treatment of ALK-positive non–small cell lung cancer. Arch Pathology & Laboratory 
Med. 2012;136(10):1201-1204. 
Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement 
to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical 
trials. EORTC Study Group on Quality of Life. Eur J Cancer. 1994;30A:635-642.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early successes and future 
challenges. Nat Rev Clin Oncol. 2012;9(5):268-277.
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase 
inhibitor crizotinib. J Clin Oncol. 2011;29:e443–e445.
DeMets DL, Lan KK. Interim analysis: The alpha spending function approach. Stat Med. 1994 
Jul 15-30;13(13-14):1341-52.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eu J Cancer 2009;45:228-247.
Fayers PM, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 Scoring Manual. 3rd edition. 
Brussels: European Organisation for Research and Treatment of Cancer; 2001.
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J Am 
Statistical Assoc. 1958;53:457-481.
Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in 
ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17. Epub 2012 Jan 25.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell 
lung cancer. N Engl J Med. 2010;363(18):1693-1703.
Pfizer Laboratories. XALKORI (crizotinib) Summary of Product Characteristics. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002489/WC500134759.pdf. Accessed: March 5, 2015.
Pfizer Laboratories. XALKORI (crizotinib) US prescribing information. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202570s011lbl.pdf. Accessed: 
March 5, 2015.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive 
lung cancer. N Engl J Med. 2014;371(23):2167-2177.
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Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various 
histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 
2009;115:1723–1733.
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22
APPENDICES
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APPENDIX A
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE)
The United States of America (USA) National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.0 (NCI CTCAE, v4.0) can be found on the following website.
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed: 
15 September 2015]
This version of CTCAE is compatible at the AE (Adverse Event) term level where each CTCAE 
term is a Medical Dictionary for Regulatory Activities Terminology (MedDRA) LLT (Lowest 
Level Term). CTCAE v4.0 includes 764 AE terms and 26 'Other, specify' options for reporting 
text terms not listed in CTCAE. Each AE term is associated with a 5-point severity scale. 
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APPENDIX B
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS
ECOG Performance 
Status*
Grade
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
*As published in Am J Clin Oncol:
Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.
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APPENDIX C
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1)
Note: These criteria are adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eu J 
Cancer 2009;45:228-247.
Choosing Target Lesions
• Select up to 5 lesions (up to 2 per organ)
• Select largest reproducibly measurable lesions
• If the largest lesion cannot be measured reproducibly, select the next largest lesion which can 
be
• Add up longest diameters (LD) of non-nodal lesions (axial plane)
• Add short axis diameters of nodes
• This is the “sum of the longest diameters” (SLD)
Non-Target Lesions
• All other sites of disease present at baseline and not classified as target lesions will be classified 
as non-target lesions, including any measurable lesions that were not chosen as target lesions
• It is possible to record multiple non-target lesions involving the same organ as a single item on 
the eCRF (e.g., “multiple enlarged pelvic lymph nodes”)
Determining Response
• Assess at baseline and on study with consistent modalities (CT, MRI, PET/CT)
- Measure target lesions and calculate SLD
- Visually assess non-target lesions
- Search for new lesions
- Combine these assessments into the overall response
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Target Lesion Response
Complete Response (CR)

Disappearance of all extranodal target lesions.

All pathological lymph nodes must have decreased to <10 mm in short 
axis
Partial Response (PR)

At least a 30% decrease in the SLD of target lesions, taking as reference 
the baseline sum diameters
Progressive Disease (PD)

SLD increased by at least 20% from the smallest value on study 
(including baseline, if that is the smallest)

The SLD must also demonstrate an absolute increase of at least 5 mm. 
(Two lesions increasing from 2 mm to 3 mm, for example, does not 
qualify)
Stable Disease (SD)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD
Non-evaluable (NE)

One or more lesions cannot be evaluated due to missing data or poor 
image quality unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the 
assigned time point response (e.g., PD based on other findings)
Non-Target Lesion Response
Complete Response (CR)

Disappearance of all extranodal non-target lesions

All lymph nodes must be non-pathological in size (<10 mm short axis)

Normalization of tumor marker level
Non-CR/Non-PD

Persistence of one or more non-target lesions(s) and/or maintenance of 
tumor marker level above the normal limits
Progressive Disease (PD)

Unequivocal progression of existing non-target lesions. (Subjective 
judgment by experienced reader)
Unable to Evaluate (UE)

One or more lesions cannot be evaluated due to missing data or poor 
image quality unless a convincing argument can be made that the
contribution of the individual missing lesion(s) would not change the 
assigned time point response (e.g., PD based on other findings)
New Lesions
• Should be unequivocal and not attributable to differences in scanning technique or findings 
which may not be a tumor (does not have to meet criteria to be “measurable”) 
• If a new lesion is equivocal, continue to next time point. If confirmed then, PD is assessed at 
the date when the lesion was first seen. 
• Lesions identified in anatomic locations not scanned at baseline are considered new 
• New lesions on ultrasound should be confirmed on CT or MRI
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Evaluation of Overall Time Point Response for Patients with Measurable Disease at 
Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or NE
No
PR
SD
Non-PD or NE
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
NE=Not Evaluable
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APPENDIX D
DRUGS THAT INTERACT WITH CYP450 ENZYMES
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: 
15 September 2015]. 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. 
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APPENDIX E
DRUGS WITH A RISK OF TORSADES DE POINTES
The website http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 
10 August 2016] lists four categories of QT-prolonging drugs and may be used as a guide for this 
protocol. Categories include “Drugs with Known TdP Risk,” “Drugs with Possible TdP Risk,” 
“Drugs with Conditional TdP Risk,” and “Drugs to be Avoided by Congenital Long QT 
Patients.” The investigator site should register (under the “For Healthcare Providers” tab) to 
access these categories. If the investigator site does not wish to register, a composite list, 
including all categories, is available. 
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study. 
Note: The website and table are only to be used as a guideline and are not comprehensive. It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes. 
Drugs Generally Accepted by the CredibleMeds® QTDrug List Advisory Board to have a 
Known Risk of Causing Torsades de Pointes; Prohibited in this Study
Generic Name
Brand Name (Partial List)
Class/Clinical Use
Amiodarone
Cordarone®, Pacerone®, 
Nexterone®
Antiarrhythmic / abnormal heart 
rhythm
Anagrelide
Agrylin®, Xagrid®
Phosphodiesterase 3 inhibitor / 
thrombocythemia
Arsenic trioxide
Trisenox®
Anticancer / cancer (leukemia)
Astemizole
Hismanal®
Antihistamine / Allergic rhinitis
Azithromycin
Zithromax®, Zmax®
Antibiotic / bacterial infection
Bepridil
Vascor®
Antianginal / angina pectoris  
(heart pain)
Chloroquine
Aralen®
Antimalarial / malaria 
Chlorpromazine
Thorazine®, Largactil®, 
Megaphen®
Antipsychotic/ Antiemetic / 
schizophrenia, nausea, many 
others
Cilostazol
Pletal®
Phosphodiesterase 3 inhibitor/ 
intermittent claudication
Ciprofloxacin
Cipro®, Cipro-XR®, 
Neofloxin®
Antibiotic / bacterial infection
Cisapride
Propulsid®
GI stimulant / increase GI 
motility
Citalopram
Celexa®, Cipramil®
Antidepressant, SSRI / 
depression
Clarithromycin
Biaxin®, Prevpac®
Antibiotic / bacterial infection
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Generic Name
Brand Name (Partial List)
Class/Clinical Use
Cocaine
Cocaine
Local anesthetic / anesthesia 
(topical)
Disopyramide
Norpace®
Antiarrhythmic / abnormal heart 
rhythm
Dofetilide
Tikosyn®
Antiarrhythmic / abnormal heart 
rhythm
Domperidone
Motilium®, Motillium®, 
Motinorm Costi®, Nomit®
Antinausea / nausea, vomiting
Donepezil
Aricept®
Cholinesterase inhibitor/dementia 
(Alzheimer’s Disease)
Dronedarone
Multaq®
Antiarrhythmic / abnormal heart 
rhythm
Droperidol
Inapsine®, Droleptan®, Dridol®, 
Xomolix®
Antipsychotic / Antiemetic / 
anesthesia (adjunct), nausea
Erythromycin
E.E.S.®, Robimycin®, 
EMycin®, Erymax®, Ery-Tab®, 
Eryc Ranbaxy®, Erypar®, 
Eryped®, Erythrocin Stearate 
Filmtab®, Erythrocot®, E-
Base®, Erythroped®, Ilosone®, 
MY-E®, Pediamycin®, 
Zineryt®, Abboticin®, 
Abboticin-ES®, Erycin®, PCE 
Dispertab®, Stiemycine®, 
Acnasol®, Tiloryth®
Antibiotic / bacterial infection, 
increase GI motility
Escitalopram
Cipralex®, Lexapro®, Nexito®, 
Anxiset-E®, Exodus®, Esto®, 
Seroplex®, Elicea®, Lexamil®, 
Lexam®, Entact®, Losita®, 
Reposil®, Animaxen®, 
Esitalo®, Lexamil®
Antidepressant, SSRI / 
depression (major), anxiety 
disorders
Flecainide
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, Flécaine®
Antiarrhythmic / abnormal heart 
rhythm
Fluconazole
Diflucan®, Trican®
Antifungal / Fungal infection
Gatifloxacin
Tequin®
Antibiotic / bacterial infection
Grepafloxacin 
Raxar®
Antibiotic / bacterial infection
Halofantrine
Halfan®
Antimalarial / malaria
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Generic Name
Brand Name (Partial List)
Class/Clinical Use
Haloperidol
Haldol®, Aloperidin®, 
Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol®, Einalon 
S®, Eukystol®, Halosten®, 
Keselan®, Linton®, Peluces®, 
Serenace®, Serenase®, 
Sigaperidol®
Antipsychotic / schizophrenia, 
agitation
Ibutilide
Corvert®
Antiarrhythmic / abnormal heart 
rhythm
Levofloxacin
Levaquin®, Tavanic®
Antibiotic / bacterial infection
Levomepromazine
Nosinan®, Nozinan®, 
Levoprome®
Antipsychotic / schizophrenia
Levomethadyl acetate
Orlaam®
Opioid agonist / narcotic 
dependence
Mesoridazine
Serentil®
Antipsychotic / schizophrenia
Methadone
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadone®
Opioid agonist / narcotic 
dependence, pain
Moxifloxacin
Avelox®, Avalox®, Avelon®
Antibiotic / bacterial infection
Ondansetron
Zofran®, Anset®, Ondemet®, 
Zuplenz®, Emetron®, 
Ondavell®, Emeset®, 
Ondisolv®, Setronax®
Antiemetic / nausea, vomiting
Oxaliplatin
Eloxatin®
Antineoplastic agent / cancer
Papaverine HCl
None
Vasodilator, coronary / 
diagnostic adjunct
Pentamidine
Pentam®
Antifungal / fungal infection 
(Pneumocystis pneumonia)
Pimozide
Orap®
Antipsychotic / Tourette's 
Disorder
Probucol
Lorelco®
Antilipemic / 
Hypercholesterolemia
Procainamide
Pronestyl®, Procan®
Antiarrhythmic / abnormal heart 
rhythm
Propofol
Diprivan®, Propoven®
Anesthetic, general / Anesthesia
Quinidine
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, Cin-
Quin®, Quinora® 
Antiarrhythmic / abnormal heart 
rhythm
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Generic Name
Brand Name (Partial List)
Class/Clinical Use
Roxithromycin
Rulide®, Xthrocin®, Roxl-
150®, Roxo®, Surlid®, 
Rulide®, Biaxsig®, Roxar®, 
Roximycinv®, Roxomycin®, 
Rulid®, Tirabicin®, Coroxin®
Antibiotic / bacterial infection
Sevoflurane
Ulane®, Sojourn®
Anesthetic, general / anesthesia
Sotalol
Betapace®, Sotalex®, Sotacor® 
Antiarrhythmic / abnormal heart 
rhythm
Sparfloxacin 
Zagam®
Antibiotic / bacterial infection
Sulpiride
Dogmatil®, Dolmatil®,
Eglonyl®, Espiride®, Modal®,
Sulpor®
Anti-psychotic, atypical / 
schizophrenia
Sultopride
Barnetil®, Barnotil®, Topral®
Antipsychotic, atypical / 
schizophrenia
Terfenadine
Seldane®
Antihistamine / allergic rhinitis
Thioridazine
Mellaril®, Novoridazine®, 
Thioril® 
Antipsychotic / schizophrenia
Vandetanib
Caprelsa®
Anticancer / cancer (thyroid)
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APPENDIX F
PROTOCOL HISTORY
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Original Protocol
Version 1.0
22 October 2015
Amendment 01
Version 2.0
21 September 2016
Amendment 02
Version 3.0
17 May 2018
Amendment 03
Version 4.0
12 May 2020
Amendment #2, Protocol Version 3.0
The primary sections of the protocol affected by the changes in Amendment 2 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change #1. Removed the exception for hormonal contraception from the list of prohibited 
concurrent medications and procedures; hormonal contraception is no longer allowed
The primary change occurs in Section 13.3 Prohibited Treatment(s) Therapy:
Deleted text: “Any other systemic anticancer therapy including, but not limited to: 
chemotherapeutic agents, immunotherapy, biological response modifiers 
(excluding
growth factors), radiotherapy, and/or systemic hormonal therapy (with the
exception of local therapies, such as SRS, used for palliative or symptomatic 
control of existing lesions, with appropriate treatment interruption at the 
discretion of the investigator). Hormonal contraception is allowed.
Rationale for change: Brigatinib induces CYP3A in vitro and may decrease concentrations of 
CYP3A substrates, including hormonal contraceptives. Coadministration of brigatinib with 
hormonal contraceptives can result in decreased concentrations and loss of efficacy of hormonal 
contraceptives. 
Section 4 Protocol Synopsis also contains this change.
Change #2: Removed all forms of hormonal contraception from the list of highly effective 
contraception methods.
The primary change occurs in Section 14.3.113.3 Pregnancy and Breastfeeding.
Deleted text: 

combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation:
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o
oral
o
injectable
o
implantable

intrauterine hormone-releasing system (IUS)
Rationale for change: Brigatinib induces CYP3A in vitro and may decrease concentrations of 
CYP3A substrates, including hormonal contraceptives. Coadministration of brigatinib with 
hormonal contraceptives can result in decreased concentrations and loss of efficacy of hormonal 
contraceptives. 
Change #3: Added new protocol deviation language.
The primary change occurs in Section 15.9 Protocol Deviations/Violations: 
Added text: 
The investigator should not deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study subjects. Should other unexpected 
circumstances arise that will require deviation from protocol-specified 
procedures, the investigator should consult with the sponsor or designee (and IRB 
or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source 
documents. In the event of a significant deviation, the site should notify the 
sponsor or its designee (and IRB or EC, as required). Significant deviations 
include, but are not limited to, those that involve fraud or misconduct, increase the 
health risk to the subject, or confound interpretation of primary study assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a 
significant degree the safety and rights of a subject or the reliability and 
robustness of the data generated, it will be reported to regulatory authorities as a 
serious breach of GCP and the protocol.
Rationale for Change: Additional protocol deviation language was added per the sponsor’s 
updated template. 
Amendment #1, Protocol Version 2.0
REASON FOR AMENDMENT: 
The amendment serves the following purposes:
1.
Added EORTC QLQ-LC13 quality of life assessment
2.
Amended the required duration for contraceptive use after end of treatment with 
crizotinib
3.
Added the definition of highly effective contraception to be used during and after the 
study
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4.
Amended wording regarding possible additional drug-drug interactions with crizotinib 
and the possibility that the effectiveness of oral contraceptives may be reduced while 
taking crizotinib
5.
Amended the recommendations and requirements for monitoring of vision dysfunction 
during treatment with brigatinib and crizotinib and management of visual loss during 
treatment with crizotinib and visual disturbance during treatment with brigatinib
6.
Clarified that patients will continue to receive study drug until discontinuation
7.
Clarified the timing of study procedures:
a.
that imaging by computed tomography (CT) or magnetic resonance imaging 
(MRI) should continue until the end of treatment, rather than disease progression, 
as some patients may remain on treatment after progressive disease (PD) 
b.
that additional pregnancy testing should be performed if recommended or 
required per local guidelines or regulations
8.
Clarified inclusion criterion #1, that patients with locally advanced or recurrent
Stage IIIB non-small cell lung cancer (NSCLC) may be included in the study
9.
Modified inclusion criterion #5 to specify that >grade 1 alopecia or peripheral 
neuropathy related to prior anticancer therapy are allowed if deemed irreversible
10.
Clarified that baseline laboratory tests that need to be repeated on Cycle 1 Day 1 
(because screening laboratory tests were performed >7 days prior to the first dose) 
should be obtained before starting treatment
11.
Clarified administrative information and processes:
a.
the process for investigator reporting of serious adverse events (SAEs)
b.
the process regarding review and approval of protocol amendments
c.
amended the sponsor contact and signatory information
12.
Corrected some typographical and grammatical errors and inconsistencies throughout 
the protocol
13.
Updated Appendix E (Drugs with a Risk of Torsades de Pointes) to be based on a 
more recent list provided by CredibleMeds® (dated 10 August 2016)
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) versus Crizotinib in 
Patients with ALK-positive Advanced Lung Cancer
NCT Number: NCT02737501
SAP Approve Date: 2020-06-03
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


AP26113-13-301
AP26113
Statistical Analysis Plan
STATISTICAL ANALYSIS PLAN
STUDY TITLE: A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) versus Crizotinib 
in Patients with ALK-positive Advanced Lung Cancer
PROTOCOL NUMBER:
AP26113-13-301
PROTOCOL DATE:
22 October 2015
PROTOCOL VERSION:
Version 4.0
PROTOCOL AMENDMENT DATE:
2020-05-12
SAP VERSION:
Version 5.0
DATE:
2020-06-03
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AP26113
Statistical Analysis Plan
2020-06-03
Page | 2
TABLE OF CONTENTS
1
INTRODUCTION........................................................................................................5
2
STUDY DESIGN..........................................................................................................9
2.1
Randomization..................................................................................................9
2.2
Study Objectives............................................................................................. 10
2.2.1
Primary Objective............................................................................... 10
2.2.2
Secondary Objectives.......................................................................... 10
2.2.3
Exploratory Objectives....................................................................... 10
2.3
Study Endpoints ............................................................................................. 10
2.3.1
Primary Endpoint............................................................................... 10
2.3.2
Secondary Endpoints .......................................................................... 11
2.3.3
Exploratory Endpoints ....................................................................... 11
3
GENERAL CONSIDERATIONS ............................................................................. 11
3.1
Determination of Sample Size........................................................................ 12
3.2
Analysis Populations ...................................................................................... 12
3.2.1
Intent–to-Treat (ITT) Population....................................................... 12
3.2.2
Treated Population ............................................................................. 13
3.2.3
FDA-Approved ALK Test Population................................................ 13
3.2.4
Per-protocol Population...................................................................... 13
3.2.5
Special Populations Specific to Baseline iCNS Disease status ........... 14
3.2.6
Crossover Population.......................................................................... 15
3.3
Demographics, Baseline Characteristics, and Subject Disposition............... 16
3.3.1
Imputation Rules for Missing Initial Cancer Diagnosis Date and Start 
Date and Stop Date for Selected Prior Anti-Cancer Therapies......... 18
3.4
Efficacy Analysis............................................................................................. 20
3.4.1
Disease Assessment ............................................................................. 20
3.4.2
Definition and Analysis of the Primary Efficacy Endpoint............... 22
3.4.3
Primary Efficacy Endpoints Analysis ................................................ 22
3.5
Definitions and Analyses of Secondary Efficacy Endpoints.......................... 29
3.5.1
General Rules for Secondary Efficacy Endpoints.............................. 29
3.5.2
Key Secondary Efficacy Endpoints and Analyses.............................. 34
3.5.3
Additional Secondary Endpoints........................................................ 36
3.6
Exploratory Analyses ..................................................................................... 38
3.6.1
Definitions of Protocol-Specified Exploratory Efficacy Endpoints...38
3.6.2
Definitions of Additional Exploratory Efficacy Endpoints and 
Sensitivity Analyses............................................................................. 39
3.6.3
The Best Response in Target Lesions................................................. 39
3.7
Safety Analysis................................................................................................ 40
3.7.1
Adverse Events.................................................................................... 40
3.7.2
Laboratory and Vital Signs Data ....................................................... 45
3.7.3
QT interval corrected (Fridericia) (QTcF) Analysis.......................... 46
3.7.4
Extent of Exposure.............................................................................. 46
4
REFERENCES........................................................................................................... 48
5
APPENDICES............................................................................................................ 49
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Statistical Analysis Plan
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TABLE OF TABLES
Table 1
Demographics and Baseline Characteristics .........................................................................16
Table 2
The Scheme of Progression and Censoring for the Analysis of PFS.....................................25
Table 3
Response Confirmation Patterns...........................................................................................32
LIST OF APPENDICES
Appendix 1
Adverse Events in Special Categories........................................................................49
Appendix 2
Details for Sensitivity Analyses of the Primary Endpoint ........................................50
Appendix 3
Anticancer Therapies Treated as Potential Censoring Events.................................52
Appendix 4
Radiotherapies Treated as Potential PFS or Censoring Events...............................53
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LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ARIAD
ARIAD Pharmaceuticals, Inc.
AST
aspartate aminotransferase
BIRC
blinded independent review committee
CNS
central nervous system (see iCNS)
CR
complete response
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organisation for Research and Treatment of Cancer
HRQoL
health-related quality-of-life
iCNS
intracranial Central Nervous System
ITT
Intention-to-treat
MRI
magnetic resonance imaging
NE
not evaluable
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRA
PRA Health Sciences
PRO
patient-reported outcomes
QLQ
Quality of Life Questionnaire
QTcF
QT interval corrected (Fridericia)
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SRS
stereotactic radiosurgery
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
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Statistical Analysis Plan
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1
INTRODUCTION
This statistical analysis plan (SAP) describes the study design and statistical analyses for study 
protocol AP26113-13-301, entitled “A Phase 3 Multicenter Open-label Study of Brigatinib 
(AP26113) versus Crizotinib in Patients with ALK-positive Advanced Lung Cancer” by ARIAD 
Pharmaceuticals, Inc.
This statistical analysis plan (SAP) has been prepared to support a clinical study report (CSR) that 
will be included in regulatory submissions intended to achieve marketing approval. CSR analyses,
as directed by this document, may also be used for other purposes such as publication of study
results, and analyses will be rerun on updated data. Evaluation of the primary endpoint will be
assessed in up to two interim analyses and one final analysis based on numbers of progression-free
survival (PFS) events observed as described in as described in Section 3.4.3.5. Since study
AP26113-13-301 will be ongoing at the time these evaluations take place additional analyses as
specified in this SAP are anticipated at least annually.
Changes from analyses planned in the study protocol will be accounted for in this document. 
Analysis specifications in this document supersede suggestions for or descriptions of analyses 
contained in other documents, such as specifications prepared by external vendors, associated with
study AP26113-13-301.
For revisions to the CSR any changes and additions to analyses specified here will be detailed in a
companion document that will be included as an appendix.
An administrative update (Version 2) was made to this plan on February 18, 2018, consisting of 
clarifications of text that were requested when creating programming specifications and analysis 
programs based on this document.
A further update (Version 3) was made to this plan on March 27, 2018, in which substantive 
changes were made.

A statement was added in Section 3.4.3.6 that formal statistical inference will be 
completed at the first successful evaluation of the primary endpoint.

Section 3.5.1 was modified to specify that analysis of ORR using BIRC or investigator 
assessments will treat all subjects assessed as having non-measurable disease at baseline
as non-responders.

The definition of DCR in Section 3.4.3.3 was modified to state that single responses of 
CR and non-CR/non-PD in subjects with non-measurable disease at baseline will be 
eligible to contribute to disease control.

The definition of the Measurable iCNS disease population (Section 3.2.5.3) was changed 
from being a subset of the ITT population to being a subset of the all iCNS disease 
population

Clarification below Table 3 that subjects assessed as having non-measurable disease at 
baseline will be summarized as non-responders, and that patients with no valid time point 
responses will also be reported as non-responders
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Statistical Analysis Plan
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
Specification in Section 3.4.3.2 that censoring for anticancer therapies recorded during 
safety follow up will occur as of the date of contact at which the first occurrence of 
therapy is noted

The definition of time to response analyses in Section 3.5.3.2 was simplified to the 
presentation of summary statistics restricted to responders. Time to event models and 
figures were eliminated.

Time to onset and duration were removed from the analyses of AEs in special categories 
in Section 3.7.1.1, and specification that incidence for each constituent PT was added.
Version 4 update was made to this plan on August 19, 2019, which included the following:

The alpha levels allocated to IA1, IA2, and FA were corrected based on
O’Brien Fleming Lan-DeMets approach (this was erroneously reported in the 
protocol and previous version of the SAP as it was inadvertently calculated 
using the O’Brien-Fleming boundary.) in Section 3.1 and 3.4.3.6. 

Based on Intent-to-Treat Principle, subjects who were randomized but did not 
take any study treatment should be analyzed the same way as any other 
randomized subjects. Therefor, censoring rule for PFS and DOR were modified 
as below:
The following sentence in Section 3.4.3.2 was removed. 
“Randomized subjects who did not receive any of their assigned study drug will 
be censored at follow-up Day1.”
The corresponding censoring rule #1 in Table 2 was removed. As a result of this 
change, subjects who were randomized but untreated will be analyzed based on 
the remaining progression and censoring rules in Table 2. The same change 
applies to Table A3-1 and Table A3-2. 
This change applies to the analysis of Duration of Response (DOR), intracranial 
Progression-free Survival (iPFS), and intracranial Duration of Response (iDOR) 
as well.

Based on RECIST criteria v1.1, subjects who only had non-measurable disease 
at baseline should be counted as a responder if they had an overall response of 
CR. The following sentence in Section 3.5.1:
“Any subjects who are identified as having only non-measurable disease at baseline by one 
of these assessment mechanisms (BIRC or investigator assessment) will not be eligible to 
be counted as responders (i.e. overall response of PR or CR) in analysis of results assessed 
by that mechanism, unless explicitly stated is exploratory analysis”
was changed to 
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“Any subjects who are identified as having only non-measurable disease at 
baseline by one of these assessment mechanisms (BIRC or investigator 
assessment) will not be eligible to be counted as responders (i.e. overall 
response of PR or CR) in analyses of results assessed by that mechanism, unless
their overall response is CR.”
Same update made to the statement below Table 3 that subjects assessed as having non-
measurable disease at baseline will be summarized as responders only if their overall 
response is CR, otherwise will be reported as non-responders. 
According to protocol amendment 3, updates (version 5) were made to this plan on May 15, 
2020, which included the following:

The primary endpoint, PFS assessed by BIRC, was met at the first pre-planned 
interim analysis and confirmed at the second pre-planned interim analysis, before 
198 events (PFS) events were observed.

The timing of the primary analysis of BIRC assessed PFS in section 3.4.3.6 was 
modified.
“The final analysis of the primary endpoint will be performed after 198 events
have been observed, and will be tested at a 2-sided alpha level of 0.044.” 
was changed to 
“The primary analysis of the primary endpoint will be performed after 198 events
have been observed or at End-of-Study, whichever comes first, and will be tested
at a 2-sided alpha level of 0.044.”

The timing of OS analysis in section 3.4.3.6 and 3.5.2.1 were modified.
“Analyses of OS will also be performed at the time of the interim and final 
analysis, if the primary endpoint is met.”
    was changed to
“Analyses of OS will also be performed at the time of the interim analysis and 
at End-of-Study, if the primary endpoint is met.”
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“The primary assessment of the first three endpoints above will be performed at 
the time when the assessment of the primary endpoint is completed, either when 
the efficacy boundary is surpassed on one of the interim analyses or at the time 
the final analysis is done.
The primary assessment of OS will be performed when 198 PFS events to
perform the final analysis of the primary endpoint have been observed, or at final 
database lock if the study is terminated prior to this occurs prior to the
observation of 198 PFS events.”
was changed to
“The primary assessment of all these four endpoints above will be performed at 
the time when the assessment of the primary endpoint is completed, either when 
the efficacy boundary is surpassed on one of the interim analyses or at the time 
the primary analysis is done.”
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2
STUDY DESIGN
This is a phase 3, randomized, open-label, comparative, multicenter, international study in which 
anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients who 
have not previously received an ALK-targeted tyrosine kinase inhibitor (TKI) will be randomized
in a 1:1 fashion to receive brigatinib (Arm A) or crizotinib (Arm B).
Patients will be stratified by the presence of central nervous system (CNS) metastases at baseline 
(Yes versus No) and prior chemotherapy used for locally advanced or metastatic disease (Yes 
versus No). For the purposes of stratification, prior chemotherapy is defined as completion of ≥1 
full cycle of chemotherapy in the locally advanced or metastatic setting. An estimated 270 patients
(135 in Arm A, 135 in Arm B) will be enrolled at approximately 150 centers.
Patients will be treated until they experience progressive disease (PD), intolerable toxicity, or 
another discontinuation criterion is met. Continuation of brigatinib beyond progression is permitted,
at the investigator’s discretion, if there is evidence of continued clinical benefit. Crossover from
Arm B (crizotinib) to brigatinib is also permitted, at the investigator’s discretion with the sponsor’s
medical monitor approval, for patients who have experienced objective progression determined by
the blinded Independent Review Committee (BIRC).
Throughout the study, Adverse Events (AEs) will be assessed and categorized by the US 
National Cancer Institute Common Terminology Criteria for Adverse Events (see protocol 
Appendix A). Patients will be evaluated according to the Schedule of Events in protocol 
Section 11.1.
2.1
Randomization
Patients will be randomized in a 1:1 ratio to receive either brigatinib 90 mg once daily (QD) orally
for 7 days followed by 180 mg QD orally continuously (Arm A) or crizotinib 250 mg twice daily
(BID) orally (Arm B). Patients will be stratified by the following two factors, each having two
levels:
1. intracranial Central Nervous System (iCNS) metastases at baseline (Yes versus No)
2. Prior chemotherapy use for locally advanced or metastatic disease (Yes versus No). For 
the purposes of stratification, prior chemotherapy is defined as completion of ?1 full 
cycle of chemotherapy in the locally advanced or metastatic setting.
Specific instructions for randomization will be supplied in the Study Reference Manual. 
Randomization procedures should be performed following completion of eligibility assessments and
prior to the initiation of treatment, and required approval by the Sponsor's Medical Monitor. This
study is unblinded; patients, investigators, and the sponsor will know the identity of each patient's
study drug assignment.
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2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is to compare the efficacy of brigatinib to that of crizotinib in 
ALK+ locally advanced or metastatic NSCLC patients naive to ALK inhibitors, as evidenced by 
PFS.
2.2.2
Secondary Objectives
The secondary objectives of the study are:
1.
To compare the efficacy of brigatinib to that of crizotinib, as evidenced by confirmed 
objective response rate (ORR), time to/duration of response, disease control rate 
(DCR), and Overall Survival (OS)
2.
To compare the efficacy in the CNS of brigatinib to that of crizotinib, as evidenced by 
intracranial response and intracranial PFS in those patients with iCNS metastases at 
baseline
3.
To assess the safety and tolerability of brigatinib in comparison with crizotinib
4.
To determine pharmacokinetic (PK) parameters of brigatinib through population PK 
modeling
5.
To assess patient-reported symptoms and health-related quality of life (HRQoL) with 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire (QLQ)-C30 (v3.0) in patients treated with brigatinib compared to 
those treated with crizotinib)
2.2.3
Exploratory Objectives
2.3
Study Endpoints
2.3.1
Primary Endpoint
The primary endpoint for this study is PFS, as assessed by the BIRC, per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer et al, 2009).
CCI
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2.3.2
Secondary Endpoints
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR, as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
The four endpoints above will be evaluated in a closed testing procedure as described in Section
3.5.2.1.
5.
Duration of response, as assessed by the BIRC
6.
Time to response, as assessed by the BIRC
7.
Disease control rate, as assessed by the BIRC
8.
Safety and tolerability
9.
Change from baseline scores in global health status/quality of life (QOL) assessed 
with the EORTC QLQ-C30 (v3.0), and time-to-deterioration in dyspnea assessed with 
the EORTC QLQ-LC13 (v3.0)
2.3.3
Exploratory Endpoints
3
GENERAL CONSIDERATIONS
The interim and final primary analyses will be conducted when the required number of PFS events
have been observed as specified in protocol Section 15.5.2, and levels for statistical significance
will be tested at the 2-sided alpha levels described in Section 3.4.3.5. Assessment of key secondary
endpoints will be assessed in a closed testing procedure as described in Section 3.5.2.1.
Comparisons between treatment groups for all other analyses will be tested at an unadjusted two-
sided alpha level of 0.05, with two-sided 95% confidence intervals when appropriate unless
specified otherwise.
Incidence of PFS events will be tracked throughout the course of the study, and the expected time
of the required events for interim and final analyses will be estimated periodically. As the number
of events approaches each of the pre-specified PFS event targets a Data Cut Off (DCO) date will
be prospectively set. This date will be selected with the intent of reasonable assurance that a
sufficient number of PFS events will be available.
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All data collected will be included in the tabulation (SDTM) datasets, but data included in the 
analysis (ADaM) datasets will be truncated at the DCO date.
Unless otherwise stated baseline values in the main study period are defined as the last valid values 
collected during the time interval from the screening visit to the first dose date (time) of the
randomized study treatment. Sites were instructed to perform C1D1 assessments prior to 
randomization and exposure to randomized study treatment. Therefore, all assessments performed 
on C1D1 are eligible for use baseline values. Descriptive statistics (such as means, medians,
standard deviations, and ranges for continuous data, and counts/percentages for categorical data) 
will be used to summarize subject characteristics, study treatment administration, efficacy, safety,
pharmacokinetic parameters, and genetic status of biomarkers. Data will also be displayed
graphically where appropriate.
For the purpose of reporting efficacy and safety at specific time points, e.g., 6-month PFS, a month
will comprise 30.4375 days. In case that at least one treated subject has been randomized to dosing
regimen of 90 mg QD to 180 mg QD but have never been unable to successfully escalated to 180
mg (either during the first 7 days or later), these subjects will still be included on all the planned
analyses for this regimen and may also be analyzed as a separate group.
Incidence for AEs and other important events will be reported at the subject level, with all subjects
in the risk set used as the denominator and all subjects with at least one qualifying event 
constituting the numerator. In safety analysis, minimum or maximum values collected after first 
exposure to study drug may be used for summaries and change from baseline summaries.
Statistical analyses will be performed using SAS Statistical Software. Specifications for creating 
datasets for review, presentation, and analysis of results will be maintained by PRA Health 
Sciences under the direction of Takeda Pharmaceuticals.
3.1
Determination of Sample Size
For the purposes of this sample size calculation, the median PFS for crizotinib is estimated as 10
months (Solomon et al, 2014). Approximately 270 subjects will be randomized in a 1:1 fashion to
receive brigatinib or crizotinib. A total of 198 events (progression or death among the randomized
subjects) will provide 90% power to detect a clinically meaningful 6-month improvement in PFS 
(hazard ratio=0.625). This power projection is based on a 2-sided log-rank test, and is controlled 
at the 2-sided 0.0044 level, adjusting for the proposed interim analysis plan. The number of
events is fixed, but the enrollment number may change based on an assessment of the overall 
event rate pooled across treatment groups (prior to the close of enrollment).
3.2
Analysis Populations
3.2.1
Intent–to-Treat (ITT) Population
The ITT population includes all subjects randomized to either regimen. The primary analyses of 
efficacy will be based on the ITT population.
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3.2.2
Treated Population
The treated population for each regimen includes all subjects receiving at least one dose of study drug.
Safety will be analyzed using the treated population.
3.2.3
FDA-Approved ALK Test Population
Section 15.5.2 of the protocol states a sensitivity analysis of the primary endpoint will be 
performed in the “FDA approved ALK test population”. This population will consist of all subjects
in the ITT population who also meet one of the two following criteria.
1) Were determined to be ALK+ by one of the tests identified in Inclusion Criterion 2a
2) Provided adequate tissue for central testing and were determined to be ALK+ at the
central laboratory by the FDA-approved test
3.2.4
Per-protocol Population
The per-protocol population will be used for sensitivity analyses in order to characterize the effects 
of the two treatment regimens when used as intended according to the study protocol. 
Considerations for inclusion include consistency with the intended treatment population, adequate
exposure to randomized treatment regimen, and sufficient post-exposure disease assessment to 
determine presence or absence of progressive disease. Per-protocol subjects will include all
subjects in the FDA-Approved ALK Test Population who met the following criteria at study entry:

Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent 
and not a candidate for definitive multimodality therapy) or stage IV NSCLC.

Have at least one measurable lesion per RECIST v1.1 as assessed by the BIRC in the 
assessment of the baseline scan. Presence of measurable disease is defined as inclusion of
at least one target lesion in the baseline RECIST assessment.

Have at least one adequate post-baseline radiographic response assessment unless the 
reason is death or early discontinuation due to disease progression.
Usage of any systemic antineoplastic therapy that is prohibited by the protocol prior to BIRC-
determined PD, death or discontinuation due to AE will disqualify a subject from the per- protocol
population. The list of therapies that will be considered disqualifying for per-protocol population
will be determined prior to the first interim analysis and updated prior to each evaluation of the 
primary endpoint. Use of radiotherapy consistent with the following condition from Section 13.2 of
the protocol will not exclude a subject from the per-protocol population:
Patients with CNS lesions requiring local radiotherapy such as stereotactic radiosurgery 
(SRS) are allowed to continue study drug after appropriate interruption, as determined by the 
investigator with sponsor agreement; however, for analysis purposes, these patients will be 
considered to have PD.
This definition of the per-protocol population is intended for sensitivity analysis of the primary 
endpoint and is only directly applicable for analysis of endpoints based on the main BIRC. If per-
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protocol analyses of endpoints based on assessments performed by the investigator or iCNS BIRC
are performed, different versions of the definition will be required.
3.2.5
Special Populations Specific to Baseline iCNS Disease status
See Section 3.4.1.2 of this document for a description of the iCNS BIRC process.
3.2.5.1
All iCNS Disease Population
The all iCNS disease population will consist of those subjects in the ITT population who were 
determined by the iCNS BIRC to have iCNS metastases at baseline regardless of whether they 
had at least one lesion that qualified as a target lesion in their baseline assessment.
3.2.5.2
No iCNS Disease Population
The no iCNS disease population will consist of those subjects in the ITT population who were not 
determined by the iCNS BIRC to have iCNS metastases at baseline.
3.2.5.3
Measurable iCNS Disease Population
Measurability of lesions is a core component definition of a potential target lesion in the RECIST 
v1.1 process and is retained in the modified RECIST used for iCNS disease assessment (Section
3.4.1.2). Therefore the measurable iCNS disease population will consist of those subjects in the all
iCNS Disease population who were determined by the iCNS BIRC to have had at least one target
lesion in their baseline assessment.
3.2.5.4
Non-Measurable iCNS Disease Population
The non-measurable iCNS disease population is intended to characterize subjects who were 
determined to have iCNS disease at baseline but did not have measurable lesions. This means that
subjects with both measurable and non-measurable lesions at baseline will not be included in this
population. Therefore the non-measurable iCNS disease population will consist of all subjects in
the all iCNS disease population who are not included in the measurable iCNS disease population.
3.2.5.5
Active iCNS Disease Population
An active brain lesion is defined for the purpose of this study as meeting either of the following 
criteria:
1) A lesion that has not previously been irradiated
2) Having had prior radiation treatment but then having definitely progressed, as assessed 
by the investigator, after being irradiated.
However, the independence between disease assessments performed by the BIRC and those 
performed by the investigators requires limits on the amount and types of information transferred 
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between sites and the central reading process. Information as to whether any radiotherapy to the 
brain prior to study entry was made available to the BIRC readers, but this did not include whether 
the therapy was targeted at individual lesions or whether any irradiated lesions subsequently
progressed. Therefore, assessment as to whether iCNS lesions are active cannot be done using BIRC
time point responses. It can, however, be determined using the RECIST v1.1 assessment performed
at baseline by the investigator since those assessments include lesion-level data on radiotherapy and
subsequent progression.
Therefore the active iCNS disease population is defined as including all subjects in the all iCNS 
disease population who have one active iCNS lesion in their baseline RECIST v1.1 scan performed
by the investigator. Analysis of efficacy in the active iCNS disease population will still be
performed using data from the modified RECIST assessments performed by the BIRC.
3.2.5.6
Active Measurable iCNS Disease Population
The active measurable iCNS disease population is defined as all subjects included in both the 
measurable iCNS disease population and the active iCNS disease population.
3.2.5.7
Active Non-Measurable iCNS Disease Population
The active measurable iCNS disease population is defined as all subjects included in both the non-
measurable iCNS disease population and the active iCNS disease population.
3.2.6
Crossover Population
Subjects in Arm B (crizotinib) who cross over to brigatinib following BIRC-assessed PD will have
their data following start of brigatinib treatment analyzed as a single treatment group. Crossover
must occur as directed in the protocol and result in the receipt of at least one dose of brigatinib.
Subjects receiving brigatinib through alternative sources, such as by prescription in areas where it
is commercially available, will not be included in the crossover population.
Indirect comparisons to other treatment experiences, such as the start of brigatinib in the Arm A 
subjects or the start of crizotinib within the same population, may be made but will usually not 
include formal statistical assessment of group differences.
Baseline values in the crossover period are defined as the last valid value prior to exposure to 
brigatinib for crossover subjects. Since no randomization date will be available for the crossover 
period the reference date for calculation of Study Day in the crossover period will be the date of 
first exposure to brigatinib. If a subject receives therapy qualifying as a censoring event in the 
period following the scan used as the baseline in the crossover period but prior to first exposure to
brigatinib then all scans in the crossover period will be censored in the main analyses of crossover 
endpoints. Rules for determination of treatment emergence for AEs are described in Section
3.7.1.3.
Statistical comparison of group differences in OS that account for the effects of changing 
treatments will be performed as described in Section 3.5.2.5.
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3.3
Demographics, Baseline Characteristics, and Subject Disposition
Demographics and baseline characteristics to be summarized using descriptive statistics are listed 
in Table 1. Continuous variables will be summarized by means, medians, standard deviations, and 
ranges; categorical prognostic factors will be summarized by counts/percentages. Other prognostic
factors (e.g., by categorizing the continuous prognostic factors and re- categorizing the categorical 
prognostic factors) may also be included in the analysis.
Subjects who cross over from crizotinib to brigatinib will be identified as having discontinued 
randomized therapy due to PD in the main disposition table, and as entered on the end of treatment
page in the crossover disposition table.
Table 1
Demographics and Baseline Characteristics
Parameters
Categories for categorical parameters
From Demographics eCRF
Age (continuous)
Age (categorized in reference to age in whole years)
18-64, ≥65
18-49, 50-64, 65-75, and ≥75
Gender
Male, Female
If Female, Is the patient of childbearing potential?
Yes, No
Race and Ethnicity
Individual responses will be presented as recorded and 
grouped based on observed responses
Geographic region/investigative sites
North America, Europe, Asia-Pacific
From Eligibility Criteria eCRF
iCNS metastases at baseline, as randomized
Yes, No
Prior chemotherapy, as randomized
Yes, No
Strata, as randomized
iCNS metastases at baseline/Prior chemotherapy
iCNS metastases at baseline/No prior chemotherapy 
No iCNS metastases at baseline/Prior chemotherapy
No iCNS metastases at baseline/No prior chemotherapy
iCNS metastases at baseline, current
Yes, No
Prior chemotherapy, current
Yes, No
Current strata
iCNS metastases at baseline/Prior chemotherapy
iCNS metastases at baseline/No prior chemotherapy 
No iCNS metastases at baseline/Prior chemotherapy
No iCNS metastases at baseline/No prior chemotherapy
From Diagnosis eCRF
Stage at initial diagnosis
IA, IB, IIA, IIB, IIIA, IIIB, IV, Unknown or not staged
Stage at study entry
IIIB, IV, Other
Time since initial diagnosis (continuous)
Time since locally advanced or
metastatic stage diagnosis (continuous)
Histopathological classification at study entry
Adenocarcinoma, Adenosquamous Carcinoma, Large
cell, Squamous, Unknown, Other
Lung involvement at Study Entry
Left Lung, Right Lung, Both Lungs, Lungs not involved
Other Organ Involvement at Study Entry
Yes, No
Individual responses will be presented as recorded and 
grouped based on observed responses
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From Substance Use Cigarettes eCRF
Cigarette smoking history
Never, Former, Current, Unknown
Current cigarette smoking amount
Less than 20 per Day, 20 To 60 per Day, More Than 60 
per Day
Former cigarette smoking amount
Less than 20 per Day, 20 To 60 per Day, More Than 60
per Day
From Vital Signs eCRF1
Weight (continuous)
Height (continuous)
BMI (continuous)
Calculated from height and weight
From ECOG Performance Status eCRF
Eastern Cooperative Oncology Group (ECOG)
Performance Status
0, 1, 2
From ALK Molecular Characterization eCRF
ALK status assessed
Yes, No
Parameters
Categories for categorical parameters
ALK assessed by FDA-approved test
Yes, No
Defined as inclusion in the 3.2.3 FDA-Approved ALK 
Test Population (Section 3.2.3).
ALK rearrangement detected
Yes, No
From Prior Radiation Therapy eCRF
Any prior radiotherapy
Yes, No
Best response to any radiotherapy
Complete Response
Partial Response 
Stable Disease 
Progressive Disease 
Unable to Assess 
Unknown
Other
Note: select first above when > 1 radiotherapy listed
Prior radiotherapy to the brain
Yes, No
Best response to radiotherapy to the brain
Complete Response
Partial Response 
Stable Disease 
Progressive Disease 
Unable to Assess 
Unknown
Other
Note: select first above when > 1 radiotherapy listed
From Prior Anticancer Surgery eCRF
Prior Surgery
Yes, No
Diagnostic surgery
Yes, No
Therapeutic surgery
Yes, No
Purpose of surgery unknown
Yes, No
Purpose of surgery other
Yes, No
Resection Type
Complete Resection
Partial Resection 
Unresectable 
Unknown
Other
Not Applicable
Note: select first above when > 1 surgery listed
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From Prior Anticancer Therapy eCRF
Any prior anticancer therapy
Yes, No
Was at least 1 full cycle of any prior anticancer therapy
administered in the locally advanced or metastatic 
setting
Yes, No
Any prior chemotherapy
Yes, No
Agents will be identified as chemotherapy agents by a 
combination of programming logic and medical review
Was at least >1 full cycle of any prior anticancer therapy
administered in the locally advanced or metastatic 
setting
Yes, No
If at least one agent in a regimen is identified as 
chemotherapy this will be the response to the question 
about a full course for that regimen
Most recent systemic therapy
Chemotherapy, Other
Number of prior systemic anticancer therapies/regimens
0, 1, 2, etc.
1 Values selected for each subject will be consistent with definition of baseline observation in the 
introduction to Section 3.
The list of characteristics described in the table above will also be used as the basis for sensitivity
subgroup analyses of efficacy endpoints.
Subject disposition will be tabulated by reasons leading to study treatment discontinuation 
including adverse event, death, documented disease progression (RECIST) by BIRC as well as by
investigator assessment, clinical progressive disease, withdrawal by subject, physician
decision, pregnancy, non-compliance with study drug, protocol violation, lost to follow-up, study
terminated by sponsor, or other reason.
When analyses include the use of the factors used in stratification the current values will be used 
unless otherwise specified.
Analyses of most recent therapy will define most recent by the end date of therapy. If more than 
one agent is used in a regimen the end date for that regimen will be the last exposure date of any 
agent in the regimen.
3.3.1
Imputation Rules for Missing Initial Cancer Diagnosis Date and Start Date and Stop 
Date for Selected Prior Anti-Cancer Therapies
In general, a diagnosis date will be imputed first and then used to adjust the imputation of the 
corresponding prior treatment start date when necessary.
Diagnosis Dates

If day is missing but month and year are non-missing (YYYY-MM-UU), impute as the 
earliest of:
o
YYYY-MM-01
o
Randomization date
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
If day and month are missing (YYYY-UU-UU), impute as the earliest of:
o
YYYY-01-01
o
Randomization date

If month is missing (YYYY-UU-DD), but day and year are non-missing, ignore the day 
and impute as the earliest of:
o
YYYY-01-01
o
Randomization date
Prior Anti-Cancer Therapies Dates Start Date

If day is missing but month and year are non-missing (YYYY-MM-UU), impute as the 
earliest of:
o
YYYY-MM-01
o
Randomization date

If day and month are missing (YYYY-UU-UU), impute as the earliest of:
o
YYYY-01-01
o
Randomization date

If month is missing (YYYY-UU-DD), but day and year are non-missing, ignore the day 
and impute as the earliest of:
o
YYYY-01-01
o
Randomization date
If after applying above rules, any prior treatment start dates are before diagnosis date, impute as 
diagnosis date.
Stop Date

If day is missing but month and year are non-missing (YYYY-MM-UU), impute as the 
earliest of:
o
The last day of the month: YYYY-01-31, YYYY-02-28 or YYYY-02-29, YYYY-
03-31, YYYY-04-30, YYYY-05-31, YYYY-06-30, YYYY-07-31, YYYY-08-31,
YYYY-09-30, YYYY-10-31, YYYY-11-30, YYYY-12-31
o
Randomization date

If day and month are missing (YYYY-UU-UU), impute as the earliest of:
o
YYYY-12-31
o
Randomization date
If after applying above rules, any prior treatment stop dates are prior to corresponding prior 
treatment start date, impute as start date.
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Duration of a selected prior anti-cancer therapy will be calculated using the following formula: 
duration = stop date – start date. Duration will be calculated with imputed dates when necessary. If
a subject is randomized after more than one regimen of chemotherapy, contrary to the entry 
criterion of no more than one regimen, only the duration of the most recent regimen will be 
reported and summarized.
Time since the stop date of a selected prior anti-cancer therapy to the first dose of study treatment
will be calculated using the following formula: time since stop date = randomization date - stop 
date. Time since the stop date to the first dose date will be missing in the case of a completely 
missing stop date.
3.4
Efficacy Analysis
3.4.1
Disease Assessment
3.4.1.1
RECIST Assessment
Radiological scans for the assessment of disease progression and tumor response are scheduled to 
be performed every 8 weeks, and unscheduled scans can be performed at other times. Images from
all scans performed from screening through the end of study participation will be transferred to the 
BIRC and evaluated per RECIST v1.1 (Eisenhauer, 2009) as described by the BIRC charter and 
associated documentation. The BIRC process is designed to account for commonly encountered
situations in the evaluation of NSCLC severity in human trials, such as scans that cannot be
evaluated and radiological assessments for a single visit performed on different days (e.g.,
computed tomography (CT) and magnetic resonance imaging (MRI)).
Validity of the findings of the BIRC will be enhanced by using two primary readers supported by 
an adjudicator; having readers of a scan blinded to all subsequent scans; keeping each reader 
blinded to the findings of the other reader; maintaining data through a transparent and documented
data management process; and, most importantly, keeping all members of the BIRC blinded to 
study treatment and any other information collected on subjects following randomization other than
the scans themselves.
Evaluable scans are defined as scans that, after completion of the BIRC assessment process, have a 
value for response that indicates a RECIST assessment of complete response (CR), partial response 
(PR), stable disease (SD), or PD. In cases where a subject was assessed as having non- measurable
disease at baseline a time point response of non-CR/non-PD will be accepted as evaluable.
Handling of scans of subjects with non-measurable disease at baseline in response analyses is
described in Section 3.5.2.1. Unevaluable scans will be assigned not evaluable (NE) and not be used
for censoring.
Expedited review of scans will continue until first occurrence of BIRC-determined disease 
progression.
For subjects who discontinue the study treatment due to a reason other than BIRC-determined 
progressive disease, additional tumor assessments should be documented, if available, until disease
progression per BIRC or start of another systemic anti-cancer therapy. For subjects in Arm A who
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continue brigatinib beyond disease progression, tumor assessments will continue to be performed
every 8 weeks. For subjects in Arm B who crossover to brigatinib after BIRC determined
progression on crizotinib, the scan at which BIRC-determined progression was determined will also 
be re-evaluated (per RECIST v1.1 criteria) as a new baseline for the Crossover Phase unless >21
days prior to the start of brigatinib therapy (Crossover C1D1), which will require a new disease
assessment prior to starting brigatinib.
RECIST assessment will also be performed by the investigator.
3.4.1.2
Modified RECIST Assessment of iCNS Disease Burden
Intracranial CNS (iCNS) disease burden will be assessed using a modified RECIST. These 
assessments will be performed by a different BIRC team of primary readers and adjudicator(s) that 
will be conducted as consistently with the process for the primary endpoint as possible. The 
important modifications in for this assessment are:
1. Standard RECIST requires that subjects have measurable disease defined as the presence 
of at least one suitable target lesion. The modified iCNS assessments will specify how to 
handle subjects whose baseline iCNS disease does not meet the criteria for measurability. 
The assessment of baseline status will consist of one of three determinations:
a.
No iCNS disease – these subjects will be followed up for new lesions in the brain
b. iCNS disease present but not measurable – in this case the readers will be 
instructed to enter as many non-target lesions as possible.
c.
Measurable iCNS disease – subjects in this category must have at least one target 
lesion (i.e., ≥10 mm in the longest diameter).
2. Standard RECIST allows up to 5 target lesions but specifies that no more than two target 
lesions can be in the same organ system. The modified iCNS assessment allows up to 5
target lesions in the brain
3. The modified RECIST will generate the following levels of response
a.
All non-readable scans will be assigned response of NE
b. Subjects without baseline brain metastases disease per iCNS BIRC can have time
point responses of PD or No Disease (ND)
c.
Time point responses for subjects with measurable disease at baseline will consist
of CR, PR, SD, and PD
d. Time point responses for subjects with only non-measurable disease at baseline
will consist of CR, non-CR/non-PD, and PD
For the analysis of intracranial CNS ORR and PFS: If a subject progresses due to lesions outside 
the intracranial CNS and continues on study treatment, this subject will continue to be evaluated as
SD, PR, or CR in the intracranial CNS until progression in the iCNS or discontinuation from the
study treatment.
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3.4.2
Definition and Analysis of the Primary Efficacy Endpoint
3.4.2.1
Definition of the Primary Efficacy Endpoint
The primary endpoint, PFS assessed by BIRC, is defined as the time interval from the date of 
randomization until the date of the PFS event as defined below. It will be censored for subjects who 
have not had a PFS event. Follow-up for PFS will also be censored in the primary efficacy analyses
upon documentation of certain other events (such as initiation of disallowed therapy) as described in
Table 2 below.
3.4.3
Primary Efficacy Endpoints Analysis
Important aspects of the definition of the PFS event and censoring are described in this section. 
The detailed scheme of progression and censoring for the primary analysis of PFS is specified in 
Table 2. These rules are defined consistently with FDA Guidance: “Clinical Trial Endpoints for 
the Approval of Non-Small Cell Lung Cancer Drugs and Biologics Guidance for Industry” (April
2015).
3.4.3.1
Data handling Rules for the Primary Analysis of PFS
Data handling rules for the primary PFS analyses will be as follows:

A PFS event is defined as death or BIRC-determined RECIST progression. Follow-up for 
any subject with a PFS event will be uncensored in the analysis of the primary endpoint 
unless one of the censoring rules in Section 3.4.3.2 takes precedence.

The PFS date is the earliest date of death or first observation of BIRC-determined 
RECIST progression events. All follow-up after the first PFS event will be excluded from 
the analysis of the primary endpoint

The determination of the PFS event will include any PD observed by BIRC on or after 
randomization even if it does not occur at a scheduled study visit or is observed after the 
End of Treatment visit

The date of progression is defined as the date at which disease progression was first 
evident and is determined by the BIRC readers in the BIRC system prior to transfer of 
data to the sponsor.

Subjects may continue the study treatment or switch from crizotinib to brigatinib beyond 
documented progressive disease per RECIST v1.1 at the investigator’s discretion. Among 
these subjects, only the date of the first documented evidence of progressive disease will 
be used to define the primary endpoint of PFS.

Scans performed after the End of Treatment visit that are assessed by BIRC will be 
included in the analysis of the primary endpoint as long as one of the censoring rules does 
not take precedence.

Per Section 13.2 of the protocol, subjects receiving radiotherapy for iCNS metastases will 
be considered as having PD in the primary analysis at the time such therapy was initiated.
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3.4.3.2
Censoring Rules for the Primary Analysis of PFS
It is central to the definition of any time-to-event analysis that, for any subject who did not 
experience the event of interest, follow-up time is treated as censored in the analysis. In addition, 
any situation that impairs the continuity of unbiased follow-up should usually be considered as a 
reason to censor follow-up for any subject affected. Therefore, the additional censoring rules 
described in this section will be applied in the primary analysis.

Subjects who cannot be evaluated for progression due to missing or incomplete baseline 
scans or because they have no evaluable on-treatment scans will also be censored at 
follow-up Day 1.

If a subject starts any other anti-cancer therapy prior to a PFS event then follow-up will 
be censored at the date of the last valid assessment prior to initiation of the anticancer 
therapy.
o
This condition does not apply to crizotinib subjects crossing over to brigatinib as 
defined in the study protocol since this event should only occur after BIRC-
determined PD. However, if a subject does receive brigatinib prior to such a 
determination, follow-up for the primary endpoint will be censored at the time of 
first exposure to brigatinib.
o
The protocol does not allow for brigatinib subjects to switch to crizotinib while on 
study, so any such event will be treated the same as the start of any other anti-
cancer therapy.
o
Anti-cancer therapies recorded during safety followup will be censored as of the 
date of contact at which the first occurrence of therapy is noted.

If a subject misses two consecutive disease assessments then follow-up for the primary 
endpoint will be censored at the time of the last non-progressive scan prior to the missed 
interval. Disease assessments are scheduled 56 days apart, so allowing a two-week 
window around two missed visits yields a period of 126 days.
o
Therefore any progression or death occurring more than 126 days after the last 
non-progressive disease assessment will not be included as a PFS event in the 
primary analysis, and follow-up will be censored on the date of the last valid 
assessment.
o
Death occurring within 126 days of the last valid non-progressive scan will be 
included as a PFS event on the date of death
o
Though this rule is implemented to ensure that PFS follow-up included in the 
analysis of the primary endpoint is conducted in a manner consistent with the 
design of the study as reflected in the Schedule of Events (Table 3 of the protocol)
adherence to the 126-day rule is not restricted to disease assessments performed at 
Day 1 of the odd cycles. Any unscheduled scan assessed by BIRC can contribute 
to PFS follow-up and restart the 126-day interval.

Censoring events must occur at least one day prior to the PFS event date as defined in 
Section 3.4.3.1. For example, a subject could commence a therapy consistent with the 
censoring rules on the same day as BIRC-confirmed PD. In such a case the latter event 
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will take precedence and the subject’s follow-up will not be censored in the primary
analysis.
3.4.3.3
PFS Events and Censoring Using On-Study Anticancer Treatments
As noted in the previous two sections, receipt of anticancer therapy other than randomized 
treatment can be treated as a PFS event (Section 3.4.3.1) or cause follow-up time in the analysis to
be censored (Section 3.4.3.2).
The process for selecting on-study therapies that will be treated as PFS or censoring events will 
start with a medical review of all therapies received by subjects on the study. A list of all the 
therapies will be compiled following DCO at each primary analysis. All occurrences of these 
therapies will be selected from the study data. An additional screen of concomitant medications 
will be used to identify antineoplastic agents. All therapies other than radiotherapy will be treated
as potential censoring events, and the earliest such therapy for each subject will be utilized in the
censoring algorithm. An example list of therapies to be treated strictly as potential censoring events
is included in Appendix 3.
Radiotherapy entries will be checked for whether they were targeted at the brain and/or central 
nervous system. If so, the event will be treated a potential PFS event and treated as being the 
same as BIRC PD in the determination of time to PFS. Otherwise the event will be treated as a 
potential censoring event in the same manner as all other on-study anticancer therapies. An 
example list of therapies to be treated as either potential PFS or censoring events is included in 
Appendix 4.
The final versions of the lists used for PFS events or censoring will be included as appendices in 
the CSR.
3.4.3.4
Calculation of Follow-up Time for the Primary Analysis of PFS
For subjects who were observed to have a PFS event follow-up time is defined as:
Follow-up = PFS date – randomization date +1 
which will be entered into the model as uncensored time. 
For other subjects follow-up time is defined as:
Follow-up = Censoring date – randomization date +1 
which will be entered into the model as censored time.
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Table 2
The Scheme of Progression and Censoring for the Analysis of PFS
#Rule
Situation
Date of progression or censoring
Outcome
1
Missing or incomplete baseline
Day 1 (randomization date)
Censored
2
No valid post-exposure assessment Day 1 (randomization date)
Censored
3
No measurable disease at baseline
Date of new lesion(s) or substantial worsening in Progressed
Date of last evaluable progression-free
Censored
4
a) Death, PD, or non-PD observed
> 126 days after
Date of last evaluable progression-free
radiographic assessment
Censored
b) Death or PD ≤126 days after
last valid RECIST
Earliest of date of death and date of 1st PD
Progressed
5
No progression or death
Date of last evaluable progression-free
Censored
6
Death before first PD assessment
or between
Date of death
Progressed
7
Death after one missed
Handled according to rule #4
8
Death after two or more missed
radiographic
Handled according to rule #4
9
New anticancer treatment started
prior to PFS event
Date of last evaluable progression-free
radiographic assessment prior to initiation
Censored
10. Cancer-related surgery prior to
documented disease
Date of last evaluable progression-free
radiographic assessment
Censored
11
Disease progression documented
between scheduled visits
Date of progression as reported by BIRC
Progressed
12. Disease progression preceded by 1
missed follow-up
Handled according to rule #4
13. Disease progression preceded
by 2 or more consecutive
Handled according to rule #4
Note:  Evaluable radiographic assessments used for censoring dates are restricted to BIRC
assessments and exclude those by iCNS BIRC and investigator.
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3.4.3.5
Evaluation of the Primary Efficacy Endpoint
The primary analysis of the primary endpoint will be performed using a 2-sided stratified log- rank
test (stratification factors: presence of iCNS metastases at baseline [Yes versus No], and prior
chemotherapy for locally advanced or metastatic disease [Yes versus No]) to compare the BIRC-
assessed PFS of subjects randomized to brigatinib with the BIRC-assessed PFS of subjects 
randomized to crizotinib. The overall (2-sided) Type I error rate will be controlled at 0.05. The 
primary analysis will be based on the ITT population. Median PFS and 95% confidence intervals 
will be estimated for each treatment arm using the Kaplan-Meier method (Kaplan and Meier, 1958).
Additionally, hazard ratios will be estimated using the Cox regression model with the stratification
factors as covariates (Cox, 1972). The analysis will use the current values of the stratification
factors.
3.4.3.6
Interim and Final Analyses of the Primary Endpoint
Two interim analyses are planned after approximately 50% and 75% of the total expected events 
(progression or death) have been observed. An O’Brien-Fleming Lan-DeMets alpha spending 
function (DeMets and Lan, 1994) will be used to control the overall alpha level at 0.05 2-sided.
The first interim analysis will be performed after the first 99 events have been observed. The
primary endpoint of PFS will be tested at a 2-sided alpha level of 0.0031. A second interim analysis 
will be performed after 149 events and the primary endpoint will be tested at a 2-sided alpha level
of 0.0183. The primary analysis of the primary endpoint will be performed after 198 events have
been observed or at End-of-Study, whichever comes first, and will be tested at a 2-sided alpha level
of 0.044. Analyses of OS will also be performed at the time of the interim analysis and at End-of-
Study, if the primary endpoint is met. If the efficacy boundary is surpassed at an interim analysis,
subjects will remain on assigned treatments unless a survival advantage is noted by the Data
Monitoring Committee.
The first occurrence of a successful evaluation of the primary endpoint, defined as surpassing the 
critical value at a pre-planned analysis, will complete the inferential statistical evaluation of the 
primary endpoint for this study. All subsequent analyses after the conclusion of the primary 
analysis will be non-inferential, even for analyses conducted as specified in the protocol for 
subsequent analyses of the primary endpoint. Interpretation of additional analyses of PFS assessed 
by BIRC, as well as secondary and exploratory endpoints, must be informed by the context that 
they are being performed for a study for which the primary endpoint has already been met.
It is possible that, when database extracts are created for a pre-specified evaluation of the primary
endpoint, there could be more PFS events than were specified in the protocol. If this happens the
following procedure will be used to determine the PFS events included in the analysis:
1) The eligible PFS events will be sorted in the order they occurred according to calendar 
date. PFS events will not be eligible in this context if they are preceded by censoring 
events such as disallowed anticancer therapy.
2) As stated in Section 3, a Data Cut Off (DCO) date will be prospectively set at the 
estimated time of the pre-specified event counts for the interim and final analyses.
3) All PFS events that occurred on or before that date will be included in the analysis
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4) Follow-up for all other subjects will be censored for PFS analyses at the time of the last 
BIRC evaluation prior to that date unless other censoring rules take precedence as 
described in step 1.
5) The number of PFS events in an evaluation of the primary endpoint could be different
from the number specified in the protocol. If this occurs it will be noted in the CSR.
If either the Cox model or log-rank test report convergence failures or unstable parameter estimates
the primary analysis will be repeat by dropping one of the stratification factors:

First the model will drop iCNS metastases at baseline.

If this does not produce a stable model then drop prior chemotherapy (while retaining 
baseline iCNS metastases from the initial model). If issues persist then drop both of the 
stratification parameters.

If the model still does not converge after dropping both stratification factors the Cox 
model estimates will be reported as NE.
3.4.3.7
Protocol-Specified Sensitivity Analyses of the Primary Endpoint
Protocol Section 15.5.2 states that the following sensitivity analyses will be performed. Sensitivity
analyses of the primary endpoint of PFS will also be performed in the following populations:

Per-protocol population, as assessed by the BIRC

FDA approved ALK test population, as assessed by the BIRC

ITT population (all subjects randomized to a treatment arm), as assessed by the 
investigator.
Subgroup analyses will be performed by baseline potential prognostic factors.
3.4.3.8
Additional Sensitivity Analyses of the Primary Endpoint
Sensitivity analyses will be performed to test the effects of specific aspects of the study design, 
conduct, and data handling on the robustness of the conclusions reached in the analysis of the 
primary endpoint. Two major sensitivity analyses are detailed in tables shown in Appendix 2.

Sensitivity Analysis 1 (Table A3-1) – Censor at date of last treatment administration if 
PFS event not observed prior to the End of Treatment Visit. Other censoring rules from 
the primary analysis of PFS remain in effect.

Sensitivity Analysis 2 (Table A3-2) – Do not censor PFS events for reasons of time lapse 
from last assessment (i.e., no 126-day rule) or usage of disallowed therapies.
Each sensitivity analysis is targeted at specific changes to the rules for the primary analysis, and any
rules not specified in the sensitivity analysis will remain as specified in the primary analysis. For
example, in Sensitivity Analysis 1 the date used for censoring will change but the censoring rules 
for disallowed therapies will remain in effect.
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Sensitivity subgroup analyses will be performed on the primary endpoint using all baseline factors
listed in Table 1 with the following considerations:

The primary efficacy models will be repeated for each level of the subgroup variable 
restricted to the subjects at the level being examined. For example, the sensitivity
subgroup analysis of gender will be run once restricted to female subjects and once 
restricted to males.

The model run will be with the same terms and specifications as the primary model to 
which it refers.
o
For example, the sensitivity subgroup analysis of gender would include the 
treatment group and stratification variables used in the primary analysis.
o
Each sensitivity subgroup model must have adequate data to support a valid 
statistical analysis. Cases where data are determined to be inadequate will be 
noted in the CSR. Such cases will include but may not be limited to the following:

Any level of the subgroup variable with fewer than 10 subjects in either of 
the treatment groups

When appropriate, as for time-to-event models, any level in which none of
the events in question were observed in either of the treatment groups

If the modeling procedure reports problems such as convergence failure or
generation of unstable parameter estimates
o
In cases where the definition of the subgroup being tested precludes specification 
of the model as used in the primary analysis the change to the model will be 
noted. For example, when running sensitivity subgroup models broken out by 
prior chemotherapy the stratification by prior chemotherapy cannot be included in 
the model.

In cases where use of the primary model specification results in conditions 
suggesting inadequate data, but where elimination of one or both of the
stratification variables addresses the data issue, then the simpler model
will be used. Any modifications to the primary model will be noted.

The main focus of sensitivity subgroup analyses will be the point estimates and 
confidence intervals of the main treatment effect between the levels of the subgroup 
variable.
o
In the primary analysis this would mean comparisons of median PFS time and 
hazard ratio between treatment groups within the levels of the subgroup variable.
o
Interpretation of the effect of the subgroup will not be based on a threshold of 
statistical significance, such as a p-value less than 0.05, but rather on 
interpretations of the estimates as compared to the primary models and to other 
level(s) of the subgroup variable. Particular attention will be paid to whether point 
estimates across levels of the subgroup variable are on the same side of the null 
value of the statistical model and whether there is substantial overlap between the 
corresponding confidence intervals.
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o
The effects of subgroups on the estimates of treatment effect will be examined 
graphically using Forest plots. Factors to be presented include current and as-
randomized values of the stratification factors as well as Age (18-49, 50-64, 65-
75, and ≥75), Race (Asian vs. non-Asian), Gender, Smoking Status (never, 
former, current, unknown), and ECOG Performance Status (0 vs. 1 or 2).
Summarization and reporting of the results of sensitivity analyses will be abbreviated as compared 
to that for the primary model unless important differences are noted.
3.5
Definitions and Analyses of Secondary Efficacy Endpoints
3.5.1
General Rules for Secondary Efficacy Endpoints
The rules outlined in this section apply to definition of response endpoints based on RECIST v1.1
evaluations performed by BIRC and the investigators as well as modified RECIST by the iCNS
BIRC.
Entry criteria required measurable disease, as evidenced by at least one target lesion, at baseline. 
This criterion, according to study conduct and randomization procedures, could only be applied to
investigator assessments, and it does not ensure that every subject would also be assessed as having 
measurable disease by the BIRC. It is also possible that after randomization all target lesions for a
subject could have been reclassified as non-target lesions in the investigator’s baseline assessment. 
Any subjects who are identified as having only non-measurable disease at baseline by one of these
assessment mechanisms (BIRC or investigator assessment) will not be eligible to be counted as 
responders (i.e. overall response of PR or CR) in analyses of results assessed by that mechanism,
unless their overall response is CR. This restriction will not be to analyses of iCNS BIRC
assessments when subjects with non-measurable iCNS disease are included. Two types of
sensitivity analyses of secondary endpoints will generally be performed:

Sensitivity analyses using investigator assessments will be performed on BIRC-assessed 
RECIST endpoints.

Analyses of all (confirmed + unconfirmed) responses will be performed as sensitivity 
analyses of confirmed responses will be performed unless the number of unconfirmed
responses is low.
Other sensitivity analyses, such as by subgroups or through modifications of model specifications,
may be performed but are not required by this plan.
3.5.1.1
Confirmation of Response
The primary analysis of any response endpoint for this study will be based on confirmed response,
as assessed by BIRC, unless otherwise specified. Confirmation requires that an initial response be
followed by observation of another response as good or better than the initial after a suitable
interval of time, which would entail one of the following pattern:
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• PR followed by PR or CR
• CR followed CR
Disease control rate (DCR) can be considered a special case of confirmed response. In this situation 
disease control is defined as at least one valid observation that the disease state on therapy has not 
progressed as compared to baseline. Therefore, DCR (or, confirmed SD) only requires one on-
study assessment, whereas confirmed ORR requires two. In subjects with measurable disease at
baseline DCR can be derived directly from best response meaning that any subject with a best 
response of CR, PR, or SD will be reported as having demonstrated DCR. For subjects without
measurable disease at baseline subjects with best responses of CR (in non-target lesions) or non-
CR/non-PD will also be reported as having demonstrated DCR. In iCNS analyses responses of CR
(in non-target lesions) or non-CR/non-PD are eligible to be reported as responses according to the
rules for response, best response, and ORR.
Censoring rules for PFS events will also apply to other RECIST-based endpoints. Time point 
responses following the first PD will be excluded, as will those observed after censoring events 
have occurred. Censoring rules based on observed RECIST assessments such as the exclusion of 
those observed after the first PD will restricted to those using the same assessment process. For 
example, BIRC assessments following the first BIRC-assessed PD will be excluded from 
consideration of confirmed response but will not be affected by iCNS BIRC or the investigator 
assessment. In addition, when a rule specifies use of the most recent valid scan date the set of dates 
to be used will be restricted to those of the same type (BIRC, iCNS BIRC, or investigator) as used
in the analysis.
In general the determination of Best Confirmed Response for each subject will be based on the 
BIRC response patterns for that subject. However, response patterns cannot be interpreted without 
incorporating the timing of the assessments that constitute that pattern. The handling of response
patterns will be described in this section, and the handling of timing will be specified in the next
section.
A strict interpretation of the RECIST v1.1 algorithm would require handling CR followed by PR or
SD as PD. If, following a time point response of CR, a reader enters any information indicating the
presence of disease into the BIRC system they will be presented with a default time point response 
of PD. The reader will, however, have the ability to override this default if so guided by their 
clinical judgment. However, for situation 1 above to be observed in the BIRC data both the initial
CR and the subsequent PR/SD would have to have agreement with the second reader or the
adjudicator, which is expected to be extremely rare if observed at all. If this situation occurs in the 
observed data its impact on analyses will be assessed and noted in the CSR, with sensitivity
analyses if warranted.
Another scenario that is reasonably likely to occur is PR followed by SD. This could occur if the 
sum of target lesions hovers around the 30% reduction threshold used in the definition of PR. 
Appendix III of the RECIST v1.1 guideline states a single SD can be observed in between the initial 
PR and its confirmatory assessment, but that more than one SD should cause confirmation of that
initial response to fail. Such an event will not, however, prevent subsequent PRs from being
confirmed.
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A single scan that cannot be interpreted, resulting in the occurrence of a time point response of NE,
that follows an initial response will not invalidate confirmation of that response. Therefore, the
following patterns of response will be considered as confirmed CR and confirmed PR, respectively:
• CR-NE-CR
• PR-NE-[PR or CR]
More than one NE such as CR-NE-NE-CR, however, will preclude the initial response from 
being confirmed.
Additional considerations in the handling of time point responses of SD and NE in the 
confirmation of response are:
• In the confirmation of PR responses of SD and NE will be treated as equivalent. 
Therefore the pattern of PR-SD-NE-PR would cause the first PR to be unconfirmed. 
However, the second PR in the series above can be confirmed if subsequent responses 
are consistent with that interpretation.
• SD and NE are not equivalent in the confirmation of CR
• NE cannot contribute to the determination of DCR but will also not, on its own,
invalidate observation of disease control on subsequent scans
• All assessments used for confirmation must meet the timing requirements described
below
Any time point response of PD precludes consideration of any subsequent responses for 
confirmation of initial response. Early Death (ED) will only be reported when death occurs with no
prior valid scan. The rules for handling confirmation of response are presented in Table 3:
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Table 3
Response Confirmation Patterns
Pattern
Confirmation of 
Initial Response?
Best 
Confirmed 
Response
Best 
Unconfirmed 
Response
1
CR-PD
N
SD
CR
2
PR-PD
N
SD
PR
3
SD-PD
N
SD
SD
4
NE-PD
N/A
PD
PD
5
PD
N/A
PD
PD
6
Early Death (ED)
N/A
ED
ED
7
CR-CR
Y
CR
CR
8
CR-NE-CR
Y
CR
CR
9
CR-SD-CR
N
SD
CR
10
CR-NE-NE-CR
N
SD
CR
11
PR-PR
Y
PR
PR
12
PR-CR
Y
PR
CR
13
PR-NE-PR
Y
PR
PR
14
PR-NE-CR
Y
PR
CR
15
PR-SD-PR
Y
PR
PR
16
PR-SD-CR
Y
PR
CR
17
PR-NE-NE-PR
N
SD
PR
18
PR-SD-SD-PR
N
SD
PR
19
PR-NE-SD-PR
N
SD
PR
20
PR-SD-NE-PR
N
SD
PR
21
PR-NE-NE-CR
N
SD
CR
22
PR-SD-SD-CR
N
SD
CR
23
PR-NE-SD-CR
N
SD
CR
24
PR-SD-NE-CR
N
SD
CR
Subjects with non-measurable disease at baseline will be reported as responders only if their 
overall response is CR. Otherwise, they will be reported as non-responders. Subjects with no 
evaluable scans will be reported as non-responders.
Per Section 13.2 of the protocol subjects receiving radiotherapy for iCNS metastases will be 
considered as having PD in the primary analysis at the time such therapy was initiated in the 
same manner as if a BIRC-assessed time point response of PD was observed at that point.
CCI
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f
of
of
s o
PD
m
ED
ED
Te
C
e T
bl
ca
ica
ca
ca
ca
SD
SD
pl
PR
PR
Ap
PR
P
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th
to
to
to
to
to
ct
Y
bje
N
Su
N
d
an
ly
On
On
On
On
On
e O
Us
l U
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3.5.1.2
Timing of Disease Assessments Used for Confirmation of Response
The following statements from the protocol inform how the timing of assessments will be handled:
1) The definition of Disease Control Rate (Protocol Section 15.5.1) requires that “in the case 
of SD, criteria for SD must have been met at least once after randomization at a minimum 
interval of 6 weeks”
2) Imaging for possible confirmation of response “should be performed at least 4 weeks 
after initial response” (Protocol Section 11.1, Item #20)
3) The scheduling of disease assessments includes a window of ± 3days (Protocol Section 
11.1, Item #20)
For DCR, six weeks would target the first eligible scan at Day 43 relative to randomization. 
Allowing a 3-day window around this target means that scans performed on or after Day 40 
relative to randomization are eligible for consideration in the establishment of disease control for a
subject. As described in the previous section the criteria for SD include unconfirmed PR and CR,
but at least one of these responses must be observed on or after Day 40 to qualify for a Best 
Confirmed Response of SD and also for DCR. If such early responses of CR, PR, or SD are 
followed by PD then the subject’s best confirmed response will be PD, otherwise it will be NE.
Early responses of CR and PR will be eligible to determine best unconfirmed response and will be
considered to be eligible for confirmation. For the purposes of response confirmation, a 
confirmation interval will be defined as:
Scan interval = scan date 2 – scan date 1 + 1
Therefore, for the purposes of response confirmation the confirmatory scan would be targeted for 
Day 29 relative to observation of initial response. Allowing for the 3-day window means that any 
scan on or before Day 25 relative to observation of initial response cannot be used for confirmation
of that response. However, to be consistent with the definition of DCR it will also be required that
the confirmatory scan meet the same rule as for determination of best confirmed response of SD. 
Therefore, a confirmatory scan must meet all of the following criteria:
1)
It must be part of a pattern leading to confirmed response in Table 3.
2)
The scan date must be after day 25 relative to the initial response date.
3)
The scan must also be on or after day 40 relative to randomization date.
In addition, using the logic specified in Section 3.4.3.2, any scan greater than 126 days after an 
initial response cannot be used for confirmation of that response. If a subject does not have at least 
one evaluable scan over any 126-day interval all scans after that interval will be excluded from the
determination of response.
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3.5.2
Key Secondary Efficacy Endpoints and Analyses
3.5.2.1
Rules Handling the Overall Type I Error Rate for Secondary Endpoints
Key secondary endpoints will be tested using a closed testing procedure to control the overall 
type I error rate at 0.05. Analysis of a key secondary endpoint will be considered significant if 
the test for that endpoint and comparisons of all other secondary endpoints with a smaller rank 
are significant at the two-sided 0.05 significance level.
Rank-ordering of key secondary endpoints:
1.
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2.
Confirmed intracranial ORR, as assessed by the BIRC
3.
Intracranial PFS, as assessed by the BIRC
4.
OS
The primary assessment of all these four endpoints above will be performed at the time when the 
assessment of the primary endpoint is completed, either when the efficacy boundary is surpassed 
on one of the interim analyses or at the time the primary analysis is done.
3.5.2.2
Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
Confirmed ORR, as assessed by the BIRC, will be performed in the ITT population. ORR will be 
calculated using the following formula:
ORR per BIRC = (#confirmed BIRC-based CR or PR) / (#Randomized subjects)*100%. 
Sensitivity analyses of this endpoint using different analysis populations (Section 3.2) will be
calculated in the same manner after first restricting subjects included in the denominator and 
eligible for inclusion in the numerator to those in the analysis population of interest.
Confirmed ORR will be analyzed with the Mantel-Haenszel test (using the stratification factors) 
on the ITT population to compare the proportion of subjects achieving objective response between 
the 2 treatment arms. The exact 2-sided 95% binomial confidence intervals will be calculated.
Sensitivity analyses to be performed on this endpoint will be:
1) ORR defined as all confirmed and unconfirmed responses as determined by BIRC
2) Confirmed ORR as determined by the investigator
3) ORR defined as all confirmed and unconfirmed responses as determined by the
investigator
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3.5.2.3
Confirmed intracranial ORR, as assessed by the BIRC
iCNS ORR will be calculated in the same manner as for RECIST v1.1 BIRC using confirmed 
time point responses from the iCNS BIRC. Confirmed iCNS ORR will be analyzed for the 
following subsets of subjects:
1) The measurable iCNS disease population
2) The non-measurable iCNS disease population
3) The all iCNS disease population
Each of these analyses will be accompanied by a sensitivity analysis restricted to the subset of 
subjects with active lesions at baseline. Responses of iCNS CR in subjects with non-measurable 
iCNS disease at baseline will be counted as time point responses in analyses of iCNS ORR as 
defined in Table 3.
Analysis will differ in that the iCNS ORR will be analyzed with the Mantel-Haenszel test using 
only the stratification factor of prior chemotherapy.
A sensitivity analysis of confirmed + unconfirmed iCNS ORR will be performed.
3.5.2.4
Intracranial PFS, as assessed by the BIRC
Intracranial PFS will be defined and analyzed in the same manner as for PFS used in the primary 
endpoint with the exceptions that the progression events used will come from the iCNS BIRC and 
the analysis will be restricted to subjects identified as having brain metastases at baseline in the
randomization.
The primary evaluation of iCNS PFS will be performed in the all iCNS disease population, with a
sensitivity analysis in the active iCNS disease population. Additional analyses will be performed in
the no iCNS disease population, in which case PFS events would consist of either the appearance
of new brain metastases or death. iCNS PFS will also be analyzed in the measurable iCNS disease
population with a sensitivity analysis in the active measurable iCNS disease population.
3.5.2.4.1
Data handling Rules Specific to Secondary Analysis of iCNS PFS
Conduct and analysis of iCNS response and progression will occur independently of systemic 
assessment of disease. If a subject progresses due to lesions outside the iCNS and continues on 
their randomized study treatment, the subject will continue to be evaluated as SD, PR, or CR in the
iCNS until disease progression in the iCNS or the subject discontinues randomized study 
treatment. Confirmation of CR or PR should be performed 4 weeks (allowing a minus 3-day 
window) or more after initial response.
The primary analysis of iCNS PFS will be based on radiographic assessments in the iCNS by the 
BIRC. The primary analysis will only include randomized subjects with active brain metastases at
baseline. In all the analyses, the progression and censoring scheme in Table 2, Section 3.5.2.4.1 will
be used except that the radiographic assessments are restricted to the disease in the CNS.
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Per Section 13.2 of the protocol subjects receiving radiotherapy for iCNS metastases will be 
considered as having PD in the analysis of iCNS PFS at the time such therapy was initiated.
3.5.2.5
OS
OS is defined as the time interval from the date of randomization until death due to any cause in 
the ITT population. OS will be censored on the date of last contact for subjects who are still alive.
Contact must provide positive evidence that the subject is alive at the time it is made. In the 
primary analysis of OS follow-up time will not be censored for initiation of non-study anticancer
therapies, including crossover from crizotinib to brigatinib.
The primary analysis of OS will be conducted using the same statistical methods as for the 
primary endpoint.
Follow-up time in the primary analysis of OS will not be censored for any other reason. Sensitivity
analyses using additional censoring rules such as initiation of disallowed anticancer therapies may
be performed (see below).
For subjects who have been randomized and are not treated, the OS will be defined as the time 
interval from randomization date to death date or date of the last contact if available.
A majority of subjects can be expected to take subsequent anticancer therapy following disease 
progression, including crossover from crizotinib to brigatinib as directed in the protocol. To adjust
for the effects of subsequent therapy, the following sensitivity analysis may be performed:
1) Primary analyses except additional censoring at the start day of subsequent anti-cancer
therapy
2) Rank preserving structural failure time (RPSFT) analysis
3) Inverse probability of censoring weighted (IPCW) analysis
3.5.3
Additional Secondary Endpoints
3.5.3.1
Duration of response, as assessed by the BIRC
The analysis of response duration will be based on disease assessment by the BIRC and use the 
progression and censoring scheme in Table 2, Section 3.5.2.4.1. The analysis of response duration
will only include ITT subjects with confirmed CR or PR. An additional analysis of duration of
response will be performed using disease assessment performed by the investigator. Censoring in
the analysis of duration of response will be the same as for PFS.

Duration of confirmed response = PFS event/censoring date – date of first response + 1 in 
subjects whose response was confirmed

Duration of response = PFS event/censoring date – date of first response + 1
Median values and 2-sided 95% confidence intervals will be estimated using Kaplan-Meier (KM)
method (Kaplan and Meier, 1958) in the ITT population. The KM-estimated PFS rates and OS rates at 
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12 and 24 months and the associated 2-sided 95% confidence intervals will be computed. Duration of
response will also be summarized with descriptive statistics for subjects with confirmed CR or PR and
the Kaplan-Meier method in which follow-up for subjects without PFS events will be censored.
Figures associated with this endpoint will use the same rules as described above.
3.5.3.2
Time to response, as assessed by the BIRC
Time to response as assessed by the BIRC will be summarized for confirmed responders using 
descriptive statistics. The primary analysis of time to response will use the same definition of 
confirmed response as used for ORR in Section 3.5.2.2. The time of response will be the date of the
initial response that was ultimately confirmed, and not the date at which the confirmatory response
was observed.
• Time to confirmed response = Date of initial response – date of randomization + 1.
3.5.3.3
Disease control rate, as assessed by the BIRC
Disease control rate will be assessed by the investigator and BIRC in the ITT population and the 
exact 2-sided 95% binomial confidence intervals will be calculated. The calculation formulas of the
disease control rate will be as follows: disease control rate per investigator = (#Investigator- based
confirmed CR or PR or SD) / (#Randomized subjects)*100%; disease control rate per BIRC = (# 
BIRC-based confirmed CR or PR or SD) / (#Randomized subjects)*100%.
Responses of CR and non-CR/non-PD in subjects with non-measurable disease will be eligible for
confirmation of DCR for BIRC, investigator, and iCNS BIRC assessments.
Disease control rate will be analyzed with the Mantel-Hanzel test (using the stratification factors) 
on the ITT population to compare the proportion of subjects achieving disease control.
3.5.3.4
Safety and tolerability
See Section 3.7 for descriptions of endpoints and analyses of safety information.
3.5.3.5
Subject-reported symptoms and HRQoL scores, assessed with the EORTC QLQ-C30 
(v3.0) and QLQ-LC13
The main subject-reported outcomes (PRO) endpoints of interest will be the Global Health 
Status/QoL Scale, based upon Question 29 and Question 30 of the QLQ-C30 (v3.0), and the 
Dyspnea Scale, based on the QLQ-LC13 Questions 3-5. The QLQ-C30 will be scored according to
the EORTC QLQ-C30 (V3) Scoring Manual (Fayers et al, 2001) including transformation of 
responses into scores for analysis and the handling of missing data. The EORTC QLQ-C30 (V3) 
Scoring Manual also includes instructions for scoring the QLQ-LC13. Analysis of the Global Health
Status/QoL Scale over time may be performed using mixed effects models that include randomized
treatment group and the stratification factors used in randomization.
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Improvement in global health status, defined as an improvement from baseline of 8.33 points or 
greater in the Global Health Status/QoL Scale, will be analyzed using the Mantel-Haenszel test as
performed for ORR. The primary evaluation of this response endpoint will be performed using the
Cycle 3, Day 1 assessment. The analysis may be repeated at other time points, and a time to
response model may also be performed.
Worsening on the Dyspnea Scale for a subject will be defined as a 50% decline from the baseline 
score. Time to worsening on the Dyspnea Scale will be analyzed using the same methods as for the 
primary analysis of PFS.
Analyses of QoL endpoints will include all subjects who have a baseline and at least one post-
baseline assessment. Time-to-event analyses of QoL will censor follow-up at the last evaluable 
QoL assessment for subjects for whom the event of interest is not observed.
3.6
Exploratory Analyses
3.6.1
Definitions of Protocol-Specified Exploratory Efficacy Endpoints
Exploratory Endpoints are specified in Section 9.1.3 of the protocol.
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CCI
CCI
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of Us
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3.7
Safety Analysis
Throughout the study, safety assessments will include physical and laboratory examinations, vital
signs, and electrocardiograms (ECGs) according to the Schedule of Events. Adverse events will be
assessed and categorized by the US National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) (see protocol Appendix A). Subjects will remain on treatment until
they meet one or more criteria for withdrawal. Subjects will be supplied with study treatment until 
they discontinue from the study.
All safety analyses will be performed using the treated population, which will include all subjects
who have received at least one dose of randomized study treatment.
Unless otherwise specified all safety analyses will be reported according to actual study treatment
received.
3.7.1
Adverse Events
All adverse events (AEs) starting/worsening on or after the first dose of study treatment and no later
than 30 days after the last dose date will be considered as treatment-emergent. Treatment- emergent 
AEs also include those with partially or completely missing start date since there is not enough 
evidence that the event started before the first dose of study treatment.
All AEs entered in the clinical database (including treatment-emergent and non-treatment- emergent 
AEs) will be listed in by-subject listings or available for review in appropriate datasets. The
incidence rates of treatment-emergent AEs, as well as the frequency of occurrence of overall toxicity
categorized by maximum toxicity grades (severity), will be described. In addition, treatment-
emergent AEs will be summarized by causal relationship to study treatment (in the opinion of the
investigator) and action taken on study treatment, including dose modifications, interruptions and 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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discontinuation. Serious treatment-emergent AEs (SAEs), both overall and by causal relationship to
study treatment, will also be summarized.
Incidence rate for treatment-emergent AEs and AE groups in special categories, e.g., pulmonary 
adverse events overall and within first 7 days, will be summarized and also be adjusted with 
subjects’ entire exposure to study treatment and exposure through the AE initial onset. AEs in 
special categories will also be summarized in terms of number of subjects with at least one event in 
the category and by number of subjects with at least one event for each constituent preferred term. 
The special categories to be analyzed will include at minimum those listed in Appendix 1, and will
align with the risk profile of brigatinib and crizotinib. All deaths occurring during a period of
exposure to randomized therapy or within a period of up to 30 days following discontinuation from
randomized therapy will be summarized by AEs leading to death and causal relationship to study
treatment. The 30-day rule will be superseded in cases of crossover from crizotinib to brigatinib
when done in compliance with the protocol, in which case all deaths on or after the first dose of
brigatinib and within a period of up to 30 days following discontinuation from brigatinib will be 
summarized in the crossover period. All deaths occurring later than 30 days but resulting from
treatment related adverse event(s) will be summarized by AEs leading to death and causal
relationship to study treatment.
3.7.1.1
Imputation Rule for Missing Causal Relationship of Treatment-Emergent Adverse 
Events
If adequate information regarding the investigator’s assessment of relationship to study 
treatment, the relationship to the study treatment will be imputed as possibly related to study 
drug for treatment-emergent AEs. This rule will be applied to events in both treatment arms.
3.7.1.2
Imputation Rules for Missing Onset Date and Resolution Date of Adverse Events
In general, the imputation will be conservative such that onset dates will be imputed to be as 
early as possible and resolution dates will be imputed to be as late as possible. Resolution date 
will be imputed first and then used to impute onset date.
Resolution Date
!
If day is missing but month and year are non-missing (YYYY-MM-UU), impute as the 
earliest of:
o
Last day of the month (28, 29, 30 or 31 depending on in which month the adverse 
event resolved)
o
Data cutoff date
o
Death date
CCI
Property of Takeda: For Non-Commercial Use 
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
If day and month are missing (YYYY-UU-UU), impute as the earliest of:
o
December 31 (YYYY-12-31)
o
Data cutoff date
o
Death date

If date is completely missing (i.e. AE is ongoing), impute as earliest of:
o
Data cutoff date
o
Treatment discontinuation date + 30 days
o
Death date
Onset Date

If day is missing but month and year are non-missing (YYYY-MM-UU), impute as 
follows:
o
If year and month are the same as year and month of first dose date:

If resolution date (or imputed resolution date) is on or after first dose date,
impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of:

First day of month

Informed consent date
o
If year is the same as year of first dose date and month is after month of first dose 
date, impute as first date of month
o
If year is the same as year of first dose date and month is before month of first 
dose date, impute as latest of:

First day of month

Informed consent date
o
If year is after year of first dose date, impute as first day of month
o
If year is before year of first dose date, impute as latest of:

First day of month

Informed consent date

If day and month are missing and year is non-missing (YYYY-UU-UU) or day and year 
are non-missing but month is missing (YYYY-UU-DD), impute as follows:
o
If year is the same as year of first dose date:

If resolution date (or imputed resolution date) is on or after first dose date,
impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of:
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
First day of month

Informed consent date
o
If year is after year of first dose date, impute as January 1 (YYYY-01-01)
o
If year is before year of first dose date, impute as latest of:

January 1 (YYYY-01-01)

Informed consent date

If date is completely missing:
o
If resolution date (or imputed resolution date) is on or after first dose date, impute 
as first dose date
o
If resolution date (or imputed resolution date) is prior to first dose date, impute as 
informed consent date.
3.7.1.3
Derivation of Treatment-Emergent Adverse Event Flag

Sites are instructed to “split” AEs that are ongoing as of first dose date into two records: 
one that ends as of first dose date and one that begins on first dose date. Therefore in 
some cases, what may at first appear as an AE that begins on first dose date is really a
continuation of an AE that began prior to first dose date. If all of the following criteria 
are true for any two AE records then the two records should be considered as one event:
o
The preferred term of the first AE = the preferred term of the second AE.
o
The start date of the first AE is before the date of first dose.
o
The end date of the first AE is one day before the date of first dose or equal to the 
date of first dose.
o
The start date of the second AE = the date of first dose.
o
The severity of the second AE ≤ the severity of the first AE. If collapsing AE for 
the purposes of reporting, use maximum severity.
o
The relatedness of both the first and the second AEs is “Not Related”.

After determining which records should be treated as a single event, the treatment-
emergent flag can be determined as follows:
o
All AEs with an onset date on or after the first dose date and no later than 30 days 
after the last dose date.

The 30-day rule will not always apply for subjects in crossover. In such 
cases any event with an onset date on or after the start of brigatinib
o
In the case of missing onset date, impute using the rules defined in Section 3.7.1.2
then determine if imputed date is on or after first dose date.
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3.7.1.4
Treatment-Related Adverse Event Flag
All AEs for which relationship to study treatment is classified as “Possibly Related”, “Probably 
Related”, or “Definitely Related” will be classified as treatment related.
If relationship to study treatment is missing, then the relationship will be imputed as treatment 
related.
3.7.1.5
Calculation Specifications for Treatment-Emergent Adverse Events
Time to onset is defined as the time interval from the first dose date until the onset date of a treatment-
emergent AE, or first occurrence of any event in a group of AEs. In case of a missing onset date, a
date imputed with the rules in Section 3.7.1.2 will be used. Time to onset will be computed with the
following formula: time to onset= AE onset date – first dose date + 1.
Time to initial onset of an individual treatment-emergent AE is defined as the time interval from 
the first dose date until the earliest onset date of the treatment-emergent AEs of the same nature. In 
case of a missing onset date, a date imputed with the rules in Section 3.7.1.2 will be used. Time to
initial onset will be computed with the following formula: time to initial onset = earliest AE onset 
date – first dose date + 1.
Duration of an adverse event, or group of AEs, is the sum of all days on or after randomization on 
which the event in question is reported. Each day will only be counted once in the case of 
overlapping intervals.
Age at onset will be computed by the following formula and rounding down to the nearest integer:
age at onset = floor ((AE start date – birth date + 1)/365.25).
Dose at onset will be defined as the dose received by subjects on AE onset date, regardless of 
treatment arm. Dose at onset will not be defined if the occurrence of a treatment-emergent AE is 
post treatment discontinuation.
Dose by onset will be defined as the last non-zero dose received by AE onset date.
3.7.1.6
Specifications for the Analyses Outputs
Adverse events will be coded with MedDRA dictionary. The version of the dictionary will be 
specified in the output listings or tables. Some preferred terms coding manifestations of similar 
medical conditions will be re-coded and re-grouped based on the synonym infrastructure determined
through sponsor medical review (An example of such an infrastructure is provided in Appendix 3).
In the summary tables, MedDRA preferred terms will be sorted in a descending order of incidence
rate first then alphabetically in case of tied incidence rates. In the tables of treatment emergent AEs 
grouped by MedDRA System Organ Class (SOC), SOCs will be put in the internationally agreed 
order.
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3.7.1.7
Special Categories of Adverse Events
In order to best characterize the safety experience of brigatinib and crizotinib in this study 
additional analyses will be performed in which preferred terms are grouped according to potential
safety signals of interest. These lists will be maintained by the ARIAD coding group in the Data
Management department and will be updated whenever MedDRA is updated.
The special category for pulmonary adverse events will include the preferred terms 
“PNEUMONITIS” and “INTERSTITIAL LUNG DISEASE”. Early Onset Pulmonary Events 
(EOPEs) are defined as treatment-emergent AEs with these preferred terms with onset within the first
14 days relative to first exposure to randomized treatment. Late onset pulmonary events occurring 15 
days or more after start of therapy will also be tabulated.
Some categories utilize Standardized MedDRA Queries (SMQs) to retrieve the conditions of 
interest, while others use Modified MedDRA Queries based on SMQs (MMQs) or Customized 
MedDRA Queries (CMQs). The current list of categories to be analyzed is provided in Appendix 1.
Each special category will consist of a list of Preferred Terms, and any such terms in the AE 
database will be included in the category. A single preferred term can be included in more than 
one special category.
3.7.2
Laboratory and Vital Signs Data
Laboratory and vital signs data in standard units will be summarized using summary statistics and 
graphically at baseline and at each cycle for which adequate data are available. Laboratory and 
blood pressures data will also be graded according to the NCI CTCAE, v.4.03 when applicable.
Change from baseline to the worst on-study result will be summarized using the changes from
baseline values in standard units. Change from baseline to the worst on-study result will also be 
summarized by shift in CTCAE grade for selected laboratories and blood pressures. Changes in
testosterone and insulin will be summarized by cross-tabulations of baseline (low, normal, high) 
and the highest/lowest value on study (low, normal, high).
Laboratory data received without reference ranges will have the values imputed using standard 
reference ranges (Kratz, et al, 2004). Results received as collected at the site will not include the 
imputed normal ranges. Standardized results, included on each observation of laboratory data, will
include the imputed ranges and will be used for all analyses unless stated otherwise.
Laboratory measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
Alkaline phosphate (ALP), and total bilirubin (TBL) will be evaluated for the potential risk of drug-
induced liver failure.
Possible Hy’s Law cases (Zimmerman 1999) are defined as subjects with ALT or AST > 3 × upper
limit of normal (ULN), with ALP < 2 × ULN and total bilirubin (TBL) ≥ 2 × ULN with no other
etiology to explain these liver-function test results. Changes in ALT, AST, ALP, and TBL over time 
will also be graphically displayed for possible Hy’s law subjects.
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3.7.3
QT interval corrected (Fridericia) (QTcF) Analysis
Descriptive statistics of maximum QTcF and change from baseline will be calculated following the 
ICH-E14 guidelines: the proportion of treated subjects with at least one on-drug QTcF value
> 450 ms, 480 ms, and 500 ms; proportion of treated subjects with a maximum change in QTcF
from baseline > 30 ms and > 60 ms. The mean change in QTcF from baseline to maximum on study
value will be calculated along with 95% confidence intervals.
3.7.4
Extent of Exposure
Exposure to brigatinib and crizotinib will be summarized using the following measures:

Time (days) on study treatment

Total cumulative dose of brigatinib or crizotinib administered

Dose intensity (mg/day)

Relative dose intensity (%)

Total person years

Dose interruption of at least 3 days
o
Number of subjects with at least one occurrence
o
Number of subjects who returned to dosing after interruption
o
Number of subjects who returned to target dose after interruption
o
Total duration (days) of time off study drug prior to treatment discontinuation

Dose reduction of at least 3 days
o
Number of subjects with at least one occurrence
o
Number of subjects who returned to dosing after interruption
o
Number of subjects who returned to target dose after interruption
o
Total duration (days) of time off study drug prior to treatment discontinuation
Time on treatment will be defined as the time interval from the first dose date to the last dosing 
date and computed with the following formula:
Time (days) on treatment= last non-zero dose date – first dose date + 1
Dose intensity will be calculated with the following formula: Dose intensity = Total cumulative 
dose/ Time (days) on study treatment. Relative dose intensity will be defined as the proportion of 
the planned dose received by subjects. In treatment Arm A the daily planned dose will be 90 mg in
the 7-day lead-in period and 180 mg from day 8 onward. In treatment Arm B the daily planned dose
will be crizotinib 250 mg twice daily (BID) orally.
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Relative dose intensity will be calculated as follows:
Relative dose intensity = Total cumulative dose administered /
Total dose planned x 100%.
Total person years for a treated subject will be calculated using the following formula: 
Total person years = Time (days) on study treatment / 365.25.
The total person years in an analysis population will be the sum of the total person years of all the
subjects in this population.
Dose modifications will be summarized by dose interruption and dose reduction. A subject will be
identified as having dose interruption if this subject had no exposure to study drug for at least 3
consecutive days. A subject will be identified as having dose reduction if this subject had a period
of reduced dosage of at least 3 consecutive days, as long as the dose received was less than the 
target dose but greater than 0 mg on some of the days in this period. Periods of time in which a
subject alternates between reduced dosing and dose interruptions will be handled in the following
manner:

The entire period of time between the last receipt of the target dose and either resumption 
at the target dose or discontinuation of treatment will be considered as a single dose 
reduction period.

Any period of 3 or more days with no receipt of study drug within that dose reduction 
period will also be treated as a dose interruption.
Study drug administration records that indicate that treatment was received on a given date but for
which a specific quantity of drug cannot be determined will be treated in the following manner:

The date will be treated as a day on which drug was taken for calculations such as total 
days exposed

It will be considered as a day of reduced dose in the dose modification analyses

No contribution will be made to the calculation of total cumulative dose administered or 
related analyses
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4
REFERENCES
Aaronson NK, Ahmedzai S, Bergman, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Cox, David R. Regression Models and Life-Tables. Journal of the Royal Statistical Society, Series 
B. 1972; 34 (2): 187–220.
DeMets DL, Lan KK. Interim analysis: The alpha spending function approach. Stat Med. 1994 Jul
15-30;13(13-14):1341-52.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eu J Cancer 2009;45:228-247.
Fayers PM, Aaronson NK, Bjordal K, et al. EORTC Scoring Manual. 3rd edition. Brussels: 
European Organisation for Research and Treatment of Cancer; 2001.
FDA Guidance: “Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer 
Drugs and Biologics Guidance for Industry” (April 2015)
ICH. Guidance for Industry: E9 Statistical Principles for Clinical Trials (September 1998) Kaplan
EL and Meier P. Nonparametric Estimation from Incomplete observations. J Am
Statistical Assoc. 1958;53:457-481.
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. N Engl J Med 
2004;351:1548-63.
NCI, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: June 14, 2010
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5
APPENDICES
Appendix 1
Adverse Events in Special Categories
Selection of AEs for special categories will be performed through the use of Standardised MedDRA Queries based 
on SMQs, Modified MedDRA Queries (MMQs), or Customized MedDRA Queries (CMQs). The adverse events in 
special categories will be listed and updated as new events occur and/or MedDRA versions change over the course 
of the study.
The following special categories of adverse events will be analyzed:

Early Onset Pulmonary Events (EOPEs) and Later Onset Pneumonitis Events

Bradycardia Events

Hypertension Events

Gastrointestinal (GI) Events

Pancreatic Events

Elevated Insulin/Hyperglycemia Events

Hepatic Events

Creatine Phosphokinase (CPK) Elevation

Anemia and Lymphopenia

Peripheral Neuropathy

Skin and Subcutaneous Events

Vision Impairment Events

QT Interval Prolongation
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Appendix 2
Details for Sensitivity Analyses of the Primary Endpoint
Table A3-1
Sensitivity 1 - Progression and Censoring for the Analysis of PFS
#Rule
Situation
Date of progression or censoring
Outcome
1.
Missing or incomplete baseline
tumor assessment
Day 1 (randomization date)
Censored
2.
No valid post-exposure assessment
Day 1 (randomization date)
Censored
3.
No measurable disease at baseline
Date of new lesion(s) or substantial
worsening in non-target disease
Date of last evaluable progression-free 
radiographic assessment
Progressed
Censored
4.
a) Death, PD, or non-PD observed > 
126 days after last valid RECIST
assessment
Date of last evaluable progression-free 
radiographic assessment prior to the 126-
day interval
Censored
b) Death or PD <= 126 days after last
valid RECIST assessment
Earliest of date of death and date of 1st PD
Progressed
5.
No progression or death
Date of last radiological assessment of
measured lesions
Censored
6.
Death before first PD assessment or
between evaluable assessment visits
Date of death
Progressed
7.
Death after one missed radiographic
assessment
Handled according to rule #4
8.
Death after two or more missed
radiographic assessments
Handled according to rule #4
9.
Treatment discontinuation prior to
documented disease progression or 
death – Added in this analysis
Date of last administration of randomized
study drug
Censored
10. New anticancer treatment started
prior to PFS event
Date of last dose of treatment to which
subject was randomized
Censored
11. Cancer-related surgery prior to
documented disease progression
Date of last evaluable progression-free
radiographic assessment prior to surgery
Censored
12. Disease progression documented
between scheduled visits
Date of progression as reported by BIRC
Progressed
13. Disease progression preceded by 1
missed follow-up disease assessment
Handled according to rule #4
14. Disease progression preceded by 2 or
more consecutive missed follow-up 
disease assessments
Handled according to rule #4
All censoring rules in the primary analysis other than the specific change above remain in effect as specified for that 
analysis.
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Table A3-2
Sensitivity 2 - Progression and Censoring for the Analysis of PFS
#Rule
Situation
Date of progression or censoring
Outcome
1.
Missing or incomplete baseline
tumor assessment
Day 1 (randomization date)
Censored
2.
No valid post-exposure assessment
Day 1 (randomization date)
Censored
3.
No measurable disease at baseline
Date of new lesion(s) or substantial
worsening in non-target disease
Date of last evaluable progression-free 
radiographic assessment
Progressed
Censored
4.
a) Death, PD, or non-PD observed >
126 days after last valid RECIST 
assessment - Modified
Earliest of date of death and date of 1st
PD
Progressed
b) Death or PD <= 126 days after last
valid RECIST assessment
Earliest of date of death and date of 1st
PD
Progressed
5.
No progression or death
Date of last radiological assessment of
measured lesions
Censored
6.
Death before first PD assessment or
between evaluable assessment visits
Date of death
Progressed
7.
Death after one missed radiographic
assessment
Handled according to rule #4
8.
Death after two or more missed
radiographic assessments
Handled according to rule #4
9.
New anticancer treatment started
prior to PFS event- Modified
Ignored – treat as censored or 
progressed as determined by rule #4
10. Cancer-related surgery prior to
documented disease progression-
Modified
Ignored – treat as censored or
progressed as determined by rule #4
11. Disease progression documented
between scheduled visits
Date of progression as reported by BIRC
Progressed
12. Disease progression preceded by 1
missed follow-up disease assessment
Handled according to rule #4
13. Disease progression preceded by 2 or
more consecutive missed follow-up 
disease assessments
Handled according to rule #4
The changes in rules 4, 9, and 10 are the only specific change in this algorithm. However, the change to rule 4 
carries over to the other bolded items in the table.
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Appendix 3
Anticancer Therapies Treated as Potential Censoring Events
Concomitant anticancer therapies will be identified by medical review, and a list of therapy terms
will be created to select all radiotherapy treatments.
The following are examples of therapies observed in brigatinib studies:
1.
"PLEURADESIS"
2.
"PLEURODESIS"
3.
"BIFRONTAL CRANIOTOMY FOR TUMOR AND ICH REMOVAL"
4.
"BIFRONTAL CRANIOTOMY FOR TUMOR AND ICH"
5.
"BRAIN SURGEY"
6.
"TALC PLEURODESIS"
7.
"RESECTION"
8.
"EXCISION OF LESION"
9.
"WEDGE RESECTION OF SEGMENT 9 AND 1 OF THE RIGHT LUNG"
Additional potential censoring events will be selected from concomitant medications records using
the following selection criterion:
From concomitant medications dataset, any medication with ATC level 2 classification of 
"Antineoplastic agents" (except the following treatment: "FLOUROURACIL 5% 
TOPICAL CREAM")
All the identified therapies will be treated as potential censoring events in the PFS event algorithm
and associated endpoints. Data from concomitant medications will be combined with other therapies
and the start date of the first such therapy for each subject will be identified as the potential
censoring event.
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Appendix 4
Radiotherapies Treated as Potential PFS or Censoring Events
Radiotherapies will be identified by medical review, and a list of therapy terms will be created to 
select all radiotherapy treatments.
The following are examples of radiotherapies observed in previous brigatinib studies:
10. "GAMMAKNIFE SURGERY"
11. "HOLOCRANEAL RADIOTHERAPY"
12. "IRRADIATION OF BRAIN METASTASIS SRS"
13. "IRRADIATION SRS"
14. "PALLIATIVE RADIOTHERAPY"
15. "RADIATION TREATMENT FOR LEFT SHOULDER BONE METASTASIS"
16. "RADIOTHERAPY"
17. "RADIOTHERAPY - CYBERKNIFE (21 GY DOSE)TO TREAT THE BRAIN METASTASIS"
18. "RADIOTHERAPY 10GY/1FRACTION"
19. "RADIOTHERAPY 30GY IN 10 FRACTIONS"
Determination of whether the identified therapies will be treated as PFS events or censoring events
will depend on whether the supporting data indicate that the treatment was directed at iCNS 
metastases. Therapies recorded as being directed at iCNS metastases will be treated as potential
PFS events in the primary analysis. Radiotherapies reported as being directed at the brain will be 
included in the iCNS category. All other tumor-directed radiotherapies will be treated as potential
censoring events.
It is possible that a subject could receive radiotherapy that is directed at both iCNS and another 
area of the body on the same day. In such an event the iCNS radiotherapy will take precedence 
and that date will be treated as a potential PFS event.
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