SINGLE-ARM STUDY TO EVALUATE THE SAFETY OF LORLATINIB IN ALK INHIBITOR-TREATED UNRESECTABLE ADVANCED AND/OR RECURRENT ALK-POSITIVE NON-SMALL CELL LUNG CANCER PARTICIPANTS IN INDIA
Phase: PHASE4
Conditions: Advanced Non-Small Cell Lung Cancer
Sponsor: Pfizer

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SINGLE-ARM STUDY TO EVALUATE THE SAFETY OF LORLATINIB IN ALK 
INHIBITOR-TREATED UNRESECTABLE ADVANCED AND/OR RECURRENT 
ALK-POSITIVE NON-SMALL CELL LUNG CANCER PARTICIPANTS IN INDIA
Protocol Number:
B7461030
Medicinal product:
Lorlatinib
United States (US) Investigational New 
Drug (IND) Number: 
N/A (Not Applicable)
European Clinical Trial Database 
(EudraCT) Number:
N/A (Not Applicable)
Universal Trial Number:
N/A (Not Applicable)
Phase:
4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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Document History
Document
Version Date
Summary of Changes
Original protocol
30 March 2020
Not Applicable (N/A)

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ABBREVIATION
Abbreviation
Definition
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AV
atrioventricular
bpm
beat per minute
BUN
blood urea nitrogen
CAP
chest abdomen pelvis
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
Clinical Study Agreement
CT
computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome
DCIS
ductal carcinoma in situ
DoR
duration of response
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic CRF
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
FDG
fluorodeoxyglucose
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HRT
hormonal replacement therapy
IC-DoR
intracranial duration of response
IC-ORR
intracranial objective response rate
ICH
International Council for Harmonisation
ILD
interstitial lung disease
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IVRS
interactive voice response system
IWRS
interactive web response system
LDL
low-density lipoprotein
LPFV
last participant last visit
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
N
number of participants
NCI
National Cancer Institute
NTI
narrow therapeutic index
NSCLC
non-small-cell lung cancer

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Abbreviation
Definition
ORR
objective response rate
P-gp
permeability glycoprotein
PASS
post-authorization safety study
PD
progressive disease
PET
positron emission tomography
PR
partial response
PS
performance status
PT
prothrombin time
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval calculated using Fridericia’s correction factor
PVC
premature ventricular complex
RECIST
Response Evaluation Criteria in Solid Tumor
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SRSD
Single Reference Safety Document
TEAE
treatment-emergent adverse event
TG
triglyceride
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
WBC
white blood cell
WOCBP
woman of childbearing potential

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PROTOCOL SUMMARY
Background
Lung cancers that harbor chromosomal rearrangements of anaplastic lymphoma kinase
(ALK) constitute about 3-5% of non-small-cell lung cancers (NSCLCs) and are highly 
responsive to small-molecule tyrosine kinase inhibitors (TKIs) that target ALK.  Standard 
treatment of patients with advanced ALK-positive NSCLC has recently shifted from 
sequential crizotinib followed by more potent second-generation ALK TKIs to front-line 
second-generation TKIs.  Whereas most patients derive clinical benefit from 
second-generation ALK TKIs, acquired resistance invariably develops and leads to clinical 
relapse.1
Lorlatinib is a third-generation, oral, reversible, adenosine triphosphate (ATP)-competitive, 
macrocyclic TKI of ALK and ROS1.  Compared with second-generation inhibitors, lorlatinib 
was specifically designed to penetrate the central nervous system (CNS) and to overcome 
known secondary resistance mutations in the ALK tyrosine kinase domain.  Preclinical 
studies demonstrate that lorlatinib is more potent than earlier-generation TKIs against 
nonmutant ALK and retains potency against most known single ALK resistance mutations, 
including the highly refractory ALK G1202R solvent front mutation.2  
In the pivotal single arm, multicenter Phase 2 study, treatment with lorlatinib showed 
clinically relevant response rates and durable response in patients with ALK-positive NSCLC 
who had previously received at least 1 ALK TKI, including the second-generation drugs 
ceritinib and alectinib.1  In the cohort of patients previously treated with a second-generation 
ALK TKI (number of patients [N]=28), objective responses were observed in 9 patients (32% 
[95% confidence interval [CI]: 15.9-52.4]). Substantial intracranial activity was also 
observed in these patients suffering from frequent brain metastases. The proportion of 
patients with objective intracranial response to lorlatinib was 55.6% (95% CI: 21.2-86.3) in 
patients with at least 1 measurable brain lesion at baseline (N=9). The overall and
intracranial median duration of response (DoR) were not reached (95% CI: 4.1 months – not
reached; duration of follow-up 7 months).  
Rationale
On the basis of pivotal Phase 1/2 Study B7461001, lorlatinib received conditional marketing 
authorization by the Indian Ministry of Health for the treatment of ALK fusion gene-positive 
unresectable advanced and/or recurrent NSCLC with resistance or intolerance to ALK 
TKI(s).  
In view of the lack of Indian participants from Study B7461001 and of the limited number 
from the ongoing Phase 3 Study B7461006 (CROWN), the Indian Ministry of Health 
requested the Sponsor to conduct a post-approval study to obtain additional data on 
participants in India.  The study will be conducted as a post-authorization safety study 
(PASS).  

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Study Objectives and Endpoints
Primary Objective

To evaluate the safety and tolerability of single-agent lorlatinib in participants with 
unresectable advanced and/or recurrent ALK-positive NSCLC with resistance or
intolerance to at least 1 prior ALK inhibitor treatment.  
Secondary Objective

To evaluate overall and intracranial antitumor activity of single-agent lorlatinib in 
participants with unresectable advanced and/or recurrent ALK-positive NSCLC with 
resistance or intolerance to at least 1 prior ALK inhibitor treatment.  
Primary Endpoint

Incidence of adverse events (AEs).  
Secondary Endpoints

Confirmed objective response rate (ORR), confirmed intracranial objective response 
rate (IC-ORR), DoR and intracranial duration of response (IC-DoR) as assessed by 
the Investigator using Response Evaluation Criteria in Solid Tumor (RECIST) 
version 1.1.  
Study Design
This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to 
evaluate the safety and tolerability of lorlatinib in adult participants with unresectable 
advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 
1 prior ALK inhibitor treatment.
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  
Study Treatments
Participants will take lorlatinib at the approved dose of 100 mg once daily (QD).  Participants
will be treated until disease progression, participant refusal/lost to follow-up, or unacceptable 
toxicity. 
At the end of study, participants who are on treatment and benefiting from lorlatinib 
treatment will be moved to commercially available lorlatinib (if considered appropriate by 
the Investigator) as soon as feasible.  

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Statistical Methods
The study’s objectives are to evaluate the safety, tolerability and antitumor activity of 
single-agent lorlatinib.  This study will enroll enough participants to ensure that 
100 participants are treated with lorlatinib.  With 100 participants, any AE rate can be 
estimated with the maximum standard error of 0.05.  All participants who receive at least 
1 dose of lorlatinib will be included in the safety and antitumor activity analyses, unless 
otherwise specified.
Analysis of Primary Endpoint
AEs will be graded by the Investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE
summaries will be on treatment-emergent adverse events (TEAEs), those with an initial onset 
or increasing in severity after the first dose of study medication to at most 35 days post last 
dosing date or the date of initiation of a new anticancer therapy.  The number and percentage 
of participants who experienced any AE, serious adverse event (SAE), treatment-related AE, 
and treatment-related SAE will be summarized.  
Additional Safety Analyses
Other safety parameters, including study treatment exposure, laboratory, electrocardiogram 
(ECG), vital signs measurements, dose reductions due to AEs, and temporary and permanent 
discontinuations due to AEs, will be summarized descriptively.  
Analysis of Secondary Endpoints
The following analyses of response will be performed according to the Investigator 
assessment using RECIST version 1.1. 
ORR
ORR is defined as the percent of participants with best overall response as confirmed 
complete response (CR) or confirmed partial response (PR) according to RECIST 
version 1.1.  ORR will be provided along with the corresponding 95% CI based on Wilson’s 
Score Method.  
IC-ORR
IC-ORR is defined as the percent of participants with intracranial response (ie, best overall 
intracranial response as confirmed CR or confirmed PR considering only intracranial lesions) 
relative to participants with CNS metastases at study entry.  IC-ORR will be provided along 
with the corresponding 95% CI based on Wilson’s Score Method.  

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DoR
DoR is defined as the time from the first documentation of objective tumor response 
(confirmed CR or confirmed PR) to the first documentation of disease progression or death 
due to any cause, whichever occurs first.  For participants whose responses proceed from PR 
to CR, the onset of PR is taken as the onset of response.  DoR will be summarized in the 
population of participants with a confirmed CR or confirmed PR using the Kaplan Meier 
method and will be displayed graphically where appropriate.  The median event time (if 
appropriate) and 2-sided 95% CI for the median will be provided.  Censoring for DoR will be 
described in the statistical analysis plan (SAP).  In case the number of participants with 
progressive disease (PD) after a confirmed CR or confirmed PR is small, the use of Kaplan 
Meier method may be limited and descriptive statistics may be provided.
IC-DoR
IC-DoR is defined as the time from the first documentation of an intracranial objective 
response in the subgroup of participants with brain metastasis at baseline.  Analyses similar 
to DoR will be repeated for IC-DoR considering participants with intracranial response (ie, 
best overall intracranial response as confirmed CR or confirmed PR considering only 
intracranial lesions).  
End of Study
The end of study is defined as 1 year after the “last participant first visit” (LPFV) date in the 
study.

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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed
information on each procedure and assessment required for compliance with the protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed on the 
Schedule of Activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the participant.  
Visit Identifier
Screening
Cycle 1
(28 days)
Visit on Day 1 of Every Cycle
End of 
Treatment
Follow-Up8
Visit Window
≤28 days
Day 1
±2 days
±7 days
Informed consent1
X
Tumor history
X
Medical history
X
Physical examination and 
vital signs
X
X
X
X
Body weight
X
X
X
ECOG performance status
X
X
X
X
Contraception check2 (as 
appropriate)
X
X
X
X
Laboratory
Hematology
X
(X)
X
X
Blood chemistry
X
(X)
X
X
Lipids
X
(X)
X
X
Pregnancy test3
X
X
X 
X
X
Cardiac Monitoring
12-Lead ECG4
X
(X)
X (every cycle up to Cycle 5)
X
Treatment
Lorlatinib
Orally once daily, continuously
Tumor Assessments
CT or MRI imaging5
X
X (every 12 weeks ±1 week)
X
Other Clinical Assessments
Serious and non-serious 
AEs6
X
X
X
X
X
Concomitant 
medications and
non-drug supportive 
interventions7
X
X
X
X
X
(X): No need to repeat if assessment performed within 7 days prior to Cycle 1 Day 1.
Abbreviations: AE=adverse event; CAP=chest abdomen pelvis; CRF=case report form; CT=computed 
tomography; CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; MRI=magnetic resonance imaging; NCI=National Cancer 
Institute; QTc=QT interval corrected for heart rate; RECIST=Response Evaluation Criteria in Solid Tumor;
SAE=serious adverse event.  
1.
Informed consent must be obtained prior to undergoing any study-specific procedures that are not 
considered standard of care.
2.
Contraceptive check: participant may be contacted by phone to confirm contraception is still appropriate 
per the protocol.

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3.
Pregnancy test: for female participants of childbearing potential, a serum or urine pregnancy test will be 
performed at Screening and at the Cycle 1 Day 1 visit.  Results must be available before investigational 
product administration.  Pregnancy tests will be also routinely repeated at every cycle during the active 
treatment period, at the end of treatment, at the short-term follow-up visit, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
4.
12-lead ECGs: 3 consecutive 12-lead ECGs pre-dose will be performed approximately 2 minutes apart to 
determine mean PR interval and QTc interval at baseline (screening and Cycle 1 Day 1 if the ECG at 
screening is performed more than 7 days before Cycle 1 Day 1) and single ECGs will be performed at Day 
1 of every cycle up to Cycle 5 and at the end of treatment.  Additional ECGs may be collected as clinically 
indicated.
5.
Tumor assessment: tumor assessments will include all known or suspected disease sites.  CT or MRI scans 
of CAP and MRI of the brain will be performed at Screening and repeated every 12 weeks (±1 week).  For 
all tumor assessments, the method of assessment that was used at Screening should be the same method 
used throughout the study. Responses will be confirmed ≥4 weeks after first occurrence of response, 
according to RECIST version 1.1 criteria.  Tumor assessment should be repeated at the end of treatment if 
more than 6 weeks have passed since the last evaluation.  
6.
AE assessments: AEs should be documented and recorded into the electronic CRF at each visit using NCI 
CTCAE version 4.03.  For AEs and SAEs, the active collection period to Pfizer or its designated 
representative begins from the time that the participant provides informed consent, through and including at 
least 28 calendar days and no more than 35 days after the last administration of the investigational product.  
If a participant begins a new anticancer therapy, the reporting period for non-serious AEs ends at the time 
the new treatment is started.  SAEs and Death must be reported if it occurs during the SAE reporting period 
after the last dose of investigational product, irrespective of any intervening treatment.  
7.
Concomitant medications and non-drug supportive interventions: all concomitant medications and 
non-drug supportive interventions should be recorded in the CRF from 28 days prior to start of study 
treatment and up to at least 28 days and no more than 35 days after the last dose of study treatment.
8.
Follow-up: at least 28 days, and no more than 35 days after discontinuation of treatment, participants will 
return to undergo contraception check, pregnancy test, review of concomitant medications, AE 
assessments, and review for resolution of any treatment-related toxicity.

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TABLE OF CONTENTS
ABBREVIATION......................................................................................................................3
LIST OF TABLES...................................................................................................................13
APPENDICES .........................................................................................................................14
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................16
3. STUDY DESIGN.................................................................................................................16
4. PARTICIPANT SELECTION.............................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................18
4.3. Life Style Guidelines...............................................................................................20
5. STUDY INTERVENTION..................................................................................................20
5.1. Allocation to Intervention/Treatment......................................................................21
5.2. Drug Supplies..........................................................................................................21
5.2.1. Dosage Form(s) and Packaging..................................................................21
5.3. Administration.........................................................................................................21
5.4. Drug Storage ...........................................................................................................22
5.5. Drug Accountability................................................................................................23
5.6. Concomitant Treatments .........................................................................................23
5.6.1. Prohibited Concomitant Treatments...........................................................24
5.6.2. Permitted Concomitant Treatments............................................................26
6. STUDY PROCEDURES .....................................................................................................27
6.1. Screening.................................................................................................................27
6.2. Study Period ............................................................................................................27
6.3. Follow-up Visit .......................................................................................................27
6.4. Participant Withdrawal............................................................................................27
7. ASSESSMENTS..................................................................................................................28
7.1. Antitumor Activity Assessments.............................................................................28
7.2. Safety Assessments .................................................................................................28
7.2.1. Physical Examination .................................................................................29

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7.2.2. Electrocardiogram.......................................................................................29
7.2.3. ECOG Performance Status .........................................................................29
7.2.4. Clinical Safety Laboratory Assessments ....................................................29
7.2.5. Pregnancy Testing ......................................................................................29
8. ADVERSE EVENT REPORTING......................................................................................30
8.1. Adverse Events........................................................................................................30
8.2. Reporting Period .....................................................................................................30
8.3. Definition of An Adverse Event..............................................................................31
8.4. Medication Errors....................................................................................................32
8.4.1. Treatment of Overdose ...............................................................................32
8.5. Abnormal Test Findings..........................................................................................32
8.6. Serious Adverse Event ............................................................................................33
8.6.1. Protocol-Specified Serious Adverse Events...............................................34
8.6.2. Potential Case of Drug-Induced Liver Injury.............................................34
8.7. Hospitalization ........................................................................................................35
8.8. Severity Assessment................................................................................................36
8.9. Causality Assessment..............................................................................................36
8.10. Exposure During Pregnancy..................................................................................37
8.11. Withdrawal Due to Adverse Events (See Also Section on participant 
Withdrawal)...............................................................................................................38
8.12. Eliciting Adverse Event Information ....................................................................38
8.13. Reporting Requirements........................................................................................38
8.13.1. Serious Adverse Event Reporting Requirements .....................................38
8.13.2. Non-serious Adverse Event Reporting Requirements..............................39
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................39
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................39
9.1. Estimands and Statistical Hypotheses.....................................................................39
9.1.1. Estimands....................................................................................................39
9.2. Sample Size Determination.....................................................................................40
9.3. Data Sources............................................................................................................40
9.4. Antitumor Activity Analysis ...................................................................................40
9.4.1. Analysis of Primary Endpoint ....................................................................40

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9.4.2. Analysis of Secondary Endpoints...............................................................40
9.5. Analysis of Other Endpoints ...................................................................................41
9.6. Safety Analysis........................................................................................................41
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................42
11. DATA HANDLING AND RECORD KEEPING .............................................................43
11.1. Case Report Forms/Electronic Data Record .........................................................43
11.2. Record Retention...................................................................................................43
12. ETHICS..............................................................................................................................44
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................44
12.2. Ethical Conduct of the Study ................................................................................44
12.3. Participant Information and Consent.....................................................................44
12.4. Participant Recruitment.........................................................................................45
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH
GCP ...........................................................................................................................46
13. DEFINITION OF END OF STUDY.................................................................................46
13.1. End of Study in Participating Country..................................................................46
14. SPONSOR DISCONTINUATION CRITERIA ................................................................46
15. PUBLICATION OF STUDY RESULTS..........................................................................46
15.1. Communication of Results by Pfizer ....................................................................46
15.2. Publications by Investigators ................................................................................46
16. REFERENCES ..................................................................................................................48
LIST OF TABLES
Table 1.
Study Intervention(s) Administered .....................................................................20
Table 2.
Dose Modification Recommendation for Adverse Reactions of Lorlatinib.........22
Table 3.
Pharmacokinetic Properties of Statins..................................................................52
Table 4.
Pharmacokinetic properties of Lipid Lowering Agents........................................53
Table 5.
Response Evaluation Criteria in Solid Tumors ....................................................58
Table 6
Protocol Required Safety Laboratory Assessments..............................................63

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APPENDICES
Appendix 1. Contraceptive Guidance......................................................................................49
Appendix 2. Pharmacokinetic Properties of Statins and Lipid Lowering Agents...................51
Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria7.............................................54
Appendix 4. ECG Findings of Potential Clinical Concern......................................................60
Appendix 5. ECOG Classification of Performance Status ......................................................62
Appendix 6. Clinical Laboratory Tests....................................................................................63

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Lorlatinib is a third-generation, oral, reversible, ATP-competitive, macrocyclic TKI of ALK 
and ROS1.  Compared with second-generation inhibitors, lorlatinib was specifically designed
to penetrate the CNS and to overcome known secondary resistance mutations in the ALK 
tyrosine kinase domain.  
1.2. Background and Rationale
Lung cancers that harbor chromosomal rearrangements of ALK constitute about 3-5% of 
NSCLCs and are highly responsive to small-molecule TKIs that target ALK.  Standard
treatment of patients with advanced ALK-positive NSCLC has recently shifted from 
sequential crizotinib followed by more potent second-generation ALK TKIs to front-line 
second-generation TKIs.  Whereas most patients derive clinical benefit from 
second-generation ALK TKIs, acquired resistance invariably develops and leads to clinical 
relapse.1
Preclinical studies demonstrate that lorlatinib is more potent than earlier-generation TKIs 
against nonmutant ALK and retains potency against most known single ALK resistance 
mutations, including the highly refractory ALK G1202R solvent front mutation.2
In the pivotal single arm, multicenter Phase 2 study, treatment with lorlatinib showed 
clinically relevant response rates and durable response in patients with ALK-positive NSCLC 
who had previously received at least 1 ALK TKI, including the second-generation drugs 
ceritinib and alectinib.1  In the cohort of patients previously treated with a second-generation 
ALK TKI (N=28), objective responses were observed in 9 patients (32%, 95% CI:
15.9-52.4). Substantial intracranial activity was also observed in these patients suffering 
from frequent brain metastases.  The proportion of patients with objective intracranial 
response to lorlatinib was 55.6% (95% CI: 21.2-86.3) in patients with at least 1 measurable 
brain lesion at baseline (N=9).  The overall and intracranial median DoR were not reached 
(95% CI: 4.1 months - not reached; duration of follow-up 7 months).  
On the basis of pivotal Phase 1/2 Study B7461001, lorlatinib received conditional marketing 
authorization by the Indian Ministry of Health for the treatment of ALK fusion gene-positive 
unresectable advanced and/or recurrent NSCLC with resistance or intolerance to ALK 
TKI(s).  
In view of the lack of participants in India from the Study B7461001 and of the limited 
number from the ongoing Phase 3 Study B7461006 (CROWN), the Indian Ministry of Health
requested the Sponsor to conduct a post-approval study to obtain additional data on 
participants in India.  The study will be conducted as a PASS.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Indian product label. 

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2. STUDY OBJECTIVES AND ENDPOINTS
Objective
Estimands
Endpoints
Primary

To evaluate the safety and 
tolerability of single-agent 
lorlatinib in participants with 
unresectable advanced and/or
recurrent ALK-positive 
NSCLC with resistance or 
intolerance to at least 1 prior 
ALK inhibitor treatment.  

The primary estimand is the 
incidence of AEs from the
time of first dose to at most
35 days post last dosing date 
or the date of initiation of a 
new anticancer therapy for all 
participants who receive at 
least 1 dose of lorlatinib, 
regardless of dosing 
interruptions or dosing 
compliance.

Incidence of AEs.  
Secondary

To evaluate overall and 
intracranial antitumor activity 
of single-agent lorlatinib in 
participants with unresectable 
advanced and/or recurrent 
ALK-positive NSCLC with 
resistance or intolerance to at 
least 1 prior ALK inhibitor 
treatment.  

The secondary estimand is the
treatment effect of lorlatinib 
as assessed by the investigator 
from time of first dose (ORR 
and IC-ORR) or time of first
response (DoR and IC-DoR) 
until progression is met, death 
or subsequent anticancer 
therapy is administered for all 
participants who receive at 
least 1 dose of lorlatinib 
without regard to tolerability 
or discontinuation from 
treatment.  

Confirmed ORR, confirmed 
IC-ORR, DoR and IC-DoR 
as assessed by the 
Investigator using RECIST 
version 1.1.  
3. STUDY DESIGN
This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to 
evaluate the safety and tolerability of lorlatinib in adult participants with unresectable 
advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 
1 prior ALK inhibitor treatment.
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  
4. PARTICIPANT SELECTION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom the protocol
intervention is considered appropriate by their health care provider.
4.1. Inclusion Criteria
Participant eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before participants are included in the study.

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Participants must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Evidence of histologically or cytologically confirmed diagnosis of unresectable 
advanced and/or recurrent NSCLC that carries an ALK rearrangement, as detected by 
an appropriate test.
2. Disease progression or intolerance to 1 previous treatment with ALK TKI.  
participants may have also had prior chemotherapy for their advanced and/or 
recurrent disease.
3. Participants with asymptomatic CNS metastases (including participants controlled 
with stable or decreasing steroid use within the last 2 weeks prior to study enrollment) 
will be eligible.  
4. Age ≥18 years. 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2.  
6. Adequate hematologic and renal function as defined as:
a.
Absolute neutrophil count (ANC) ≥1,000/mm3;
b. Platelets ≥50,000/mm3;
c.
Hemoglobin ≥8 g/dL;
d. Estimated creatinine clearance ≥30 mL/min as calculated using the method 
standard for the institution.
7. Adequate liver function, including:
a.
Total serum bilirubin ≤1.5 × upper limit of normal (ULN); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN (≤5.0 × ULN in case of liver metastases).
8. Adequate pancreatic function, including:
a.
Serum total amylase ≤1.5 × ULN.*
b. Serum lipase <1.5 × ULN.
*if total amylase >1.5 × ULN, but pancreatic amylase is within the ULN, the 
participant may be enrolled.

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9. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade 
<1 except for AEs that in the Investigator’s judgment do not constitute a safety risk 
for the participant.  
10. Systemic anticancer therapy completed within a minimum of 5 half-lives of study 
enrollment (unless clinically meaningful tumor flare per discretion of the Investigator, 
in which discussion with the Sponsor is warranted). 
11. Evidence of a personally signed and dated informed consent document indicating that 
the participant (or a legally acceptable representative) has been informed of all 
pertinent aspects of the study.  
12. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures.
13. Pregnancy test for females of childbearing potential negative at Screening or female 
participants who are not of childbearing potential (refer to Appendix 1 for definition).  
Male and female participants of childbearing potential and at risk for pregnancy must 
agree to use a highly effective method of contraception from the time of Screening, 
throughout the study and for 3 months after the last dose of assigned treatment, 
6 months if female participants. 
4.2. Exclusion Criteria
Participants presenting with any of the following will not be included in the study:
1. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study 
enrollment. Palliative radiation (<10 fractions) must have been completed at least 
48 hours prior to study enrollment.  Stereotactic or small field brain irradiation must 
have completed at least 2 weeks prior to study enrollment.  Whole brain radiation 
must have completed at least 4 weeks prior to study enrollment.  Prior irradiation to 
>25% of the bone marrow.
2. Major surgery within 4 weeks prior to enrollment.  Minor surgical procedures (eg, 
port insertion) are not excluded, but sufficient time should have passed for adequate 
wound healing.
3. Known prior or suspected severe hypersensitivity to study drug or any component in
its formulation.
4. Active and clinically significant bacterial, fungal, or viral infection. 
5. Clinically significant vascular (both arterial and venous) and non-vascular cardiac 
conditions (active or within 3 months prior to enrollment), which may include, but are 
not limited to:
a.
Arterial disease such as cerebral vascular accident/stroke (including transient 
ischemic attack [TIA]), myocardial infarction, unstable angina;

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b. Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary 
embolism;
c.
Non-vascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥II), second degree or third degree 
atrioventricular (AV) block (unless paced) or any AV block with PR interval 
>220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, 
uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 beats per 
minute (bpm) (unless participant is otherwise healthy such as long distance 
runners, etc.), machine read ECG with QT interval corrected for heart rate (QTc) 
>470 msec, or congenital long QT syndrome.
6. History or known presence of interstitial fibrosis, interstitial lung disease (ILD), 
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative 
bronchiolitis, and pulmonary fibrosis.
7. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the participant 
inappropriate for enrollment in this study.
8. Evidence of active malignancy (other than current NSCLC, non-melanoma skin 
cancer, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ 
[DCIS] of the breast or localized and presumed cured prostate cancer) within the last 
3 years prior to enrollment.
9. Concurrent use of any of the following food or drugs (consult the Sponsor if in doubt 
whether a food or a drug falls into any of the categories described below) within 
12 days prior to the first dose of lorlatinib:
a.
Known strong cytochrome (CYP)3A inducers (eg, carbamazepine, enzalutamide, 
mitotane, rifampin, St. John’s Wort).  
b. Known strong CYP3A inhibitors (eg, grapefruit juice or grapefruit/grapefruit 
related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat,
clarithromycin, conivaptan, diltiazem, idelalisib, indinavir, itraconazole, 
ketoconazole, lopinavir, nelfinavir, paritaprevir, posaconazole, ritonavir alone and 
with elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or 
dasabuvir or saquinavir or tipranavir, telaprevir and voriconazole).  The topical 
use of these medications (if applicable), such as 2% ketoconazole cream, is 
allowed.  
c.
Known CYP3A substrates with narrow therapeutic index, such as pimozide, 
quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including 
transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine).  

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d. Known permeability glycoprotein (P-gp) substrates with a narrow therapeutic 
index (eg, digoxin).  
10. Participants who are investigational site staff members directly involved in the 
conduct of the study and their family members, site staff members otherwise 
supervised by the Investigator, or participants who are Pfizer employees directly
involved in the conduct of the study. 
11. Participation in other studies involving investigational drug(s) (Phases 1-4) during 
study participation. 
12. Breastfeeding female participants.  
4.3. Life Style Guidelines
See Appendix 1 for mandatory contraception information.  
Refrain from consumption of grapefruit/grapefruit related citrus fruits (eg, Seville oranges
pomelos) from 1 day before the start of study intervention until after the final dose.   
Lorlatinib has moderate influence on the ability to drive and use machines.  Caution should 
be exercised when driving or operating machinery as participants may experience CNS 
effects.
5. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.  
Table 1.
Study Intervention(s) Administered
ARM name
Lorlatinib 100 mg QD
Intervention name
Lorlatinib
Type
Small molecule
Dosage form
Tablet
Dose strength
25 mg
Dosage
100 mg QD
Route of administration
Oral
Sourcing
Provided centrally by the Sponsor
Packaging and labeling
Study intervention will be provided in bottles.  Each bottle will be labeled as 
required per country requirement.
Current/former name(s) or 
alias(es)
PF-06463922/lorlatinib
Abbreviation: QD=once daily.  

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5.1. Allocation to Intervention/Treatment
This is an open-label study; however, the specific intervention to be taken by a participant 
will be assigned using an interactive voice response system (IVRS)/interactive web response 
system (IWRS).  The site will contact the IVRS/IWRS prior to the start of study intervention 
administration for each participant.  The site will record the intervention assignment on the 
applicable case report form (CRF), if required.
5.2. Drug Supplies
5.2.1. Dosage Form(s) and Packaging
Lorlatinib (PF-06463922) will be supplied by Pfizer Global Clinical Supply for oral 
administration as 25 mg tablets in high-density polyethylene (HDPE) bottles with desiccant 
and labeled according to local regulatory requirements. 
Drug supplies will be shipped to the study sites with a Drug Shipment and Proof of Receipt
form.  This form will be completed and filed, as directed on the bottom of the Drug Shipment 
and Proof of Receipt form.  The Investigator shall take responsibility for and shall take all
steps to maintain appropriate records and ensure appropriate supply, storage, handling,
distribution, and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.
5.3. Administration
The product will be administered in accordance with the label.  
The recommended dosage of lorlatinib is 100 mg orally QD, with or without food, until 
disease progression, unacceptable toxicity, or participant refusal/lost to follow-up.  Tablets 
should be swallowed whole.  Tablets should not be chewed, crushed, or split.  Tablets should 
not be taken if they are broken, cracked, or otherwise not intact.  Lorlatinib should be taken
at the same time each day.  If a dose is missed, then the missed dose should be taken unless 
the next dose is due within 4 hours.  Two (2) doses should not be taken at the same time to 
make up for a missed dose.  An additional dose should not be taken if vomiting occurs after 
lorlatinib but the next scheduled dose should be continued.  Dosing interruption or dose 
reduction may be required based on individual safety and tolerability.
Lorlatinib dose reduction levels are summarized below:

First dose reduction: 75 mg taken orally QD; 

Second dose reduction: 50 mg taken orally QD.  
Lorlatinib should be permanently discontinued if the participant is unable to tolerate the 
50 mg dose taken orally QD.  Dose modification recommendations for adverse reactions are 
provided in Table 2.  

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Table 2.
Dose Modification Recommendation for Adverse Reactions of Lorlatinib
Adverse Reaction
Lorlatinib Dosing
CNS Effect
Grade 1
Continue lorlatinib at same dose or withhold the 
dose until recovery to baseline.  Resume lorlatinib at 
the same dose or at a reduced dose.
Grade 2 or Grade 3
Withhold dose until Grade 0 or 1.  Resume lorlatinib 
at a reduced dose. 
Grade 4
Permanently discontinue lorlatinib.  
Hyperlipidemia
Grade 4 hypercholesterolemia or Grade 4 
hypertriglyceridemia
Withhold lorlatinib until recovery of 
hypercholesterolemia and/or hypertriglyceridemia to 
less than or equal to Grade 2. Resume lorlatinib at 
the same dose.  If severe hypercholesterolemia 
and/or hypertriglyceridemia recurs, resume lorlatinib 
at a reduced dose.
AV block
Second-degree AV block
Withhold lorlatinib until PR interval is less than 
200 msec.  Resume lorlatinib at a reduced dose.
First occurrence of complete AV block
Withhold lorlatinib until:

pacemaker placed, or

PR interval less than 200 msec.
If a pacemaker is placed, resume lorlatinib at the 
same dose.  If no pacemaker is placed, resume 
lorlatinib at a reduced dose.
Recurrent complete AV block
Place pacemaker or permanently discontinue 
lorlatinib.
ILD/Pneumonitis
Any grade treatment–related ILD/Pneumonitis
Permanently discontinue lorlatinib.  
Other adverse reactions
Grade 1 or Grade 2
Continue lorlatinib at same dose or reduced dose.  
Grade 3 or Grade 4
Withhold lorlatinib until symptoms resolve to less 
than or equal to Grade 2 or baseline.  Resume 
lorlatinib at reduced dose.
Grade based on NCI CTCAE version 4.0. 
Abbreviations: AV=atrioventricular; CNS=central nervous system; CTCAE=Common Terminology Criteria 
for Adverse Events; ILD=interstitial lung disease; NCI=National Cancer Institute.  
5.4. Drug Storage
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff.  At a minimum, daily 
minimum and maximum temperatures for all site storage locations must be 

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documented and available upon request.  Data for nonworking days must indicate the 
minimum and maximum temperature since previously documented for all site storage 
locations upon return to business.
3. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.
4. Study interventions should be stored in their original containers and in accordance
with the labels.
5. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
6. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention 
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion.  Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation.  Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the investigational product manual.
5.5. Drug Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).  All study interventions will be
accounted for using an investigational product accountability form/record.  Further guidance 
and information for the final disposition of unused study interventions are provided in the 
investigational product manual. 
The Sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the investigator site, 
the Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.  
5.6. Concomitant Treatments
The use of permitted concomitant medication must be in accordance with the study drug
label.
All concomitant medications and non-drug supportive interventions should be recorded in the 
CRF from 28 days prior to start of study treatment and to at least 28 days and no more than 
35 days after the last dose of study treatment.

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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or
receives during the study must be recorded along with reason for use and dates of
administration including start and end dates.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
5.6.1. Prohibited Concomitant Treatments
Concomitant treatment considered necessary for the participant’s wellbeing may be given at 
discretion of the treating physician.  Prior to giving any concomitant medication, the 
following lorlatinib drug interaction information should be considered.
Lorlatinib is a substrate of CYP3A.  This is supported by drug interaction studies in healthy 
volunteers, in which lorlatinib exposure was decreased by a strong CYP3A inducer
(rifampin) and increased by a strong CYP3A inhibitor (itraconazole).  
Thus, the following cautions are provided: 

Lorlatinib metabolism may be inhibited by strong CYP3A inhibitors leading to a
potential increase in lorlatinib toxicities.  Concomitant administration of lorlatinib 
with strong CYP3A inhibitors (eg, boceprevir, cobicistat, clarithromycin, conivaptan, 
diltiazem, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nelfinavir, 
paritaprevir, posaconazole, ritonavir alone and with elvitegravir or indinavir or 
lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, 
telaprevir and voriconazole) may increase lorlatinib plasma concentrations.  
Grapefruit products may also increase lorlatinib plasma concentrations and should be 
avoided.  An alternative concomitant medicinal product with less potential to inhibit 
CYP3A should be considered.  If a strong CYP3A inhibitor must be co-administered, 
the starting lorlatinib dose of 100 mg QD should be reduced to 75 mg dose QD.  In 
participants who have had a dose reduction to 75 mg orally QD due to adverse 
reactions and who initiate a strong CYP3A inhibitor, reduce lorlatinib dose to 50 mg 
orally QD.  If concurrent use of the strong CYP3A inhibitor is discontinued, lorlatinib 
should be resumed at the dose used prior to the initiation of the strong CYP3A 
inhibitor and after a washout period of 3 to 5 half-lives of the strong CYP3A 
inhibitor.  The participant should be closely monitored for safety and reduction of the 
lorlatinib dose if necessary.  
In the B7461011 study, in which lorlatinib was co-administered with rifampin, significant 
increases in AST and ALT were observed.  In subsequent studies in cynomolgus monkeys, 
lorlatinib in combination with carbamazepine demonstrated similar AST and ALT elevations 
as well.  

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Thus, the following clinical guidance is provided: 

The use of a strong CYP3A inducer (eg, carbamazepine, enzalutamide, mitotane, 
rifampin, St. John’s Wort) with lorlatinib is contraindicated, as they may also reduce 
lorlatinib plasma concentration.  Furthermore, when lorlatinib was coadministered 
with rifampin (Study B7461011), increases in AST and ALT were noted.  
Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A 
inducer prior to initiating lorlatinib and until study treatment discontinuation.  In 
addition, use with moderate CYP3A inducers should be avoided due to the potential 
reduction in lorlatinib exposure.  
In vivo results show that lorlatinib 100 mg QD at steady state is a moderate inducer of 
CYP3A.  In addition, a drug interaction study conducted in NSCLC participants indicated 
that lorlatinib is a moderate inducer of P-gp.
Thus, the following clinical guidance is provided:  

Lorlatinib is a net moderate inducer of CYP3A at steady state.  Thus, concurrent 
administration of lorlatinib with CYP3A substrates with narrow therapeutic indices 
(NTIs), including but not limited to alfentanil, ciclosporin dihydroergotamine,
ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and 
tacrolimus, should be avoided since the concentration of these medicinal products 
may be reduced by lorlatinib. However, if it is absolutely necessary to use, Sponsor
approval is required and the dose of the CYP3A substrate may need to be increased.  
The narrow NTI CYP3A substrate should be started only after at least 14 days of
continuous lorlatinib dosing.  If there is a change in the lorlatinib dosing regimen 
such as a dosing interruption or dose reduction, the administration of the NTI CYP3A
substrate should be stopped and resumed at a readjusted dose only after at least 14
days of resumed lorlatinib dosing.

Lorlatinib is a net moderate inducer of P-gp at steady state. The concurrent use of 
drugs which are P-gp substrates with NTI, such as digoxin is not permitted at study 
entry.  The use of these drugs during the study is not recommended and alternate 
medications should be considered.  If absolutely necessary to use during the study, it 
should be initiated following sponsor approval, and be used then with caution. 
Other Antitumor or Experimental Drugs
No additional systemic antitumor therapy will be permitted while participants are receiving 
a study therapy.  Additionally, the concurrent use of select herbal supplements (St John’s 
wort, ginseng, and goldenseal) is not permitted. 
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first cycle but they may be used to treat treatment-emergent neutropenia as per standard 
of care.  

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If approved and available for use per country regulations, erythropoietin may be used at the 
Investigator’s discretion for the supportive treatment of anemia.
5.6.2. Permitted Concomitant Treatments
Bisphosphate Therapy
Bisphosphonate therapy for metastatic bone disease is permitted.  Bisphosphonate therapy 
should be given as per local medical practice.
Lipid-Lowering Therapy
Since statins can be metabolized or inhibited by the same CYP450 pathways as lorlatinib 
(Appendix 2), pitavastatin or pravastatin followed by rosuvastatin should be the agents to use 
concomitantly with lorlatinib since they are the least involved with the CYP450 enzyme
systems. However, no clinical drug-drug interactions have been formally studied with 
lorlatinib and careful monitoring is advised.  
If hypertriglyceridemia requires treatment beyond a statin that was administered for 
hypercholesterolemia, fenofibrate or fish oils followed by nicotinic acid should be 
administered as they have the least involvement with the CYP450 enzyme systems 
(Appendix 2).  No clinical drug-drug interactions have been formally conducted with 
lorlatinib and agents listed in Appendix 2, so careful monitoring is advised. 
Radiotherapy

Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing the lesions were known at the time of study entry and the Investigator 
clearly indicates that the need for palliative radiotherapy is not indicative of disease 
progression.  In view of the current lack of data about the interaction of lorlatinib with 
radiotherapy, lorlatinib treatment should be interrupted during palliative radiotherapy, 
stopping 1 day before and resuming treatment after recovery from acute radiation 
toxicities to baseline.
Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study. The
appropriate interval of time between surgery and lorlatinib required to minimize the risk of 
impaired wound healing and bleeding has not been determined. Stopping lorlatinib is 
recommended at least 2 days prior to surgery.  Postoperatively, the decision to reinitiate 
lorlatinib treatment should be based on a clinical assessment of satisfactory wound healing 
and recovery from surgery.

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6. STUDY PROCEDURES
6.1. Screening
All participants being considered for the study and eligible for screening must sign an 
informed consent for the study before completing any study-specific procedures.  Participants 
will be screened within 28 days prior to first dosing of lorlatinib to confirm that they meet the
eligibility criteria for the study.  The required screening assessments are summarized in the 
Schedule of Activities and Section 7 Assessments.  
6.2. Study Period
For study treatment period procedures, see Schedule of Activities and Section 7 Assessments.  
6.3. Follow-up Visit
At least 28 days, and no more than 35 days after discontinuation of treatment, participants 
will return to undergo contraception check, pregnancy test, review of concomitant
medications, AE assessments, and review for solution of any treatment-related toxicity.  
6.4. Participant Withdrawal

Participants who request to discontinue study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further 
contact with him/her or persons previously authorized by participant to provide this 
information.  Participants should notify the Investigator of the decision to withdraw 
consent from future follow-up in writing, whenever possible.  The withdrawal of 
consent should be explained in detail in the medical records by the Investigator, as to 
whether the withdrawal is from further treatment with study drug only or also from 
study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 

All reasonable efforts must be made to locate participants to determine and report 
their ongoing status.  This includes follow-up with persons authorized by the 
participant as noted above.  Lost to follow-up is defined by the inability to reach the 
participant after a minimum of 3 documented phone calls, faxes, or emails as well as 
lack of response by participant to 1 registered mail letter.  All attempts should be 
documented in the participant’s medical records.  If it is determined that the 
participant has died, the site will use permissible local methods to obtain the date and
cause of death.  If Investigator’s use of third-party representative to assist in the 
follow-up portion of the study has been included in the participant’s informed 
consent, then the Investigator may use a Sponsor retained third-party representative to 
assist site staff with obtaining participant’s contact information or other public vital 
status data necessary to complete the follow-up portion of the study.  The site staff 
and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If after all 
attempts, the participant remains lost to follow-up, then the last known alive date as 

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determined by the Investigator should be reported and documented in the 
participant’s medical records.
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator. 
If a participant does not return for a scheduled visit, every effort should be made to contact
the participant.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s medical record. In any 
circumstance, every effort should be made to document participant’s outcome, if possible.  
The Investigator should inquire about the reason for withdrawal, request the participant to 
return for a final visit, if applicable, and follow up with the participant regarding any 
unresolved AEs.
If the participant withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should 
be collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.  
7. ASSESSMENTS
7.1. Antitumor Activity Assessments
Tumor assessments will include all known or suspected disease sites. Computed tomography 
(CT) or magnetic resonance imaging (MRI) scans of chest abdomen pelvis (CAP) and MRI
of the brain will be performed at Screening.  Gadolinium contrast enhanced MRI must be 
used for assessment of CNS lesions with contingent slices of 1 mm for lesions 5 mm to 
10 mm in size, 5 mm for lesions greater than 10 mm.  For all tumor assessments, the method 
of assessment that was used at Screening should be the same method used throughout the 
study.  CT and MRI scans to be done at every 12 weeks ±1 week till the end of treatment.  
Tumor assessment should be repeated at the end of treatment if more than 6 weeks have 
passed since the last evaluation.  Moreover, radiological tumor assessments will be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration).  
Assessment of response will be made using RECIST version 1.1 (Appendix 3).  
Confirmation of response will be required at least 4 weeks after initial response is observed.
All participants’ files and radiologic images must be available for source verification.
7.2. Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 

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7.2.1. Physical Examination

Participants will have a physical examination to include major body systems, body 
weight, blood pressure, pulse rate, and assessment of ECOG performance status at the 
time points described in the Schedule of Activities.  Blood pressure and pulse rate 
should be taken with the participant in the seated position after the participant has 
been sitting quietly for at least 5 minutes. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
7.2.2. Electrocardiogram

ECG will be obtained as outlined in the Schedule of Activities using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  

PR interval prolongation and AV block have been reported in participants receiving 
lorlatinib. If at any time the mean PR interval is prolonged (≥200 msec) or QTc is 
prolonged (≥470 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  

ECG values of potential concern are listed in Appendix 4. Dose modifications for 
AV block is provided in Table 2.  
7.2.3. ECOG Performance Status
Refer to Appendix 5 for ECOG PS criteria.  
7.2.4. Clinical Safety Laboratory Assessments
The required laboratory tests are listed in Appendix 6. 

Hematology and blood chemistry will be collected at the time points described in the 
Schedule of Activities and analyzed at local laboratories. They may also be 
performed when clinically indicated.  Local laboratory certification(s) and reference 
ranges should be provided to the Sponsor prior to study participant screening activity.
7.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in woman of childbearing potential 
(WOCBP) at the times listed in the Schedule of Activities.  Following a negative pregnancy 
test result at Screening, appropriate contraception must be commenced, and a second 
negative pregnancy test result will be required at Cycle 1 Day 1 prior to the participant’s 
receiving the study intervention.  Pregnancy tests will also be repeated at every cycle during 
the active treatment period, at the end of treatment, and at the short-term follow-up visit to be 
performed at least 28 days and no more than 35 days after the last dose.  Pregnancy tests will 
also be done whenever 1 menstrual cycle is missed during the active treatment period (or 

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when potential pregnancy is otherwise suspected). If a urine test cannot be confirmed as 
negative (eg, an ambiguous result), a serum pregnancy test is required.  In such cases, the 
participant must be excluded if the serum pregnancy result is positive.  
In the case of a confirmed pregnancy, the participant will be withdrawn from study 
medication and from the study.  
Pregnancy tests may also be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations. 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of 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 both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the 
AE.  The Investigator is required to assess causality. Follow-up by the Investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
Investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For AEs and SAEs, the active reporting period to Pfizer or its designated representative 
begins from the time that the participant provides informed consent, which is obtained prior 
to the participant’s participation in the study, ie, prior to undergoing any study-related
procedure and/or receiving investigational product, through and including at least 28 calendar
days and no more than 35 days after the last administration of the investigational product.  
SAEs occurring to a participant after the active reporting period has ended should be reported 
to the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.
If a participant begins a new anticancer therapy, the AE reporting period for nonserious AEs 
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.

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8.3. Definition of An Adverse Event
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure; 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.  

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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong participant, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the AE CRFs 
and on the SAE form when appropriate.  In the event of medication dosing error, the Sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error and, if applicable, any associated AE(s) are captured on an 
AE CRF page (refer to Section 8 Adverse Event Reporting section for further details).  
8.4.1. Treatment of Overdose
For this study, any dose of lorlatinib greater than 100 mg within a 24-hour time period will
be considered an overdose.  Sponsor does not recommend specific treatment for an overdose.  
There is no antidote for lorlatinib.  
In the event of an overdose, the Investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AE/SAE and given the dose dependent effect 
on PR interval, ECG monitoring is recommended.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to safety only when associated with a SAE.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Event
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria (CTC) 
Grade 5 (see Section 8.8 Severity Assessment). 

Lack of efficacy should be reported as an AE when it is associated with an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  The important medical event should be reported as serious, 
if it is determined that the event may jeopardize the participant or may require intervention to
prevent 1 of the other AE outcomes.
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 development of drug dependency or drug abuse.  

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8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
Investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements).  
8.6.2. Potential Case of Drug-Induced Liver Injury
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the participant’s individual baseline values and underlying conditions.  
Participants who present with the following laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values:

participants with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT values ≥3 × ULN concurrent with 
a total bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value ≤2 × ULN or not available;

For participants with preexisting ALT or AST or total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For participants with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).

Concurrent with:

For participants with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased by 1 × ULN or ≥3 × ULN (whichever is smaller).
The participant should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  

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Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test abnormalities identified at the time, 
should be considered potential Hy’s law cases irrespective of availability of all the results of 
the investigations performed to determine etiology of the abnormal liver function tests.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, participant has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual participant;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
AEs will be graded by the Investigator according to the CTCAE version 4.03.  
Grade
Clinical Description of Severity
1
Mild adverse event
2
Moderate adverse event
3
Severe adverse event
4
Life-threatening consequences; urgent intervention indicated
5
Death related to adverse event
8.9. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An Investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided. If the Investigator does not know whether or not the investigational product 
caused the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the Sponsor (see Section 8.13 Reporting Requirements).  If 
the Investigator’s causality assessment is “unknown but not related to investigational 
product,” this should be clearly documented on study records.  
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.

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8.10. Exposure During Pregnancy
For investigational products and for marketed products, an EDP occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.  An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman 
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).
2. A male participant has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy. 
If a study participant or study participant’s partner becomes or is found to be pregnant during 
the study participant’s treatment with the investigational product, the Investigator must 
submit this information to the Pfizer drug safety unit on a SAE Report Form and EDP 
supplemental form, regardless of whether an SAE has occurred.  In addition, the Investigator 
must submit information regarding environmental exposure to a Pfizer product in a pregnant 
woman (eg, a participant reports that she is pregnant and has been exposed to a cytotoxic 
product by inhalation or spillage) using the EDP supplemental form.  This must be done
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion or until pregnancy termination and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.

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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to investigational product. 
Additional information regarding the EDP may be requested by the Investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
Investigator will provide the study participant with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the source
documents that the participant was given the Pregnant Partner Release of Information Form 
to provide to his partner.
8.11. Withdrawal Due to Adverse Events (See Also Section on Participant Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a participant withdraws because of an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study participant or legally acceptable representative.  In addition, each study participant 
or legally acceptable representative will be questioned about AEs.
8.13. Reporting Requirements
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of Investigator awareness of the 
event.  
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP and exposure via breastfeeding cases.  
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study participant initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.

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For all SAEs, the Investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an Investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a participant death, 
a summary of available autopsy findings must be submitted as soon as possible to Pfizer or 
its designated representative.
8.13.2. Non-serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in an SAP, which will be maintained by the Sponsor.  This document 
may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Estimands and Statistical Hypotheses
The primary objective of the study is to evaluate the safety and tolerability of single-agent 
lorlatinib in participants with unresectable advanced and/or recurrent ALK-positive NSCLC 
with resistance or intolerance to at least 1 prior ALK inhibitor treatment.  
The secondary objective of the study is to evaluate overall and intracranial antitumor activity 
of single-agent lorlatinib in participants with unresectable advanced and/or recurrent 
ALK-positive NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor
treatment.  
9.1.1. Estimands
The primary estimand is the incidence of Adverse Events from the time of first dose to at 
most 35 days post last dosing date or the date of initiation of a new anticancer therapy for all 
participants who receive at least one dose of lorlatinib, regardless of dosing interruptions or 
dosing compliance.

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The secondary estimand is the treatment effect of lorlatinib as assessed by the investigator 
from time of first dose (ORR and IC-ORR) or time of first response (DoR and IC-DoR) until 
progression is met, death or subsequent anticancer therapy is administered for all participants 
who receive at least one dose of lorlatinib without regard to tolerability or discontinuation 
from treatment.
9.2. Sample Size Determination
This study will enroll enough participants to ensure that 100 participants are treated with 
lorlatinib.  With 100 participants, any AE rate can be estimated with the maximum standard 
error of 0.05. All participants who receive at least 1 dose of lorlatinib in this study will be 
included in the safety and antitumor activity analyses unless otherwise specified.
9.3. Data Sources
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The Investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.  
9.4. Antitumor Activity Analysis
All antitumor activity analyses will be performed on the safety set.  Participants with 
inadequate baseline or no follow-up assessments will be considered as non-responders.  
9.4.1. Analysis of Primary Endpoint
Not applicable.  
9.4.2. Analysis of Secondary Endpoints
The following analyses of response will be performed according to the Investigator 
assessment using RECIST version 1.1. 
ORR
ORR is defined as the percent of participants with best overall response as confirmed CR or 
confirmed PR according to RECIST version 1.1.  ORR will be provided along with the 
corresponding 95% confidence interval based on Wilson’s Score Method. 
IC-ORR
IC-ORR is defined as the percent of participants with intracranial response (ie, best overall 
intracranial response as confirmed CR or confirmed PR considering only intracranial lesions) 
relative to participants with CNS metastases at study entry. IC-ORR will be provided along 
with the corresponding 95% CI based on Wilson’s Score Method. 

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DoR
DoR is defined as the time from the first documentation of objective tumor response 
(confirmed CR or confirmed PR) to the first documentation of disease progression or death 
due to any cause, whichever occurs first.  For participants whose responses proceed from PR 
to CR, the onset of PR is taken as the onset of response.  DoR will be summarized in the 
population of participants with a confirmed CR or confirmed PR using the Kaplan Meier 
method and will be displayed graphically where appropriate.  The median event time (if 
appropriate) and 2-sided 95% CI for the median will be provided. Censoring for DoR will be
described in the SAP.  In case the number of participants with PD after a confirmed CR or 
confirmed PR is small, the use of Kaplan Meier method may be limited and descriptive 
statistics may be provided.
IC-DoR
IC-DoR is defined as the time from the first documentation of an intracranial objective 
response in the subgroup of participants with brain metastasis at baseline.  Analyses similar 
to DoR will be repeated for IC-DoR considering participants with intracranial response (ie, 
best overall intracranial response as confirmed CR or confirmed PR considering only 
intracranial lesions).  
9.5. Analysis of Other Endpoints
Not applicable.  
9.6. Safety Analysis
All safety analysis will be conducted on the safety set. 
Primary Endpoint
AEs will be graded by the Investigator according to the CTCAE version 4.03 and coded 
using the MedDRA.  The focus of AE summaries will be on TEAEs, those with an initial 
onset or increasing in severity after the first dose of study medication up to at most 35 days 
post last dosing date or the date of initiation of a new anticancer therapy.  The number and 
percentage of participants who experienced any AE, SAE, treatment-related AE, and 
treatment-related SAE will be summarized.  
Adverse events leading to death or discontinuation of study treatment, events classified as
NCI CTCAE version 4.03 Grade ≥3, study drug-related events, SAEs, dose reductions due to 
AEs, and temporary and permanent discontinuations due to AEs will be summarized.
Detailed information collected for each AE will be listed with a description of the event, 
duration, whether the AE was serious, intensity, relationship to study treatment, action taken, 
and clinical outcome.

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Study Treatment Exposure
Drug exposure will be summarized using descriptive statistics.  The number and percentage 
of participants with drug interruptions and the corresponding reasons will be summarized.  
The number and percentage of participants with dose reductions and the corresponding 
reasons will also be summarized.
Laboratory Abnormalities
Laboratory test results will be graded according to NCI CTCAE version 4.03.  Data will be 
summarized by the type of laboratory test.  Summary of laboratory abnormalities will be 
presented by maximum CTCAE grade.  For laboratory tests without an NCI CTCAE grade 
definition, results will be categorized as normal (within normal ranges), abnormal, or not 
done.  Shift tables will be provided to examine the distribution of laboratory abnormalities.
Vital Signs
Vital signs data will be summarized using descriptive statistics (mean, standard deviation, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (ie, unscheduled assessments will be excluded). 
Electrocardiograms
All ECGs obtained during the study will be evaluated for safety.  The triplicate pre-dose data 
will be averaged. Summary statistics and data presentations for pre-dose will use the 
averaged data.  Any data obtained from ECGs repeated for safety reasons after the nominal 
time points will not be averaged along with the preceding.
QT intervals will be corrected for heart rate using standard correction factors (ie, Fridericia’s 
[default correction], Bazett’s [if necessary], and possibly a study-specific factor, as 
appropriate).  However, safety assessments as to QTc prolongation will be based on the 
Fridericia's correction formula.  Data will be summarized and listed for QT, HR, RR, PR, 
QRS, QTc.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) of QTc 
and other ECG parameters will be used to summarize absolute values and changes from 
baseline on treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT, PR, and QRS and the maximum post-baseline corrected QT 
interval.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.

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The study site may be subject to review by the Institutional Review Board (IRB)/Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included participant.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the participant’s chart in the hospital or the 
physician’s office.  In these cases, data collected on the CRFs must match the data in those 
charts.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating participants (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Council for Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer. The investigator must ensure that the records continue to be stored 
securely for so long as they are retained.

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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the participants. 
In that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World
Medical Association 1996 & 2008) and Schedule Y, Drug and Cosmetics Act 1940 and 
Rules 1945. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local India regulatory requirements and laws.
12.3. Participant Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant personal data.
Such measures will include omitting participant names or other directly identifiable data in 
any reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 

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study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data is compiled for transfer to Pfizer and other authorized parties, 
participant names, addresses, and other identifiable data will be replaced by a numerical code
consisting of a numbering system provided by Pfizer in order to de-identify study 
participants.  The study site will maintain a confidential list of participants who participated 
in the study linking their numerical code to the participant’s actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of participant 
personal data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study participant, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  
Whenever consent is obtained from a participant’s legally acceptable representative, the 
participant’s assent (affirmative agreement) must subsequently be obtained when the 
participant has the capacity to provide assent, as determined by the IRB/EC. If the 
investigator determines that a participant’s decisional capacity is so limited he/she cannot 
reasonably be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the participant’s assent may be waived with source documentation 
of the reason assent was not obtained.  If the study participant does not provide his/her own 
consent, the source documents must record why the participant did not provide consent (eg, 
minor, decisionally impaired adult), how the investigator determined that the person signing 
the consent was the participant’s legally acceptable representative, the consent signer’s 
relationship to the study participant (eg, parent, spouse) and that the participant’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant or the participant’s legally acceptable representative, when 
applicable, before any study-specific activity is performed.  The investigator will retain the 
original of each participant’s signed consent document.  
12.4. Participant Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.

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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
13. DEFINITION OF END OF STUDY
13.1. End of Study in Participating Country
End of study in participating country is defined as 1 year after the LPFV date in the study.  
At the end of study, participants who are on treatment and benefiting from lorlatinib 
treatment will be moved to commercially available lorlatinib (if considered appropriate by 
the Investigator) as soon as feasible.  
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating participants 
and the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), www.ctri.nic.in (Clinical Trials 
Registry-India) and other public registries in accordance with applicable local 
laws/regulations.
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product. 
15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational drug.  

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However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the Study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.

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16. REFERENCES
1. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive 
non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 
2018;19(12):1654-67. 
2. Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and 
Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 
2016;6(10):1118-33.
3. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: 
mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80(6):565-81.
4. Miller M. “What Are the Effects of Statins on Triglycerides and What Are the Results of 
Major Outcomes Studies?” 2009 Mar 12; http://www.medscape.org/viewarticle/589010.
5. Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacy and safety profiles of a novel 
synthetic HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 2003;21(3):199-215.
6. Schaefer EJ, McNamara JR, Tayler T, et al. Comparisons of effects of statins 
(atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and 
postprandial lipoproteins in patients with coronary heart disease versus control subjects. 
Am J Cardiol 2004;93(1):31-9.
7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.

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Appendix 1. Contraceptive Guidance 
Definition
WOCBP: A woman is considered fertile following menarche and until becoming
post-menopausal unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other
than the above, (eg, mullerian agenesis, androgen insensitivity), Investigator 
discretion should be applied to determining study entry.  
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in 
the participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high FSH level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or HRT.

Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.

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Contraception Guidance
Contraception – For Women
Female participants must use highly effective contraception while taking study intervention 
and for at least 6 months after stopping study intervention.
Lorlatinib may reduce the effectiveness of hormonal contraceptive methods; therefore, 
hormonal contraceptives may not be considered highly effective.  If hormonal contraception 
is unavoidable, it must be used in combination with a condom.
Highly effective methods that have low user dependency includes:  
1. Intrauterine device (IUD).
2. Bilateral tubal occlusion.
3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Contraception – For Men
Male participants must use a condom while taking study intervention and for at least 
3 months after stopping study intervention. 

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Appendix 2. Pharmacokinetic Properties of Statins and Lipid Lowering Agents
The PK properties of statins and lipid lowering agents are provided in Table 3 and Table 4, 
respectively.  

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Table 3.
Pharmacokinetic Properties of Statins
Generic Name
Pitavastatin
Pravastatin
Rosuvastatin
Atorvastatin
Simvastatin
Lovastatin
Fluvastatin
Metabolism†
++
+
+
+++
+++
+++
+++
Metabolizing CYP enzyme
(of lactone or acid form)
(2C9)
(3A4)
2C9 (2C19)
3A4 (2C8)
3A4 2C8
3A4 2C8
2C9
Inhibitor of CYP3A4‡
-
-
+
+
+
+
+
Inhibitor of CYP2C9‡
-
-
(+)
-
-
-
+
Triglyceride lowering effect
22%-31%**
11%-14%*
17%*
14%-19%*
10%-14%*
13%*
5%***
Adapted from Neuvonen et al, 2006.3
Parentheses indicate minor significance.
†Three (3) plus signs indicate extensively metabolized, and 1 plus sign indicates limited metabolism, eliminated mainly unchanged.
‡A plus sign indicates yes, and a minus sign indicates no.
*Baseline TG 100-200 mg/dL; Effect of Statins vs Placebo on Triglyceride Levels in 10 Primary and Secondary Placebo-Controlled Outcome Trials table in 
Miller 2009.4
**Baseline TG 150 mg/dL; Kajinami et al, 2003.5
***Schaefer et al, 2004.6
Abbreviations:  CYP=cytochrome P450; TG=triglyceride.  

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Table 4.
Pharmacokinetic properties of Lipid Lowering Agents
Fibric Acids
Fish Oils
Generic Name
Nicotinic Acid
Gemfibrozil
Fenofibrate
Ethyl esters of omega-3 
fatty acids
Dose
100–2000 mg QD
600 mg BID
200 mg QD
4 gm QD/2 gm BID
Metabolism‡
-
-
-
-
Metabolizing CYP enzymes 
(of lactone or acid form)‡
-
-
-
-
Inhibitor of CYP3A4‡
-
-
-
-
Inhibitor of CYP2C9‡
-
+++
++
-
Inhibitor of CYP2C19‡
-
++
+
-
Inhibitor of CYP1A2‡
-
+
-
-
Triglyceride lowering effect
(TG 150 mg/dL)
20%-50%*
20%-50%*
36%-55%e
45%
Drug interactions
Caution should be used 
when prescribing niacin with
statins
Concomitant administration 
with statins is 
contraindicated
May increase exposure to 
pravastatin and its metabolite 
(13%-26%) when used 
concomitantly
-
‡A plus sign indicates yes, and a minus sign indicates no.
*NCEP-ATP III, 2001.
Abbreviations: BID=twice daily; QD=once daily.
a.
PI, 4/2015.
b.
PI, 11/2014.
c.
PI, 12/2014.
d.
PI, 05/2014.
e.
Primary hypertriglyceridemia – severe hypertriglyceridemia (baseline TG levels 500 to 1500 mg/dL).

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Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria7
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or not, according to the criteria summarized below.  
1. Measurable Lesions
Lesions that can be accurately measured in at least 1 dimension (longest diameter in
the plane of measurement is to be recorded) with a minimum size of:  

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan 
slice thickness no greater than 5 mm);

10 mm for lesions assessed clinically by caliper measurement (lesions which 
cannot be accurately measured with calipers should be recorded as 
non-measurable);

20 mm for lesions assessed by chest X-ray;

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). 
2. Non-measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or 
pathological lymph nodes with a ≥10 but <15 mm short axis) as well as truly 
non-measurable lesions.  Truly non-measurable lesions include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses identified by physical 
examination and not measurable by reproducible imaging techniques.   
Nodes that have a short axis <10 mm are considered non-pathological and should not 
be recorded or followed. 
3. Special Considerations Regarding Specific Lesions
Bone lesions

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such 
as CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.

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
Blastic bone lesions are non-measurable.
Cystic lesions

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above.  However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions.
Lesions with prior local treatment

Tumor lesions situated in a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion.
Solitary lesions

If a measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. 
One (1) exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as 
2 dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The 
smaller of these measures is the short axis. 

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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present”, “absent”, or in rare cases “unequivocal progression”.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the CRF (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
Definition of Tumor Response
Target Lesions
Response in target lesions is defined as follows:  

CR: disappearance of all target lesions. 

PR: at least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.

PD: at least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  The appearance of 1 or more new 
lesions is also considered a sign of progression.

Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of “0” on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.  
Response in non-target lesions is defined as follows:  

CR: disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (<10 mm short axis).  

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
Non-CR/Non-PD: persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.  

PD: unequivocal progression of existing non-target lesions. (Note: the appearance of 
one or more new lesions is also considered progression).  
Cytology, Histology
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or SD and PD.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF.  Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF. 
New Lesions
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
The use of fluorodeoxyglucose (FDG)-PET is sometimes reasonable to complement a CT 
scan assessment of a PD (particularly for possible “new” disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up.  

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.

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Confirmation of Tumor Response
Confirmation of response is required for non-randomized trials with primary endpoint of 
response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data.  
Determination of Overall Response by RECIST Version 1.1
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in 
Table 5.  
Table 5.
Response Evaluation Criteria in Solid Tumors
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
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
Abbreviations: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, 
NE=none-evaluable
Best Overall Response
The best overall response is determined once all the data for the patient is known.  Best 
response in trials in which confirmation of CR or PR is not required (ie, randomized trials) is 
defined as the best response across all time points (for example, a patient who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall response
of PR).  When SD is believed to be the best response, it must also meet the protocol-specified 
minimum time from baseline.  If the minimum time is not met when SD is otherwise the best 
time point response, the patient’s best response depends on the subsequent assessments.  For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD.  The same patient lost to follow-up after the 
first SD assessment would be considered non-evaluable. 
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  CR or PR may be claimed only if the criteria for each are met at a following 
time point as specified in the protocol (generally 4 weeks later).

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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy.  The objective 
response status of such patients is to be determined by evaluation of target and non-target 
lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. 

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Appendix 4. ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >200 msec.

New prolongation of QTcF to >470 msec (absolute) or by ≥60 msec from baseline.

New onset atrial flutter or fibrillation, with controlled ventricular response rate, ie, 
rate <120 bpm.

New onset Type I second-degree (Wenckebach) AV block of >30 seconds’
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New onset left bundle branch block (QRS >120 msec).

New onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 

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pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the Investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
Abbreviations: AE=adverse event; AV=atrioventricular; ECG=electrocardiogram; PVC=premature 
ventricular complex; QTcF=QT interval calculated using Fridericia’s correction factor; SAE=serious adverse 
event.  

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Appendix 5. ECOG Classification of Performance Status
Score
Definition
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, eg, light house work or office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead

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Appendix 6. Clinical Laboratory Tests
The laboratory tests detailed in Table 6 will be performed by the local laboratory and must be 
performed in fasted condition.  Investigators must document their review of each laboratory 
safety report.
Pregnancy testing:  

Refer to Section 4.1 Inclusion Criteria for screening pregnancy criteria.

For details of timing of recommended pregnancy testing see Section 7.2.5.  
Table 6
Protocol Required Safety Laboratory Assessments
Hematology
Clinical Chemistry1
Other Tests
Platelet count
Hemoglobin
WBC count with differential:
Neutrophils2
Lymphocytes2
Monocytes2
Eosinophils2
Basophils2
BUN or urea
Creatinine
Glucose (fasting)
Uric acid
Potassium
Sodium
Total calcium
Magnesium
AST
ALT
Alkaline phosphatase
Albumin
Total bilirubin
Phosphorus or phosphate
Serum total amylase3
Serum lipase
Highly sensitive serum or urine hCG 
pregnancy test (as needed for women of 
childbearing potential).  
Lipids: total cholesterol, LDL,4 HDL, 
and triglycerides.  
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CRF=case report form; hCG=human chorionic gonadotropin; HDL=high-density lipoprotein; INR=international 
normalized ratio; LDL=low-density lipoprotein; SAE=serious adverse event; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=woman of childbearing potential.  
1.
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR 
>1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE.  
2.
Values in percentages (%) are acceptable.  
3.
Pancreatic isoenzyme required if serum total amylase not within normal limits per local institutional ranges.
4.
A measured LDL value is preferable instead of calculated LDL.  If LDL value is calculated from 
Friedewald equation, this can be considered only in absence of the following circumstances: plasma 
dysbetalipoproteinemia (Type III hyperlipoproteinemia).