Clinical trial NCT03542305
Conditions: Renal Impairment
Sponsor: Pfizer
Start date: 2018-08-23; Completion date: 2020-02-20
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment.

Detailed description:
This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment. Each subject will receive a single oral dose of lorlatinib administered in the fasted state. Subjects with mild, moderate, and severe renal impairment will be enrolled and normal healthy subjects will be enrolled as matched controls.

Arms: arm 1: Mild renal impairment arm 2: Moderate renal impairment arm 3: Severe renal impairment arm 4: Normal renal function
Interventions: intervention 1: Lorlatinib
Intervention descriptions: intervention 1: Lorlatinib single oral dose

Protocol documents:
Prot_000.pdf: 
Lorlatinib
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CLINICAL PHARMACOLOGY STUDIES
A PHASE 1, SINGLE DOSE OPEN-LABEL STUDY TO EVALUATE THE 
PHARMACOKINETICS OF LORLATINIB IN SUBJECTS WITH IMPAIRED 
RENAL FUNCTION
Investigational Product Number:
PF-06463922
Investigational Product Name:
Lorlatinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
B7461010
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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 and Rationale
Original protocol
26 March 2018
Not applicable (N/A)
Protocol 
Amendment 1
22 June 2018
1. In accordance with the updated FDA
and Pfizer guidelines for renal 
impairment studies, renal function 
stratification will be determined by 
using estimated glomerular filtration 
rate (eGFR) as calculated using the 
MDRD equation, instead of CLcr 
calculated using the Cockcroft-Gault 
equation. 
2. The upper limit for the enrollment 
criterion on BMI is increased from 
30.5 to 36 kg/m2 based on site feedback 
of feasibility in enrolling higher body 
weight subjects in renally impaired 
groups.
3. The enrollment criterion for AST/ALT 
is changed from 1 x ULN to 1.5 x ULN 
based on site feedback of feasibility in 
enrolling renally impaired subjects who 
may have higher AST/ALT values.
This is also in line with other Pfizer 
healthy volunteer studies.
4. The contraception requirements have 
been updated to require 1 form of 
highly effective contraception instead 
of 2. This is the recommendation for 
studies in which female subjects of 
child-bearing potential will not be 
enrolled. 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................8
1. INTRODUCTION ...............................................................................................................12
1.1. Mechanism of Action/Indication.............................................................................12
1.2. Background .............................................................................................................12
1.3. Non Clinical Pharmacokinetics, Metabolism and Safety of Lorlatinib ..................12
1.3.1. Clinical Summary.......................................................................................16
1.3.1.1. Safety and Pharmacokinetics ....................................................16
1.4. Study Rationale .......................................................................................................24
1.5. Dose Rationale ........................................................................................................25
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................26
3. STUDY DESIGN.................................................................................................................27
3.1. Study Overview.......................................................................................................27
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................29
4.1. Inclusion Criteria.....................................................................................................29
4.1.1. All Subjects.................................................................................................29
4.1.2. Subjects with Normal Renal Function (Group A)......................................30
4.1.3. Subjects with Renal Impairment (Groups B, C, and D) .............................30
4.2. Exclusion Criteria....................................................................................................31
4.2.1. All Subjects.................................................................................................31
4.2.2. Subjects with Normal Renal Function (Group A)......................................32
4.2.3. Subjects with Renal Impairment (Groups B, C, and D) .............................32
4.3. Lifestyle Requirements ...........................................................................................33
4.3.1. Meals and Dietary Restrictions...................................................................33
4.3.2. Alcohol, Caffeine, and Tobacco .................................................................34
4.3.3. Activity .......................................................................................................34
4.3.4. Contraception..............................................................................................34
4.4. Sponsor’s Qualified Medical Personnel..................................................................35
5. STUDY TREATMENTS.....................................................................................................36
5.1. Allocation to Treatment ..........................................................................................36


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5.2. Subject Compliance.................................................................................................36
5.3. Investigational Product Supplies.............................................................................36
5.3.1. Dosage Form and Packaging ......................................................................36
5.3.2. Preparation and Dispensing........................................................................36
5.4. Administration.........................................................................................................37
5.5. Investigational Product Storage ..............................................................................37
5.6. Investigational Product Accountability...................................................................38
5.6.1. Destruction of Investigational Product Supplies ........................................38
5.7. Concomitant Treatment(s).......................................................................................38
6. STUDY PROCEDURES .....................................................................................................39
6.1. Screening.................................................................................................................39
6.2. Study Period ............................................................................................................40
6.2.1. Day -1 .........................................................................................................40
6.2.2. Day 1...........................................................................................................41
6.2.3. Day 2...........................................................................................................42
6.2.4. Day 3...........................................................................................................43
6.2.5. Day 4...........................................................................................................43
6.2.6. Day 5...........................................................................................................43
6.2.7. Day 6...........................................................................................................43
6.3. Follow-up ................................................................................................................44
6.3.1. Follow-up Visit...........................................................................................44
6.4. Follow-up Contact...................................................................................................45
6.5. Subject Withdrawal /Early Termination .................................................................45
7. ASSESSMENTS..................................................................................................................46
7.1. Safety.......................................................................................................................47
7.1.1. Laboratory Tests .........................................................................................47
7.1.2. Physical Examinations................................................................................48
7.1.3. Blood Pressure and Pulse Rate ...................................................................48
7.1.4. Electrocardiogram.......................................................................................49
7.2. Pharmacokinetics ....................................................................................................49
7.2.1. Plasma for Analysis of Lorlatinib and Its Metabolite(s) ............................49
7.2.2. Urine for Analysis of Lorlatinib .................................................................50


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7.3. Pharmacogenomics..................................................................................................51
7.3.1. Genotyping Analysis (If Applicable; Pertains but is not Limited to 
Blood, Buccal Swabs, Saliva, and/or Tissue) ..................................................51
.............................................................................................51
....................................................................................52
7.5. Blood Volume .........................................................................................................52
7.6. Potential Cases of Acute Kidney Injury..................................................................52
8. ADVERSE EVENT REPORTING......................................................................................53
8.1. Requirements...........................................................................................................53
8.1.1. Additional Details on Recording Adverse Events on the CRF...................55
8.1.2. Eliciting Adverse Event Information..........................................................55
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal /Early Termination Section)............................................55
8.1.4. Time Period for Collecting AE/SAE Information......................................55
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................56
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................56
8.1.5. Causality Assessment .................................................................................56
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................56
8.2. Definitions...............................................................................................................57
8.2.1. Adverse Events...........................................................................................57
8.2.2. Abnormal Test Findings .............................................................................57
8.2.3. Serious Adverse Events ..............................................................................58
8.2.4. Hospitalization............................................................................................58
8.3. Severity Assessment................................................................................................60
8.4. Special Situations ....................................................................................................60
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................60
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................62
8.4.2.1. Exposure During Pregnancy......................................................62
8.4.2.2. Exposure During Breastfeeding ................................................63
8.4.2.3. Occupational Exposure .............................................................63
8.4.3. Medication Errors .......................................................................................64
8.4.3.1. Medication Errors......................................................................64
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9. DATA ANALYSIS/STATISTICAL METHODS...............................................................64
9.1. Sample Size Determination.....................................................................................65
9.2. Pharmacokinetic Analysis.......................................................................................65
9.2.1. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................65
9.2.2. Statistical Methods......................................................................................66
9.3. Analysis of Other Endpoints ...................................................................................67
9.4. Safety Analysis........................................................................................................67
9.4.1. Electrocardiogram Analysis........................................................................67
9.5. Interim Analysis ......................................................................................................68
9.6. Data Monitoring Committee ...................................................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................68
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................69
11.2. Record Retention...................................................................................................69
12. ETHICS..............................................................................................................................70
12.1. Institutional Review Board/Ethics Committee......................................................70
12.2. Ethical Conduct of the Study ................................................................................70
12.3. Subject Information and Consent..........................................................................70
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................71
13. DEFINITION OF END OF TRIAL...................................................................................71
13.1. End of Trial in the United States...........................................................................71
14. SPONSOR DISCONTINUATION CRITERIA ................................................................71
15. PUBLICATION OF STUDY RESULTS..........................................................................71
15.1. Communication of Results by Pfizer ....................................................................71
15.2. Publications by Investigators ................................................................................72
16. REFERENCES ..................................................................................................................74
LIST OF TABLES
Table 1.
Summary of Lorlatinib Single Dose PK Parameters – B7461001 Phase 1..........18
Table 2.
Summary of Lorlatinib Steady-State PK Parameters After Repeated QD 
Dosing – B7461001 Phase 1.................................................................................19


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Table 3.
Summary of Lorlatinib 100 mg QD PK Parameters after Single and 
Multiple Doses in B7461001................................................................................20
Table 4.
Renal Function Groups.........................................................................................27
Table 5.
Safety Laboratory Tests........................................................................................47
Table 6.
Derivation of Pharmacokinetic Parameters ..........................................................65
Table 7.
Safety QTc Assessment ........................................................................................67
Table 8.
Safety PR Interval.................................................................................................68
APPENDICES
Appendix 1. Abbreviations......................................................................................................75


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the 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 in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Protocol Activity
Screeninga
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Follow-upq
Hours After Dose
pre-
dose 
0
0.5
1
1.5
2
4
6
8
12
24
48
72
96
120
Informed consent
X
CRU confinementb
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Inclusion/exclusion
criteria
X
X
Medical historyc
X
X
Physical examinationd
X
X
X
Xq
Safety laboratorye
X
X
X
X
Demographyf
X
Height
X
Weight
X
X
Xq
FSH testg
X
Contraception checkh
X
X
X
Xq
eGFRi
X
X
Urine drug testingj
X
X
Triplicate ECGk
X
X
X
X
X
X
X
X
Blood pressure and 
pulse ratel
X
X
X
X
X
X
X
X
Xq
HIV, HepBsAg, 
HepBcAb, HCVAb 
testing
X
Lorlatinib
administrationm
X
Pharmacokinetic blood 
samplingn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Collectiono
X
X
→
→
→
→
→
→
→
→
→
→
→
→
X
 
X
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Protocol Activity
Screeninga
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Follow-upq
Hours After Dose
pre-
dose 
0
0.5
1
1.5
2
4
6
8
12
24
48
72
96
120
Pharmacogenomic 
blood samplingp
X
Prior and Concomitant 
Medication(s)
X
X















X
CRU discharge 
X
Serious and non-
serious adverse event 
monitoring
X
→















X
Abbreviations: = ongoing/continuous event; BP= blood pressure; CRU = clinical research unit; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
FSH = follicle-stimulating hormone; HepBcAb = hepatitis B core antibody; HepBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HIV = human 
immunodeficiency virus.
a.
Screening should be performed within 14 days prior to the dose of lorlatinib.
b.
All subjects will be admitted to the clinical research unit (CRU) on Day -1 and discharged after the last PK sample collection on Day 6.
c.
Medical history will include a history of prior illegal drug, alcohol, and tobacco uses.  Medical history will be recorded on screening and updated on Day -1. 
d.
A full physical exam (PE) will be performed by trained medical personnel at the investigator site at screening or at Day -1.  A limited PE may be performed 
at other designated time points at the discretion of the investigator. 
e.
Clinical safety laboratory tests will be performed following an overnight fast and will include hematology, clinical chemistry, and urinalysis.  
f.
Demographics will include subject race, ethnicity, date of birth, age, and gender during the screening visit.
g.
For postmenopausal (amenorrheic for at least 12 consecutive months) female subjects only.  
h.
On screening, Day -1 and discharge day, and during follow-up visit if performed, the investigator or his/her designee will discuss with the subject the need to 
use highly effective contraception consistently and correctly according to the contraception guidelines.
i.
Subjects will need to demonstrate stable renal function during the screening period within approximately a 2-week timeframe prior to dosing. Stable renal 
function is defined as 2 eGFR values [calculated using the Modification of Diet in Renal Disease (MDRD) equation] obtained at least 3 days but not more 
than 14 days apart being within 25% of each other.  The average value of the 2 eGFR values will be used for enrollment and initial renal function 
stratification.  The SCr value used to calculate eGFR collected within 24 hours prior to lorlatinib dosing will be used for final subject stratification, group 
assignment, and PK analysis.  The CLcr value on Day -1 (calculated by Cockcroft-Gault equation) will also be calculated and recorded.
j.
Urine drug (mandatory) and alcohol breath test (at the discretion of the investigator) will be performed at screening and on Day -1.  These tests may be 
performed at any other time at the discretion of the investigator.
k.
Triplicate 12-lead ECG readings, approximately 2 minutes apart, will be taken at times specified in the table.  All ECG assessments will be made after at 
least a 10-minute rest in a supine position and prior to any blood draws or vital sign measurements.
l.
Single supine blood pressure and pulse rate measurements will be performed following at least a 5-minute rest in a supine position.  BP and PR assessments 
will be performed after the collection of ECGs and prior to the collection of blood draws if scheduled at the same time.
m. On Day 1, a single oral dose of lorlatinib will be administered in the fasted state as directed. The time of lorlatinib administration will be designated as time 
0.
n.
Serial PK blood samples will be collected prior to lorlatinib dose (time 0) and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 
and 120 (Day 6) hours post dosing.


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o.
Total urine collection will be performed on all subjects.  A blank urine sample of at least 50 mL will be collected prior to lorlatinib administration. Post-
dose urine collection will be separated into 0-24, 24-48, 48-72, 72-96, and 96-120 hour intervals.
p.
 one 4 mL blood sample for Pharmacogenomics should be drawn on Day -1. If not collected on the 
designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a subject visit.
q.
Follow-up activities (if necessary) will be performed at the discretion of the principal investigator, if there is an unresolved AE(s) at discharge, or in case of 
an early withdrawal.  These activities may include, but are not limited to, limited PE and weight, contraception check, and supine BP and pulse rate, adverse 
events, and concomitant medications.  Follow-up contact will be completed at least 28 calendar days after the last administration of the investigational 
product to capture any potential adverse events.
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Pharmacokinetic Sampling and ECG Collection Schema
Study Day(s)
1
2
3
4
5
6
Hours Before/After Dose
Pre-
dosea
0
0.5
1
1.5
2
4
6
8
12
24
48
72
96
120
Study treatment 
administration
X
PK blood sampling 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Triplicate ECGb
X
X
X
X
X
X
Urine Collectionc
X
X












X
Abbreviation: PK = pharmacokinetic.
a.
Pre-dose sample collection.
b.
Triplicate 12-lead ECG readings, approximately 2-4 minutes apart, will be taken at times specified in the table.  All ECG assessments will be made after at 
least a 10-minute rest in a supine position and prior to any blood draws or vital sign measurements.
c.
Total urine collection will be performed on all subjects that produce urine.  A blank urine sample of at least 50 mL will be collected prior to lorlatinib 
administration. Post-dose urine collection will be separated into 0-24, 24-48, 48-72, 72-96, and 96-120 hour intervals.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Lorlatinib, also known as PF-06463922, is a selective, adenosine triphosphate (ATP) 
competitive small molecule tyrosine kinase inhibitor (TKI) of the Anaplastic Lymphoma 
Kinase (ALK) or c-ROS oncogene 1 (ROS1) receptor tyrosine kinases (RTK) that also 
potently inhibits ALK kinase domain mutations responsible for resistance to crizotinib.  
Lorlatinib is currently being developed as a novel anticancer agent for the treatment of 
patients with advanced ALK-positive non-small-cell lung carcinoma (NSCLC) or 
ROS1-positive NSCLC.  
1.2. Background 
In 2007, two research groups independently reported the discovery of an NSCLC oncogenic 
fusion gene (echinoderm microtubule-associated protein- like 4 [EML4]-ALK) that combines 
portions of the EML4 gene and the ALK gene.1,2  This fusion gene encodes for the 
cytoplasmic fusion protein EML4-ALK which upon dimerisation, results in constitutive 
activation of the kinase domain of ALK.  ROS1 fusions were identified as potential driver 
mutations in a NSCLC cell line (HCC78: SLCA2-ROS1) and a NSCLC patient sample 
(CD74-ROS1).1  Approximately 3-5% of NSCLC is molecularly defined as ALK-positive
and 1-2% ROS1-positive.3,4
In vivo, lorlatinib demonstrated marked cytoreductive activity in mice bearing tumor 
xenografts that express ALK or ROS1 fusion variants, including the crizotinib resistant 
EML4-ALKL1196M or EML4-ALKG1269A mutations.  Lorlatinib treatment also significantly 
reduced the tumor size and prolonged animal survival in the orthotopic brain models 
(EML4-ALK and EML4-ALKL1196M) in mice.
The anti-tumor efficacy of lorlatinib was dose dependent and demonstrated strong 
correlations to inhibition of ALK or ROS1 phosphorylation.  The plasma concentrations 
associated with inhibitory activity of lorlatinib against EML4-ALKL1196M phosphorylation, 
and anti-tumor efficacy in EML4-ALKL1196M dependent human NSCLC cell line models, was 
utilized to project target human efficacious plasma concentrations for clinical studies.  The 
effective plasma concentration (Ceff) (unbound) for lorlatinib for EML4-ALK, 
EML4-ALKL1196M, and EML4-ALKG1202R is 6.5 nM, 51 nM, and 125 nM, respectively; when 
corrected for human plasma protein binding results in efficacious concentration (Ceff) (total) 
of 7.6 ng/mL, 62 ng/mL, and 150 ng/mL, respectively.
1.3. Non Clinical Pharmacokinetics, Metabolism and Safety of Lorlatinib
The single-dose pharmacokinetics (PK) of lorlatinib was evaluated in nonclinical species 
following intravenous (IV) and oral administration.  Plasma clearance (CL) in rats and dogs 
were 16 mL/min/kg and 9 mL/min/kg, respectively.  Lorlatinib was rapidly absorbed after a 
single oral dose to rats and dogs, with high oral bioavailability observed in both species 
(~100% rats; 97% dogs).  Renal excretion of the parent drug was limited in rats and dogs.  
Systemic exposures (peak concentration [Cmax] and area under the concentration-time curve 
[AUC]) to lorlatinib increased with increasing dose in an approximately proportional manner 


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in the pivotal toxicology studies in rats (up to 30 mg/kg/day) and dogs (up to 25 mg/kg/day).  
The binding of lorlatinib to plasma proteins were 70%, 71%, and 66% for rat, dog, and 
human, respectively.  The mean whole blood to plasma concentration ratios (Cb/Cp) of 
lorlatinib in mouse, rat, rabbit, dog and human were 0.776, 0.838, 1.05, 0.809 and 0.985, 
respectively.  After oral administration of a 10 mg/kg dose of lorlatinib to male rats, the free 
(unbound) AUC ratios of unbound brain/plasma and cerebrospinal fluid (CSF)/plasma were 
approximately 0.25 and 0.37, respectively.  This data from preliminary study indicates that 
lorlatinib can cross the blood brain barrier. 
Contribution of individual cytochrome P450 (CYP) enzymes and non-CYP enzymes to 
lorlatinib metabolism was tested in-vitro using human hepatocytes, human liver microsomes
(HLM), and recombinant enzymes. Lorlatinib was metabolized primarily by CYP3A4 and 
UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
The potential for lorlatinib (0.1 to 100 M) to inhibit human CYP1A2, 2B6, 2C8, 2C9, 2C19, 
2D6, or 3A4/5 enzymes was investigated in human liver microsomes (HLM).  The 
50% inhibitory concentration [IC50] values of lorlatinib for the direct inhibition of CYP1A2, 
2B6, 2C8, 2C19, 2D6 were >100 M.  The IC50 value for the direct inhibition of CYP2C9 
was 44 M.  The IC50 values for the direct inhibition CYP3A measured by inhibition of 
testosterone 6-hydroxylase, midazolam 1´-hydroxylase, and nifedipine oxidase activities 
were 23, 10, and 22 M, respectively.
In vitro assessment utilizing HLM indicate that lorlatinib has a low potential to inhibit 
UGT1A1, 1A4, 1A6, 1A9, 2B7, and 2B15 at clinically relevant concentrations.
Studies addressing the potential for lorlatinib to inhibit intestinal, hepatic, and renal 
transporters were carried out.  Lorlatinib did inhibit digoxin efflux, in in-vitro Madin Darby 
canine kidney with multidrug resistance protein 1(MDCK-MDR1) cells, with an IC50 value 
of 3 M, indicating that that lorlatinib may have the potential to inhibit P-glycoprotein 
(P-gp).  Lorlatinib has a low potential for drug-drug-interaction (DDI) with compounds that 
are substrates of OATP1B1 and 1B3 at clinically relevant concentrations.  Lorlatinib did not 
inhibit OAT1 and OCT2 (IC50 >50 M), but did inhibit OAT3 with an IC50 value of 2.7 M.  
This data suggest that lorlatinib may have the potential to inhibit OAT3 at clinically relevant 
concentrations.
Time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 enzymes was not 
observed after preincubation with lorlatinib in the absence or presence of the reduced form of 
nicotinamide adenine dinucleotide phosphate (NADPH), as evidenced by the absence of a 
shift in the IC50 values.  Lorlatinib demonstrated time-dependent inhibition of CYP3A as IC50
values shifted approximately 28, 14, and 25-fold to 0.81, 0.74, and 0.87 M for testosterone 
6-hydroxylase, midazolam 1´-hydroxylase, and nifedipine oxidase activities, respectively, 
after preincubation with NADPH.  Additional evaluations in HLM and hepatocytes using 
midazolam and testosterone as marker substrates confirmed that lorlatinib is a 
time-dependent inhibitor of CYP3A.


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Induction of CYP1A2, 2B6, and 3A4 by lorlatinib (0.03 to 125 M) was assessed in human 
cryopreserved hepatocytes from 3 donors and compared with induction by the positive 
controls, omeprazole, phenobarbital, and rifampin, respectively.  CYP1A2 messenger 
ribonucleic acid (mRNA) levels and activity was not induced by lorlatinib at concentrations 
up to 30 M.  Lorlatinib did induce mRNA levels and the activity of CYP2B6 and CYP3A4 
at concentrations 0.5 M and 0.1 M, respectively. 
Lorlatinib was evaluated in genetic toxicology assays consisting of definitive bacterial 
reverse mutation, in vitro micronucleus, and in vivo rat micronucleus assays.  In addition, an 
assessment of centromere staining was included as part of an exploratory in vitro 
micronucleus assay.  Lorlatinib was not mutagenic when tested in the bacterial reverse 
mutation assay at up to 5000 g/plate with or without metabolic activation.  In the in vitro 
micronucleus assay in human TK6 lymphoblastoid cells, lorlatinib was associated with a 
statistically significant increase in micronuclei formation in the 4-hour treatment conditions 
with and without metabolic activation.  Lorlatinib was negative for inducing micronuclei in 
the 27-hour treatment without metabolic activation up to the highest evaluated concentration 
(142 M; based on cytotoxicity).  Lorlatinib was also positive in the in vivo (rat) 
micronucleus assessment at 100 mg/kg/day.  A no observed effect level (NOEL) of 
30 mg/kg/day was identified with associated unbound area under the concentration-time 
curve from time 0 to 24 hours (AUC24) up to 54,000 ng•h/mL and unbound Cmax up to 
3010 ng/mL (female rats) with a projected human safety margin of 20 times (unbound Cmax
exposure of 167 ng/mL and area under the concentration-time curve from time 0 extrapolated 
to time infinity (AUCinf) exposure of 2594 ng•h/mL for a single 100 mg human dose).  
Centromere staining of micronucleated cells using fluorescent in situ hybridization (FISH) 
analysis was demonstrated in micronucleated TK6 cells and provides strong evidence for an 
aneugenic mechanism.  Based on the lack of direct deoxyribonucleic acid (DNA) interaction 
and the projected safety margin for aneugenic activity, genetic toxicity risks to humans after 
a single 100 mg dose of lorlatinib is considered to be minimal. 
Lorlatinib was well-tolerated in rats (male) and dogs given up to 100 mg/kg as a single dose.  
Minimal degeneration of pancreatic islet cells was observed in rats after a single dose at 
100 mg/kg.  Systemic unbound AUC24 exposures at 100 mg/kg in rats and dogs after the 
single dose were 4212 and 16,849 ng•h/mL, respectively, with a projected human safety 
margin of 6.5× (unbound AUCinf exposure of 2594 ng•h/mL for a single 100 mg human 
dose).  In 1-month repeated-dose nonclinical toxicity studies conducted with lorlatinib, the 
primary target organ findings were observed as effects on the pancreas, liver, hematopoietic 
and cardiovascular systems, and peripheral nerve of the rat and/or dog following single
repeat doses.  Additional findings identified in the rat or dog included an effect on the testis 
and epididymis, cognition and neurological function, gastrointestinal system, and skin.  
Findings of uncertain risk to humans included a non-specific inflammatory response, and 
effects on the thymus and clinical chemistry parameters related to the kidney.  Lorlatinib also 
has the potential to be a phototoxicant.  For additional information on repeat-dose nonclinical 
study findings refer to the single reference safety document [SRSD], which is the 
Investigator’s Brochure (IB) for lorlatinib.


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Lorlatinib was assessed in a series of safety pharmacology studies for potential effects on 
cardiovascular, central nervous system, and pulmonary function.  Given that lorlatinib is a 
central nervous system (CNS) penetrable compound and a potent inhibitor of TrkB receptors 
that have been implicated in synaptic plasticity, long-term potentiation, and memory 
processes, additional ex vivo and in vivo assessments were included as part of the safety 
pharmacology package to evaluate the potential to cause cognitive deficits.  Lorlatinib was 
evaluated for its effect on the human ether-a-go-go related gene (hERG) potassium channel, 
stably expressed in Chinese Hamster Ovary (CHO) cells.  The IC50 value for hERG current 
inhibition is >100 M (>40,641 ng/mL).  As such, it is considered unlikely for lorlatinib to 
cause QT prolongation after a single human dose of 100 mg (unbound Cmax exposure of 
167 ng/mL).  An in vivo cardiovascular assessment was performed following administration 
of a single dose in a telemetered rat study.  Dose-dependent increases in blood pressure 
(systolic, diastolic, and mean) compared to vehicle control were observed at all doses tested 
with maximal increases (22 and 37 mm Hg at 10 and 30 mg/kg, respectively) observed 
2-3 hours post-dose.  Effects started immediately post-dose and continued for up to 21 hours 
post-dose.  A biphasic heart rate response was also observed at 10 and 30 mg/kg, with an 
initial decrease during the first 2 hours post-dose and a subsequent increase at 12 or 15 hours 
post-dose that continued to 21 hours post-dose.  The maximal decrease in heart rate was 
36 beats per minute (bpm) and the maximal increase was 31 bpm.  The unbound Cmax
associated with cardiovascular changes at 10 mg/kg/day is projected to be 623 ng/mL, based 
on a single-dose rat toxicity study, approximately 4 times the unbound Cmax projected at a 
single human dose of 100 mg (167 ng/mL).  Additional cardiovascular findings were 
observed following repeat dose cardiovascular assessments in rats and dogs, and are 
summarized in the SRSD. 
To evaluate potential effects on the central nervous system, a functional observation battery 
(FOB) was incorporated into a 14-day repeat-dose and 1-month toxicity study in rats.  FOB 
effects were primarily observed in moribund animals at 60 mg/kg/day following 3 and 
13 days of dosing, including abnormal behavior (noted as teeth chattering), involuntary 
movements (noted as retropulsion and trembling), abnormal gait, uncoordinated air righting 
reflex, and reduced extensor thrust response.  There were no FOB changes identified 
following 1 month of dosing in the definitive rat study at comparable Cmax exposures 
achieved at the highest dose tested (30 mg/kg/day); therefore, it is not clear if the 
observations were directly due to effects on the CNS or related to morbidity.  The CNS 
effects at 60 mg/kg/day were associated with Day 14 unbound Cmax values of 1926 ng/mL 
that are approximately 12 times the unbound Cmax projected after a single human dose of 
100 mg (167 ng/mL).  The potential for an effect on cognitive function was suggested from 
an ex vivo hippocampal brain slice assay and an exploratory in vivo model, the rat contextual 
renewal model.  Lorlatinib caused a significant reduction in amplitude of long term 
potentiation, a measure that is widely considered as one of the cellular mechanisms that 
underlie learning and memory formation.  This effect was observed at 1 M (406 ng/mL) but 
not at 100 nM (41 ng/mL).  As TrkB receptors have been implicated in synaptic plasticity, 
long term potentiation, as well as memory processes in rats, the results with lorlatinib may 
reflect a potential to affect cognitive function that is driven by secondary pharmacology at
the TrkB receptor; however, these results cannot be used to assess safety margins relevant to 
human exposure due to the exploratory nature and variability in sensitivity of the model.


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Range-finding developmental toxicity studies were conducted in rats and rabbits.  Embryonic 
and fetal toxicity (including embryo lethality and fewer and smaller viable fetuses with some 
external and visceral malformations) was observed in both species at all dose levels, with the 
lowest observed adverse effect level (LOAEL) of 1 and 4 mg/kg/day in rats and rabbits, 
respectively with unbound AUC24 exposures of 2315 and 1138 ng•h/mL, respectively.  The 
projected human safety margins were determined to be 1 times and 0.4 times in rats and 
rabbits, respectively (unbound AUCinf of 2594 ng•h/mL at a single dose of 100 mg in 
humans).
Additional information for lorlatinib may be found in the single reference safety document 
(SRSD), which for this study is the Investigator’s Brochure (IB).  
1.3.1. Clinical Summary 
1.3.1.1. Safety and Pharmacokinetics
There are 3 ongoing clinical studies with lorlatinib in patients with ALK-positive or 
ROS1-positive NSCLC.  B7461001 is a single-agent study currently in Phase 2 and described 
in detail below.  B9991005 is a Phase 1b/2 open-label, dose finding study to evaluate safety, 
efficacy, pharmacokinetics and pharmacodynamics of avelumab [MSB0010718C] in 
combination with either crizotinib or lorlatinib in patients with advanced or metastatic 
NSCLC. B7461006 is an open-label, multicenter, randomized Phase 3 study comparing 
lorlatinib to crizotinib in treatment-naïve ALK-positive advanced NSCLC.
Eight (8) healthy volunteer studies that have been completed are described in detail below 
and include B7461004, B7461017, B7461005, B7461007, B7461008, B7461011, B7461012, 
and B7461016.  These studies also utilized the recommended Phase 2 dose (RP2D) of 
100 mg once daily (QD) for a single dose administration.  B7461004 and B7461017 are
completed radio-labelled mass balance studies.  B7461005 is a completed relative 
bioavailability study.  B7461007 is a completed absolute bioavailability study.  B7461008 is 
a completed study that evaluated the effects of acid-reducing agents and food on PK of 
lorlatinib.  B7461011 is a completed study that evaluated the effect of a strong enzyme 
inducer rifampin on the PK of single-dose lorlatinib. B7461012 is a completed study that 
evaluated the effect of a strong CYP3A4/5 inhibitor, itraconazole, on the PK of single-dose 
lorlatinib. B7461016 is a completed bioequivalence study.
1.3.1.1.1. Study B7461001
Study B7461001 is a Phase 1/2, open-label, multicenter, multiple-dose, dose-escalation, 
safety, PK, pharmacodynamic (PD) and anticancer efficacy exploration study of lorlatinib as 
a single-agent in patients with advanced ALK-positive and advanced ROS1-positive NSCLC.
B7461001 is being conducted in 2 parts: Phase 1 and Phase 2.  The Phase 1 portion of the 
study was aimed at estimating the maximum tolerated dose (MTD) for single-agent lorlatinib
in dose-escalation cohorts in patients with advanced ALK-positive or advanced 
ROS1-positive NSCLC with or without asymptomatic CNS metastases, and was planned to 
enroll up to 36 patients (depending on toxicities observed).  The Phase 2 portion of the study 
is being conducted with single-agent lorlatinib at the identified recommended Phase 2 dose 


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(RP2D) and is enrolling patients with advanced ALK-positive NSCLC and patients with 
advanced ROS1-positive NSCLC, with or without asymptomatic CNS metastases.
The Phase 1 portion of this study employed a modified continual reassessment method 
(CRM) to estimate the MTD.  The CRM was initiated at 25 mg QD and recommended 
escalation to 75, 100, 150, and 200 mg QD based on no dose limiting toxicities (DLTs) 
observed at the previous dose levels tested.  At 200 mg QD, one (1) DLT occurred in a 
patient who failed to receive 16 of the planned 21 lorlatinib doses in Cycle 1 due to Grade 1 
vision change, abnormal dreams and photosensitivity reaction, and Grade 2 aphasia and 
cognitive disorder.  Although the CRM model recommended continuation to the next higher 
dose above 200 mg QD, a decision was made among the treating investigators and the 
sponsor to re-test lower doses (ie, outside of the CRM model) to better understand and 
evaluate the CNS effects observed at the higher dose levels.  These CNS effects observed 
consisted of mostly Grade 1 and Grade 2 transient effects including changes in speech, 
cognition, memory and mood. 
Overall, 100 mg QD was a well-tolerated dose.  None of the patients at this dose required 
dose reduction and dose delays were not attributed to CNS effects, but rather to 
hypercholesterolemia or hypertriglyceridemia or disease related events.  The data from dose 
escalation portion of B7461001 study identified lorlatinib to be well-tolerated.  Based on the 
PK data observed, simulated patient exposure showed the 100 mg QD dose to be the lowest 
dose exceeding the lorlatinib Ceff of 150 ng/mL during the majority of the dosing cycle once 
steady-state was reached.  The Ceff of 150 ng/mL was a concentration predicted to result in 
>80% tumor growth inhibition of the ALKG1202R resistance mutation.
The 100 mg QD dose was chosen as the RP2D based on the entirety of the safety, efficacy, 
and clinical pharmacology data.  The RP2D was not based on formal DLT and MTD 
determinations due to the nature of the cognitive effects. 
As of May 2016, lorlatinib had been administered to a total of 54 patients across 7 QD doses 
(10, 25, 50, 75, 100, 150, and 200 mg) and 3 twice a day (BID) doses (35, 75, and 100 mg).  
The most commonly occurring treatment-related adverse event (AE) was 
HYPERCHOLESTEROLEMIA reported in 68.5 % patients, CNS EFFECTS reported in 
44.4% of patients, HYPERTRIGLYCERIDEMIA and peripheral edema reported each in 
37.0% of patients, and PERIPHERAL NEUROPATHY reported in 35.2% of the patients.  
All of the treatment-related AEs were reported with a maximum Common Terminology 
Criteria (CTC) Grade 3, with the exception of 2 patients with Grade 4 
HYPERCHOLESTEROLEMIA and 1 patient with Grade 4 gamma-glutamyltransferase 
increased.  Of note, terms in all caps are cluster terms as defined in the IB.  
The Phase 2 began enrollment in September 2015.  Enrollment has been rapid, with 
111 patients dosed as of May 2016.  The overall the safety profile has been consistent with 
that observed in the Phase 1.  


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As of March 2017, single and multiple dose PK data from Phase 1 have been analyzed from 
10-200 mg QD and 35-100 mg BID dose cohorts.  All 54 patients had at least 1 measurable 
PK concentration and 1 PK parameter of lorlatinib. PK parameters are summarized in Table 
1 and Table 2 after single and multiple dose administration. 
Table 1.
Summary of Lorlatinib Single Dose PK Parameters – B7461001 Phase 1
Day -7 Lead In: QD Doses
10 mg QD
50 mg QD
75 mg QD
100 mg QD
200 mg QD
N, n
3, 1
2, 2
12, 11
16, 15
3, 3
AUCinf [ng•hr/mL]
698.0
(7210, 7240)
7663 (79)
8236 (25)
18340 (61)
AUCinf(dn)[ng•hr/mL/mg]
69.80
(144, 145)
102.2 (79)
82.36 (25)
91.68 (61)
AUCtau [ng•hr/mL]
488.2 (21)
(3310, 3880)
3990 (55)
5110 (28)
11410 (43)
AUCtau(dn) [ng•hr/mL/mg]
48.82 (21)
(66.1, 77.7)
53.14 (54)
51.10 (28)
57.13 (43)
CL/F [L/hr]
14.30
(6.91, 6.94)
9.788 (79)
12.14 (25)
10.90 (61)
Cmax [ng/mL]
50.80 (17)
(390, 423)
489.1 (45)
595.5 (37)
1201 (19)
Cmax(dn) [ng/mL/mg]
5.080 (17)
(7.80, 8.46)
6.523 (45)
5.955 (37)
6.003 (19)
MRT [hr]
23.7
(27.7, 43.1)
36.0 11.7
27.0 7.04
25.8 6.36
Tmax[hr]
1.98 
(1.00-2.97)
1.25 
(0.500-2.00)
1.09 
(0.500-4.03)
1.96 
(0.517-4.33)
2.00 
(1.18-3.00)
Vz/F [L]
373.0
(166, 307)
367.9 (54)
356.3 (39)
307.8 (41)
t½ [hr]
18.0
(16.6, 30.8)
27.2 8.30
20.9 5.03
19.8 3.30
Day -7 Lead In: BID Doses
35 mg BID
75 mg BID
100 mg BID
N, n
3, 2
3, 1
4, 4
AUCinf [ng•hr/mL]
(2630, 3690)
6860
6318 (56)
AUCinf(dn)[ng•hr/mL/mg]
(75.1, 105)
91.40
63.18 (56)
AUCtau [ng•hr/mL]
982.4 (9)
2996 (20)
2925 (47)
AUCtau(dn)[ng•hr/mL/mg]
28.03 (9)
40.00 (20)
29.25 (47)
CL/F [L/hr]
(9.48, 13.3)
10.9
15.83 (56)
Cmax [ng/mL]
202.2 (57)
594.9 (27)
507.2 (51)
Cmax(dn) [ng/mL/mg]
5.776 (57)
7.933 (27)
5.072 (51)
MRT [hr]
(30.8, 37.7)
33.0
22.1 6.76
Tmax[hr]
1.20 
(0.500-1.97)
1.23
(1.00-2.00)
2.00
(1.10-3.07)
Vz/F [L]
(362, 472)
410.0
378.3 (54)
t½ [hr]
(24.6, 26.5)
26.00
17.18 5.19
Cycle 1 Day 1: QD Doses
25 mg QD
150 mg QD
N, n
3, 3
3, 3
AUCtau[ng•hr/mL]
1387 (35)
7474 (73)
AUCtau(dn) [ng•hr/mL/mg]
55.49 (35)
49.80 (73)
Cmax [ng/mL]
149.2 (71)
760.0 (58)
Tmax [hr]
2.00 (0.500-2.05)
1.05 (1.00-3.00)
Source: B7461001 CSR Table 14.4.4.1.1.1
Geometric mean (geometric %CV) for all except:  median (range) for Tmax; arithmetic mean (standard deviation) for t½
and MRT.  The single observation was reported when n=1 and the range was reported when n=2.
N = Number of patients in the treatment group; n= number of patients where t½, MRT, AUCinf, CL/F and Vz/F were 
determined.


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Table 2.
Summary of Lorlatinib Steady-State PK Parameters After Repeated QD Dosing – B7461001 Phase 1
Cycle 1 Day 15: QD Doses
10 mg QD
25 mg QD
50 mg QD
75 mg QD
100 mg QD
150 mg QD
200 mg QD
N,nb, nc
3, 3, 1
3, 3, 0
3, 2, 2
12, 12, 11
16, 15, 14
3, 3, 0
2, 2, 2
AUCtau [ng•hr/mL]
752.1 (26)
1701 (29)
3367 (39)
4107 (53)
5121 (30)
6157 (9)
(4480, 12900)
AUCtau(dn) [ng•hr/mL/mg]
75.21 (26)
68.12 (29)
67.50 (39)
56.62 (48)
51.21 (30)
41.02 (9)
(22.4, 64.7)
CL/F [L/hr]
13.27 (26)
14.72 (29)
14.84 (39)
176.66 (48)
19.52 (30)
24.37 (9)
(15.5, 44.6)
Cmax [ng/mL]
67.29 (18)
138.1 (35)
359.7 (27)
429.6 (48)
550.2 (32)
541.0 (42)
(760, 1430)
Cmax(dn) [ng/mL/mg]
6.729 (18)
5.522 (35)
7.193 (27)
5.925 (44)
5.502 (32)
3.604 (42)
(3.80, 7.15)
Rac
1.54 0.075
1.24 0.210
(0.879, 1.33)
1.12 0.446
1.07 0.311
1.00 0.791
(0.571, 0.729)
Rss
0.993
ND
(0.401, 0.719)
0.613 0.290
0.660 0.186
ND
(0.384, 0.403)
Tmax [hr]
1.00 
(1.00-1.08)
1.00 
(1.00-2.00)
2.00
(1.92-2.75)
1.03
(0.500-2.00)
1.13
(1.00-4.00)
1.30
(1.00-24.0)
1.61 
(1.22-2.00)
Cycle 1 Day 15: BID Doses
35 mg BID
75 mg BID
100 mg BID
N,nb, nc
1, 1, 1
3, 3, 1
3, 3, 3
AUCtau [ng•hr/mL]
2140
3574 (35)
4058 (33)
AUCtau(dn) [ng•hr/mL/mg]
61.30
47.67 (35)
44.66 (47)
CL/F [L/hr]
16.30
20.99 (35)
22.37 (47)
Cmax [ng/mL]
370.0
550.0 (23)
600.5 (27)
Cmax(dn) [ng/mL/mg]
10.60
7.333 (23)
6.609 (37)
Rac
2.090
1.23 0.352
1.52 0.296
Rss
0.8150
0.5420
0.769 0.136
Tmax [hr]
0.500
0.550 (0.500-2.05)
2.00 (1.00-2.00)
Source: B7461001 CSR Table 14.4.4.1.1.1
N = Number of patients in the treatment group; nb=number of patients where Rac were determined; nc=number of patients where Rss were determined.
Geometric mean (geometric %CV) for all except:  median (range) for Tmax; arithmetic mean (standard deviation) for t½, MRT Rac and Rss.  Single observation was reported 
when n=1 and range when n=2.
Rac is the observed accumulation ratio calculated by Day 15 AUCtau/Lead In Day -7 AUCtau or Day 1 AUCtau.
Rss is the steady state accumulation ratio calculated by Day 15 AUCtau/Lead In Day -7 AUCinf.


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After single oral administration of the 
 form of lorlatinib under fasted 
conditions, median peak plasma concentrations were observed between 1 and 2 hours.  
Following attainment of Cmax, lorlatinib plasma concentrations showed a bi-exponential 
decline with mean terminal elimination half-life ranging across the tested dose groups from 
17.2 to 27.2 hours, apparent oral clearance (CL/F) of 9.8 to 15.8 L/hr and volume of 
distribution (Vz/F) of 308 to 410 L.  Variability in PK was observed with a coefficient of 
variation (%CV) of 25-79% across tested doses for AUCinf and 17-45% for Cmax following 
single oral administration.
After repeated QD oral administration, steady state should have been achieved before Day 15 
based on the lorlatinib single dose terminal elimination half-life.  The observed and steady 
state accumulation ratios (Rac and Rss, respectively) seemed to be less than the predicted 
values based on the calculated lorlatinib elimination rate and the frequency of administration, 
which suggests auto-induction may play a role in lorlatinib disposition. The auto-induction 
seems more significant at higher dose level, as the observed accumulation index becomes 
smaller while the predicted accumulation index stays similar with increase of dose.
PK data (March 2017) after 100 mg single and multiple dosing in Phase 1 with 
 
 drug form and in Phase 2 with 
 drug form are summarized in Table 3.
Table 3.
Summary of Lorlatinib 100 mg QD PK Parameters after Single and 
Multiple Doses in B7461001
Dose
N
AUC
(ng•hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t½
(hr)
CL/F
(L/hr)
Vz/F
(L)
Phase 1: 
Formulation
Single Dose
16
8236 (25)
595.5 (37)
1.96 
(0.517-4.33)
20.9 ± 5.03
12.14 (25)
356.3 (39)
Multiple Doses
16
5121 (30)
550.2 (32)
1.13 
(1.00-4.00)
NA
19.52 (30)
NA
Phase 2: 
Formulation
Single Dose
19
9088 (35)
695.2 (40)
1.15 
(0.500-4.02)
23.6 ± 9.37
11.01 (35)
351.5 (37)
Multiple 
Doses
22
5650 (39)
576.5 (42)
1.96 
(0.500-22.7)
NA
17.70 (39)
NA
Source: B7461001 CSR, Table 14.4.4.1.2.1.
Geometric mean (%CV) for AUC, Cmax, CL/F, and Vz/F; arithmetic mean (± standard deviation) for t½; median (range) 
for Tmax.
AUCinf for single-dose and AUCτ for multiple doses.
Vz/F is calculated by Dose/(lambda z × AUCinf) for single dose.
In vitro data indicated that lorlatinib is associated with time-dependent inhibition and 
induction of CYP3A.  In order to assess the net clinical effect of lorlatinib on CYP3A, the
CYP3A substrate drug midazolam was given alone and 14 days after administration of 25 mg 
QD and 150 mg QD of lorlatinib to a total of 6 patients.  Midazolam area under the 
concentration-time curve from time 0 to the time of the last quantifiable concentration
(AUClast) geometric mean values (coefficient of variation [%CV]) decreased from 
51.3 (47%) to 20.4 (18%) ng•hr/mL and from 36.5 (20%) to 14.4 (25%) ng•hr/mL, 
respectively, with 25 mg QD and 150 mg QD lorlatinib dosing. Likewise, midazolam Cmax
CCI
CCI
CCI
CCI
CCI


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geometric mean values (CV) decreased from 16.1 (42%) to 9.7 (40%) ng/mL and from 
11.6 (48%) to 5.73 (43%) ng/mL, respectively, with 25 mg QD and 150 mg QD lorlatinib 
dosing.  These results indicated that at clinical dose levels, lorlatinib has the potential to 
reduce the exposure of CYP3A substrates. Concomitant use of lorlatinib with medications 
which are either sensitive CYP3A substrates or substrates with narrow therapeutic indices
should be avoided.
1.3.1.1.2. Study B7461004 and Study B7461017
Study B7461004 is a completed Phase 1 study which evaluated the mass-balance of 
radiolabeled lorlatinib in 6 healthy male subjects after a single oral 100 mg dose of lorlatinib
containing approximately 100 Ci of [14C]lorlatinib.
Results indicated a mean 47.7% radioactivity recovery in urine and 40.9% recovery in feces 
through the last collection interval.  Most of the administered radioactivity was recovered in 
the first 144 hours post-dose (85.11%).  The overall mean recovery of radioactivity in urine 
and feces samples was 88.6% over the 288-hour study, with recovery in individual subjects 
ranging from 83.6 to 90.8%. The urinary excretion of unchanged lorlatinib was found to be a 
minor route of elimination with less than 1% of the administered parent drug, excreted 
unchanged in the urine over the 168-hour collection period. The geometric mean renal 
clearance (CLR) was 1.57 mL/min.
Metabolic profiling indicated that the most abundant circulating metabolite was a benzoic 
acid metabolite resulting from cleavage of the ring structure of lorlatinib and accounting for 
21.0% of the total circulating radioactivity in plasma.  The plasma concentration of this
metabolite (PF-06895751) is currently monitored in clinical studies.  In the urine, the 2 major 
metabolites identified were an N-oxide and a glucuronide product, accounting for 16.3% and 
10.9% of the dose, respectively.  
Study B7461017 is a second absorption, distribution, metabolism, excretion (ADME) study 
with 100 µCi/100 mg [14C]lorlatinib conducted in 6 healthy male volunteers that has 
completed as of January 2018 and the analyses of the results are still ongoing. The objective 
of this study was to further the understanding of human metabolism of lorlatinib, specifically 
with respect to the metabolic pathway involving the formation of PF-06895751, a benzoic 
acid metabolite identified in Study B7461004 as the major lorlatinib metabolite in plasma, 
and the metabolic fate of the resultant “bottom half” of the lorlatinib molecule. For this 
purpose, the location of the radiolabel was moved from the original location on the carbonyl 
carbon (B7461004) to the pyrazole ring (B7461017). Additional objectives included: the 
evaluation of the PK of lorlatinib and its PF-06895751 metabolite, evaluation of the 
differences in total radioactivity profile resulting from the change in the location of the 
radiolabel on the lorlatinib molecule, as well as confirmation of mass balance and the relative 
contributions from urinary and fecal routes of excretion with the change in radiolabel 
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Metabolic profiling analysis in plasma, urine and feces from Study B7461017 is still 
currently ongoing. However, based on preliminary data it is not anticipated that there will be 
a meaningful change in the identification of the drug metabolizing enzymes contributing to 
the metabolic clearance of lorlatinib. There are no new metabolites identified with 
abundance greater than or close to that of PF-06895751.
1.3.1.1.3. Study B7461005
Study B7461005 is a completed Phase 1, randomized open-label study in 19 healthy 
volunteers to estimate the relative bioavailability of two new lorlatinib formulations (
 
, [Test]) compared to the 
 formulation (Reference). 
The results supported the switch to 
 formulation of lorlatinib in all future clinical 
trials including this study (see IB for more details).
1.3.1.1.4. Study B7461007
Study B7461007 is a completed Phase 1 study in 12 healthy volunteers, designed to estimate 
the absolute bioavailability of lorlatinib after oral administration relative to intravenous (IV) 
administration.
The results of this study indicated that the absolute bioavailability of lorlatinib when 
administered as single oral dose in the fasted state was 80.78% in humans.
1.3.1.1.5. Study B7461008
Study B7461008 is a completed Phase 1 study in 24 healthy volunteers, designed to evaluate 
the effect of rabeprazole and food on the pharmacokinetics of lorlatinib and to assess the 
relative bioavailability (BA) of an oral solution of lorlatinib to the tablet formulation of 
lorlatinib. 
Results indicate that a high fat meal has no effect on the systemic exposure of lorlatinib.  
Similarly, proton pump inhibitor (PPI) rabeprazole had only a marginal effect on the 
systemic exposure of lorlatinib.  Based on these results, the current recommendation is that 
lorlatinib can be given without regard to food or any acid reducing agents such as PPIs or 
H2-receptor antagonists. 
In one healthy volunteer, the PR interval prolongation was associated with one episode of 
transient second degree atrioventricular (AV) block (Mobitz type 1; Wenkebach).  
Subsequently, retrospective review of patients in Study B7461001, found one patient with the 
PR interval prolongation that may have been associated with the progression of pre-existing 
AV block to complete heart block.  When the complete heart block was identified, the patient 
was immediately evaluated and subsequently treated by placement of an implanted 
pacemaker. 
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In response to the observation of PR interval prolongation, data from all available human 
studies (approximately 100 patients in Study B7461001 and 45 in single dose healthy 
volunteer studies) were reviewed.  Additional instances were identified of asymptomatic 
increases in the PR interval (>200 msec), usually most notable at the time of Cmax (1-2 hours 
post-dose) in healthy volunteers.  Of note, the subjects with a PR interval >200 msec were 
generally those with a baseline values at the upper end of the normal range.
The electrocardiogram (ECG) changes appear limited to the PR interval, with no impact on 
QRS or QT intervals.  This impact on the PR interval is supported by preclinical animal 
studies, as described in the current IB.
Although isolated PR interval prolongation (first or second degree AV block) may not pose 
an immediate risk to patient safety, the potential for development of complete heart block 
warrants that future studies exclude patients with a baseline PR interval 220 msec, or 2nd or 
3rd degree AV block (unless an implanted pacemaker is in place).  Further, for the healthy 
volunteers in this study the upper limit of normal for PR interval will be defined as PR 
interval of 180 msec.
1.3.1.1.6. Study B7461011
Study B7461011 was a Phase 1 open-label, two-period, two-treatment, fixed-sequence 
crossover study to estimate the effect of multiple doses of rifampin on a single dose of 
lorlatinib in healthy volunteers.  The study involved the administration of a single 100-mg 
lorlatinib dose in the first period followed by a washout period of at least 10 days prior to the 
second period.  The second period involved the administration of 600 mg once daily rifampin 
from Days 1 to 12 and a 100-mg lorlatinib single dose administration concurrently on Day 8.  
Twelve subjects were enrolled in the study per protocol, and all subjects completed Period 1.  
During Period 2, on Day 10 (2 days after having received the single 100-mg lorlatinib dose 
with 600 mg QD rifampin) all volunteers were noted to have elevated values for aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT), and the rifampin dose was 
withheld.  No elevations in bilirubin were observed and the subjects were asymptomatic 
other than nausea (mild in 7 subjects, and moderate in 2 subjects) and vomiting (mild in 
3 subjects and severe in 1 subject).  On Day 11, the AST and ALT values were still elevated, 
and a decision was made to withhold the Day 11 and Day 12 rifampin doses for all subjects.  
Five (5) subjects were hospitalized for observation and these events were reported as serious 
adverse events (SAEs).  The subjects were subsequently discharged within 2 days and with 
no further clinical sequelae. The elevations in AST and ALT trended down or normalized 
following the suspension of rifampin.   
A Dear Investigator Letter describing the safety observations from this study was distributed 
to all sites participating in lorlatinib clinical trials.  The letter also reminded investigators that 
concomitant use of rifampin and all strong CYP3A inducers is prohibited in all lorlatinib
clinical studies, as described in the exclusion criteria of the protocols, and in the 2015 and 
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1.3.1.1.7. Study B7461012
Study B7461012 was a Phase 1 open-label, two-period, two-treatment, fixed-sequence 
crossover study to estimate the effect of multiple doses of itraconazole on a single dose of 
lorlatinib in healthy volunteers. 
The study was designed to potentially evaluate up to 6 treatments: single dose of lorlatinib
50 mg, 75 mg or 100 mg in Period 1 and lorlatinib 50 mg, 75 mg or 100 mg on Day 5 in
combination with multiple dose itraconazole 200 mg QD on Days 1 to 4 and Days 6 to 11 in 
Period 2, following a washout period of at least 10 days between lorlatinib doses in the 
2 periods. Subjects were enrolled sequentially, starting with lorlatinib dosing at the lowest 
dose level of 50 mg. The next lorlatinib dose level was initiated only after 96 hours past 
lorlatinib dosing in the previous dose levels and no safety concerns were observed.  A total of 
16 subjects were screened, assigned to treatment, and completed the study.
Co-administration of multiple oral doses of 200 mg QD itraconazole resulted in an increase 
in total systemic exposure of lorlatinib (of approximately 42% for AUCinf relative to a single 
100 mg lorlatinib dose, given alone), indicating that metabolism of lorlatinib is sensitive to 
inhibition of CYP3A enzymes. The relative increase in peak exposure (Cmax) was 24%. 
Lorlatinib was well-tolerated in this study, no deaths, SAEs, severe AEs, permanent 
discontinuations, temporary discontinuations, or dose reductions due to AEs were reported.
1.3.1.1.8. Study B7461016
Study B7461016 was a Phase 1, randomized, single-dose, open-label, 4-period, 4-treatment,
4-sequence, crossover study balanced for first order residual effect in 20 healthy adult 
volunteer subjects employing administration of the Phase 2 clinical lorlatinib tablets 
(Reference: 4 × 25-mg tablets) and the 3 proposed commercial lorlatinib tablet strengths 
(Test formulations: 4 × 25-mg tablets, 2 × 50-mg tablets, 1 × 100-mg tablet) under fasted 
conditions.
A total of 20 subjects were screened with 5 subjects assigned to each of the 4 sequences. All 
subjects completed the study. 
Bioequivalence was demonstrated for each of the Test formulations (lorlatinib commercial 
4 × 25-mg tablets, commercial 2 × 50-mg tablets and commercial 1 × 100-mg tablet) versus 
the Reference (lorlatinib clinical 4 × 25-mg tablets) in healthy volunteers under fasted 
conditions. The 90% CIs of ratios of adjusted geometric means (Test/Reference) fell wholly 
within the bioequivalence limits (80%-125%) for AUCinf and Cmax for all 3 treatment 
comparisons. All treatments were safe and well-tolerated in healthy volunteers evaluated in 
this study under fasted conditions.
1.4. Study Rationale 
In humans, unchanged lorlatinib accounted for less than 1% of dose in urine, indicating 
minimal urinary excretion of parent drug in humans.  Therefore, renal impairment would not 
be expected to have a major effect on lorlatinib PK.  A population PK analysis was 
conducted with data from 95 healthy volunteers from 6 healthy volunteer studies (B7461004, 


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B7461005, B7461007, B7461008, B7461011 and B7461016) and 330 ALK-positive or 
ROS1-positive NSCLC patients from the B7461001 clinical study 
(PMAR-EQDD-B746a-DP4-681). Baseline renal function was evaluated in the model as a 
potential covariate for lorlatinib PK. The analysis population for single dose PK included 
226 healthy volunteers and patients with baseline normal renal function (defined as creatinine 
clearance [CLcr] ≥90 mL/min), 120 with mild renal impairment (defined as CLcr ≥60 mL/min 
and CLcr <90 mL/min), 45 with moderate renal impairment (defined as CLcr ≥30 mL/min and 
CLcr <60 mL/min), and 1 patient with severe renal impairment (defined as 
CLcr <30 mL/min). Baseline creatinine clearance was determined to be a statistically 
significant predictor of lorlatinib clearance in the covariate analysis. The median estimated 
single dose lorlatinib clearance was 18% and 26% lower in mild and moderate renal 
impairment (8.04 L/hr and 7.22 L/hr), respectively, compared to those with baseline normal 
renal function (9.80 L/hr), suggesting potentially higher exposure in the impaired 
subpopulations. Despite the estimated decrease in median lorlatinib clearance, the range of 
individual estimates of lorlatinib clearance for patients with mild and moderate renal 
impairment heavily overlapped with the range estimated for those with normal renal 
function. No conclusions could be drawn for patients with severe renal impairment due to 
the small sample size (n=1). As a result of this analysis, this present study is being 
conducted to evaluate the greatest potential effect of varying extent of renal impairment
(ie, mild, moderate, and severe) on lorlatinib PK with single dose administration. 
In this study, the PK of lorlatinib after a single oral dose of lorlatinib will be evaluated in 
non-cancer subjects with normal renal function, mild renal impairment, moderate renal 
impairment (defined as estimated glomerular filtration rate [eGFR] ≥30 mL/min and eGFR
<60 mL/min), and severe renal impairment (defined as eGFR <30 mL/min not requiring 
dialysis) who are otherwise healthy. Data from this study would allow for the estimation of 
any changes in lorlatinib plasma exposure with varying extent of renal impairment.
 
 
 
 
 
 
1.5. Dose Rationale
As discussed in Section 1.3, lorlatinib was evaluated in a series of in vitro and in vivo genetic 
toxicity studies.  The no effect level for micronucleus induction was identified at 
30 mg/kg/day, and is associated with unbound AUC24 exposures up to 54,000 ng•h/mL 
(female rats), offering a safety margin 7 times over the total AUCinf observed (7629 ng•h/mL 
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for 
tablets, Study B7461005) from a single oral dose of 100 mg in humans.  Based 
on the lack of direct DNA interaction and the expected safety margin for aneugenic activity, 
genetic toxicity risks to humans after a single 100 mg dose of lorlatinib is considered to be 
minimal.
The recommended Phase 2 dose for lorlatinib is 100 mg QD, which, in the Phase 1 
dose-escalation portion of Study B7461001, was well-tolerated and associated with antitumor 
activity.  It is two dose levels below the dose (and 50% of the dose) at which a DLT was 
observed: 200 mg QD.  MTD was not reached for lorlatinib with highest clinically tested 
dose being 200 mg QD. Lorlatinib 100 mg single-dose administered as a single agent was 
demonstrated to be safe and well-tolerated in healthy volunteer studies. As tested in cancer 
patients, single doses of lorlatinib up to 200 mg have been safely administered and there is a
large safety margin based on preclinical and clinical data. Hence, potential increases in 
lorlatinib exposure that may be observed with renal impairment should be safe for up to a 
2-fold increase from the proposed 100 mg single dose. The 18% decrease in clearance and 
resultant exposure increase following a single 100 mg dose of lorlatinib in mild renal 
impairment NSCLC patients from Study B7461001 (as described in Section 1.4) is expected 
to be below the 2-fold threshold of exposure known to be safe and well-tolerated for single 
dose administration.  To be conservative, subjects with varying degrees of renal impairment 
will not be dosed simultaneously, but rather enrollment will occur sequentially starting first 
with the subjects with mild renal impairment, then the subjects with moderate renal 
impairment, and finally the subjects with severe renal impairment. Enrollment in each group 
will initiate only until safety data from the prior less severe renal impairment population is 
first characterized. This present study will evaluate the 100 mg single dose of lorlatinib first 
in mild and moderate renal impairment subjects.  Based on the initial PK, safety, and 
tolerability data from the prior less severe renal impairment population(s), dose reduction 
may be adopted for subjects with more severe renal impairment as determined by the 
Sponsor and in Section 3.1.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 
•
To evaluate the effect of renal impairment on the 
single dose pharmacokinetics of lorlatinib on 
otherwise healthy subjects.
•
Plasma AUCinf and Cmax for lorlatinib.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the safety and tolerability of a single 
dose of lorlatinib in healthy subjects and subjects 
with renal impairment.
•
Clinical laboratory tests, physical examination 
findings, vital sign measurements, ECGs, and 
adverse events.
Tertiary Objective(s): 
Tertiary Endpoint(s): 
•
To evaluate the pharmacokinetics of lorlatinib 
metabolite(s) in healthy subjects and subjects 
with renal impairment who are otherwise 
healthy.
•
Plasma AUClast, Tmax, t½, CL/F, Vz/F, CLR, Ae 
and Ae% for lorlatinib.
•
Plasma AUCinf, AUClast, Cmax, Tmax, t½, MRCmax, 
MRAUCinf, MRAUClast for lorlatinib 
metabolite(s).
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Exploratory Objective(s): 
Exploratory Endpoint(s): 
 
 
 
  
 
 
 
 
3. STUDY DESIGN
3.1. Study Overview
This will be a Phase 1, open-label, multi-center, single treatment study in subjects with 
normal renal function and varying degrees of renal impairment.  Each subject will receive a 
single oral dose of lorlatinib administered in the fasted state.
This study is aimed toward enrolling approximately 32 evaluable subjects who complete the 
PK assessments. Subjects with the following renal function will be enrolled (Table 4).
Table 4.
Renal Function Groups
Group (n)
Renal Function
eGFR
A (n=8)
normal 
≥90 mL/min
B (n=8)
mild renal impairment
≥60 - <90 mL/min
C (n=8)
moderate renal impairment
≥30 - <60 mL/min
D (n=8)
severe renal impairment
<30 mL/min and not requiring 
dialysis
Subjects who do not complete all PK collections may be replaced to ensure 8 evaluable 
subjects in Groups A, B, and C and at least 4 evaluable subjects in Group D.
eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation 
as follows:
eGFR (mL/min/1.73m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American)
where Scr, std denotes serum creatinine measured with a standardized assay for serum 
creatinine. Note that the value of eGFR, which is directly obtained from the lab or calculated 
using the equation above, is generally normalized to an average body size of 1.73 m2 for 
diagnosis, prognosis and treatment of renal disease.  In terms of clearance of renally filtrated 
drugs (including secreted drugs), renal elimination capacity is related to absolute glomerular 
filtration rate (GFR) in mL/min.  The MDRD-derived, body surface area (BSA)-adjusted 
value of eGFR used to obtain absolute GFR (mL/min) for renal disease classification or 
subject assignment into different renal disease groups should be multiplied by the individual 
subject’s normalized body surface area (ie, measured BSA/1.73 m2).  The BSA of an 
individual can be calculated by the following formula as described below:
BSA = (Weight0.425 x Height0.725) x 0.007184
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In addition CLcr will be calculated using the Cockcroft-Gault equation as follows:
CLcr (mL/min) = [140 – age (years)] × total body weight (kg) × (0.85 for females) 
72 × serum creatinine (mg/dL)
Subjects will need to demonstrate stable renal function during the screening period within 
approximately a 2-week timeframe prior to dosing. Stable renal function is defined as 
2 eGFR values obtained at least 3 days but not more than 14 days apart being within 25% of 
each other.  The average value of the 2 eGFR values will be used for study enrollment and 
initial renal function stratification.  The SCr value used to calculate eGFR collected within 
24 hours prior to lorlatinib dosing will be the value used for final subject stratification, group 
assignment, and PK analysis.  The CLcr value will be recorded at the same time eGFR is 
determined.  The CLcr value on Day -1 (calculated by Cockcroft-Gault equation) will be 
calculated and recorded.
In order to safeguard subject safety, this study will enroll subjects with renal impairment in a 
staggered fashion. A single oral dose of 100 mg lorlatinib will be administered first to 
subjects with mild renal impairment (Group B).  After single 100 mg oral dose of lorlatinib is 
tolerated in at least 3 subjects with mild renal impairment, subjects with moderate renal 
impairment (Group C) will be enrolled one at a time and administered a single oral dose of 
lorlatinib.  There will be an observation period of at least 1 week after dosing of the first 
3 subjects to evaluate safety and tolerability.  Based on the safety and tolerability of the first 
3 subjects in Group B, a dose lower than 100 mg of lorlatinib may be considered for 
Group C, as determined by the Sponsor. After dosing of 3 moderate renal impairment 
subjects, the PK, safety, and tolerability will be evaluated during an observation period of at 
least 1 week to confirm whether the selected dose is appropriate. If yes, the remaining 
subjects in Group C and the subjects in severe group (Group D) will be enrolled and dosed at 
the same dose. If not, a new, lower dose will be proposed for the remaining subjects in 
Group C and all subjects in Group D based on available information. 
Subjects with normal renal function (Group A) will be matched to the subjects with renal 
impairment (Groups B, C, and D) and will receive a single oral lorlatinib dose corresponding 
to the dose level(s) administered in this study with respect to demographically pooled 
average age (10 years), weight (20 kg), and gender (ratio 1:1, 2 patients per gender).  
Therefore, enrollment of Group A will begin after all subjects from Groups B, C, and D have 
completed the PK collection.  If a reduced lorlatinib dose is necessary for any renal impaired 
group(s), an additional control group will be added to match the reduced dose using the same 
match criteria of average age, weight, and gender.
Plasma samples for the determination of lorlatinib and potential metabolite(s) concentrations 
and urine samples for the determination of lorlatinib concentrations will be collected up to 
120 hours after lorlatinib dose. Therefore, subjects would be expected to be on study for at 
least 6 days after receiving the lorlatinib dose. Since lorlatinib is not highly protein bound 
(fraction unbound, fu = 34%),7 unbound concentrations of lorlatinib will not be measured in 
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Subjects will be admitted to the study unit on Day -1 (1 day before dosing) and will be 
administered a single oral dose of lorlatinib on Day 1.  Subjects will be confined to the 
Clinical Research Unit (CRU) for PK sample collection and AE monitoring until Day 6, 
through the last PK sample collection.  A subject will be considered evaluable at the 
discretion of the Sponsor Clinical Pharmacologist.  Additional subjects may be enrolled to 
obtain 8 evaluable subjects per group (for Groups A, B, and C) to complete the study.  
Eight (8) subjects with severe renal impairment (Group D) are expected to be enrolled, but at 
least 4 subjects in this group should be evaluable (as determined by Sponsor Clinical 
Pharmacologist) to complete the study. 
Physical examinations, triplicate 12-lead ECG, vital sign measurements, and clinical 
laboratory tests will be conducted and adverse events will be monitored throughout the study 
to assess safety.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
In case of screen failure, a subject may be re-screened once after a 30 day period, if the initial 
screen failure is not due to an Inclusion/Exclusion criterion that results in permanent 
disqualification from enrollment (eg, medical history). This will be done in consultation with 
the Sponsor.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
4.1.1. All Subjects
1. Healthy (with the exception of defined renal impairment as described above in 
Section 3) female subjects of non-childbearing potential and/or male subjects who, at 
the time of screening, are between the ages of 18 and 75 years, inclusive. Healthy is 
defined as no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure (BP) and pulse rate 
measurement, 12-lead ECG, or clinical laboratory tests.
Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
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b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligation) are
considered to be of childbearing potential.
2. Body mass index (BMI) of 17.5 to 36 kg/m2; and a total body weight >50 kg (110 lb).
3. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
4. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.1.2. Subjects with Normal Renal Function (Group A)
1. Normal renal function (eGFR ≥90 mL/min) during the 2-week screening period, 
based on the average of 2 eGFR values (calculated by the MDRD equation) using
2 SCr values obtained at least 3 days but not more than 14 days apart, as specified in 
the SCHEDULE OF ACTIVITIES.  The 2 eGFR values will need to be within 25% 
of each other, calculated as (first eGFR– second eGFR)/first eGFR. The eGFR 
collected within 24 hours of lorlatinib dosing will be used for final subject 
stratification, group assignment, and PK analysis.
2. Group A subjects will be matched to subjects with renal impairment (Groups B, C, 
and D) with respect to age, weight and gender.
4.1.3. Subjects with Renal Impairment (Groups B, C, and D)
1. Good general health commensurate with the population with chronic kidney disease.
2. Stable drug regimen, defined as not starting a new drug or changing dosage of 
currently used medications within seven days or 5 half-lives (whichever is longer) 
before lorlatinib dosing.
3. Study enrollment and initial renal function stratification is based on the average of 
2 eGFR values (calculated by the MDRD equation) using 2 SCr obtained at least 
3 days but not more than 14 days apart during the 2-week screening period, as defined 
in the SCHEDULE OF ACTIVITIES and in Section 3 for mild, moderate, and severe 
renal impairment. Subjects should demonstrate stable renal function where the 
2 eGFR values will need to be within 25% of each other, calculated as (second eGFR
– first eGFR)/first eGFR. If the second eGFR value falls outside of 25% of the first
eGFR value, a third eGFR may be obtained after at least 3 days and within 14 days of 
the second eGFR. This third eGFR value will need to be within 25% of the second 
eGFR value to demonstrate stable renal function, calculated as (third eGFR – second
eGFR)/second eGFR. The eGFR collected within 24 hours of lorlatinib dosing will 
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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
4.2.1. All Subjects
1. Renal allograft recipients.
2. Any condition possibly affecting drug absorption (eg, gastrectomy).
3. A positive urine drug test.
4. History of regular alcohol consumption exceeding 7 drinks/week for female subjects 
or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months 
before screening.
5. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of investigational product
(whichever is longer).  
6. Screening supine triplicate 12-lead ECG demonstrating a corrected QT (QTc) interval 
>450 msec or a QRS interval >120 msec, except for subjects with severe renal 
impairment (Group D).  For subjects with severe renal impairment (Group D), the 
threshold is screening supine triplicate 12-lead ECG demonstrating a QTc interval 
>470 msec or a QRS interval >120 msec.
7. Second-degree or third-degree AV block (unless paced) or baseline PR interval 
>180 msec at any time prior to dosing of study treatment.
8. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:  

AST or ALT level 1.5 × upper limit of normal (ULN);

Total bilirubin level 1 × ULN; subjects with a history of Gilbert's syndrome may 
have direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin level is ULN.
9. Pregnant female subjects; breastfeeding female subjects; fertile male subjects who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 97 days after the last dose of 
investigational product.  
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11. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive 
testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody 
(HepBcAb), or hepatitis C antibody (HCVAb).
12. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
13. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members,
directly involved in the conduct of the study.
14. Other 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 subject inappropriate for entry into this 
study.
4.2.2. Subjects with Normal Renal Function (Group A)
1. Evidence or history of clinically significant hematological, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease 
(including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at 
the time of dosing).
2. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to the first dose of investigational product.  As 
an exception, acetaminophen/paracetamol may be used at doses of 1 g/day.  Limited 
use of nonprescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor.
4.2.3. Subjects with Renal Impairment (Groups B, C, and D)
1. Evidence or history of clinically significant disease that may affect the safety of the 
subject or that may affect the pharmacokinetics of lorlatinib. A history of diabetes 
mellitus, hypertension and/or ischemic heart disease are not cause for exclusion as 
long as the subject is medically stable and any drugs that are administered for these 
conditions are not expected to interfere with the pharmacokinetics of lorlatinib.
2. Subjects with any significant hepatic, cardiac or pulmonary disease (apart from stable 
ischemic heart disease), or subjects who are clinically nephrotic.
3. Subjects requiring dialysis.


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4. Use of food, drugs, or dietary supplements that may affect the PK of lorlatinib within 
7 days or 5 half-lives (whichever is longer) prior to the first dose of lorlatinib. Use of 
medications that are not believed to affect subject safety and are medically necessary 
for the treatment and maintenance of renal disease and other pre-existing and/or 
concurrent stable comorbid conditions are only permitted following approval by the 
Sponsor. Limited use of nonprescription medications that are not believed to affect 
subject safety or the overall results of the study may be permitted on a case-by-case 
basis following approval by the Sponsor.
5. 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 above categories) within 12 days prior 
to the first dose of lorlatinib. 
a.
Known strong CYP3A inhibitors (eg, boceprevir, cobicistat, clarithromycin, 
conivaptan, diltiazem, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, tipranavir,
troleandomycin, voriconazole, grapefruit juice or grapefruit/grapefruit-related 
citrus fruits [eg, Seville oranges, pomelos]). The topical use of these medications 
(if applicable), such as 2% ketoconazole cream, is allowed.
b. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifabutin, rifampin, St. John’s Wort). 
c.
Known P-gp substrates with a narrow therapeutic index (eg, digoxin).
6. Concurrent use of CYP3A substrates with narrow therapeutic indices (eg, alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl including transdermal patch, 
pimozide, quinidine, sirolimus, tacrolimus) within 12 days prior to the first dose of 
lorlatinib.
4.3. Lifestyle Requirements
The following guidelines are provided:
4.3.1. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 4 hours prior to 
any safety laboratory evaluations and 10 hours prior to the collection of the pre-dose 
PK sample.  Water is permitted until 1 hour prior to investigational product
administration.  

On Day 1, subjects will continue to fast for 4 hours after lorlatinib dosing, except for 
diabetics who may have a snack 2 hours after dosing, if required.

On Day 1, water may be consumed without restriction beginning 1 hour after 
lorlatinib dosing.  Non-caffeinated drinks (except grapefruit or grapefruit-related 
citrus fruit juices-see below) may be consumed with meals and the evening snack.


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
On Day 1, lunch will be provided approximately 4 hours after lorlatinib dosing.

On Day 1, dinner will be provided approximately 9 to 10 hours after lorlatinib dosing.

An evening snack may be permitted.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of 
investigational product until collection of the final PK blood sample.

While confined, the total daily nutritional composition will be approximately 
55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake per subject 
will not exceed approximately 3200 kcal.
4.3.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample.  Subjects 
may undergo an alcohol breath test or blood alcohol test at the discretion of the 
investigator at any time during the study.

Subjects will abstain from caffeine-containing products for 24 hours prior to the start 
of lorlatinib dosing until collection of the final PK sample.  

Subjects will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to lorlatinib dosing and during confinement in the CRU.  
4.3.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, and aerobics) for at least 48 hours prior to each blood collection for 
clinical laboratory tests.  Walking at a normal pace will be permitted.
4.3.4. Contraception
All malesubjects who, in the opinion of the investigator, are biologically capable of having 
children and are sexually active must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for 97 after the 
last dose of investigational product.  The investigator or his/her designee, in consultation 
with the subject, will confirm the subject has selected the most appropriate method of 
contraception for the individual subject and his female partner from the permitted list of 
contraception methods (see below) and instruct the subject in its consistent and correct use.  
Subjects need to affirm that they meet at least one of the selected methods of contraception.  
The investigator or his/her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the SCHEDULE OF 
ACTIVITIES and document such conversation in the subject’s chart.  In addition, the 
investigator or his/her designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected. 


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 97 days after the last 
dose of lorlatinib.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list (roster) located in the team SharePoint site.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 


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advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product is lorlatinib.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
5.2. Subject Compliance
Investigational product will be administered under the supervision of investigator site 
personnel.  The oral cavity of each subject will be examined following dosing of lorlatinib
tablets to ensure the investigational product was taken.
5.3. Investigational Product Supplies
5.3.1. Dosage Form and Packaging
Lorlatinib 25 mg 
 tablets will be supplied by Pfizer to the CRU in bulk along with 
individual dosing containers and desiccants for individual oral subject dosing as needed.  
Lorlatinib 25 mg tablets will be presented to the subjects in an individual dosing container.
Lorlatinib 25 mg tablets will be supplied to the CRU as packaged bulk bottles and labeled 
according to local regulatory requirements.  The bottles will be provided to the site for 
dispensing by the pharmacy. 
5.3.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities. 
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The 100 mg dose consisting of four 25 mg oral tablets of lorlatinib will be prepared at the 
CRU in the individual dosing containers by 2 operators, one of whom is an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, practitioner, or pharmacist). The tablets will be provided in individual subject 
bottles along with appropriate desiccant canister(s), and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements.
5.4. Administration
Following an overnight fast of at least 10 hours, subjects will receive a 100 mg dose (or an 
appropriately selected dose based on subject PK, safety, and tolerability) of lorlatinib tablets 
with approximately 240 mL of ambient temperature water at approximately 0800 hours (plus 
or minus 3 hours).
Subjects will swallow the lorlatinib tablets whole, and will not manipulate or chew the 
medication prior to swallowing.
In order to standardize the conditions on PK sampling days, all subjects will be required to 
refrain from lying down (except when required for BP, pulse rate, and ECG measurements), 
eating, and drinking beverages other than water during the first 4 hours after dosing of 
lorlatinib.
5.5. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Lorlatinib should be stored in their original containers and in accordance with the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 


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Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site. 
5.6. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (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.
5.7. Concomitant Treatment(s)
Subjects will abstain from concomitant treatments as described in Section 4.2, except for the 
treatment of AEs. Limited use of nonprescription medications that are not believed to affect 
subject safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. For subjects with renal impairment (Groups B, C, and 
D), any drugs that are administered for renal disease or other pre-existing conditions as 
specified in Section 4.2 are permitted, following approval of the Sponsor, as long as the 
subject is medically stable and use of the drugs are not expected to interfere with the 
pharmacokinetics of lorlatinib. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments.


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6. STUDY PROCEDURES
6.1. Screening
Subjects will be screened within 14 days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in the Subject Information and Consent
section.  If the time between Screening and dosing exceeds 14 days as a result of unexpected 
delays (eg, delayed drug shipment), then subjects do not require rescreening if the Day -1
laboratory results meet the eligibility criteria.
A subject who qualified for this protocol but did not enroll from an earlier cohort/group may 
be used in a subsequent cohort/group without rescreening, provided the Day -1 laboratory 
results meet the eligibility criteria for this study.  
 
 
  
The following procedures will be completed:
•
Obtain written informed consent.
•
Confirm and document that the subject meets the inclusion/exclusion criteria.
•
The investigator or his/her designee will discuss with the subject the need to use 
highly effective contraception consistently and correctly according to the 
contraception guidelines and will confirm highly-effective, proper contraception is 
being used.
•
Collect demography (subject race, ethnicity, date of birth, age, gender).
•
Collect height and weight.
•
Obtain medical history, including history of prior illegal drug, alcohol, and tobacco 
use.
•
Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 28 days prior to the planned first dose.
•
Obtain single supine BP and pulse rate pulse rate after at least 5 minutes of rest in a 
supine position.
•
Conduct full physical examination (PE) (to be performed by trained medical 
personnel at the investigator site).  The screening physical examination may be 
performed on Day -1.
•
Collect triplicate 12-lead ECG.
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
Assess baseline symptoms/AEs.

Following at least an overnight fast, collect blood and urine specimens for the 
following:

Safety laboratory tests (hematology, clinical chemistry, and urinalysis);

Urine drug test (mandatory) and alcohol breath test at discretion of the 
investigator;

Serum FSH concentration for any female subjects who has been amenorrheic for 
at least 12 consecutive months;

Collect blood for HIV, HepBsAg, HepBcAb or HCVAb testing;

Serum creatinine and eGFR calculation.
To prepare for study participation, subjects will be instructed on the information in the 
Section 4.3 and Section 5.7 of the protocol.
6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

ECGs: obtain prior to vital sign measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection;

BP/pulse rate: obtain as close as possible to the scheduled time, but prior to blood 
specimen collection;

PK blood specimens: obtain at the scheduled time;

Other procedures: obtain all other procedures as close as possible to the scheduled 
time, but may be obtained before or after blood specimen collection.
When an intravenous (IV) catheter is utilized for blood sample collections, ECGs and vital 
sign assessments (pulse rate, BP, and oral temperature) should be collected prior to the 
insertion of the catheter.
6.2.1. Day -1
Subjects will be admitted to the CRU on Day -1 prior to Day 1 dosing. The following 
procedures will be completed following admission to the CRU:

Review inclusion and exclusion criteria.


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•
Obtain blood and urine samples for safety laboratory tests (hematology, clinical 
chemistry, urinalysis) after overnight fast. The results must have no clinically 
significant findings, as judged by the Investigator, in order for a subject to be given 
investigational product on Day 1.
•
Obtain weight.
•
Collect urine for drug testing (mandatory) and alcohol breath test at discretion of the 
Investigator.  These tests may be performed at any other time at the discretion of the 
investigator.
•
The investigator or his/her designee will discuss with the subject the need to use 
highly effective contraception consistently and correctly according to the 
contraception guidelines and will confirm highly effective contraception is being 
used.
•
Serum creatinine, eGFR, and creatinine clearance calculation.
•
Collect triplicate 12-lead ECG.
•
Obtain single supine BP and pulse rate pulse rate after at least 5 minutes of rest in a 
supine position.
•
Collect 
a blood sample for 
pharmacogenomics on Day -1.  
 
•
Assess baseline symptoms/AEs.
•
Review prior and concomitant medication(s).
•
Review changes in the subject’s medical history, including medication history since 
Screening.
•
Conduct full PE, if deferred from the Screening visit.  A limited PE may be 
performed at other designated time points at the discretion of the investigator.
6.2.2. Day 1
Prior to lorlatinib dosing, the following procedures will be completed: 
•
Assess baseline symptoms/AEs.
•
Collect triplicate 12-lead ECG measurements prior to insertion of the IV catheter.
•
Collect supine BP and pulse rate prior to insertion of the IV catheter.
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
Collect blood samples for PK analysis of lorlatinib and its metabolite(s).

Collect a blank urine sample of at least 50 mL for all subjects.  Each subject will 
empty his or her bladder just prior to dosing.  

After all pre-dose procedures have been completed, administer the investigational 
product (see Section 5.4). 
After dosing, the following procedures will be completed:

Subject should be supine for at least 10 minutes prior to triplicate 12-lead ECG 
measurements at 1, 2, 4 hours after dosing.

Assess supine BP and pulse rate at 1, 2, and 4 hours after dosing.

Collect blood samples for PK analysis at 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours following 
dosing on Day 1.

Collect urine during the interval of 0 to 24 hours after dosing on Day 1.

Review concomitant treatments.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.3. Day 2
The following procedures will be completed:

Assess supine BP and pulse rate 24 hours after dosing on Day 1.

Obtain triplicate 12-lead ECG measurements 24 hours after dosing on Day 1.

Collect fasting blood and urine samples for safety laboratory tests (hematology, 
clinical chemistry, urinalysis) 24 hours after dosing on Day 1.

Collect blood samples for PK analysis of lorlatinib and its metabolite(s) at 24 hours 
after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Review concomitant treatments.

Collect urine during the interval of 24 to 48 hours after dosing on Day 1.


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6.2.4. Day 3
The following procedures will be completed:

Collect blood samples for PK analysis 48 hours after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Collect urine during the interval of 48 to 72 hours after dosing on Day 1. 

Review concomitant treatments.
6.2.5. Day 4
The following procedures will be completed:

Collect blood samples for PK analysis 72 hours after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Collect urine during the interval of 72 to 96 hours after dosing on Day 1. 

Review concomitant treatments.
6.2.6. Day 5
The following procedures will be completed:

Collect blood samples for PK analysis 96 hours after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Collect urine during the interval of 96 to 120 hours after dosing on Day 1. 

Review concomitant treatments.
6.2.7. Day 6
Subjects may be discharged from the CRU after the completion of assessments.  The 
following procedures will be completed 120 hours after lorlatinib dosing on Day 1:

A limited PE will be conducted.

Collect fasting blood and urine sample for safety laboratory tests (hematology, 
clinical chemistry, urinalysis).


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
The investigator or his/her designee will discuss with the subject the need to use 
highly effective contraception consistently and correctly according to the 
contraception guidelines and will confirm highly-effective, proper contraception is 
being used.

Subject should be supine for at least 10 minutes prior to triplicate 12-lead ECG 
measurements. 

Assess supine BP and pulse rate.

Collect blood samples for PK analysis 120 hours after dosing on Day 1.

Collect urine during the interval of 120 hours after dosing on Day 1.

Review concomitant treatments.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”

Discharge from CRU confinement.  
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.
6.3. Follow-up 
6.3.1. Follow-up Visit
Subjects will return to the CRU for follow-up visit at the discretion of the principal
investigator (PI) or if the subject withdraws consent or if there are unresolved AE at 
discharge. At this visit, the following procedures may include, but are not limited to:

Conduct limited PE and weight measurement.

The investigator or his/her designee will discuss with the subject the need to use 
highly effective contraception consistently and correctly according to the 
contraception guidelines and will confirm highly-effective, proper contraception is 
being used.

Assess supine BP and pulse rate.


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
Obtain information regarding the use of concomitant treatment and the occurrence of 
AEs.

Review concomitant treatments.
6.4. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days after the last administration of 
the investigational product to capture any potential adverse events (see Section 8.1.4) and to 
confirm appropriate contraception usage (see Section 4.3.4).  Contact with the subject may be 
done via a phone call.
6.5. Subject Withdrawal /Early Termination
Withdrawal of consent: 
Subjects who request to discontinue receipt of 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 subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate case report form (CRF) page.  In the event 
that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
Lost to follow-up:
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the investigator 
may use a sponsor-retained third-party representative to assist site staff with obtaining the 
subject’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 subject remains lost to follow-up, then the 
last-known-alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.
Subjects 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 or sponsor for safety (see 
Section 8.1.3) or behavioral reasons, or the inability of the subject to comply with the 


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protocol-required schedule of study visits or procedures at a given investigator site.  The 
early termination visit applies only to subjects who are randomized and then are prematurely 
withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal,
request that the subject return for a final visit, if applicable, and follow up with the subject 
regarding any unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the 
early-withdrawal visit, every effort must be made to complete the following assessments:

Limited PE, if there is a new or open AE or clinically significant abnormal physical 
finding from the last visit;

Supine BP and pulse rate measurements;

Triplicate 12-lead ECG measurement;

Blood and urine specimens for safety laboratory;

Blood sample for PK analysis.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
If the subject 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.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 


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actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical laboratory measurements may be 
obtained at any time during the study to assess any perceived safety concerns.
Table 5.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Lipase
Amylase
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
FSHb
Urine drug screening
Hepatitis B surface 
antigenc
Hepatitis B core 
antibodyc
Hepatitis C core 
antibodyc
HIVc
Additional Tests 
(Needed for Hy’s Law):
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b At Screening only, in females who are amenorrheic for at least 12 consecutive months.
c At Screening only.


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•
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines, and amphetamines.
•
Subjects may undergo random urine drug testing at the discretion of the Investigator.  
Drug testing conducted prior to dosing must be negative for subjects to receive 
investigational product. 
 
 
 
 
 
7.1.2. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
and gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 
7.1.3. Blood Pressure and Pulse Rate
BP and pulse rate will be measured at times specified in the SCHEDULE OF ACTIVITIES
section of this protocol.  Additional collection times, or changes to collection times, of BP
and pulse rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Subjects should be 
instructed not to speak during measurements.  
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP
and pulse rate should be obtained prior to the nominal time of the blood collection.
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7.1.4. Electrocardiogram 
Triplicate 12-Lead ECGs should be collected at times specified in the SCHEDULE OF 
ACTIVITIES section of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected at pre-dose of Day 1 will serve as each subject’s 
time-controlled baseline QTc value.
If the average of QTc values from the triplicate measurements remains above the threshold 
value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner, at the discretion of the investigator).
If subject develops new first degree block as defined by PR interval greater than 280 msec, if 
patient is found to have a second degree or higher AV block, or if patient has symptomatic 
bradycardia, patient should undergo continuous cardiac monitoring with 12-lead ECG taken 
every hour until PR interval returns to <220 msec, until AV block resolves or until symptoms 
resolve.  If patient develops high degree AV block defined as second degree AV block, 
Mobitz II or third degree block, patient should be referred to a cardiologist for further 
evaluation.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of Lorlatinib and Its Metabolite(s)
Plasma samples for characterization of PK of lorlatinib and its metabolite(s) will be collected 
at the designated times listed in SCHEDULE OF ACTIVITIES table.  
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs and the date and time of 
blood sample collection and of last dosing prior to PK collection documented on the CRF.


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The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a
60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF)
At each designated time, blood samples (8.0 mL) to provide approximately 3.5 mL plasma 
(aliquoted into 3 × 2 mL tubes, approximately 1.0 mL plasma in each tube) for determination 
of the plasma concentrations of lorlatinib and its potential metabolite(s) will be collected into 
appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic acid 
(K2EDTA).  Details regarding the sample handling and shipping will be provided in the Lab 
Manual.
Lorlatinib is light sensitive; all steps must be performed out of direct light. It should be noted 
that once collected, samples should be processed immediately and kept out of direct light due 
to the light sensitive nature of lorlatinib. Once frozen, samples must not thaw, including 
during shipment.
•
Samples will be analyzed for lorlatinib and metabolite(s) using a validated analytical 
method in compliance with Pfizer standard operating procedures (SOPs).
•
The PK samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from 
the PK sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor. On a case-by-case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.
•
As part of understanding the PK of the investigational product, samples may be used 
for metabolite identification and/or evaluation of the bioanalytical method, 
 
  These data will not be included in the CSR.
7.2.2. Urine for Analysis of Lorlatinib
Urine will be collected at times specified in the SCHEDULE OF ACTIVITIES section of the 
protocol.  Each subject will empty his or her bladder just prior to dosing.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
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On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
 
7.3. Pharmacogenomics
7.3.1. Genotyping Analysis (If Applicable; Pertains but is not Limited to Blood, Buccal 
Swabs, Saliva, and/or Tissue)
Blood samples for genotyping will be examined to assess the impact of allelic variants of 
drug-metabolizing enzymes and transporters.  Additionally, these samples may also be used 
for retrospective evaluation of additional genetic variants associated with variation in PK or 
to explore AEs should these be observed.  Samples will be retained for a period of up to 
3 years after regulatory approval.
A 4-mL blood sample will be collected from each subject into a plastic K2EDTA tube at 
times specified in the SCHEDULE OF ACTIVITIES section of the protocol.  
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures 
The pharmacogenomic (PGx) samples must be processed and shipped as indicated in the 
instructions provided to the investigator site to maintain sample integrity.  Any deviations 
from the PGx processing steps, including any actions taken, must be documented and 
reported to the sponsor. On a case-by-case basis, the sponsor may make a determination as 
to whether sample integrity has been compromised. Any sample deemed outside of 
established stability, or of questionable integrity, will be considered a protocol deviation.
 
 
 
 
 
 
 
 
 
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7.5. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
158 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
7.6. Potential Cases of Acute Kidney Injury
Abnormal values in serum creatinine concurrent with presence or absence of increase in 
blood urea nitrogen (BUN) that meet the criteria below, in the absence of other causes of 
kidney injury, are considered potential cases of acute kidney injury and should be considered 
important medical events. 
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An increase of 0.3 mg/dL (or 26.5 mol/L) in SCr level relative to the subject’s own 
baseline measurement should trigger another assessment of SCr as soon as practically
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of 0.3 mg/dL (or 26.5 mol/L) in SCr
relative to the subject’s own baseline measurement) is 0.4 mg/dL (or 35.4 mol/L), the 
subject should be discontinued from the study and adequate, immediate, supportive measures 
taken to correct apparent acute kidney injury.
Subjects should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the second assessment confirming abnormal SCr result.  
This evaluation should include laboratory tests, detailed history, and physical assessment.  In 
addition to repeating SCr, laboratory tests should include serum BUN, serum creatinine 
kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices.  All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr.  If 2 healthy subjects in any renal function group are noted to have 
2 consecutive SCr results of 0.3 mg/dL (or 26.5 mol/L), an assessment of whether the 
finding may be considered an adverse drug reaction should be undertaken.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE),
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of renal function group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
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 


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investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal /Early Termination Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including the 
follow-up visit.  At least 28 calendar days after the lorlatinib dose, the subject will be 
contacted by telephone to inquire about SAEs, including hospitalizations and newly 
diagnosed chronic medical conditions since the last visit.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety 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 investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.
8.1.5. 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 on the CRF, 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.  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, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

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 (outside of any protocol-specified dose 
adjustments) 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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event 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.
Or that is considered to be:

An important medical event.
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.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of 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 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is 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 a persistent pretreatment laboratory abnormality);

Social admission (eg, subject 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);

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 subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab sample).  In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:


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
Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

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).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The subject should return to the investigator 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.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.


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A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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).

A male 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 subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an 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 subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety 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 Safety 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 


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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 baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety 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 the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.


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8.4.3. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject 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 subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a Statistical Analysis Plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their
analyses will also be reflected in a protocol amendment.


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9.1. Sample Size Determination
Approximately, 8 subjects will be enrolled into each of the normal, mild, moderate, and 
severe renal impairment groups as described in Section 3.1. The sample size is based on 
recommendations from the “Food and Drug Administration (FDA) Guidance for Industry -
Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis, 
and Impact on Dosing and Labeling”.
Subjects who discontinue from the study before completing all assessments may be replaced 
at the discretion of the investigator and Sponsor to ensure 8 evaluable subjects in each of 
normal, mild, and moderate impairment groups (Groups A, B, and C) and at least 4 evaluable 
subjects in severe group (Group D).
9.2. Pharmacokinetic Analysis
The PK concentration population is defined as all subjects enrolled and treated and who have 
at least 1 lorlatinib concentration.
The PK parameter analysis population is defined as all subjects enrolled and treated who 
have at least 1 of the PK parameters of primary interest.
Subjects are considered PK evaluable if all PK concentrations are available or at the 
discretion of the Sponsor Clinical Pharmacologist.
9.2.1. Derivation of Pharmacokinetic Parameters Prior to Analysis
Pharmacokinetic parameters following single dose administration will be derived from the 
concentration-time profile as follows:
Table 6.
Derivation of Pharmacokinetic Parameters
Parameters
Definition 
Method of Determination
AUClast  
Area under the plasma concentration 
time curve from time 0 to the time of 
the last quantifiable concentration
Linear-log trapezoidal method. 
AUCinf
Area under the plasma 
concentration-time curve from time 0 
extrapolated to time infinity
AUCinf =AUClast + (Clast/kel)
Clast, plasma concentration at the last quantifiable 
time point estimated from the log-linear 
regression analysis.
kel, terminal elimination phase rate constant 
estimated by linear regression based on the 
observations justified to describe the terminal 
phase on log-linear concentration-time profile. 
Cmax
peak or maximum observed plasma 
concentration
Observed directly from data
Tmax
Time to Cmax
Observed directly from data as time of first 
occurrence
t½
Terminal plasma elimination half-life
Ln(2)/kel
CL/F
Apparent clearance after oral dose
Dose/AUCinf after oral dose
Vz/F
apparent oral volume of distribution
Dose/(AUCinf × kel) after oral dose
CLR
Renal clearance
Ae/AUClast


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Table 6.
Derivation of Pharmacokinetic Parameters
Parameters
Definition 
Method of Determination
Ae
Cumulative amount of drug recovered 
unchanged in the urine, from zero to 
time 120 hours post-dose
Sum of [urine concentration × sample volumea] 
for each collection interval.
Ae%
Cumulative amount of drug recovered 
unchanged in the urine, from zero to 
time 120 hours post-dose, expressed as 
fraction of administered dose
Ae/Dose*100%
MRCmax
Metabolite(s) to parent ratio for Cmax
(Cmax/MW)metabolite/(Cmax/MW)parent
MRAUClast
metabolite(s) to parent ratio for AUClast
(AUClast/MW)metabolite/AUClast/MW)parent
MRAUCinf
metabolite(s) to parent ratio for AUCinf
(AUCinf/MW)metabolite/AUCinf/MW)parent
MW: Molecular Weight   
a Sample volume = (urine weight in g/1.020), where 1.020 g/mL is the approximate specific gravity of urine.
Actual PK sampling times will be used in the derivation of PK parameters.  In the case of 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
9.2.2. Statistical Methods
Analysis of variance (ANOVA) will be used to compare the natural log transformed AUCinf
(if data permit), AUClast and Cmax between the normal renal function group and each of the
renal impairment groups. Point estimates and associated 90% confidence intervals (CIs) for 
the difference of each comparison will be estimated and exponentiated to provide geometric 
mean ratios and associated 90% CIs.
Regression analysis will be conducted to characterize the relationship between renal function
and PK parameter CL/F. Both CLcr calculated from the C-G formula and eGFR obtained 
from the MDRD equation on Day -1 will be used in regression analysis.  Analysis results will 
include estimates of parameters for the chosen model as well as measures of precision such 
as CI or standard errors.
PK parameters AUCinf, Cmax, AUClast, time for Cmax (Tmax), terminal plasma elimination 
half-life (t½), CL/F, CLR, Vz/F, cumulative amount of drug recovered unchanged in the urine, 
from zero to time 120 hours post-dose (Ae), cumulative amount of drug recovered unchanged 
in the urine, from zero to time 120 hours post-dose, expressed as fraction of administered 
dose (Ae%), will be summarized descriptively by analyte (eg, lorlatinib and its metabolite(s)) 
and renal function group.  Metabolite(s) to parent ratio for Cmax (MRCmax), metabolite(s) to 
parent ratio for AUClast (MRAUClast), and metabolite(s) to parent ratio for AUCinf
(MRAUCinf) will also be summarized descriptively by renal function group.
For AUCinf, AUClast and Cmax, box-whisker plots of the parameters will be plotted by analyte 
and renal function group. Individual concentrations will be listed and summarized 
descriptively by group and PK sampling time. Individual subject and summary profiles 
(means and medians) of the concentration-time data will be plotted across different groups.


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For summary statistics and summary plots by renal function group and sampling time, the 
nominal PK sampling time will be used; for individual subject plots by time, the actual PK 
sampling time will be used.
9.3. Analysis of Other Endpoints 
Pharmacogenomic and biomarker data will be collected and retained for future analyses, but 
may not be analyzed, specifically, for this study. 
9.4. Safety Analysis
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of subjects.  Any clinical laboratory, 
ECG, BP, and pulse rate abnormalities of potential clinical concern will be described.  Safety 
data will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.
9.4.1. Electrocardiogram Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum post-dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Table 7.
Safety QTc Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
--
480
Absolute change
30-<60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
The number (%) of subjects with maximum post-dose PR interval values, maximum 
increases from baseline and second degree atrioventricular block (AVB) type 2 or higher in 
the following categories will be tabulated by renal function group (Table 8): 


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Table 8.
Safety PR Interval
msec
Absolute Value
200 - <220
220 - <240
240 - <260
260
Absolute Change
40-<60
60-<80
80
Relative Change from baseline
>25%
Second-degree AVB type 2 or highera
a.
Second degree block type 2 or higher would be determined by the ECG machine and confirmed by a 
physician.
9.5. Interim Analysis 
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating PK/PD modeling, and/or supporting clinical development.
9.6. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, 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 are 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.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.


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For studies conducted at non-Pfizer investigator sites, 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/Data Collection Tools/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 subject.  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 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 are 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 hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(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, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
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. 


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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/Ethics Committee
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 subjects. 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 the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.


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The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. 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 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that 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 subjects 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 TRIAL
13.1. End of Trial in the United States 
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
lorlatinib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects 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 study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is 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.


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The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  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, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the 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 CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Rikova K, et al. (2007) Global Survey of Phosphotyrosine Signaling Identifies 
Oncogenic Kinases in Lung Cancer. Cell 131(6):1190-1203.
2.
Soda M, et al. (2007) Identification of the transforming EML4-ALK fusion gene in non-
small-cell lung cancer. Nature 448(7153):561-566.
3.
Sasaki T, Rodig SJ, Chirieac LR, & Jänne PA (2010) The biology and treatment of 
EML4-ALK non-small cell lung cancer. European Journal of Cancer 46(10):1773-
1780.
4.
Bergethon K, et al. (2012) ROS1 Rearrangements Define a Unique Molecular Class of 
Lung Cancers. Journal of Clinical Oncology 30(8):863-870.
5.
JANSSEN_Pharmaceuticals (2014) SPORANOX- itraconazole solution label.
6.
SmPC Sporanox, Belgium.
7.
PF-06463922 Investigator’s Brochure 2016.


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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
Abs
Absolute
ADME
absorption, distribution, metabolism, excretion
Ae
cumulative amount of drug recovered unchanged in the urine, from 
zero to time 120 hours post-dose
Ae%
cumulative amount of drug recovered unchanged in the urine, from 
zero to time 120 hours post-dose, expressed as fraction of 
administered dose
AE
adverse event
ALK
Anaplastic Lymphoma Kinase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate 
AUC
area under the curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the plasma concentration-time curve from time 0 
extrapolated to time infinity
AUClast
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration
AV
Atrioventricular
AVB
atrioventricular block
BA
Bioavailability
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen
Cb/Cp
blood to plasma concentration ratios
Ceff
efficacious concentration
CHO
Chinese Hamster Ovary
CI
confidence interval
CK
creatine kinase
CL
Clearance
CLcr
creatinine clearance
CL/F
apparent clearance after oral dose
CLr
renal clearance
Cmax
peak or maximum observed concentration
CCI


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Abbreviation
Term
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRM
continual reassessment method
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTC
Common Terminology Criteria
%CV
coefficient of variation
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug-interaction
DILI
drug-induced liver injury
DLT
dose limiting toxicities
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
Electrocardiogram
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EML4
echinoderm microtubule-associated protein-like 4
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FISH
fluorescent in situ hybridization
FOB
functional observation battery
FSH
follicle-stimulating hormone
fu
fraction unbound
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
HCVAb
hepatitis C antibody
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
hERG
human ether-a-go-go related gene
HIV
human immunodeficiency virus
HLM
human liver microsomes
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICH
International Council on Harmonisation


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Abbreviation
Term
ID
Identification
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LOAEL
lowest observed adverse effect level
LFT
liver function test
LSLV
last subject last visit 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDCK-MDR1
Madin Darby canine kidney with multidrug resistance protein 1
MDRD
Modification of Diet in Renal Disease
MRAUCinf
metabolite(s) to parent ratio for AUCinf
MRAUClast
metabolite(s) to parent ratio for AUClast
MRCmax
metabolite(s) to parent ratio for Cmax
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
MW
molecular weight
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate
NOEL
no observed effect level
NSCLC
non-small-cell lung carcinoma
PCD
primary completion date
PD
pharmacodynamic(s)
PE
physical examination
P-gp
P-glycoprotein
PGx
pharmacogenomic(s)
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PT
prothrombin time
QD
once daily
QTc
corrected QT
qual
Qualitative
Rac
observed accumulation ratio
RBC
red blood cell
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose


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Abbreviation
Term
RNA
ribonucleic acid
Rss
steady state accumulation ratios
RTK
receptor tyrosine kinases
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
Scr,std
serum creatinine measured with a standardized assay for serum 
creatinine
SOP
standard operating procedure
SRSD
single reference safety document
t½
terminal plasma elimination half-life
TBili
total bilirubin
THC
Tetrahydrocannabinol
TKI
tyrosine kinase inhibitor
Tmax
time for Cmax
ULN
upper limit of normal
US
United States
Vz/F
volume of distribution
WBC
white blood cell

SAP_001.pdf: 
Protocol B7461010 (PF-06463922) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B7461010
A PHASE 1, SINGLE DOSE OPEN-LABEL STUDY TO 
EVALUATE THE PHARMACOKINETICS OF LORLATINIB IN 
SUBJECTS WITH IMPAIRED RENAL FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
Date:
28-AUG-2018
PPD


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PFIZER CONFIDENTIAL
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Final
Aug 28, 2018
Not Applicable
PPD


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................8
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................8
5.1.1. Concentration Analysis Set...........................................................................8
5.1.2. Parameter Analysis Set.................................................................................8
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................8
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
7.1. Concentrations Below the Limit of Quantification.................................................10


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7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................11
8.3. Safety Analysis........................................................................................................14
8.3.1. Treatment and Disposition of Subjects.......................................................14
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................15
8.3.8. Other Safety Data .......................................................................................16
8.3.9. Concomitant Treatments.............................................................................16
8.3.10. Screening and Other Special Purpose Data ..............................................16
8.3.11. Analysis of Other Endpoints.....................................................................16
9. REFERENCES ....................................................................................................................17
10. APPENDICES ...................................................................................................................18
LIST OF TABLES
Table 1.
Group Assignment Based on Creatinine Clearance Estimates...............................5
Table 2.
Noncompartmental PK Parameters.......................................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Group..................................13
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................18


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
In this study, the PK of lorlatinib after a single oral dose of lorlatinib will be evaluated in 
non-cancer subjects with normal renal function, mild renal impairment (defined as CLcr ≥60 
mL/min and CLcr <90 mL/min), moderate renal impairment (defined as CLcr ≥30 mL/min and 
CLcr <60 mL/min), and severe renal impairment (defined as CLcr <30 mL/min not requiring 
dialysis) who are otherwise healthy. Data from this study would allow for the estimation of any 
changes in lorlatinib plasma exposure with varying extent of renal impairment.
2.1. Study Design
This will be a Phase 1, open-label, multi-center, single treatment study in subjects with 
normal renal function and varying degrees of renal impairment. Each subject will receive a 
single oral dose of lorlatinib administered in the fasted state. 
This study is aimed toward enrolling approximately 32 evaluable subjects who complete the 
PK assessments. Subjects with the following renal function will be enrolled (Table 1).
Table 1.
Group Assignment Based on Creatinine Clearance Estimates
Group
Description
Estimated eGFR
A (n=8)
Normal
90 mL/min
B (n=8)
Mild Renal Impairment
60- <90 mL/min
C (n=8)
Moderate Renal Impairment
30- <60 mL/min
D (n=8)
Severe Renal Impairment
<30 mL/min and not requiring 
dialysis
Subjects who do not complete all PK collections may be replaced to ensure 8 evaluable 
subjects in Groups A, B, and C and at least 4 evaluable subjects in Group D. 
Estimated glomerular filtration rate (eGFR) will be calculated using the MDRD equation as 
follows:
eGFR (mL/min/1.73m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American)


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where Scr, std denotes serum creatinine measured with a standardized assay for serum 
creatinine.  Note that the value of eGFR, which is directly obtained from the lab or 
calculated using the equation above, is generally normalized to an average body size of 
1.73 m2 for diagnosis, prognosis and treatment of renal disease.  In terms of clearance of 
renally filtrated drugs (including secreted drugs), renal elimination capacity is related to 
absolute glomerular filtration rate (GFR) in mL/min.  The MDRD-derived, body surface area 
(BSA)-adjusted value of eGFR used to obtain absolute GFR (mL/min) for renal disease 
classification or subject assignment into different renal disease groups should be multiplied 
by the individual subject’s normalized body surface area (ie, measured BSA/1.73 m2).  The 
BSA of an individual will be calculated by the following formula as described below:
BSA = (Weight0.425 x Height0.725) x 0.007184
In addition CLcr will be calculated using the Cockcroft-Gault equation as follows:
CLcr (mL/min) = [140 – age (years)] × total body weight (kg) × (0.85 for females) 
72 × serum creatinine (mg/dL)
Subjects will need to demonstrate stable renal function during the screening period within 
approximately a 2-week timeframe prior to dosing.  Stable renal function is defined as 
2 eGFR values obtained at least 3 days but not more than 14 days apart being within 25% of 
each other.  The average value of the 2 eGFR values will be used for study enrollment and 
initial renal function stratification.  The eGFR value within 24 hours prior to lorlatinib 
dosing will be the value used for final subject stratification, group assignment, and PK 
analysis.  The CLcr value will be recorded at the same time eGFR is determined.  The CLcr
value on Day -1 (calculated by Cockcroft-Gault equation) will be calculated and recorded.
In order to safeguard subject safety, this study will enroll subjects with renal impairment in a 
staggered fashion. A single oral dose of 100 mg lorlatinib will be administered first to 
subjects with mild renal impairment (Group B). After single 100 mg oral dose of lorlatinib is 
tolerated in at least 3 subjects with mild renal impairment, subjects with moderate renal 
impairment (Group C) will be enrolled one at a time and administered a single oral dose of 
lorlatinib. There will be an observation period of at least 1 week after dosing of the first 
3 subjects to evaluate safety and tolerability. Based on the safety and tolerability of the first 
3 subjects in Group B, a dose lower than 100 mg of lorlatinib may be considered for Group C, as 
determined by the Sponsor. After dosing of 3 moderate renal impairment subjects, the PK, 
safety, and tolerability will be evaluated during an observation period of at least 1 week to 
confirm whether the selected dose is appropriate. If yes, the remaining subjects in Group C and 
the subjects in severe group (Group D) will be enrolled and dosed at the same dose. If not, a 
new, lower dose will be proposed for the remaining subjects in Group C and all subjects in 
Group D based on available information. 


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Subjects with normal renal function (Group A) will be matched to the subjects with renal 
impairment (Groups B, C, and D) and will receive a single oral lorlatinib dose 
corresponding to the dose level(s) administered in this study with respect to demographically 
pooled average age (±10 years), weight (±20 kg), and gender (ratio 1:1, ±2 patients per 
gender). Therefore, enrollment of Group A will begin after all subjects from Groups B, C, 
and D have completed the PK collection. If a reduced lorlatinib dose is necessary for any 
renal impaired group(s), an additional control group will be added to match the reduced 
dose using the same match criteria of average age, weight, and gender. 
2.2. Study Objectives
Primary Objective
•
To evaluate the effect of renal impairment on the single dose pharmacokinetics of
lorlatinib on otherwise healthy subjects.
Secondary Objective
•
To evaluate the safety and tolerability of a single dose of lorlatinib in healthy subjects
and subjects with renal impairment.
Tertiary Objective
•
To evaluate the pharmacokinetics of lorlatinib metabolite(s) in healthy subjects and
subjects with renal impairment who are otherwise healthy.
Exploratory Objective
•
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis will be conducted for this study. Final analysis will follow the official 
database release.  As this will be an open-label study, there is no formal unblinding of the 
randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
CCI


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5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all subjects enrolled and treated and who 
have at least 1 lorlatinib plasma concentration.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all subjects enrolled and treated who 
have at least 1 of the PK parameters of primary interest. 
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are allocated but not treated.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.


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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events;

laboratory data;

vital signs data;

ECG results.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood and urine samples for PK analysis of PF-06463922 (and its metabolite) will be taken 
according to the Schedule of Activities given in the protocol.
The following PK parameters will be calculated for PF-06463922 and the PF-06895751
metabolite (if possible) from the concentration-time data using standard noncompartmental 
methods:


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Table 2.
Noncompartmental PK Parameters
Matrix
PK 
Parameter
Analysis Scale
PF-06463922
PF-06895751
Plasma
AUCinf
*
ln
A, D
D
AUClast
ln
A, D
D
Cmax
ln
A, D
D
MRAUCinf
*
ln
NA
D
MRAUClast
ln
NA
D
MRCmax
ln
NA
D
Tmax
R
D
D
t1/2
*
R
D
D
CL/F*
ln
A, D
D
VZ/F*
ln
D
D
Urine
CLR
ln
A, D
NA
Ae
R
D
NA
Ae(%)
R
D
NA
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics, MR=Metabolite
(PF-06895751) to parent ratio of,ln=natural-log transformed, R=raw (untransformed), *=if data permits.
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.


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7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular renal function group with ≥3 evaluable measurements.  For 
statistical analyses (ie analysis of variance), PK parameters coded as NC will also be set to 
missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The relationship between PK parameters and renal function (eGFR) will be determined by a 
linear regression model.
The effect of the renal impairment on PK parameters will be assessed by constructing 90% 
confidence intervals around the estimated difference between each of the Test (renally
impaired groups) and the Reference (normal renal function group) using a one-way ANOVA 
model based on natural log transformed data.
8.2. Statistical Analyses
Analysis of variance (ANOVA) will be used to compare the natural log transformed AUCinf
(if data permit), AUClast and Cmax between the normal renal function group and each of the 
renal impairment groups. If a mixture of doses are used within the study, then the previous 
analysis will utilize dose normalized PK parameters instead.  Point estimates and associated 
90% confidence intervals (CIs) for the difference of each comparison will be estimated and 
exponentiated to provide geometric mean ratios and associated 90% CIs. 
Regression analysis will be conducted to characterize the relationship between renal 
function and PK parameters CL/F and CLR. Both eGFR obtained from the MDRD equation 
and CLcr calculated from the C-G formula on Day -1 will be used in regression analysis.
Analysis results will include estimates of parameters for the chosen model as well as 
measures of precision such as CI or standard errors.  PK parameters AUCinf, Cmax, AUClast, 
time for Cmax (Tmax), terminal plasma elimination half-life (t½), CL/F, CLR, Vz/F, cumulative 
amount of drug recovered unchanged in the urine, from zero to time 120 hours post-dose 
(Ae), cumulative amount of drug recovered unchanged in the urine, from zero to time 
120 hours post-dose, expressed as fraction of administered dose (Ae%), will be summarized 
descriptively by analyte (eg, lorlatinib and its metabolite(s)) and renal function group. 


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Metabolite(s) to parent ratio for Cmax (MRCmax), metabolite(s) to parent ratio for AUClast
(MRAUClast), and metabolite(s) to parent ratio for AUCinf (MRAUCinf) will also be 
summarized descriptively by renal function group. 
For AUCinf, AUClast and Cmax, box-whisker plots of the parameters will be plotted by analyte 
and renal function group and overlaid with geometric means. Individual concentrations will 
be listed and summarized descriptively by group and PK sampling time. Individual subject 
and summary profiles (means and medians) of the concentration-time data will be plotted 
across different groups. 
For summary statistics and summary plots by renal function group and sampling time, the 
nominal PK sampling time will be used; for individual subject plots by time, the actual PK 
sampling time will be used.
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
The following PK parameters will be summarized by renal function group:


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Table 3.
PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
AUClast, AUCinf, Cmax, 
MRAUClast, 
MRAUCinf, MRCmax, 
CLR, CL/F and VZ/F
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2, Ae, Ae(%)
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum.
Supporting data from the estimation of t½ and AUCinf will be listed by analyte and group: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel. This data may be included in the clinical study 
report.
Presentations for PF-06463922 concentrations and any metabolite(s) will include:

a listing of all concentrations sorted by renal function group (present in heading), 
subject id and nominal time postdose.  The concentration listing will also include the 
actual times.  Deviations from the nominal time will be given in a separate listing.

a summary of concentrations by renal function group and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.

median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by renal function group (all renal function groups on the same plot per 
scale, based on the summary of concentrations by renal function group and time 
postdose).

mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by renal function group (all renal function groups on the same plot per 
scale, based on the summary of concentrations by renal function group and time 
postdose).

individual concentration time plots by renal function group (on both linear and 
semi-log scales) against actual time postdose (there will be separate spaghetti plots 
for each renal function group per scale).

a listing of all urine concentration interval sorted by renal function group (present in 
heading), subject ID and nominal collection duration postdose.


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For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables split by renal function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-06463922.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by renal
function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break-down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by renal function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by renal
function group.
8.3.5. Laboratory Data
The baseline measurement is the last planned pre-dose measurement.
For each planned time point, baseline values and change from baseline values within each 
treatment group will be summarized with descriptive statistics (using sponsor default 
standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
Supine blood pressure and pulse rate will be measured at the time points as per the schedule 
of activities mentioned in the protocol.
The baseline measurement is the last predose measurement.


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For each planned time point, baseline values and change from baseline values within each 
renal function group will be summarized with descriptive statistics (using sponsor default 
standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the last planned predose triplicate measurement.
The average of the replicate readings collected at each assessment time will be calculated 
prior to summarizing the data across subjects.
Baseline values and changes from baseline for the ECG parameters QT interval, heart rate, 
QTcF interval, PR interval, and QRS interval will be summarized by treatment group and 
time. 
The number (%) of subjects with maximum post-dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment:
Borderline (msec)
Polonged (msec)
Absolute value
--
≥480
Absolute change
30-<60
≥60
In addition, the number of subjects with corrected and uncorrected QT values ≥500 msec will 
be summarized. 
The number (%) of subjects with maximum post-dose PR interval values, maximum increases 
from baseline and second degree atrioventricular block (AVB) type 2 or higher in the 
following categories will be tabulated by renal function group as below:


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Msec
Absolute Value
≥200 - <220
≥220 - <240
≥240 - <260
≥260
Absolute Change
40 - <60
60 - <80
≥80
Relative Change from baaseline
>25%
Second-degree AVB type 2 or highera
a: Second degree block type 2 or higher would be determined by the ECG machine and confirmed by a 
physician. 
These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Other Safety Data
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will not 
be reported in the Clinical study report.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine B-hCG for all females of childbearing potential, urine or blood cotinine 
concentration, HIV, HepBsAg, HepBcAb, and HCVAb testing will be obtained at Screening.
These data will not be brought in-house, and therefore will not be listed.
8.3.11. Analysis of Other Endpoints
Pharmacogenomic and biomarker data will be collected and retained for future analyses, but will 
not be analyzed or reported for this study.


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9. REFERENCES
1.
FDA Guidance for Industry – Pharmacokinetics in Patients with Impaired Renal 
Function - Study Design, Data Analysis, and Impact on Dosing and Labeling.  05/98.
2.
PF-06463922 Investigator’s Brochure 2016. 


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
CCI