Clinical trial NCT03726333
Conditions: Advanced Cancers
Keywords: hepatic impairment lorlatinib cancer pharmacokinetic Lung cancer
Sponsor: Pfizer
Start date: 2020-01-14; Completion date: 2021-07-08
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1 study in advanced cancer patients with varied hepatic functions to evaluate the potential effect of hepatic impairment on pharmacokinetics and safety of lorlatinib and provide dose recommendation for patients with hepatic impairment if possible.

Detailed description:
This will be a Phase 1, open label, multi center, multiple dose, non randomized, Phase 1 clinical trial of lorlatinib in advanced cancer patients with varying degrees of hepatic impairment and necessary age , weight , and gender matched prospect normal hepatic function patients. This study is intended to evaluate the potential effect of hepatic impairments on the PK and safety of lorlatinib after daily administration of lorlatinib and to provide dosing recommendation for patients with varied degree of hepatic impairment if possible.

Patients in the study will be assigned to different groups (A1, normal liver function, control for group B; A2, normal liver function, control for group C; B, mild hepatic impairment; C, moderate hepatic impairment; D, severe hepatic impairment) according to their liver function. The enrollment of approximately 76 advanced cancer patients is anticipated in this study in order to have 8 PK-evaluable patients in each of Groups A1, A2, B and C, and 6 PK-evaluable patients in Group D for final statistical analysis. Evaluable patients are those who complete the planned PK sample collection on Cycle 2 Day 1 and have no lorlatinib dose modification until completion of Cycle 2 Day 1 PK evaluation. Patients who are not evaluable for PK will be replaced. Each patient will be treated with repeated oral once daily doses of lorlatinib in 21-day cycles until disease progression, patient refusal, or unacceptable toxicity occurs. The dose schedule may be modified as necessary for individual patients according to tolerability.

Arms: arm 1: continued daily administration of lorlatinib in patients with normal hepatic function arm 2: continued daily administration of lorlatinib in patients with normal hepatic function arm 3: continued daily administration of lorlatinib in patients with mild hepatic impairment arm 4: continued daily administration of lorlatinib in patients with moderate hepatic impairment arm 5: continued daily administration of lorlatinib in patients with severe hepatic impairment
Interventions: intervention 1: lorlatinib intervention 2: lorlatinib intervention 3: lorlatinib intervention 4: lorlatinib intervention 5: lorlatinib
Intervention descriptions: intervention 1: continued daily administration of 100 mg lorlatinib intervention 2: continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards intervention 3: continued daily administration of 100 mg QD lorlatinib intervention 4: continued daily administration of lorlatinib at 50 mg QD initially and may be adjusted based on PK and safety results from the initial several patients intervention 5: continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C

Protocol documents:
Prot_000.pdf: 
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A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT
ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED
CANCER PATIENTS
Investigational Product Number:
PF-06463922
Investigational Product Name:
Lorlatinib 
United States (US) Investigational New 
Drug (IND) Number:
118,296
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
B7461009
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
25 June 2018
Not applicable (N/A)
Amendment 1
11 Jan 2019
1. SOA: Hematology, Blood Chemistry, 
Coagulation, and Lipids as well as LVEF 
assessments, clarified that assessments are not 
required for Cycle 1 Day 1 if screening tests 
were done within 7 days prior to Cycle 1 Day 
1.
2. SOA, physical examination, removed last 
sentences to reduce confusion.
3. SOA, urinalysis, added assessments in day 1 of 
each cycle.
4. SOA, 12-Lead ECG, the assessment of single 
reading ECG frequency changed from every 
other cycle to every cycle after cycle 3 day 1.
5. SOA, Tumor Assessments, added additional 
clarification.
6. SOA, End of Treatment/Withdrawal, changed 
from “… during the previous 4 weeks…” to 
“… during the previous 3 weeks…”, as the 
treatment cycle is 3 weeks for this study.
7. Section 2, added AUC24, Cmax, Clast, Tlast after 
single dose, Tmax at steady state for lorlatinib, 
Clast after single dose and at steady state for 
metabolite as secondary endpoints.
8. Section 4.2, exclusion criteria updated 
according to new program level guideline.
9. Section 4.3.1, updated according to new 
program level guideline.
10. Section 4.3.2, corrected the drug name from 
crizotinib to lorlatinib.
11. Section 5.5, updated dose modification table 


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Document
Version Date
Summary of Changes and Rationale
according to lorlatinib Core Data Sheet.
12. Section 5.9.1, updated to be consistent with 
product label and other studies.
13. Section 5.9.6 Anti Diarrheal, Anti-Emetic 
Therapy, deleted as it is not relevant for this 
study.
14. Section 5.9.7, Anti-Inflammatory Therapy, 
deleted as it is not relevant for this study.
15. Section 5.9.8, Corticosteroids, deleted as it is 
not relevant for this study.
16. Section 7.1, sentence “Ophthalmologic
examinations will be performed in all patients” 
was deleted as it is not applicable for this 
study. 
17. Section 7.1.1, updated to be consistent with 
other lorlatinib protocol.
18. Section 7.1.3, Table 7, updated to include 
direct bilirubin and make some corrections and 
clarifications for urinalysis and glucose, etc.
19. Section 7.1.5, deleted sentence “Two blood 
pressure readings will be taken at least 1 hour 
apart at each clinic visit”, as it was not 
applicable for this study.
20. Section 7.1.6, minor editing.
21. Section 7.2.1, blood volume was reduced from 
8.0 mL to 5.0 mL as only two 1 mL samples 
are required with more information available 
for metabolic profile of lorlatinib.
22. Section 7.3, minor editing.
23. Section 7.6, added reference for C-SSRS and 
minor editing.
24. Section 9.3.2, Table 9, definition for Tlast was 


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Document
Version Date
Summary of Changes and Rationale
added.
Amendment 2
14 November
2019
This amendment is intended to adjust the Inclusion
criteria to allow more robust patient enrollment while 
ensuring patients’ safety:
1. SOA: ECOG performance was added on Cycle 
2 Day 1.
2. SOA: clarified the days for LFT assessment to 
make the table, footnote and section 7.1.4 clear 
and consistent.
3. Section 3.1, page 29, the second line under 
Table 4, “Table 6” should be referenced.
4. Section 4.1, Inclusion criterion #1, added “who 
have the capability to consent for themselves”
to the end.
5. Section 4.1, the following Inclusion criteria are 
updated:
a. #6: Platelets changed from “100,000/mm3”
to “50,000/mm3”; Hemoglobin from 
“9 g/dL” to “8 g/dL”.
b. #7: both serum total amylase and lipase 
changed from “≤1.5 x ULN” to “≤2.0 x 
ULN without symptom of acute or chronic 
pancratitis”.
c. #8: Adequate Renal Function changed from 
“Serum creatinine ≤1.0 x ULN or CLcr
90 mL/min as calculated using the method 
standard for the institute” to “eGFR 
60 mL/min/1.73m2 calculated using the 
Modification of Diet in Renal Disease 
(MDRD) equation”.
6. Section 4.1, Inclusion criterion #11, deleted “or 
a legally acceptable representative)”.
7. Section 4.2, Exclusion criterion #13, PR 
changed from “>220 msec” to “>200 msec”; 


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Version Date
Summary of Changes and Rationale
deleted “unless patient is otherwise healthy 
such as long distance runner, etc.)”.
8. Section 4.2, Exclusion criterion #24, deleted 
“in the past 6 months”.
9. Section 5.4, page 41, the second line under
Table 5, “Table 6” should be referenced.
10. Appendix 1: Addition of eGFR and HRT in 
the table.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
APPENDICES .........................................................................................................................10
SCHEDULE OF ACTIVITIES................................................................................................11
1. INTRODUCTION ...............................................................................................................16
1.1. Mechanism of Action/Indication.............................................................................16
1.2. Background and Rationale ......................................................................................16
1.2.1. Background.................................................................................................16
1.2.1.1. Non Clinical Pharmacokinetics, Metabolism and Safety of 
Lorlatinib...........................................................................................16
1.2.1.2. Clinical Summary......................................................................18
1.2.2. Study Rationale...........................................................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................28
3. STUDY DESIGN.................................................................................................................28
3.1. Study Overview.......................................................................................................28
4. PATIENT ELIGIBILITY CRITERIA.................................................................................32
4.1. Inclusion Criteria.....................................................................................................32
4.2. Exclusion Criteria....................................................................................................34
4.3. Lifestyle Requirements ...........................................................................................36
4.3.1. Contraception..............................................................................................36
4.3.1.1. Women of Childbearing Potential (WOCBP)...........................37
4.3.1.2. Approved Methods of Contraception........................................38
4.3.2. Alcohol, Caffeine, and Tobacco .................................................................38
4.4. Sponsor’s Qualified Medical Personnel..................................................................39
5. STUDY TREATMENTS.....................................................................................................39
5.1. Allocation to Treatment ..........................................................................................39
5.2. Patient Compliance .................................................................................................40
5.3. Lorlatinib Supplies ..................................................................................................40
5.3.1. Dosage Form(s) and Packaging..................................................................40
5.3.2. Preparation and Dispensing........................................................................40
5.4. Administration.........................................................................................................40
5.5. Recommended Dose Modifications ........................................................................41


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5.6. Management of Overdose .......................................................................................44
5.7. Lorlatinib Storage....................................................................................................45
5.8. Lorlatinib Accountability........................................................................................45
5.8.1. Destruction of Lorlatinib Supplies..............................................................46
5.9. Concomitant Treatment(s).......................................................................................46
5.9.1. Inhibitors, Inducers and Substrates of CYP Enzymes................................46
5.9.2. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................48
5.9.3. Supportive Care ..........................................................................................48
5.9.4. Other Prohibited Concomitant Medications and Therapies........................48
5.9.5. Hematopoietic Growth Factors...................................................................49
5.9.6. Surgery........................................................................................................49
5.9.7. Concomitant Radiotherapy.........................................................................49
6. STUDY PROCEDURES .....................................................................................................49
6.1. Screening.................................................................................................................49
6.2. Study Period ............................................................................................................50
6.3. Follow-up ................................................................................................................50
6.4. Patient Withdrawal..................................................................................................50
7. ASSESSMENTS..................................................................................................................52
7.1. Safety Assessment...................................................................................................52
7.1.1. Pregnancy Testing ......................................................................................52
7.1.2. Adverse Events ...........................................................................................53
7.1.3. Laboratory Safety Assessment ...................................................................53
7.1.4. Liver Function Assessment.........................................................................55
7.1.5. Vital Signs and Physical Examination........................................................55
7.1.6. (12-Lead) Electrocardiogram......................................................................55
7.1.7. Echocardiograms/MUGA Scans.................................................................57
7.2. Pharmacokinetics Assessments...............................................................................57
7.2.1. Plasma for PK Analysis of Lorlatinib.........................................................57
7.3. Tumor Response Assessments ................................................................................58
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7.6. Assessment of Suicidal Ideation and Behavior.......................................................60
8. ADVERSE EVENT REPORTING......................................................................................60
8.1. Requirements...........................................................................................................60
8.1.1. Additional Details on Recording Adverse Events on the CRF...................61
8.1.2. Eliciting Adverse Event Information..........................................................61
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal Section) ............................................................................62
8.1.4. Time Period for Collecting AE/SAE Information......................................62
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................62
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................62
8.1.5. Causality Assessment .................................................................................63
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................63
8.2. Definitions...............................................................................................................63
8.2.1. Adverse Events ...........................................................................................63
8.2.2. Abnormal Test Findings .............................................................................64
8.2.3. Serious Adverse Events..............................................................................65
8.2.4. Hospitalization............................................................................................65
8.3. Severity Assessment................................................................................................67
8.4. Special Situations ....................................................................................................67
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................67
8.4.2. Exposure to the Lorlatinib During Pregnancy or Breastfeeding, and 
Occupational Exposure....................................................................................69
8.4.2.1. Exposure During Pregnancy......................................................69
8.4.2.2. Exposure During Breastfeeding ................................................70
8.4.2.3. Occupational Exposure .............................................................70
8.4.3. Medication Errors and Lack of Efficacy ....................................................71
8.4.3.1. Medication Errors......................................................................71
8.4.3.2. Lack of Efficacy........................................................................71
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................72
9.1. Analysis Sets ...........................................................................................................72
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9.2. Sample Size Determination.....................................................................................72
9.3. Analysis of Pharmacokinetics and Pharmacodynamics ..........................................72
9.3.1. Analysis of Pharmacokinetics.....................................................................72
9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................73
9.3.3. Statistical Methods......................................................................................73
9.4. Safety Analysis........................................................................................................74
9.4.1. Electrocardiogram.......................................................................................74
9.5. Efficacy Analysis ....................................................................................................75
9.5.1. Antitumor Activity Analysis.......................................................................75
9.6. Data Monitoring Committee ...................................................................................76
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................76
11. DATA HANDLING AND RECORD KEEPING .............................................................77
11.1. Case Report Forms/Electronic Data Record .........................................................77
11.2. Record Retention...................................................................................................78
12. ETHICS..............................................................................................................................78
12.1. Institutional Review Board/Ethics Committee......................................................78
12.2. Ethical Conduct of the Study ................................................................................78
12.3. Patient Information and Consent...........................................................................79
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................80
13. DEFINITION OF END OF TRIAL...................................................................................80
14. SPONSOR DISCONTINUATION CRITERIA ................................................................80
15. PUBLICATION OF STUDY RESULTS..........................................................................80
15.1. Communication of Results by Pfizer ....................................................................80
15.2. Publications by Investigators ................................................................................81
16. REFERENCES ..................................................................................................................83


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LIST OF TABLES
Table 1.
Summary of Lorlatinib Single Dose PK Parameters – B7461001 
Phase 1......................................................................................................20
Table 2.
Summary of Lorlatinib Steady State PK Parameters After Repeated 
QD Dosing – B7461001 Phase 1..............................................................21
Table 3.
Summary of Lorlatinib 100 mg QD PK Parameters after Single and 
Multiple Doses in B7461001....................................................................22
Table 4.
Lorlatinib Dosing Schedule......................................................................30
Table 5.
Lorlatinib Dose Levels for Intrapatient Dose Modification .....................41
Table 6.
Recommended Dose Modifications for lorlatinib Related Adverse 
Reactions...................................................................................................42
Table 7.
Safety Laboratory Tests............................................................................54
Table 8.
Pharmacokinetic Parameter Derivation ....................................................73
APPENDICES
Appendix 1. Abbreviations......................................................................................................84
Appendix 2. ECOG Performance Status..................................................................................88
Appendix 3. Child-Pugh Classification (CPC) of Liver Dysfunction .....................................89
Appendix 4. Bone Marrow Reserve in Adults.........................................................................90
Appendix 5. Medications with Potential PR Prolongation Effect ...........................................92
Appendix 6. RECIST Version 1.1 ...........................................................................................93


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each 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 patient.
Screenin
g1
Study Treatment2
End of 
Treatment
/withdrawal24
Follow up25
CYCLE 1
(21 Days)
CYCLE 2
(21 Days)
CYCLE ≥3
(21 Days)
Visit Identifiera
28 days 
prior to 
first dose
Day 13
Day 
8
Day 
15
Day 1
Day 15
Day 1
Visit Window
-1
2
2
2
2
2; 7 for LVEF and imaging
Informed consent4
X
Medical/oncology history5
X
X
Baseline signs and 
symptoms6
X
Physical examination7
X
X
X
X
X
X
X
X
ECOG Performance 
status8
X
X
X
X
X
Liver Function 
Assessment9
X
X
X
X
X
X
X
X
Laboratory
Hematology10
X
(X)
X
X
X
X
X
Blood Chemistry10
X
(X)
X
X
X
X
X
Coagulation10
X
(X)
X
X
X
X
X
Lipids10
X
(X)
X
X
X
X
X
Urinalysis11
X
(X)
X
X
X
HBV, HCV
X
Pregnancy test12
X
X
X
X
X
Contraception check13
X
X
X
X
X
X
X
X
12 Lead ECG14
X
X
X
X
X
X
X
LVEF assessment15
X
(X)
X (every odd-numbered cycle)
X
Enrollment and 
Treatment 
Enrollment16
X
Lorlatinib administration
Orally on a continued QD dosing regimen


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Screenin
g1
Study Treatment2
End of 
Treatment
/withdrawal24
Follow up25
CYCLE 1
(21 Days)
CYCLE 2
(21 Days)
CYCLE ≥3
(21 Days)
Visit Identifiera
≤28 days 
prior to 
first dose
Day 13
Day 
8
Day 
15
Day 1
Day 15
Day 1
Visit Window
-1
±2
±2
±2
±2
±2; ±7 for LVEF and imaging
Tumor assessments17
CT or MRI scan or 
equivalent 
X
X (Every odd-numbered cycle or 
according to the standard practice 
at the site)
X
Other clinical 
assessments
Serious and non-serious 
adverse event monitoring18
X
→
→
→
→
→
→
X
Concomitant 
treatment(s)19
X
→
→
→
→
→
→
X
Suicidal Ideation and 
Behavior20
X
X
X (up to Cycle 6 and then Day 1 of 
every other cycle)
X
Other assessments
Pharmacokinetics21
X
X
X
X
 
Abbreviations: →= ongoing/continuous event; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO 
= echocardiogram; HBV = hepatitis B virus; HCV = hepatitis C virus; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition scan; RECIST= Response Evaluation Criteria for Solid Tumors. (X) – to be completed if not performed within 7 days of the 
first dose of lorlatinib.
a.
Day relative to start of study treatment (Day 1).
1.
Screening: To be obtained within 28 days prior to the start of study treatment.
2.
Study Treatment: All assessments should be performed prior to dosing with lorlatinib unless otherwise indicated.  Acceptable time windows for performing each assessment 
are described in the column headers.  All cycles are 21 days in duration.  Following completion of Cycle 2, ongoing patients on lorlatinib will need to visit the clinic on Day 1 
of every cycle for assessments.  Enough study medication for one cycle of treatment will be dispensed at each clinic visit. Some assessments such as Liver Function 
Assessment and physical examination could be performed more frequently at the discretion of investigator according to the standard practice at the site.  Tumor assessments 
may occur at every odd-numbered cycle or according to standard practice for the indication at the site.
3.
Cycle 1/Day 1: Blood chemistry, hematology, coagulation, lipids, and physical examination not required if acceptable corresponding screening assessment was performed 
within 7 days prior to the start of study treatment. Values closest prior to the first dose of lorlatinib will be used for baseline. 
4.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
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5.
Medical/Oncological History: To also include information on prior medications, smoking history, prior treatment regimens. Will be updated on Cycle 1 Day 1 before the 
start of treatment.
6.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to the first dose of lorlatinib on Cycle 1 Day 1 (as 
baseline values).
7.
Physical Examination: Includes an examination of major body systems, height (at screening only), weight, blood pressure and pulse rate, and will be conducted weekly in 
the first cycle, on the first day of the following cycles, at the end of treatment, and at the follow-up visit. 
8.
Performance Status: Use ECOG classification – see Appendix 2.
9.
Liver Function Assessment: Liver function will be assessed during screening and confirmed before the start of lorlatinib treatment.  Liver Function Assessment should at 
least include tests for AST, ALT, albumin, alkaline phophatase, total bilirubin, and direct bilirubin. Tests done for blood chemistry can be used for liver function assessment. 
Additional tests should be performed to complete the liver function assessment if necessary. All liver function assessments for patient categorization must be completed 
within 24 hours prior to the start of lorlatinib treatment on Cycle 1 Day 1.  Patients will be assigned to different groups according to their liver function before the start of 
lorlatinib treatment.  Criteria for stratification based on liver function are provided in Section 3.1 of the protocol.  Liver function assessments will be performed weekly until
the start of Cycle 2, on Cycle 2 Day 15, on day 1 of each following cycle, at the End of Treatment, and as clinically indicated. There should be more frequent testing for liver 
function in case of Grade 2-4 elevations or in case of signs or symptoms consistent with hepatotoxicity or hepatic failure (eg, fatigue, weakness, anorexia, nausea, vomiting, 
right upper quadrant adnominal pain, jaundice, dark urine, and in rare cases, fever and rash). More frequent monitoring could be performed as the discretion of investigator at 
any time.  Child-Pugh scores will also be calculated and recorded in conjunction with liver function tests prior to the start of the first lorlatinib dose, but will not be used to
stratify patients. Liver function tests should be repeated within 48 hours if the following is observed and repeated weekly until recovery to baseline levels: If a patient 
entered study with AST or ALT baseline values within the normal range  who subsequently presented with AST or ALT ≥3 × ULN concurrent with total bilirubin 
≥2 × ULN, OR a patient with baseline AST or ALT values above the normal range who subsequently presented with AST or ALT ≥2 × the baseline values concurrent with 
a total bilirubin increased by ≥2 × baseline or >3 × ULN (whichever is smaller) and alkaline phosphate <2 × ULN or not available. A 4-mL serum sample obtained just prior 
to the first dose of lorlatinib will be stored frozen on site through completion of the study for possible use as a baseline reference should additional laboratory tests be 
indicated, for example, additional testing to exclude other causes of liver injury (see ADVERSE EVENT REPORTING).
10. Hematology, Blood Chemistry, Coagulation, and Lipids: will be performed at screening, days 1, 8 and 15 in Cycle 1, and Day 1 of every cycle thereafter.  More frequent 
monitoring could be performed at the discretion of the investigator or when clinically indicated.  Cycle 1 Day 1 tests will only be required if the screening tests were not done 
within 7 days.  Required tests are listed in Section 7.1.3 of the protocol.  
11. Urinalysis: Dipstick is acceptable.  Microscopic analysis to be conducted if dipstick abnormal and/or if this is the local standard.  Will be performed at screening and Day 1 of 
each cycle and repeated as clinically indicated, for example, upon diagnosis of renal cysts (more frequent assessment may be performed based on local requirement). See 
ASSESSMENTS section for Laboratory Tests list. Cycle 1 Day 1 tests will only be required if the screening tests were not done within 7 days.  
12. Serum or Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, must be performed on two occasions prior to starting study 
therapy, once at screening (serum) and once at the baseline visit (serum or urine, prior to the first lorlatinib dose), whose results must be available before lorlatinib
administration. Pregnancy tests also need to be routinely repeated at every cycle during the active treatment period, at the end of treatment and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected. Additional pregnancy tests to be conducted if requested by IRB/IECs or by local regulations. 
13. Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to follow the contraception guidelines in 
Section 4.3.1. 


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14. 12-Lead ECG: Triplicate ECG will be performed at screening, times 0 (predose) 1, 2, 4, 10 and 24 hours post dose on Cycle 1 Day 1 and Cycle 2 Day 1, predose on days
8 and 15 in cycle 1, and at the end of treatment. At each time point, 3 consecutive 12-lead ECGs are to be performed approximately 2 minutes apart. The ECG must occur 
prior to any blood sample collections or venipuncturing or collection of vital signs. All ECGs scheduled at 0 hours must be collected prior to dosing. All efforts should be 
made to ensure the ECG collections completed within 15 minutes prior to the PK collection if they are planned at the same time. Additional ECGs may be collected as 
clinically indicated. Single reading ECG will be collected pre-dose on Day 1 of Cycle 3 and every cycle thereafter.
15. LVEF Assessment: Echocardiogram or MUGA to be performed at Screening, at pre-dose (0 hour) on Cycle 1 Day 1 (not required if screening LVEF was obtained within 
7 days prior to Cycle 1 Day 1) and on Day 1 of every other cycle thereafter, and at the EOT visit. The same method should be used at each time point.
16. Enrollment: Enrollment number and treatment group allocation assigned by Pfizer Inc based on AST and total bilirubin values.  
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites. Imaging may include CT or MRI scans of chest, abdomen, and pelvis.  Brain 
scans and bone scans will be performed at screening if disease is suspected and on study as appropriate to follow disease.  The Investigator evaluation will be used for 
response analysis according to RECIST v1.1. Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation. 
18. Serious and non-serious adverse event monitoring: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03. The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient 
begins from the time the patient provides informed consent through and including a minimum of 28 calendar days after the last lorlatinib administration. If the patient begins 
a new anticancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
19. Concomitant Treatments: All concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF from 28 days prior to start of the study 
treatment and up to 28 days after the last dose of study treatment.
20. Suicidal Ideation and Behavior: An assessment of suicidal ideation and behavior via the Columbia Suicide Severity Rating Scale (C- SSRS) will be administered to patients 
prior to the first day of investigational drugs dosing (ie, Cycle 1 Day1) and then prior to dosing on Day 1 of Cycle 2 through Cycle 6.  After Cycle 6 Day 1, this test will be 
administered prior to dosing on Day 1 of every other cycle (ie, Cycle 8 Day 1, Cycle 10 Day 1, etc.) and at EOT.
21. Pharmacokinetics plasma samples for characterization of pharmacokinetics (PK) of lorlatinib and its metabolite(s) will be collected at times 0 (predose), 0.5, 1, 2, 4, 6, 10, 
and 24 hours post lorlatinib dose on Cycle 1 Day 1 and Cycle 2 Day 1.  Predose PK samples will also be collected prior to the lorlatinib dose on Days 8 and 15 of Cycle 1. 
 
 
24. End of Treatment/Withdrawal: Obtain these assessments if not completed during the previous 3 weeks on study (last 6 weeks for tumor assessments).  If the subject 
withdraws from lorlatinib treatment during a cycle visit, then this will be considered the subject’s End of Treatment visit.
25. Follow up: At least 28 calendar days, and preferrable no more than 35 calendar days, after discontinuation of treatment, patients will return to undergo review of concomitant 
treatments, vital signs, contraception check, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further
improvement is expected.
CCI


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Pharmacokinetic and ECG Sampling Schema
Hours post lorlatinib dose
0 (predose)
0.5
1
2
4
6
10
24
Cycle 1 Day 1
Plasma sample for PK analysis
X
X
X
X
X
X
X
X
12 Lead ECG
X
X
X
X
X
X
Cycle 1 Days 8 and 15
Plasma sample for PK analysis
X
Cycle 2 Day 1
Plasma sample for PK analysis
X
X
X
X
X
X
X
X
12 Lead ECG
X
X
X
X
X
X
Abbreviation: PK = pharmacokinetics: ECG=electrocardiogram


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Lorlatinib is a selective, adenosine triphosphate (ATP) competitive small molecule tyrosine 
kinase inhibitor (TKI) of the Anaplastic Lymphoma Kinase (ALK)-positive or c-ROS 
oncogene 1 (ROS1)-positive 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 ALK-positive 
or ROS1-positive advanced non small-cell lung cancer (NSCLC). 
1.2. Background and Rationale
1.2.1. 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% as 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.5  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 
predicted 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 predicted efficacious concentration 
(Ceff) (total) of 7.6 ng/mL, 62 ng/mL, and 150 ng/mL, respectively.
1.2.1.1. Non Clinical Pharmacokinetics, Metabolism and Safety of Lorlatinib
Details of the nonclinical absorption, distribution, metabolism and excretion properties of 
lorlatinib are provided in the Investigator’s Brochure (IB).  Lorlatinib was well 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. The fraction unbound of lorlatinib to plasma proteins were 0.303, 0.287, and 0.340 for 
rat, dog, and human, respectively.


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In rats, dogs, and humans, lorlatinib undergoes metabolism via oxidation and/or 
glucuronidation. In vitro, lorlatinib was metabolized primarily by cytochrome P50 
(CYP)3A4 and uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A4, with minor
contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3. In vitro, lorlatinib is not a 
substrate for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux 
transporters nor for the hepatic uptake transporters organic-anion-transporting polypeptide 
(OATP)1B1 and OATP1B3.
The likelihood of metabolic drug-drug interaction (DDI) resulting from inhibition by 
lorlatinib of the clearance of concomitant drugs that are substrates of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, and CYP2D6 is low at clinically relevant concentrations. In 
vitro, lorlatinib is a reversible and a time-dependent inhibitor of CYP3A4/5, and also induces 
CYP3A4 and activates human pregnane X receptor (hPXR). In humans, lorlatinib exhibited
a net induction effect on CYP3A4/5. In vitro, lorlatinib induced CYP2B6 and activated 
hCAR1, and may have the potential for induction of drugs that are metabolized by CYP2B6.
Induction of CYP1A2 by lorlatinib is unlikely at clinically relevant concentrations.
PF-06895751, a major circulating metabolite for lorlatinib, is unlikely to cause DDI by 
induction of CYP1A2, CYP2B6, and CYP3A4, or inhibition of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
Assessments based on in vitro evaluations indicate that lorlatinib and PF-06895751 has a low 
risk to cause inhibitory pharmacokinetic DDI with substrates for UGT1A1, UGT1A4, 
UGT1A6, UGT1A9, UGT2B7, and UGT2B15 at clinically relevant concentrations. The 
potential for lorlatinib to cause DDI by inhibiting BCRP (systemically), OATP1B1, 
OATP1B3, organic anion transporter (OAT)1, organic cation transporter (OCT)2, and 
multidrug and toxin extrusion 2K (MATE2K) was low at clinically relevant concentrations, 
but may have the potential to inhibit P-gp (systemically and gastrointestinal [GI] tract), 
BCRP (GI tract), OCT1, OAT3, and MATE1.  PF-06895751 is unlikely to cause DDI by 
inhibiting these evaluated drug transporters at clinically relevant concentrations.
Lorlatinib was administered to rats and dogs in toxicity studies up to 13 weeks in duration 
with twice daily (BID) dosing.  Moribundity preceded by clinical signs of intolerance was 
observed in repeat-dose toxicity studies at 60 mg/kg/day in rats and 50 mg/kg/day in dogs 
where systemic exposure exceeded exposure at clinically relevant doses.  Based on the 
nonclinical safety studies conducted with lorlatinib, the important toxicities included changes 
associated with inflammation across multiple tissues, and changes in the pancreas 
(degeneration and/or atrophy of pancreatic acinar cells and associated higher amylase and 
lipase), hepatobiliary system (bile duct hyperplasia and elevations in alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
glutamate dehydrogenase [GLDH], and/or gamma-glutamyl transferase [GGT]), male 
reproductive system (degeneration of seminiferous tubules in the testis and epididymal 
inflammation), cardiovascular system (see below), and gastrointestinal tract (emesis, 
ulceration/erosion, edema) of rats and/or dogs.  Additional important findings were observed 
in peripheral nerves (axonal degeneration), central nervous system (CNS) (cognitive and 
neurological function), and the kidney (glomerulopathy, hyaline casts, arterial 
degeneration/necrosis, tubular basophilia/pigmentation) of rats.  Reversibility (full or partial) 
was established for all lorlatinib-related target organ toxicities with the exception of hepatic 


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bile duct hyperplasia after 13 weeks of lorlatinib administration in rats. Lorlatinib was 
evaluated in in vitro, ex vivo, and/or in vivo safety pharmacology studies to identify potential 
effects on the cardiovascular system.  Lorlatinib was identified as a weak inhibitor of the 
human Ether-a-go-go-Related Gene (hERG) potassium channel and L-type calcium channels, 
and also increased late sodium currents.  Lorlatinib increased PR and QRS intervals ex vivo 
and/or in vivo and induced changes in blood pressure and heart rate in vivo.  Non-adverse 
histological changes in the heart and increases in heart weight were also observed after 
administration of lorlatinib for ≥4 weeks to rats. The potential for mild, non-dose dependent 
impairment of cognitive function in rats was identified in a contextual renewal model. 
Lorlatinib was also associated with the potential for embryo-fetal toxicity and was identified 
as an aneugen.  Some of the nonclinical findings were likely due to off-target inhibition of 
tropomyosin receptor kinase B (TrkB) including effects on the peripheral and central nervous 
system, and changes in lipid profiles and body weight.  The major human circulating 
metabolite PF-06895751 did not show primary or secondary pharmacologic activity against 
ALK and ROS1 kinase targets, or against a broad panel of receptors, enzymes, transporters, 
and ion channels.  PF-06895751 did not inhibit the hERG potassium channel and was not 
genotoxic. The no-observed-adverse-effect-level (NOAEL)s in the pivotal 13-week toxicity 
studies were 8/4 mg/kg/day in male/female rats (unbound maximal plasma concentration 
[Cmax] of 442/451 ng/mL and area under the curve [AUC] of 6240/7820 ng•hr/mL and 
associated AUC exposure margins of 3.3/4.1x at the recommended human dose of 100 mg 
once a day [QD]) and 7 mg/kg/day in dogs (unbound Cmax of 330 ng/mL and AUC of 
2980 ng•hr/mL and an associated AUC exposure margin of 1.6x).  Further details of the 
nonclinical safety program are provided in the current Investigator’s Brochure.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure.
1.2.1.2. Clinical Summary
1.2.1.2.1. Safety and Pharmacokinetics
There are three 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 study to evaluate the combination of 
lorlatinib with avelumab. B7461006 is an open-label, multicenter, randomized Phase 3 
study comparing lorlatinib to crizotinib in treatment-naïve ALK-positive advanced NSCLC.
Seven (7) healthy volunteer studies that have been completed are described in detail below 
and include B7461004, B7461005, B7461007, B7461008, B7461011, B7461012, B7461016 
and B7461017.  These studies also utilized the recommended Phase 2 dose (RP2D) of 
100 mg QD as a single dose administration.  B7461004 and B7461017 are completed
radiolabelled mass balance studies.  B7461005 is a completed relative bioavailability study. 
B7461007 is a completed study which estimated the absolute oral bioavailability of 
lorlatinib.  B7461008 is a completed study which evaluated the effects of acid-reducing 
agents and food on pharmacokinetics (PK) of lorlatinib.  Study B7461011 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.


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1.2.1.2.1.1. 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 ALK-positive or ROS1-positive advanced 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 ALK-positive or ROS1-positive advanced NSCLC 
with or without asymptomatic central nervous system (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 
(RP2D) and is enrolling patients with ALK-positive NSCLC or ROS1-positive 
advanced 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 the 
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 March 2017, 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 72.2% patients, EDEMA reported in 53.7% of 
patients and HYPERTRIGLYCERIDEMIA reported in 42.6% of patients, PERIPHERAL 
NEUROPATHY reported in 40.7% of patients, and COGNITIVE EFFECTS reported in 
25.9% of the patients.  All of the treatment-related AEs were reported with a maximum 


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common terminology criteria (CTC) Grade 3, with the exception of 3 patients with Grade 4 
HYPERCHOLESTEROLEMIA and 1 patient with Grade 4 gamma-glutamyltransferase 
increased.  Of note, terms that are in all capitalized letters are cluster terms as defined in the 
Investigator’s Brochure (IB).  
The Phase 2 began enrollment in September 2015.  Enrollment has been rapid, with 
111 patients dosed as of March 2017.  The overall the safety profile has been consistent with 
that observed in the Phase 1.  
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)
Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic mean ± Std Dev 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.
Source: Table 14.4.4.1.1.1


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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± Std Dev 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.
After single oral administration of the acetate solvate 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, mean apparent oral clearance (CL/F) of 9.8 to 15.8 L/hr and mean 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.


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After repeated QD oral administration, steady state should have been achieved before Day 15 
based on the lorlatinib apparent terminal elimination half-life (Table 3).  The observed steady 
state accumulation rations (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 prominant with increasing dose levels, as the observed accumulation index 
becomes smaller.
PK data (March 2017) after 100 mg single and multiple dosing in Phase 1 with acetate 
solvate drug form and in Phase 2 with free base 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)
t1/2
(hr)
CL/F
(L/hr)
Vz/F
(L)
Phase 1: Acetate Solvate
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 
(1.0-4.0)
NA
19.52 (30)
NA
Phase 2: Free Base
Single Dose
19
9088 (35)
695.2 (40)
1.55 
(0.50-4.02)
23.6±9.37
11.01 (35)
351.5 (37)
Multiple Doses
26
5650 (39)
576.5 (42)
1.96 
(0.50-22.7)
NA 
17.70 (39)
NA
Source data: B7461001 CSR, Table 14.4.4.1.2.1.
Geometric mean (%CV) for AUC, Cmax, CL/F, and Vz/F; arithmetic mean ± SD for t1/2; median (range) for Tmax.
AUCinf for single-dose and AUCfor multiple doses.
Vz/F is calculated by Dose/(lambda Z x 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 AUClast geometric mean 
values (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 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 CYP3A substrates with narrow therapeutic indices should be avoided.
1.2.1.2.1.2. Study B7461004
Study B7461004 is a completed Phase 1 study which evaluated the mass-balance and PK of 
lorlatinib in 6 healthy male subjects after a single oral 100 mg dose of radiolabeled lorlatinib
containing approximately 100 Ci of [14C]lorlatinib.


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The results indicate a mean of 47.73% of the radioactivity was recovered in urine and 
40.91% was recovered in feces through the last collection interval.  Most of the administered 
radioactivity was recovered in the first 144 hours postdose (85.11%).  The overall mean 
recovery of radioactivity in urine and feces samples was 88.64% 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 indicates that the major 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.  In the current B7461009 study, samples will be collected to 
describe the PK of lorlatinib metabolite(s).
1.2.1.2.1.3. Study B7461017
Study B7461017 is a completed Phase 1 Study which evaluate the mass-balance and PK of 
lorlatinib in 6 healthy male subjects after a single oral 100 mg dose of radiolabeled lorlatinib 
containing approximately 100 Ci of [14C]lorlatinib. The 14C label is placed in the other half 
of the ring structure compared to the 14C label in study B7461004. The results from the two 
studies fully characterized the metabolic pathway of lorlatinib.
The overall mean cumulative recovery of radioactivity from urine and fece are 91.59% over 
the 264 hour collection period with recovery in individual subjects ranging from 84.6 to 
94.3%. A mean of 63.69% of the dose was recovered in feces and 27.90% was recovered in 
urine. Most of the administered radioactivity was recovered in the first 144 hours post dose 
(86.68%). Unchanged lorlatinib was observed as a minor component in urine, accounting for
1.1% of the renally excreted dose. While, unchanged lorlatinib comprised 5.9% of the total 
dose excreted in feces.
Metabolic profiling indicates that no new metabolites of lorlatinib associated with the 
pathway leading to the formation of PF-06895751 were identified in plasma. An additional 
region of early eluting radioactivity was observed in feces (~6.3% of the dose) and urine 
(~2.4% of the dose) but was not detected in plasma. This region is proposed to be comprised 
of derivatives of an intermediate metabolite, PF-06898840, the pyrido-pyrazole substructure 
resulting from oxidative and hydrolytic cleavage of lorlatinib.
1.2.1.2.1.4. 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 (free 
base and maleate, [Test]) compared to the acetate solvate formulation (Reference). 
The results supported the switch to free base formulation of lorlatinib in all future clinical 
trials including this study (see IB for more details).


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1.2.1.2.1.5. 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 of 100 mg dose relative to 
intravenous (IV) administration of 50 mg dose.
The absolute bioavailability of lorlatinib when administered as a single oral dose in the fasted 
state is 80.8% in healthy adult subjects.
1.2.1.2.1.6. 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. 
Safety data from this study recently identified asymptomatic PR prolongation.  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 the clinical 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. 
In response to the observation of PR interval prolongation, data from all available human 
studies (approximately 100 patients in clinical 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 healthy 
volunteers in this study the upper limit of normal for PR interval will be defined as PR 
interval of 180 msec.
Additional information for this compound may be found in the SRSD, which for this study is 
the IB.


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1.2.1.2.1.7. Study B7461011
Study B7461011 was a Phase 1 open-label, two-period, two-treatment, fixed-sequence 
crossover study to estimate the effect of multiple dose 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 
uneventfully.  During Period 2, on Day 10 (2 days after having received the single 100-mg 
lorlatinib dose with 600 mg once daily [QD] rifampin) all volunteers were noted to have 
elevated values for AST and 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 subjects were 
hospitalized for observation only and discharged within 2 days; these were all reported as 
serious adverse events (SAEs).  The elevations in AST and ALT have all trended down or 
normalized following the suspension of rifampin.  Subjects have also been discharged from 
the study site, and are being followed up.  The Sponsor is working to understand the possible 
causes for this unexpected finding, which will include the pharmacokinetic evaluation of 
lorlatinib, rifampin, and their metabolites.  
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 
2016 versions of the IB.
1.2.1.2.1.8. 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 two 
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 


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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.
1.2.1.2.1.9. 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.
Additional information for this compound may be found in the single reference safety
document (SRSD), which for this study is the investigator’s brochure.
1.2.2. Study Rationale
Lorlatinib elimination occurs primarily through liver metabolism as noted in both in vitro and 
clinical assessments. CYP3A is one of the primary metabolizing enzymes involved in the 
metabolism of lorlatinib. Furthermore lorlatinib demonstrates both inhibitory and inducing 
effects on CYP3A. With continuous once daily dosing, the net effect of lorlatinib on its own 
metabolizing enzyme, CYP3A, is auto-induction at the majority of clinically tested dose 
levels including the RP2D of 100 mg QD. The change in liver function may potentially 
change the inhibitory and/or inducing potential of the liver metabolizing enzymes. Thus the 
effect of lorlatinib on its own metabolism in patients with hepatic impairment may differ 
from patients with normal hepatic function. As there may be a need to use lorlatinib to treat 
cancer patients who also have impaired liver function, it is important to determine the effects 
of hepatic impairment on the pharmacokinetics and safety of lorlatinib and also, if possible, 
determine whether dose modification would be necessary in these patients.  
The current study is designed to primarily evaluate the effect of hepatic impairment on the 
steady state pharmacokinetics and safety of lorlatinib in advanced cancer patients, and if 
possible, provide dosing recommendations for patients with impaired liver function. 


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Since lorlatinib induces its own metabolism at the relevant dose levels, multiple dose 
lorlatinib exposures may not be predicted from single dose PK data. The potential effect of 
the liver dysfunction on the inhibitory and inducing effects of lorlatinib can only be seen 
after multiple administrations at steady-state. Hence the current hepatic impairment study 
will be conducted following multiple dosing with lorlatinib. Since the administration of 
multiple doses to healthy volunteers is precluded, the current study will be conducted in 
patients with solid tumors who do not have other treatment options. 
The preliminary PK data from the lorlatinib clinical study B7461001 in ALK-positive 
NSCLC pateints showed that systemic exposure of lorlatinib is comparable in patients with 
mild hepatic impairment and patients with normal hepatic impairment. These results 
suggested a therapeutic dose of 100 mg QD (same as the current RP2D of 100 mg QD) may 
be tolerable in patients with mild hepatic impairment. Theoretically, liver enzyme activity 
may be affected by worsening liver dysfunction, thus, use of a lower starting dose of 
lorlatinib for patients with moderate hepatic impairment may be necessary before an 
appropriate dose level in this population of patients is identified. An initial dose of 50 mg 
QD of lorlatinib will be administered to patients with moderately impaired liver function, 
while, patients with mildly impaired liver function will start at the proposed fulldose of 
100 mg QD of lorlatinib. Dosage modifications may be applied during the study based on 
the tolerability of the starting doses. Dosing patients with severe hepatic impairment will not 
be initiated until initial PK and safety information is available for patients with moderate 
hepatic impairment.
This study will permit enrolment of patients with cancer who may or may not harbor ALK or 
ROS1 mutations. Patients who do not harbor ALK or ROS1 mutations may not derive 
clinical benefit with lorlatinib, and should not have a high expectation of therapeutic benefit 
from lorlatinib treatment.
 
 
 
 
 
  
 
 
 
 
 
 
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited by local regulations or ethics committee (EC) decision.
CCI
CCI
CCI
CCI


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 
•
To evaluate the effect of hepatic impairment on 
the steady state pharmacokinetics of lorlatinib 
in advanced cancer patients.
• Plasma PK parameters of lorlatinib at steady state: 
AUC24 and Cmax.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the effect of hepatic 
impairment on the safety of lorlatinib in 
advanced cancer patients.
•
To evaluate the antitumor activity of 
lorlatinib in advanced cancer patients.
•
Type, incidence, severity, seriousness, and 
relationship to study medications of adverse 
events (AE) and any laboratory 
abnormalities.
•
Objective response rate (ORR).
•
Duration of response (DR).
•
Plasma PK parameters of lorlatinib, if 
possible:
•
After single dose: AUC24, Cmax, AUClast, 
Tmax, Clast, and Tlast.
•
At steady-state: Cmin, AUClast, Tmax, Tlast, 
and CL/F.
•
Plasma PK parameters for metabolite(s) if 
possible: After single dose and at steady-
state: AUC24, AUClast, Cmax, Clast, Tmax, Tlast,
MRAUC24, MRAUClast, and MRCmax.
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
3.1. Study Overview
This will be a Phase 1, open-label, multi-center, multiple-dose, non-randomized, Phase 1 
clinical trial of lorlatinib in advanced cancer patients with varying degrees of hepatic 
impairment and necessary age-, weight-, and gender-matched prospect normal hepatic 
function patients.  
CCI


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Patients in the study will be assigned to different groups according to their liver function.  
The criteria for stratification of patients based on their liver function (according to National 
Cancer Institute (NCI) guidance,
https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Organ_Dysfunction_Protocol_Te
mplate.docx) are listed below:
Group
Groups A1 
and A2
Group B
Group C
Group D
Hepatic 
Function
Normal
Mild impairment
Moderate 
impairment
Severe
impairment
Total 
Bilirubin
≤ ULN (Upper 
Limit of 
Normal)
B1: ≤ ULN
B2: >1.0 x – 1.5 x ULN
>1.5 x – 3 x 
ULN
>3 x ULN
AST 
(SGOT)
≤ ULN
B1: > ULN
B2: Any
Any
Any

Patients must fulfill both total bilirubin and AST (serum glutamic oxaloacetic 
transaminase [SGOT]) criteria to be included in a group.  

No distinction will be made between liver dysfunction due to metastases or liver 
dysfunction due to other causes.

All liver function tests for stratification must be completed within 24 hours prior to 
the start of treatment. 

Group B (Mild hepatic impairment): for the purpose of this study, the “mild” liver 
dysfunction may be defined according to either of two criteria (Groups B1 and B2), so 
that patients in Group B may come from either of these groups. Patients in Group B1
and B2 are thus considered to have comparable liver dysfunction and will be 
combined for dose level allocation and all analysis. 

Patients whose degree of hepatic dysfunction changes (becomes worse or better) 
between screening and initiation of protocol therapy may be re-assigned to a different 
hepatic dysfunction group.  This change should be discussed with the Sponsor and 
properly documented.  Patient stratification will only be done prior to initiation of the 
study treatment. Patients will not be re-assigned to a different hepatic dysfunction 
group once treatment with lorlatinib has been started.

Groups A1 and A2 (Normal): patients with normal liver function will be included in 
this study as matching control patients (Group A1 for Group B and Group A2 for 
Group C). If the dose for moderate hepatic impairment group (Group C) is selected 
to be the recommended clinical dose of 100 mg QD, the control group A2 will not be 
needed to be enrolled. There will be no control group designated to match severe 
group. However, if a decision has been made to use the same dose for severe and 
moderate patients, the half of the control Group A2 will be matching Group C and 
half will be matching Group D.


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Child-Pugh scores (criteria listed in Appendix 3) will be calculated and recorded as part of 
the liver function testing prior to the start of the first lorlatinib dose, but will not be used to 
stratify patients into treatment groups.
The enrollment of approximately 76 advanced cancer patients is anticipated in this study in 
order to have 8 PK-evaluable patients in each of Groups A1, A2, B and C, and 
6 PK-evaluable patients in Group D for final statistical analysis.  Evaluable patients are those 
who complete the planned PK sample collection on Cycle 2 Day 1 and have no lorlatinib 
dose modification until completion of Cycle 2 Day 1 PK evaluation. Patients who are not 
evaluable for PK will be replaced.
Each patient will be treated with repeated oral once daily doses of lorlatinib in 21-day cycles 
until disease progression, patient refusal, or unacceptable toxicity occurs.
The planned dosing schedule for each treatment group is as follows (Table 4):
Table 4.
Lorlatinib Dosing Schedule
Group B
Group C
Group D
Group A1
Group A2
Hepatic 
Function
Mild
Moderate
Severe
Normal
Normal
Starting 
Lorlatinib Dose 
100 mg QD
50 mg QD or 
otherwise 
determined 
in the first 
stage 
determined 
based on 
preliminary 
safety and 
PK data
100 mg QD
the same 
dose as 
Group C 
at the 
second 
stage 
Lorlatinib Dose 
After PK 
Assessment
100 mg QD
50 mg QD or 
otherwise 
determined 
in the first 
stage
determined 
based on 
preliminary 
safety and 
PK data
100 mg QD
100 mg 
QD
The dose schedule may be modified as necessary for individual patients according to 
tolerability (see Table 6 for detailed dose modification strategy). 
For Group C, a two-stage enrollment will be applied. 

In the first stage, 3 PK-evaluable patients will be enrolled to receive the starting dose 
of 50 mg QD lorlatinib. On completion of PK sample collection through Cycle 2 
Day 1 from these 3 patients, PK analysis will be performed. Upon review of the PK 
and tolerability of these 3 patients, a decision on dose schedule for remaining patients 
in the second stage will be made. 


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
In the second stage:

If it is decided to keep the planned dosing schedule (50 mg QD) for patients in 
Group C with moderately impaired liver function, 5 additional patients will be 
enrolled to have a total of 8 PK evaluable patients. 

If a different dosing schedule is proposed for the remaining patients in Group C 
based on safety and PK in the first 3 subjects, then more patients will be enrolled 
to this group to have 8 PK evaluable patients and receive the proposed dosing 
schedule.  The control patients in Group A2 should receive the same lorlatinib 
dose as proposed for the second stage in Group C until completion of PK 
assessment on Cycle 2 Day 1 and then switch to 100 mg QD beyond Cycle 2 
Day 1. At the new dose level, the first 3 patients should be dosed one at a time 
with at least one week apart until some safety information at this dose level is 
obtained. 
The enrollment for patients with severe hepatic impairment (Group D) will only be started 
when the dose for patients in the second stage of Group C has been determined and has been 
tolerated in at least one patient.  The initial lorlatinib dose for Group D might be the same as 
the second stage Group C dose or otherwise determined by sponsor based on available 
preliminary safety and PK data at that time. The dosing regimen for Group D will be 
communicated to sites. Patients in Group D will not be matched by any control group. 
Initially (the first 3 patients), the patient should be dose one by one with at least 1 week apart 
until some safety information is obtained at the dose level.  
Patients in Groups A1 (Normal hepatic function) and B (Mild hepatic impairment) will 
receive a starting lorlatinib dose of 100 mg (4 × 25-mg tablets) QD. The first 3 patients in in 
Group C (Moderate hepatic impairment) will receive a starting lorlatinib dose of 50 mg 
(2 × 25-mg tablets) QD.  Patients in control Group A2 (Normal hepatic function) will receive 
the same starting lorlatinib dose as stage 2 of Group C, which could be 50 mg (2 × 25-mg 
tablets) QD or as otherwise determined during the second stage of Group C, and switch to 
100 mg (4 × 25-mg tablets) QD after completion of PK assessment on Cycle 2 Day 1.  
Enrollment into control Group A2 will only be started after the first stage for Group C has 
been completed and a decision on dose schedule for the stage 2 subjects in Group C has been 
made.  Patients in control group should match patients in the respective hepatic impaired 
group by the following criteria:

The mean body weight in control group will be within 20 kg of the mean body 
weight of the patients in respective hepatic impaired group.

The mean age in control group will be within 10 years the mean age of the patients 
in respective hepatic impaired group.

The gender ratio in control group will be similar (2 patients per gender) to those in 
respective hepatic impaired group.


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Once all the patients complete their planned PK collection, data collection for the primary 
objective of the study will be accomplished. After data collection for the primary objective 
has been completed, the sponsor could generate a study report including all PK data and 
other data, as defined in the Sponsor-maintained statistical analysis plan. In this case, a
supplement study reported will then be generated when all patients completed the study.
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients 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 patient is suitable for this protocol.
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the
study:
Females and/or male patients age ≥18 who have the capability to consent for 
themselves. 
Histologically or cytologically confirmed solid malignancy or lymphoma that is 
metastatic or unresectable, and for which standard curative or palliative measures do 
not exist, or are no longer effective.  
In case of hepatocellular carcinoma, the diagnosis should be based on at least one of 
the following:
a.
The presence of at least one lesion, measuring ≥2 cm, with characteristic arterial
enhancement and venous washout in the setting of liver cirrhosis and/or hepatitis 
B or C infection;
b. The presence of liver lesion(s) (as defined in a.) with alpha-fetoprotein (AFP)
≥400 ng/mL;
c.
Tissue confirmation.
Biliary obstruction for whom a biliary drain or stent has been placed are eligible, 
provided that the drain or stent have been in place for at least 10 days prior to the first 
dose of lorlatinib, and the liver function has stabilized as defined by 2 measurements 
at least 5 days apart that put the patient in the same hepatic dysfunction stratum as 
defined in Section 3.1.
Presence of gliomas and brain metastases only if neurologically stable and treated
without ongoing requirement for corticosteroids for at least 2 weeks prior to the first 
lorlatinib dose.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.


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Adequate Bone Marrow Function, including:
d. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
e.
Platelets 50,000/mm3 or 50 x 109/L;
f.
Hemoglobin 8 g/dL.
Adequate Pancreatic Function, including:
g. Serum total amylase ≤2. 0 x upper limit of normal (ULN) without symptom of 
acute or chronic pancreatitis;
h. Serum lipase ≤2.0 x ULN without symptom of acute or chronic pancreatitis.
Adequate Renal Function, including:
eGFR 90 mL/min as calculated using the Modification of Diet in Renal Disease 
(MDRD) equation as follows: eGFR (mL/min/1.73 m2) = 175 × (Scr,std)-1.154 ×
(Age)-0.203 × (0.742 if female) × (1.212 if African American).  
Resolved acute effects of any prior therapy to baseline severity or Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 except for adverse 
events (AEs) not constituting a safety risk by investigator judgment. 
Serum pregnancy test (for females of childbearing potential) negative at screening.
Female patients of nonchildbearing potential must meet at least 1 of the following
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are
considered to be of childbearing potential. 
Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures. 


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4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
Untreated esophageal varices observed on esophagogastroduodenoscopy (EGD) or 
imaging study; however, patients with known portal hypertension and evidence of 
varices on EGD or imaging study who have undergone appropriate therapy as 
indicated within the last 6 months (if applicable) are eligible for enrollment.
Uncontrolled ascites that is not stable with medical management (ie, on diuretics and 
salt restriction) as defined by requiring therapeutic paracentesis more than once every 
4 weeks.
Episodes of hepatic encephalopathy within the last 4 weeks.  Patients with prior 
episodes of hepatic encephalopathy who are clinically stable on lactulose, neomycin, 
and/or xifaxan therapy are allowed.
Spinal cord compression unless the patient has good pain control attained through 
therapy, and there is stabilization or recovery of neurological function for the 4 weeks 
prior to enrollment.
Major surgery within 4 weeks prior to enrollment. Minor surgical procedures (eg, 
port insertion) are not excluded, but sufficient time should have passed for adequate 
wound healing.
Radiation therapy within 2 weeks prior to enrollment, including stereotactic or partial 
brain irradiation. Whole brain irradiation within 4 weeks prior to randomization. 
Palliative radiation therapy outside of the CNS (eg bone mets) more than 48 hours 
prior to randomization is allowed.
Last anti-cancer treatment within 2 weeks prior to screening.
Previous high-dose chemotherapy requiring stem cell rescue.
Prior irradiation to >25% of the bone marrow (see Appendix 4 Bone Marrow Reserve
in Adults).
Gastrointestinal abnormalities, including inability to take oral medication; 
requirement for intravenous alimentation; prior surgical procedures affecting 
absorption including total gastric resection or lap band; active inflammatory 
gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment 
for active peptic ulcer disease in the past 6 months; malabsorption syndromes.
Known prior or suspected severe hypersensitivity to lorlatinib or any component in 
lorlatinib tablet.


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For patients who do not have liver cancer, active and clinically significant bacterial, 
fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus 
(HCV) (eg, in case of known hepatitis B surface antigen [HBsAg] or HCV antibody 
positivity), known human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS)-related illness.
Clinically significant cardiovascular disease, that is, active or within 3 months prior to 
enrollment: cerebral vascular accident/stroke, myocardial infarction, unstable angina, 
congestive heart failure (New York Heart Association Classification Class ≥II), 
second-degree or third-degree AV block (unless paced) or any AV block with PR 
>200 msec; or
Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial 
fibrillation of any grade, bradycardia defined as <50 bpm, machine-read ECG with 
QTc >470 msec, or congenital long QT syndrome.
Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
Patients with predisposing characteristics for acute pancreatitis according to 
investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) in 
the last month prior to randomization.
History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative 
bronchiolitis, and pulmonary fibrosis.
Active hemolysis or evidence of biliary sepsis.
Patients who had prior major gastrointestinal surgery removing part of 
gastrointestinal tract (>1/3 of colon and/or any other part) and/or gall bladder.
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 inducers (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort).
b. known strong CYP3A inhibitors (eg, grapefruit juice or 
grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos], 
boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, 
ritonavir [alone or with danoprevir or elvitegravir or indinavir or lopinavir or 
paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir], telaprevir, 
troleandomycin, voriconazole,). The topical use of these medications (if 
applicable), such as 2% ketoconazole cream, is allowed.
c.
known P-gp substrates with a narrow therapeutic index (eg, digoxin).


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d. known CYP3A substrates with narrow therapeutic indices (eg, alfentanil, 
cyclosporine, ergot alkaloid [dihydroergotamine, ergotamine], fentanyl [including 
transdermal patch], pimozide, quinidine, tacrolimus).
Prior treatment with lorlatinib.
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 lorlatinib administration or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study.
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 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential 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 if male or 21 days if female after the last dose of 
lorlatinib.
Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis or melena.
4.3. Lifestyle Requirements
4.3.1. Contraception
Lorlatinibis teratogenic and an aneugen and can therefore cause harm when administered to a 
pregnant woman. Therefore, use of an appropriate method of contraception during treatment 
with lorlatinib is mandatory.
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected a highly effective method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
below, Section 4.3.1.2) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use a highly effective 
method of contraception consistently and correctly and document the conversation and the 
participant’s affirmation in the participant’s chart (participants need to affirm their consistent 
and correct use of at least one of the appropriate methods of contraception listed below, 
Section 4.3.1.2).  


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Women of childbearing potential (WOCBP, definition provided below, Section 4.3.1.1) must 
agree to use a highly effective nonhormonal method of contraception, because lorlatinib can 
render hormonal contraceptives ineffective. If a hormonal method of contraception is 
unavoidable, then a condom must be used in combination with the hormonal method.
Contraception must be continued for at least 21 days after completing therapy. 
During treatment with lorlatinib and for at least 97 days after the final dose, male patients 
with WOCBP partners must agree to use a highly effective method of contraception, 
including a condom, and male patients with pregnant partners must be agreed to use condoms 
(see Section 4.3.1.2).
In addition, the investigator or designee will instruct the patient to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.
4.3.1.1. Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
Premenopausal female with 1 of the following:
Documented hysterectomy;
Documented bilateral salpingectomy;
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.


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Postmenopausal female:
A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. A high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormone replacement therapy 
(HRT). Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonhormonal appropriate contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
4.3.1.2. Approved Methods of Contraception
Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided a condom is used in combination with the 
hormonal method.  The patient must have been using that hormonal contraceptive for 
an adequate period of time to ensure effectiveness.
Correctly placed copper-containing intrauterine device (IUD).  
Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Male condom must be used in association with a female highly effective method of 
contraception.
Male sterilization with absence of sperm in the postvasectomy ejaculate.
NOTE: For subjects not sexually active, sexual abstinence, defined as completely and 
persistently refraining from all heterosexual intercourse (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. Investigator should 
assess at each visit if a change of patient lifestyle occurred and in case reconsider, in 
consultation with the patient, to select an appropriate method of contraception for the 
individual patient and his/her partner(s) from the list of permitted contraception 
methods.
4.3.2. Alcohol, Caffeine, and Tobacco

Patients must abstain from alcohol prior to enrollment in the study and continue 
abstaining from alcohol until collection of the final PK sample on Cycle 2 Day 1.  
Patients may undergo an alcohol breath test at the discretion of the investigator.

Patients must abstain from the use of tobacco- or nicotine-containing products prior to 
the start of lorlatinib treatment and the collection of final pharmacokinetic sample on 
Cycle 2 Day 1. 


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
Patients are recommended to abstain from caffeine-containing products for 24 hours 
prior to the start of lorlatinib treatment until collection of the final pharmacokinetic 
sample on Cycle 2 Day 1.
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 located in the Study contact list located in the 
study manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient 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 
patient’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 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient 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 Conference 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(s) is lorlatinib.
5.1. Allocation to Treatment
After a patient has been shown to have a liver function within the scope of this study, 
provided written informed consent specifically for this protocol, completed the necessary 
screening assessments, and found to be eligible, the study manager (or equivalent role) will 
then register the patient in the study.
Once eligibility is verified, the study manager (or equivalent role) will assign enrollment 
numbers (provided by the Pfizer randomization Group) sequentially to eligible patients as 
they are screened for the study and will provide this information to the clinical site.  Patients 
will be assigned to different groups according to their liver function (See Section 3.1 for 
stratification criteria).


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5.2. Patient Compliance
Patients will be required to return all unused study treatment at the beginning of each cycle. 
The number of lorlatinib tablets returned by the patient will be counted, documented, and 
recorded.
A patient diary will be provided to the patients to aid in patient compliance with the dosing 
instructions. The diary will be maintained by the patient to include missed or changed 
lorlatinib doses.  Patients will be required to return all bottles of lorlatinib every cycle.  The 
number of lorlatinib tablets remaining will be documented and recorded at each cycle.  The 
patient diary may also be used to support this part of the lorlatinib accountability process. 
5.3. Lorlatinib Supplies
5.3.1. Dosage Form(s) and Packaging
Lorlatinib will be provided as tablets for oral administration. The 25-mg tablets will be 
supplied in separate bottles (or blister cards, as appropriate) and labeled according to local 
regulatory requirements. 
5.3.2. Preparation and Dispensing
Lorlatinib should be dispensed at each visit per the schedule of treatment.  A qualified staff 
member will dispense lorlatinib in the bottles (or blister cards, as appropriate) provided, in 
quantities appropriate for the study visit schedule.  The patient/caregiver should be instructed 
to maintain the product in the bottle (or blister cards, as appropriate) provided throughout the 
course of dosing, keep lorlatinib away from children, and return the bottle (or blister cards, as 
appropriate) to the site at the next study visit. 
5.4. Administration
All trial treatments will be administered on an outpatient basis.
A cycle is defined as 21 days, irrespective of any dose delays/dosing interruptions or missed 
doses which may affect nominal days of each cycle.
Lorlatinib will be administered orally QD at approximately the same time of the day on a 
continuous daily dosing schedule, ie, without a break in dosing in the absence of drug-related 
toxicity. Patients must swallow the study medication whole and must not manipulate or 
chew the medication prior to swallowing. A dosing card will be provided to the patients to 
provide guidance for the correct use of lorlatinib. Patients must be instructed that should 
they miss a dose or vomit any time after taking a dose, they must not “make it up” with an 
extra dose. Instead, resume the subsequent doses as originally prescribed. Any missed dose 
may be taken up to 6 hours prior to the next scheduled lorlatinib dose, otherwise it should be 
skipped and dosing resumed with subsequent doses as prescribed. The patient must be 
instructed to record all doses (including missed or vomited) in a dosing diary supplied by the 
site. If doses are missed or vomited, this must be indicated in the source documents and Case 
Record Forms (CRFs).


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On PK sampling days, the lorlatinib dose should be taken in the clinic under the supervision 
of the study site personnel. The lorlatinib dose should be administered after the 0 hour 
(predose) PK sample has been collected (within 15 minutes prior to lorlatinib dosing). On 
ECG assessment days, the lorlatinib dose should also be taken in the clinic under the 
supervision of the study site personnel so that timing of assessments is appropriately 
synchronized.
Since no clinically meaningful effect of food on the PK of lorlatinib has been observed, 
lorlatinib can be administered with or without food.
Lorlatinib treatment may continue until confirmation of disease progression, patient refusal, 
or unacceptable toxicity despite of dose reduction or interruption, whichever occurs first.
5.5. Recommended Dose Modifications
Every effort should be made to administer lorlatinib on the planned dose and schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below. In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed. Patients are to be instructed to notify their investigators at the first 
occurrence of any adverse event.
If a dosing interruption longer than 6 weeks due to ongoing treatment-related toxicity is 
necessary, study treatment should be permanently discontinued, unless there is a discussion 
of the clinical circumstance with the sponsor’s medical monitor and agreement that the 
patient may resume treatment after a lapse of greater than 6 weeks.
Dose levels for lorlatinib dose modifications are provided in Table 5. All dose modifications 
will be reported in the CRF.
In case of adverse events, Investigators are encouraged to employ best supportive care 
according to local institutional clinical practices or follow the dose modification guidance for 
lorlatinib related adverse reactions provided in Table 6. 
Table 5.
Lorlatinib Dose Levels for Intrapatient Dose Modification
Dose 
Level
Lorlatinib Dose
Lorlatinib Dose
Lorlatinib Dose
0 (starting 
dose)
100 mg QD
75 mg QD
50 mg QD
-1
75 mg QD
50 mg QD
25 mg QD
-2
50 mg/QD
25 mg QD
-


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Patients will be monitored closely for toxicity, and lorlatinib treatment may be adjusted by 
dosing interruption or reduction as indicated in Table 6. If the patient started at 100 mg QD, 
then dosing interruption and/or intrapatient dose reduction by 1, and if needed, 2 dose 
level(s) will be allowed depending on the type and severity of toxicity encountered.*  If the 
patient started at 50 mg QD, only one dose level down (to 25 mg QD) may be allowed and 
should be discussed with the Sponsor based on individual benefit/risk assessment.
Re-escalation is not allowed except if discussed with and approved by the sponsor’s medical 
monitor.
* it is recommended that in case of lorlatinib dose decrease, the patient be assigned a new 
drug bottle rather than using fewer tablets from the bottle assigned at previous visit.
Table 6.
Recommended Dose Modifications for lorlatinib Related Adverse Reactions 
Adverse Reaction
Lorlatinib Dosing
Hypercholesterolaemia or Hypertriglyceridaemia 
Mild hypercholesterolaemia
(cholesterol between ULN and 300 mg/dL or 
between ULN and 7.75 mmol/L)
OR
Moderate hypercholesterolaemia
(cholesterol between 301 and 400 mg/dL or 
between 7.76 and 10.34 mmol/L)
Introduce or modify lipid-lowering therapya in accordance 
with respective prescribing information; continue 
LORLATINIB at same dose. 
Mild hypertriglyceridaemia
(triglycerides between 150 and 300 mg/dL or 
1.71 and 3.42 mmol/L)
OR
Moderate hypertriglyceridaemia
(triglycerides between 301 and 500 mg/dL or 
3.43 and 5.7 mmol/L)
Severe hypercholesterolaemia
(cholesterol between 401 and 500 mg/dL or 
between 10.35 and 12.92 mmol/L)
OR
Severe hypertriglyceridaemia
(triglycerides between 501 and 1000 mg/dL or 
5.71 and 11.4 mmol/L)
Introduce the use of lipid-lowering therapya if currently on 
lipid-lowering therapy, increase the dose of this therapya in 
accordance with respective prescribing information; or 
change to a new lipid-lowering therapy. Continue 
LORLATINIB at the same dose without interruption. 


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Adverse Reaction
Lorlatinib Dosing
Life-threatening hypercholesterolaemia
(cholesterol over 500 mg/dL or over 
12.92 mmol/L)
OR
Life-threatening hypertriglyceridaemia
(triglycerides over 1000 mg/dL or over 
11.4 mmol/L)
Introduce the use of lipid-lowering therapya or increase the 
dose of this therapya in accordance with respective 
prescribing information or change to a new lipid-lowering 
therapy. Withhold lorlatinib until recovery of 
hypercholesterolaemia and/or hypertriglyceridaemia to 
moderate or mild severity grade.
Re-challenge at same lorlatinib dose while maximizing 
lipid-lowering therapya in accordance with respective 
prescribing information.
If severe hypercholesterolaemia and/or 
hypertriglyceridaemia recur(s) despite maximal 
lipid-lowering therapya in accordance with respective 
prescribing information, reduce lorlatinib by 1 dose level.
Central nervous system effectsb,c
Grade 2: Moderate
OR 
Grade 3: Severe
Withhold dose until toxicity is less than or equal to 
Grade 1. Then resume lorlatinib at 1 reduced dose level. 
Grade 4: Life-threatening/Urgent intervention 
indicated
Permanently discontinue lorlatinib.
Pneumonitis 
Grade 1: Mild
OR 
Grade 2: Moderate
Withhold lorlatinib until symptoms have returned to 
baseline and consider initiating corticosteroids. Resume 
lorlatinib at 1 reduced dose level.
Permanently discontinue lorlatinib if ILD/pneumonitis 
recurs or fails to recover after 6 weeks of lorlatinib hold 
and steroid treatment.
Grade 3: Severe 
OR
Grade 4: Life-threatening/Urgent intervention 
indicated
Permanently discontinue lorlatinib.
PR interval prolongation/Atrioventricular (AV) block 
First degree AV block:
Asymptomatic
Continue lorlatinib at the same dose without interruption. 
Consider effects of concomitant medicinal products, and 
assess and correct electrolyte imbalance that may prolong 
PR interval. Monitor ECG/symptoms potentially related to 
heart block closely. 
First degree AV block:
Symptomatic 
Withhold lorlatinib. Consider effects of concomitant 
medicinal products, and assess and correct electrolyte 
imbalance that may prolong PR interval. Monitor 
ECG/symptoms potentially related to AV block closely. If 
symptoms resolve, resume lorlatinib at 1 reduced dose 
level.
Second degree AV block:
Asymptomatic 
Withhold lorlatinib. Consider effects of concomitant 
medicinal products, and assess and correct electrolyte 
imbalance that may prolong PR interval. Monitor 
ECG/symptoms potentially related to heart block closely.


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Adverse Reaction
Lorlatinib Dosing
If subsequent ECG does not show second degree AV 
block, resume lorlatinib at 1 reduced dose level.
Second degree AV block:
Symptomatic 
Withhold lorlatinib. Consider effects of concomitant 
medicinal products, and assess and correct electrolyte 
imbalance that may prolong PR interval. Refer for cardiac 
observation and monitoring. Consider pacemaker 
placement if symptomatic AV block persists. If symptoms 
and the second degree AV block resolve or if patients 
revert to asymptomatic first degree AV block, resume 
lorlatinib at 1 reduced dose level.
Complete AV block
Withhold lorlatinib. Consider effects of concomitant 
medicinal products, and assess and correct electrolyte 
imbalance that may prolong PR interval. Refer for cardiac 
observation and monitoring. Pacemaker placement may be 
indicated for severe symptoms associated with AV block. 
If AV block does not resolve, placement of a permanent 
pacemaker may be considered. 
If pacemaker placed, resume lorlatinib at full dose. If no 
pacemaker placed, resume lorlatinib at 1 reduced dose 
level only when symptoms resolve and PR interval is less 
than 200 msec.
Other adverse reactionsc
Grade 1 
OR
Grade 2 
Consider no dose modification or reduce by 1 dose level, 
as clinically indicated.
Greater than or equal to Grade 3
Withhold lorlatinib until symptoms resolve to less than or 
equal to Grade 2 or baseline. Then resume lorlatinib at 
1 reduced dose level.
ECG=electrocardiogram; HMG CoA=3-hydroxy-3-methylglutaryl coenzyme A; ULN=upper limit of normal.
a Lipid-lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid, or ethyl esters 
of omega-3 fatty acids.
b Examples of CNS effects comprise hallucination and changes in cognition, mood, mental status, or speech 
c Grade categories are based on CTCAE classifications.
5.6. Management of Overdose
An overdose is defined as any dose of lorlatinib >100 mg QD. Any overdose must be 
recorded in the trial drug section of the CRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE 
(serious or not), must be reported to the sponsor (see Section 8.2.1).
Investigators should use their clinical judgment and treat potential cases of overdose with the 
appropriate general supportive measures.


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5.7. Lorlatinib Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all lorlatinib, 
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 lorlatinib 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 nonworking 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.
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, lorlatinib must be quarantined and not used until the Pfizer 
provides permission to use lorlatinib.  It will not be considered a protocol deviation if Pfizer 
approves the use of lorlatinib after the temperature excursion. Use of lorlatinib 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. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct patients on the proper storage requirements for take home lorlatinib. 
5.8. Lorlatinib Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of lorlatinib supplies. All lorlatinib will be accounted for using a drug 
accountability form/record.


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All bottles of study drug must be returned to the investigator by the patient at every visit and 
at the end of the trial.
5.8.1. Destruction of Lorlatinib Supplies 
The sponsor or designee will provide guidance on the destruction of unused lorlatinib (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.
5.9. Concomitant Treatment(s)
Depending on the treatment arm a patient is randomized to receive, medications specifically 
prohibited in the Exclusion Criteria may not be allowed during the active treatment period. 
If there is a clinical indication for one of these or other medications specifically prohibited 
during the trial, discontinuation from study therapy or medication may be required. The final 
decision on any supportive therapy rests with the Investigator and/or the patient’s primary 
physician.  However, the decision to continue the patient on study therapy or medication 
schedule requires the mutual agreement of the Investigator, the sponsor, and the patient. 
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
Concomitant medications and treatments will be recorded from 28 days prior to the start of 
study treatment and up to 28 days after the last dose of study treatment.  All concomitant 
medications should be recorded in the CRF including supportive care drugs (eg, antiemetic 
treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, 
and non-drug supportive interventions (eg, transfusions).
Medications intended solely for supportive care (eg, antiemetics, analgesics, megestrol 
acetate for anorexia, bisphosphonates or RANK-ligands for metastatic bone disease or 
osteoporosis) are allowed.
There are no prohibited therapies during the Post-Treatment Follow-Up Phase.
5.9.1. Inhibitors, Inducers and Substrates of CYP Enzymes
In vitro studies have demonstrated that CYP3A, and UGT1A4 are primarily involved in the 
metabolism of lorlatinib, with additional minor contributions from CYP2C19 and CYP2C8. 
Inhibition or induction of the above enzymes may result in potential alteration of lorlatinib 
systemic exposure. 
Initial in vitro assessment for inhibition and induction drug-drug interaction potential 
indicated that lorlatinib is a time-dependent inhibitor of CYP3A and also an inducer of 
CYP3A and CYP2B6. At substantially higher concentrations than those observed clinically, 
lorlatinib also inhibited CYP2C9 in vitro studies. 


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To protect patient safety, the following cautions are provided:  

Lorlatinib metabolism may be inhibited by strong CYP3A inhibitors leading to a 
potential increase in lorlatinib toxicities.  Coadministration of strong CYP3A 
inhibitors (eg, boceprevir, cobicistat, conivaptan, grapefruit juice, itraconazole, 
ketoconazole, lopinavir, paritaprevir and, posaconazole, ritonavir alone and with 
danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or 
dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole, 
grapefruit juice or grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, 
pomelos]) is not recommended and alternate medications should be considered. If the 
concomitant use of the strong CYP3A inhibitor cannot be avoided, reduce the starting 
dose of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In 
patients who have had a dose reduction to 75 mg orally once daily due to adverse 
reactions and who initiate a strong CYP3A inhibitor, reduce the lorlatinib dose to 
50 mg orally once daily. The patient should be closely monitored for safety and 
reduction of the lorlatinib dose if necessary. If concomitant use of a strong CYP3A 
inhibitor is discontinued, increase the lorlatinib dose (after 3 plasma half-lives of the 
strong CYP3A inhibitor) to the dose that was used before starting the strong inhibitor.

Use of strong CYP3A inducers with lorlatinib is contraindicated.
lorlatinib metabolism may be induced when taking strong CYP3A inducers 
(eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort)
resulting in reduced plasma concentrations. Furthermore, when lorlatinib was 
coadministered with rifampin, increases in AST and ALT were noted. Discontinue 
strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to 
initiating lorlatinib and until study treatment discontinuation. In addition, use with 
moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil) should be 
avoided due to the potential reduction in lorlatinib exposure.

Lorlatinib inhibits CYP2C9 (in vitro), so concurrent use of drugs that are 
CYP2C9 substrates with narrow therapeutic indices, such as warfarin, phenytoin or 
celecoxib, may have increased effect.  Concomitant CYP2C9 substrates should be 
used with caution, as the net clinical effect of lorlatinib on CYP2C9 is currently being 
investigated.

Lorlatinib induces CYP2B6 (in vitro) so concurrent use of drugs that are 
CYP2B6 substrates, such as bupropion and efavirenz, may have less effect.  
Concomitant CYP2B6 substrates should be used with caution, as the net clinical 
effect of lorlatinib on CYP2B6 is currently being investigated. 

Lorlatinib induces CYP3A (in vivo) which may lead to a decreased effect of 
concurrently used CYP3A substrates (eg. hormonal contraceptives etc.).  
Coadministration of lorlatinib with CYP3A substrates with a narrow therapeutic 
index (NTI) such as alfentanil, fentanyl (including transdermal patch), astemizole*, 
cisapride*, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine* (*withdrawn from US market) is not permitted at 


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study entry. However if it is absolutely necessary to use, sponsor approval is required 
and the dose of the CYP3A substrate may need to be increased. The NTI CYP3A 
substrate should be started only after at least 14 days of continuous lorlatinib dosing.
If there is a change in the lorlatinib dosing regimen such as a dosing interruption or 
dose reduction, the administration of the NTI CYP3A substrate should be stopped and 
resumed at a readjusted dose only after at least 14 days of resumed lorlatinib dosing.

Lorlatinib inhibits P-gp (in vitro) so concurrent use of drugs which are P-gp 
substrates with a narrow therapeutic index may have increased effect.  The concurrent 
use of drugs which are P-gp substrates with narrow therapeutic index, such as digoxin 
is not permitted at study entry. The use of these drugs during the study is not 
recommended and alternate medications should be considered. If absolutely 
necessary to use during the study, it should be initiated following sponsor approval, 
and be used then with caution. The net clinical effect of lorlatinib on P-gp is 
currently being investigated.
The Sponsor can be contacted with questions regarding concomitant use of specific drugs.
5.9.2. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not 
permitted.
5.9.3. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines. 
Patients currently being treated with a gonadotropin-releasing hormone agonist (GnRH 
agonist) may continue treatment while on clinical study B7461009 as long as the GnRH 
agonist treatment has been well tolerated for at least 3 months prior to study entry.
5.9.4. Other Prohibited Concomitant Medications and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 

Investigational agents other than lorlatinib. 

Radiation therapy (with the exception noted in the Concomitant Radiotherapy
Section). 

Other experimental pharmaceutical products.


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•
Herbal remedies with anticancer properties or known to potentially interfere with 
major organ function or study drug metabolism (eg, hypericin).
5.9.5. Hematopoietic Growth Factors
Use of granulocyte colony stimulating factors should follow the current American Society of 
Clinical Oncology (ASCO) guidelines.6 Patients who enter the study on stable doses of 
erythropoietin or darbepoetin may continue this treatment, and patients may start either drug 
during the study at the discretion of the investigator.
5.9.6. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and lorlatinib administration required to 
minimize the risk of impaired wound healing and bleeding has not been determined.  
Stopping lorlatinib is recommended at least 2 days prior to surgery.  Postoperatively, the 
decision to reinitiate lorlatinib treatment should be based on a clinical assessment of 
satisfactory wound healing and recovery from surgery.
5.9.7. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline, otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression. 
Lorlatinib must be stopped 24 hours before and at least 24 hours after completion of radiation 
therapy. In view of the current lack of data about the interaction of lorlatinib with 
radiotherapy, lorlatinib treatment should be interrupted during palliative radiotherapy, 
stopping 1 day before and resuming treatment after recovery from acute radiation toxicities 
to baseline.
6. STUDY PROCEDURES 
As applicable, all visits must occur within the pre-defined windows outlined in this protocol.
6.1. Screening
Informed Consent must be obtained prior to undergoing any study specific procedures. 
Informed consent for use of tissue for 
 diagnostic development 
must also be obtained.
For screening procedures see the Schedule of Activities and ASSESSMENTS sections.
 
CCI
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6.2. Study Period
For the treatment period procedures, see the Schedule of Activities and ASSESSMENTS
sections.
6.3. Follow-up 
For follow-up procedures see the Schedule of Activities and ASSESSMENTS sections.
6.4. Patient Withdrawal
Withdrawal of consent: 
Patients 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 patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information. 
Patients 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 lorlatinib or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the patient 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 patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter. All attempts should be documented in the patient’s medical records. If it is 
determined that the patient 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 patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
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with obtaining the patient’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 patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from treatment 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 also the 
Withdrawal from the Study Due to Adverse Events (see also the Patient Withdrawal Section)
or behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given investigator site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.


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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused lorlatinib, request 
that the patient return for a final visit, if applicable, and follow up with the patient regarding 
any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival (if 
survival is a secondary endpoint) unless the patient withdraws consent for disclosure of 
future information or for further contact.  In this case, no further study-specific evaluations 
should be performed and no additional data should be collected.  The sponsor may retain and 
continue to use any data collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, 12 lead ECGs, echocardiogram/multigated acquisition scan (MUGA), 
laboratory assessments, including pregnancy tests and verification of concomitant treatments.  
Assessment for mood and suicidal ideation and behavior will also be performed (see 
Schedule of Activities).
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the AE CRF page.
7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  For female patients of 
childbearing potential, 2 negative pregnancy tests are required before receiving lorlatinib
treatment (1 negative pregnancy test at screening and 1 at the baseline visit immediately 
before lorlatinib administration).  Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced and the second negative pregnancy test result 


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will then be required at the baseline visit before the patient may receive the lorlatinib 
treatment.  In the absence of regular menstrual bleeding, the study candidate should have 
used 2 forms of contraception for at least 1 month before the second pregnancy test.  
Pregnancy tests will also be repeated at every cycle during the active treatment period, and at 
the end of the study to confirm that the patient has not become pregnant during the study.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period and when potential pregnancy is otherwise suspected, and may be repeated 
if requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the patient will be 
withdrawn from administration of lorlatinib.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the schedule 
of activities and analyzed at local laboratories.


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Table 7.
Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis§
Pregnancy Test
Hemoglobin
ALT
PT /INR
Urinalysis (including 
protein, glucose, 
occult blood as well 
as albumin) with 
reflex to microscopic. 
Positive protein may 
require additional 
24-hour urine 
collection at the 
investigator’s 
discretion.
For female 
patients of 
childbearing 
potential, serum 
or urine.
Platelets
AST
aPTT
WBC
Alk Phos
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Absolute Eosinophils
Chloride
Absolute Basophils
Calcium
Total bilirubin***
Direct bilirubin
BUN or Urea
Creatinine
Uric Acid
Lipids
Glucose
Total Cholesterol
Albumin
LDL
Phosphoros or 
Phosphate
HDL
Total protein
Triglycerides
Amylase*
Infections 
Gamma glutamyl 
transferase (GGT)
HBV, HCV (Screening 
only)
Lipase
Creatine kinase
C-reactive protein 
(CRP)
Lactate 
dehydrogenase 
(LDH)
*** For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin 
time (PT)/INR, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels. 
*Serum total amylase (pancreatic isoenzyme required if serum total amylase >1.5x ULN per local institutional 
ranges (ie, CTCAE Grade >1)).
§ Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal and/or if this is the local 
standard. To be repeated as clinically indicated.
ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CRP=C-reactive protein, GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, 
HCV=hepatitis C virus, HDL=high-density lipoprotein, INR=international normalized ratio, LDH=lactate 
dehydrogenase, LDL=low-density lipoprotein, PT=prothrombin time, WBC=white blood cell.


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7.1.4. Liver Function Assessment
Liver function will be assessed during screening and confirmed before the start of lorlatinib 
treatment. Liver Function Assessment should at least include tests for AST, ALT, albumin, 
alkaline phophatase, total bilirubin, and direct bilirubin.  Tests done for blood chemistry can 
be used for liver function assessment. Additional tests should be performed to complete the 
liver function assessment if necessary.  All liver function assessments for patient 
categorization must be completed within 24 hours prior to the start of lorlatinib treatment on 
Cycle 1 Day 1.  Patients will be assigned to different groups according to their liver function 
before the start of lorlatinib treatment.  Criteria for stratification based on liver function are
provided in Section 3.1 of the protocol.  Liver function assessments will be performed 
weekly until the start of Cycle 2, on Cycle 2 Day 15, on day 1 of each following cycle, at the 
End of Treatment, and as clinically indicated.  There should be more frequent testing for liver 
function in case of Grade 2-4 elevations or in case of signs or symptoms consistent with 
hepatotoxicity or hepatic failure (eg, fatigue, weakness, anorexia, nausea, vomiting, right 
upper quadrant adnominal pain, jaundice, dark urine, and in rare cases, fever and rash).  More 
frequent monitoring could be performed as the discretion of investigator at any time.  
Child-Pugh scores will also be calculated and recorded in conjunction with liver function 
tests prior to the start of the first lorlatinib dose, but will not be used to stratify patients. 
Liver function tests should be repeated within 48 hours if the following is observed and 
repeated weekly until recovery to baseline levels: If a patient entered study with AST or 
ALT baseline values within the normal range who subsequently presented with AST or ALT 
≥3 × ULN concurrent with total bilirubin ≥2 × ULN, OR a patient with baseline AST or 
ALT values above the normal range who subsequently presented with AST or ALT ≥2 × the 
baseline values concurrent with a total bilirubin increased by ≥2 × baseline or >3 × ULN 
(whichever is smaller) and alkaline phosphate <2 × ULN or not available.  A 4-mL serum 
sample obtained just prior to the first dose of lorlatinib will be stored frozen on site through 
completion of the study for possible use as a baseline reference should additional laboratory 
tests be indicated, for example, additional testing to exclude other causes of liver injury (see 
ADVERSE EVENT REPORTING).
7.1.5. Vital Signs and Physical Examination
Patients will have a physical examination to include major body systems, weight, blood 
pressure, pulse rate, assessment of ECOG performance status, and height (height will be 
measured at screening only) at the time points described in the Schedule of Activities.  Blood 
pressure and pulse rate should be taken with the patient in the seated position after the patient 
has been sitting quietly for at least 5 minutes.  
7.1.6. (12-Lead) Electrocardiogram
A triplicate 12-lead (with a 10-second rhythm strip) tracing at supine position will be used 
for all ECG assessments.


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All patients require a triplicate ECG measurement at screening.  On treatment ECGs will be 
performed as outlined in the Schedule of Activity (SOA) table.  At each time point requiring 
triplicate ECGs, 3 consecutive 12 lead ECGs will be performed approximately 2 minutes 
apart to determine mean QTc (average of triplicates).  When they coincide with blood sample 
draws for PK, the ECG assessment should be performed within 15 minutes prior to a PK 
blood sample collection, such that the PK blood sample is collected at the planned nominal 
time. 
Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec (ie, CTCAE Grade >2), ECG must be reviewed by 
qualified personnel at the site as soon as the finding is made, including verifying that the 
machine reading is accurate and that the Fridericia correction formula is applied.  If the 
manual reading verifies a rate corrected QTc of >500 msec, repeat ECG should be 
immediately performed at least two times approximately 2 to 4 minutes apart. 
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc is due to study drug, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by a specialist.  If QTc reverts to less than 500 msec, and in the judgment of investigator and 
sponsor is determined to be due to a cause other than study drug, treatment may be continued 
with regular ECG monitoring.
Prior to concluding that an episode of prolongation of the QTc interval is due to lorlatinib, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If a patient experiences PR interval prolongation >200 msec or second-degree or third-degree 
AV block, while on treatment with lorlatinib, refer to Section 5.5, Table 6.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), triplicate ECGs should be obtained at time of the event.  If the mean QTc is 
prolonged (>500 msec), or new or worsened AV block is noted, then ECGs should be 
re- evaluated by a qualified person at the institution for confirmation and repeated as 
clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 


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7.1.7. Echocardiograms/MUGA Scans
In order to monitor potential left ventricular ejection fraction (LVEF) dysfunction, an 
echocardiogram or MUGA will be performed at the time point described in the Schedule of 
Activities. The same method should be used at each time point.
7.2. Pharmacokinetics Assessments
7.2.1. Plasma for PK Analysis of Lorlatinib 
Plasma samples for characterization of pharmacokinetics (PK) of lorlatinib and its 
metabolite(s) will be collected at the designated times listed in SOA table.  
In addition to samples collected at the scheduled times, an additional blood sample may 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.
All efforts will be made to obtain the PK samples at the scheduled 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).  During the trial, actual collection times may change, but the number of samples 
will remain the same.  If scheduled blood sample collection cannot be completed for any 
reason, it may be re-scheduled with agreement of the clinical investigator, patient, and 
sponsor.
At each designated time, blood samples (5.0 mL) to provide approximately 2.5 mL plasma 
(aliquoted into 2 x 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 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.
PK samples will be assayed for lorlatinib and its metabolite(s) using validated analytical 
method(s) in compliance with Pfizer standard operating procedures (SOPs). Lorlatinib 
metabolite(s) to be assayed may include but not limited to PF-06895751.
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.


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7.3. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis computed tomography (CT) or magnetic resonance imaging 
(MRI) scans; brain CT or MRI scan for patients with known or suspected brain metastases; 
bone scan and/or bone x-rays for patients with known or suspected bone metastases.
The same imaging technique used to characterize each identified and reported lesion at 
screening is preferred to be employed in the subsequent tumor assessments.
Tumor assessments will be conducted at screening (as baseline), during treatment as 
specified in the schedule of activities, whenever disease progression is suspected (eg, 
symptomatic deterioration), and at the time of withdrawal from treatment (if not done in the 
previous 6 weeks).
Assessment of response will be made using Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (see Appendix 6).
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
 
 
 
 
 
 
 
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7.6. Assessment of Suicidal Ideation and Behavior
To assess suicidal ideation behaviors, the Columbia Suicide Severity Rating Scale (C-SSRS)7
will be administered to patients at the time points described in the Schedule of Activities
table. The C SSRS is a unique, simple and short method of assessing both behavior and 
ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the 
lethality of attempts and other features of ideation (frequency, duration, controllability, 
reasons for ideation, and deterrents), all of which are significantly predictive of completed 
suicide.
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 lorlatinib under study during 
pregnancy or breastfeeding, and occupational exposure. 
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 lorlatinib 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 treatment group or suspected causal 
relationship to lorlatinib (s) will be reported as described in the following paragraphs.
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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 
lorlatinib 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 
patient 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 
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 patient/legally acceptable representative.  In addition, each study 
patient/legally acceptable representative will be questioned about the occurrence of AEs in a 
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8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient
Withdrawal 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 patient 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 patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving lorlatinib), through and including a minimum of 
28 calendar days after the last administration of lorlatinib.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient 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 lorlatinib 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.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
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.


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If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
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 lorlatinib 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 lorlatinib caused the event, then the event will be handled as “related to 
lorlatinib” for reporting purposes, as defined by the sponsor.  If the investigator's causality 
assessment is “unknown but not related” to lorlatinib, 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.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient 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;

Drug abuse;

Drug dependency.


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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.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
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

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 
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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 patient 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.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
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 
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.


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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, patient 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 patient;

Admission exclusively for the administration of blood products.
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 
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
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 patient’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 patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are “susceptible” to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients 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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (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.


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The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients 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:

Patients 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 patients 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 patient 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. 


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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. 
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 Lorlatinib During Pregnancy or Breastfeeding, and Occupational 
Exposure
Exposure to lorlatinib 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 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 lorlatinib; or the 
female becomes or is found to be pregnant after discontinuing and/or being exposed 
to lorlatinib;

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 
lorlatinib prior to or around the time of conception and/or is exposed during his 
partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with lorlatinib, 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 patient 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).


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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 
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 lorlatinib. 
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 patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient 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.


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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 patient 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.
8.4.3. Medication Errors and Lack of Efficacy
Other exposures to lorlatinib under study may occur in clinical trial settings, such as 
medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
Medication errors and lack of 
efficacy*
All (regardless of whether 
associated with an AE)
Only if associated with 
an SAE
*For lack of efficacy (particularly for studies conducted with vaccines, contraceptives, and products used in the 
treatment of life-threatening diseases or conditions [eg, anti-infectives]), see the Lack of Efficacy section below.
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of lorlatinib by the 
wrong patient, or at the wrong time, or at the wrong dosage strength. Medication errors 
include:

Medication errors involving patient exposure to lorlatinib;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
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 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.
8.4.3.2. Lack of Efficacy 
Lack of efficacy in an approved indication should be reported as an SAE to Pfizer Safety.
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.


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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.
9.1. Analysis Sets 
Safety analysis set:
The safety analysis set includes all enrolled patients who receive at least one dose of 
lorlatinib.
Full analysis set:
The full analysis set includes all enrolled patients.
PK analysis sets:
The PK concentration population is defined as all enrolled patients who are treated 
and have at least 1 analyte concentration.
The PK parameter analysis population is defined as all enrolled patients treated who 
have sufficient information to estimate at least 1 of the PK parameters of interest.
The PK evaluable analysis population is defined as all patients in the PK parameter 
analysis population who have (1) completed Cycle 2 Day 1 PK collection; (2) 
received lorlatinib dose on Cycle 2 day 1; (3) received at least 80% of total dose 
within 14 days prior to Cycle 2 Day 1; (4) no dose reduction in the first cycle.
Response Evaluable set – includes all patients in the safety analysis population who 
have an adequate baseline tumor assessment.
9.2. Sample Size Determination
The sample size for this study is determined empirically based on feasibility and regulatory 
recommendation.  Sufficient numbers of patients will be enrolled and dosed to obtain 
approximately 38 PK evaluable subjects (approximately 16 subjects in normal group, 
8 patients each in mild and moderate groups, and 6 in severe group).
Subjects may be replaced if not PK evaluable.
9.3. Analysis of Pharmacokinetics and Pharmacodynamics
9.3.1. Analysis of Pharmacokinetics
PK analysis could be performed and PK results could be reported after all patients complete 
PK collection. See Section 3.1.  


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9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
Pharmacokinetic parameters will be derived from the lorlatinib and metabolite(s) 
concentration-time profile as described in Table 8.
Table 8.
Pharmacokinetic Parameter Derivation
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast)
linear-log trapezoidal method
AUC24
Area under the plasma concentration-time 
profile during one dosing interval 
(24 hours)
linear-log trapezoidal method
Cmax
Maximum plasma concentration
Observed directly from data
Cmin
Minimum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first occurrence
Tlast
Time or Clast
Observed directly from the data as time of the last 
quantifiable concentration
CL/F
Apparent clearance
Dose/AUC24 at steady-state
MRAUClast
Metabolite ratio for AUClast
(AUClast/MW)metabolite/(AUClast/MW)lorlatinib
MRAUC24
Metabolite ratio for AUC24
(AUC24/MW)metabolite/(AUC24/MW)lorlatinib
MRCmax
Metabolite ratio for Cmax
(Cmax/MW)metabolite/(Cmax/MW)lorlatinib
MW= molecular weight; F= oral bioavailiability
Actual PK sampling times will be used in the derivation of PK parameters.  In the case that 
actual PK sampling times are not available, nominal PK sampling times will be used in the 
derivation of PK parameters. 
9.3.3. Statistical Methods
One-way analysis of variance (ANOVA) will be used to compare the natural log transformed 
AUClast, AUC24 and Cmax at steady state for each of the hepatic impairment groups (Test) to 
the corresponding normal hepatic function group with the same dosing schedule (Reference).  
Estimates of the mean differences (Test-Reference) and corresponding 90% confidence 
intervals for all comparisons will be obtained from the model.  The mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratio of geometric means (Test/Reference) and 90% confidence intervals for the ratios.  
The PK parameters (defined in Table 8) Cmax, Cmin, AUClast, AUC24, Tmax, CL/F, MRAUClast, 
MRAUC24, MRCmax, for lorlatinib and its metabolite(s), as appropriate, will be summarized 
descriptively by analyte, hepatic function group and cycle.  For lorlatinib AUClast, AUC24 and 
Cmax, individual patient parameters will be plotted by hepatic function group and cycle.  For 
AUClast, AUC24 and Cmax box-whisker plots of the parameters will be plotted by analyte and 
hepatic impairment group.
Individual concentrations in plasma will be listed and summarized descriptively by analyte, 
hepatic function group, cycle and nominal PK sampling time.  Individual patient 
concentration-time data will be plotted by hepatic function group and cycle.  Median profiles 
of the concentration-time data will be presented by hepatic function group and dose level 
with all hepatic function groups plotted together with separate plots for each analyte and each
cycle.  


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For summary statistics and summary plots by sampling time, the nominal PK sampling time 
will be used; for individual subject plots by time, actual PK sampling time will be used.
9.4. Safety Analysis
The safety analysis population will be the primary population for evaluating patient 
characteristics, treatment administration, and safety.
Safety data will be reviewed on an ongoing basis during the study.  Safety data will be 
presented in tabular and/or graphical format and summarized descriptively, where
appropriate.
Adverse Events
Adverse Events (AEs) will be coded by system organ class (SOC) and preferred term 
according to Medical Dictionary for Regulatory Activities (MedDRA) terminology.  AE 
severity will be graded according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.3. 
A listing of all AEs including detailed information collected for each AE (description of 
event, onset date/time, duration, seriousness, severity, relationship to study drug, action 
taken, clinical outcome) will be presented. 
The number and percentage of patients who experienced any: AE, serious AE (SAE), 
treatment related AE, and treatment related SAE will be summarized.  Emphasis in the 
analyses will be placed on AEs classified as treatment emergent. The analyses will 
summarize AEs both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1).
Additional summaries of adverse events (AE) and of other safety data will be presented in 
tabular and/or graphical format and summarized descriptively, as appropriate.
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the distribution of 
laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
9.4.1. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline
and on-treatment ECG data.


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ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (HR) (QTc) using standard correction factors 
(ie, Fridericia’s (default correction), Bazett’s, and possibly a study-specific factor, as 
appropriate).  Data will be summarized and listed for QT intervals, HR, RR intervals, PR
intervals, QRS intervals, and QTcF (and other correction factors, eg, QTcB as appropriate) 
by hepatic function and dose.  Individual QT (all evaluated corrections) intervals will be 
listed by study hepatic function, time and dose.  The most appropriate correction factor will 
be selected and used for the following analyses of central tendency and outliers and used for 
the study conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the absolute corrected QT interval and changes 
from baseline in corrected QT after treatment by hepatic function, dose and time point.  For 
each patient and by treatment, the maximum change from baseline will be calculated as well 
as the maximum post-baseline interval across time-points.  Categorical analysis will be 
conducted for the maximum change from baseline in corrected QT and the maximum 
post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline may be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models. The results 
of such analyses will not be included in the study report.
Predose ECG on Cycle 1 Day 1 will be used as baseline for all related analysis. If the 
predose ECG on Cycle 1 Day 1 is not available, the ECG collected closest to Cycle 1 Day 1 
(prior to the first lorlatinib dose) will be sued as baseline.
9.5. Efficacy Analysis
9.5.1. Antitumor Activity Analysis
The response-evaluable population is defined as all patients in the safety analysis population
who have an adequate baseline tumor assessment. The response-evaluable population will be 
the primary population for evaluating clinical antitumor activity data.  


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Objective Response Rate (ORR) is defined as the percent of patients with complete response 
(CR) or partial response (PR) based on investigator evaluation, according to RECIST v1.1 
(Appendix 6), relative to the response-evaluable population.  Designation of best response of 
stable disease (SD) requires the criteria to be met at least once after the first dose of 
medication, at a minimum interval of 6 weeks.
Duration of response (DR) will be measured from the date that an objective tumor response 
(CR or PR) is first documented (whichever occurs first) to date of objective tumor 
progression or death due to any cause, whichever occurs first.
Descriptive statistics will be used to summarize baseline characteristics, treatment
administration, and antitumor activity endpoints overall and, if applicable, separated by
treatment group (as defined by hepatic function and starting dose level) and/or tumor type, as 
applicable.  Data will also be displayed graphically, where appropriate.  The ORR will be 
summarized along with the exact 2-sided 95% confidence interval using the exact method 
based on the F-distribution.  DR will be summarized using Kaplan-Meier method, where 
appropriate. 
Patients who have prior major gastrointestinal surgery removing part of the gastrointestinal 
tract and/or gall bladder will be excluded from descriptive summary and statistical analysis 
for efficacy endpoints, but will be listed for their tumor assessment.
9.6. Data Monitoring Committee
This study will not use a data monitoring committee (DMC).
For the purpose of this protocol, Sponsor procedures for periodic safety review will be
applied to review individual and summary data collected in the safety and clinical 
databases. Procedures include:

Surveillance for serious adverse events (SAEs) according to regulatory guidelines;

Routine monitoring of non-serious adverse events as they are recorded in the CRFs.
Periodic teleconferences with the principal investigators on individual studies to share 
experiences and ensure communication.
Findings of the periodic safety reviews, according to Sponsor procedures will be documented 
in the project files and action taken as appropriate. Findings having immediate implication 
for the management of patients on study will be communicated to all principal investigators 
in the timeframe associated with unexpected and drug-related SAEs.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct 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.


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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 patient'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.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs 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 the data in 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.


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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 patients
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent[/assent] documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports). The 
records should be retained by the investigator according to ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/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 patients.  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. 


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12.3. Patient Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system define by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data
consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient
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 patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the subject’s personal data.  The investigator further must 
ensure that each study subject or his or her legally acceptable representative, is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he or she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 


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must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally,
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative, before any 
study-specific activity is performed. The investigator site will retain the original of each 
patient'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 lorlatinib, 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 patients 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
End of trial is defined as last subject last visit (LSLV).
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 patients and the hospital pharmacy 
(if applicable) within a time period set by Pfizer.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), 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 patient 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 has 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 patients, 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.
Bergethon K, et al. (2012) ROS1 rearrangements define a unique molecular class of 
lung cancers. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 30(8):863-870.
4.
Sasaki T, Rodig SJ, Chirieac LR, & Janne PA (2010) The biology and treatment of 
EML4-ALK non-small cell lung cancer. European journal of cancer 46(10):1773-1780.
5.
Zou HY, et al. (2015) PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to 
First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell
28(1):70-81.
6.
Smith TJ, et al. (2015) Recommendations for the Use of WBC Growth Factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology
33(28):3199-3212.
7.
Posner K, et al. (2011) The Columbia-Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. 
Am J Psychiatry 168(12):1266-1277.


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Appendix 1. Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
AIDS
acquired immunodeficiency syndrome
AFP
Alpha-fetoprotien
ALK
Analplastic Lymphoma Kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AV
Atrioventricular
BA
Bioavailability
BAL
bronchoalveolar lavage
BCRP
breast cancer resistance protein
BID
twice daily
Bpm
beats per minute
BUN
blood urea nitrogen
BNP
B-type natriuretic peptide
Cb
blood concentration
Ceff
effective concentration
CHF
congestive heart failure
CHO
Chinese Hamster Ovary
CK
creatine kinase
CL
Clearance
CL/F
oral clearance
CLR
renal clearance
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system
Cp
plasma concentation
CPC
Child-Pugh classification
CR
complete response
CRF
case report form
CRM
Continual Reassessment Method
CRP
C-reactive protein
CCI


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Abbreviation
Term
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLI
Donor Lymphocyte Infusion
DLT
dose-limiting toxicity
DMC
data monitoring committee
DR
duration of response
EC
ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
external data monitoring committee
EDP
exposure during pregnancy
EEG
Electroencephalogram
EGD
esophagogastroduodenoscopy
eGFR
estimated glomerular filtration rate
EML4
echinoderm microtubule-associated protein- like 4
EOT
End of Treatment
Etc
‘and other things’ or ‘and so forth’
EU
European Union
EudraCT
European Clinical Trials Database
FOB
functional observation battery
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
Gastrointestinal
GLDH
glutamiate dehydrogenase 
GnRH
gonadotropin-releasing hormone
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high-density lipoprotein
hERG
human ether-a-go-go related gene
HIV
human immunodeficiency virus
HLM
human liver microsome
CCI


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Abbreviation
Term
hPXR
human pregnane X receptor
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
IC50
inhibitor concentration achieving 50% inhibition
ICH
International Conference on Harmonisation
IND
investigational new drug 
INR
international normalized ratio
IP manual
Investigational Product manual
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function test
LOAEL
lowest observed adverse effect level
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
MATE2K
multidrug and toxin extrusion 2K
MedDRA
Medical Dictionary for Regulatory Activities
MRAUC
metabolite ratio for AUC
MRCmax
Metabolite ratio for Cmax
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
MW
molecular weight
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate
NCI 
National Cancer Institute 
NOAEL
no-observed-adverse-effect-level
NOEL
Non observed effect level
NSCLC
non small cell lung cancer
OAT
Organic Anion Transporter
OATP
Organic Anion-Transporting Polypeptide
OCT
Organic Cation Transporter
ORR
Objective Response Rate
PT
prothrombin time
PCD
primary completion date
PD
pharmacodynamics
P-gp
P-glycoprotein
C
CI


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Abbreviation
Term
PI
principal investigator
PK
Pharmacokinetic(s)
PPI
proton pump inhibitor
PR
partial response
PS
performance status
PT
prothrombin time
QD
once a day
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose
Rss
steady state accumulation ratio
RTK
receptor tyrosine kinases
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SGOT
serum glutamic-oxaloacetic transaminase
SOA
Schedule of Activity
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
t1/2
terminal elimination half-life
TBili
total bilirubin
TKI
tyrosine kinase inhibitor
TrkB
tropomyosin receptor kinase B
Tmax
Time for Cmax
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal
US
United States
UVB
ultraviolet B 
V
volume of distribution
Vz/F
oral volume of distribution
vs.
versus
WBC
white blood cell 
CCI


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Appendix 2. ECOG Performance Status
Score Definition
0
Fully active, able to carry on all pre-disease activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work or office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any selfcare.  Totally confined to bed or chair.
5
Dead.


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Appendix 3. Child-Pugh Classification (CPC) of Liver Dysfunction
CPC score is calculated from the sum of the points for each CPC criteria:
CPC Classification
Level of dysfunction
Score
A
Mild
5-6
B
Moderate
7-9
C
Severe
10
Assessment parameters
Assigned score for observed findings
CPC Criteria
1
2
3
Encephalopathy grade
(see table below)
0
1 or 2
3 or 4
Ascites
Absent
Asymptomatic
Requiring intervention
Serum total bilirubin, 
mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, sec 
prolonged
<4
4 to 6
>6
Encephalopathy 
Grade
Definition
(electroencephalogram [EEG] required for Gr. 2,3,4)
0
Normal consciousness, personality, neurological exam
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired 
handwriting
2
Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow 
triphasic waves on EEG
3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, 
rigidity, slower waves on EEG
4
Unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps 
delta activity on EEG


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Appendix 4. Bone Marrow Reserve in Adults 
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.  5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head:
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle:
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs: 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar):
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0


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Appendix 5. Medications with Potential PR Prolongation Effect 
Please note that the drugs listed below are examples and this is not intended to be an 
all-inclusive listing (from Nada A, et al. Am Heart J 2013;165:489-500).
Electrophysiologic Effects of Select Drugs on PR Interval Based on Product Labeling
Drug
Action
Indications
Affecting AV nodal conduction (PR interval
Adenosine
Adenosine receptor
PSVT
Amiodarone
Cardiac ion channels
Antiarrhythmics
Disopyramide
Encainide
Flecainide
Moricizine
Propafenone
Verapamil
Arsenic trioxide
Multiple actions
Acute promyelocytic Leukemia
Atazanavir
HIV-protease inhibitors
Antiretroviral inhibitor
Lopinavir/Ritonavir
Saquinavir
Digoxin
Multiple actions
Congestive heart failure
Dolasetron
5HT3 receptor antagonist
Antiemetic
Fingolimod
S1P receptor modulator
Multiple sclerosis
Lacosamide
Not fully characterized
Partial-onset seizures
Pregabalin
Not fully characterized
Neuropathic pain
Mefloquine
Plasmodicidal effects
Antimalarial
Drugs were initially screened using the PDR3D database for PR interval prolongation using terms “PR 
interval prolongation”, “AV block”, “AV conduction delay”, or “heart block”.  Drugs were subsequently 
selected for inclusion on the basis on descriptions of PR prolongation/AVB contained with Warning or 
Precautions sections of drug labels. 
PSVT, Paroxysmal supraventricular tachycardia.


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Appendix 6. RECIST Version 1.1
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation. 
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable: 
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable: All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin, or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques.
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 


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The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 
diameter to be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent.”
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Definitions of Tumor Response
Target Lesions

Complete response (CR) is defined as the disappearance of all target lesions.  Any
pathological lymph nodes (whether target or non-target) must have reduction in short 
axis to <10 mm.

Partial response (PR) is defined as a 30% decrease in the sum of the longest 
dimensions of the target lesions taking as a reference the baseline sum longest 
dimensions.

Progressive disease (PD) is defined as a 20% increase in the sum of the longest 
dimensions of the target lesions taking as a reference the smallest sum of the longest 
dimensions recorded since the treatment started, or the appearance of one or more 
new lesions.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.

Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as a reference the smallest sum of the 
longest dimensions since the treatment started. 
Non-Target Lesions

Complete response (CR) is defined as the disappearance of all non-target lesions.  
All lymph nodes must be non-pathological in size (<10 mm short axis).

Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.


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
Progressive disease (PD) is defined as unequivocal progression of existing
non-target lesions, or the appearance of 1 new lesion.

The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease and 
progressive disease.
Confirmation of Tumor Response
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 8 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.
Response Evaluation Criteria in Solid Tumors
Target Lesions1
Non-Target Lesions2
New Lesions3
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
1 Measurable lesions only.
2 May include measurable lesions not followed as target lesions or non-measurable lesions.
3 Measurable or non-measurable lesions.
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest
measurements recorded since the treatment started).  For CR and PR, the patient’s best
response assignment will depend on the achievement of both measurement and confirmation 
criteria.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 8 weeks.


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NOTE: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment.  It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation to 
document whether or not objective tumor progression has occurred. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy before 
confirming the complete response status. 

SAP_001.pdf: 
Protocol A7461009 (PF-06463922) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B7461009
A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT ON 
THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED
CANCER PATIENTS
Statistical Analysis Plan
(SAP)
Version: 1.0
Date:  24 August 2018


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PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives .......................................................................................................4
2.2. Study Design .............................................................................................................4
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint(s) ..................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................8
3.3. Baseline Variables.....................................................................................................8
3.4. Analysis Sets .............................................................................................................8
3.4.1. Full Analysis Set...........................................................................................9
3.4.2. PK analysis sets ............................................................................................9
3.4.3. Safety Analysis Set.......................................................................................9
3.4.4. Response Evaluable Analysis Set.................................................................9
4. GENERAL METHODOLOGY AND CONVENTIONS......................................................9
4.1. Hypotheses and Decision Rules ................................................................................9
4.2. General Methods .....................................................................................................10
4.2.1. Analyses for Binary Data............................................................................10
4.2.2. Analyses for Continuous Data....................................................................10
4.2.3. Analyses for Categorical Data....................................................................10
4.2.4. Analyses for Time to Event Data................................................................10
4.3. Methods to Manage Missing Data ..........................................................................10
4.3.1. Pharmacokinetic Concentrations ................................................................10
4.3.2. Pharmacokinetic Parameters.......................................................................11
4.3.3. Efficacy Endpoints......................................................................................11
4.3.4. ECG Parameters..........................................................................................11
5. ANALYSES AND SUMMARIES ......................................................................................11
5.1. Primary Endpoint(s) ................................................................................................12
5.1.1. Pharmacokinetic Analysis ..........................................................................12
5.2. Efficacy Analyses....................................................................................................14
5.2.1. Best Overall Response................................................................................14
5.2.2. Duration of Response .................................................................................15


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Page 3
5.3. Subset Analyses.......................................................................................................15
5.4. Baseline and Other Summaries and Analyses.........................................................16
5.4.1. Baseline Summaries....................................................................................16
5.4.2. Study Conduct and Subject Disposition .....................................................16
5.4.3. Study Treatment Exposure .........................................................................17
5.4.4. Concomitant Medications and Non-Drug Treatments................................17
5.4.5. Columbia Suicide Severity Rating Scale (C- SSRS)..................................17
5.5. Safety Summaries and Analyses .............................................................................17
5.5.1. Adverse Events...........................................................................................18
5.5.2. Laboratory Data..........................................................................................19
5.5.3. Vital Signs ..................................................................................................19
5.5.4. Electrocardiogram.......................................................................................20
5.5.5. Left Ventricular Ejection Fraction..............................................................21
5.5.6. Physical Examination .................................................................................22
5.5.7. ECOG Performance Status .........................................................................22
6. INTERIM ANALYSES.......................................................................................................22
7. REFERENCES ....................................................................................................................23
8. APPENDICES .....................................................................................................................24


Protocol A7461009 (PF-06463922) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B7461009 is based on the Protocol dated
25 June 2018.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7461009.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.  This analysis plan is meant to supplement the study 
protocol. Any deviations from this analysis plan will be described in the Clinical Study 
Report.
2.1. Study Objectives
Primary: 

To evaluate the effect of hepatic impairment on the steady state pharmacokinetics of 
lorlatinib.
Secondary:

To evaluate the effect of hepatic impairment on the safety of lorlatinib in advanced 
cancer patients.

To evaluate the antitumor activity of lorlatinib in advanced cancer patients.
 
 
2.2. Study Design 
This will be a Phase 1, open-label, multi-center, multiple-dose, non-randomized, Phase 1 
clinical trial of lorlatinib in advanced cancer patients with varying degrees of hepatic 
impairment and necessary age-, weight-, and gender-matched prospect normal hepatic 
function patients. 
Patients in the study will be assigned to different groups according to their liver function.  
The criteria for stratification of patients based on their liver function (according to National 
Cancer Institute (NCI) guidance,1
CCI


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PFIZER CONFIDENTIAL
Page 5
https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Organ_Dysfunction_Protocol_Te
mplate.docx) are listed below:
Group
Groups A1 
and A2
Group B
Group C
Group D
Hepatic 
Function
Normal
Mild impairment
Moderate 
impairment
Severe
impairment
Total 
Bilirubin
ULN (Upper 
Limit of 
Normal)
B1: ULN
B2: >1.0 x – 1.5 x ULN
>1.5 x – 3 x 
ULN
>3 x ULN
AST 
(SGOT)
ULN
B1: >ULN
B2: Any
Any
Any

Patients must fulfill both total bilirubin and AST (serum glutamic oxaloacetic 
transaminase [SGOT]) criteria to be included in a group. 

No distinction will be made between liver dysfunction due to metastases or liver 
dysfunction due to other causes.

All liver function tests for stratification must be completed within 24 hours prior to 
the start of treatment. 

Group B (Mild hepatic impairment): for the purpose of this study, the “mild” liver 
dysfunction may be defined according to either of two criteria (Groups B1 and B2), so 
that patients in Group B may come from either of these groups.  Patients in Group B1
and B2 are thus considered to have comparable liver dysfunction and will be 
combined for dose level allocation and all analysis. 

Patients whose degree of hepatic dysfunction changes (becomes worse or better) 
between screening and initiation of protocol therapy may be re-assigned to a different 
hepatic dysfunction group.  This change should be discussed with the Sponsor and 
properly documented.  Patient stratification will only be done prior to initiation of the 
study treatment.  Patients will not be re-assigned to a different hepatic dysfunction 
group once treatment with lorlatinib has been started.

Groups A1 and A2 (Normal): patients with normal liver function will be included in 
this study as matching control patients (Group A1 for Group B and Group A2 for 
Group C).  If the dose for moderate hepatic impairment group (Group C) is selected 
to be the recommended clinical dose of 100 mg QD, the control group A2 will not be 
needed to be enrolled.  There will be no control group designated to match severe 
group.  However, if a decision has been made to use the same dose for severe and 
moderate patients, the half of the control Group A2 will be matching Group C and 
half will be matching Group D.


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Page 6
The enrollment of approximately 76 advanced cancer patients is anticipated in this study in 
order to have 8 PK-evaluable patients in each of Groups A1, A2, B and C, and 6 
PK-evaluable patients in Group D for final statistical analysis.  Evaluable patients are those 
who complete the planned PK sample collection on Cycle 2 Day 1 and have no lorlatinib 
dose modification until completion of Cycle 2 Day 1 PK evaluation.  Patients who are not 
evaluable for PK will be replaced.
Each patient will be treated with repeated oral once daily doses of lorlatinib in 21-day cycles 
until disease progression, patient refusal, or unacceptable toxicity occurs.
The planned dosing schedule for each treatment group is as follows:
Table 2.
Lorlatinib Dosing Schedule
Group B
Group C
Group D
Group A1
Group A2
Hepatic 
Function
Mild
Moderate
Severe
Normal
Normal
Starting 
Lorlatinib Dose 
100 mg QD
50 mg QD or 
otherwise 
determined 
in the first 
stage 
determined 
based on 
preliminary 
safety and 
PK data
100 mg QD
the same 
dose as 
Group C 
at the 
second 
stage  
Lorlatinib Dose 
After PK 
Assessment
100 mg QD
50 mg QD or 
otherwise 
determined 
in the first 
stage
determined 
based on 
preliminary 
safety and 
PK data
100 mg QD
100 mg 
QD
The dose schedule may be modified as necessary for individual patients according to 
tolerability (see Table 2 for detailed dose modification strategy). 
For Group C, a two-stage enrollment will be applied. 

In the first stage, 3 PK-evaluable patients will be enrolled to receive the starting dose 
of 50 mg QD lorlatinib.  On completion of PK sample collection through Cycle 2 
Day 1 from these 3 patients, PK analysis will be performed.  Upon review of the PK 
and tolerability of these 3 patients, a decision on dose schedule for remaining 
patients in the second stage will be made. 

In the second stage:

If it is decided to keep the planned dosing schedule (50 mg QD) for patients in 
Group C with moderately impaired liver function, 5 additional patients will be 
enrolled to have a total of 8 PK evaluable patients. 


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
If a different dosing schedule is proposed for the remaining patients in Group C 
based on safety and PK in the first 3 subjects, then more patients will be enrolled 
to this group to have 8 PK evaluable patients and receive the proposed dosing 
schedule.  The control patients in Group A2 should receive the same lorlatinib 
dose as proposed for the second stage in Group C until completion of PK 
assessment on Cycle 2 Day 1 and then switch to 100 mg QD beyond Cycle 2 
Day 1.  At the new dose level, the first 3 patients should be dosed one at a time 
with at least one week apart until some safety information at this dose level is 
obtained. 
The enrollment for patients with severe hepatic impairment (Group D) will only be started 
when the dose for patients in the second stage of Group C has been determined and has been 
tolerated in at least one patient.  The initial lorlatinib dose for Group D might be the same as 
the second stage Group C dose or otherwise determined by sponsor based on available 
preliminary safety and PK data at that time.  The dosing regimen for Group D will be 
communicated to sites.  Patients in Group D will not be matched by any control group.  
Initially (the first 3 patients), the patients should be dosed one by one with at least 1 week 
apart until some safety information is obtained at the dose level. 
Patients in Groups A1 (Normal hepatic function) and B (Mild hepatic impairment) will 
receive a starting lorlatinib dose of 100 mg (4 × 25-mg tablets) QD.  The first 3 patients in in 
Group C (Moderate hepatic impairment) will receive a starting lorlatinib dose of 50 mg 
(2 × 25-mg tablets) QD.  Patients in control Group A2 (Normal hepatic function) will 
receive the same starting lorlatinib dose as stage 2 of Group C, which could be 50 mg 
(2 × 25-mg tablets) QD or as otherwise determined during the second stage of Group C, and 
switch to 100 mg (4 × 25-mg tablets) QD after completion of PK assessment on Cycle 2 
Day 1. 
Enrollment into control Group A2 will only be started after the first stage for Group C has 
been completed and a decision on dose schedule for the stage 2 subjects in Group C has been 
made.  Patients in control group should match patients in the respective hepatic impaired 
group by the following criteria:

The mean body weight in control group will be within 20 kg of the mean body 
weight of the patients in respective hepatic impaired group.

The mean age in control group will be within 10 years the mean age of the patients 
in respective hepatic impaired group.

The gender ratio in control group will be similar (2 patients per gender) to those in 
respective hepatic impaired group.
Once all the patients complete their planned PK collection, data collection for the primary 
objective of the study will be accomplished.  After data collection for the primary objective 
has been completed, the sponsor could generate a study report including all PK data and 
other data, as defined in the Sponsor-maintained statistical analysis plan.  In this case, a 
supplement study reported will then be generated when all patients completed the study.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Plasma PK parameters of lorlatinib at steady state: AUC24 and Cmax.
3.2. Secondary Endpoint(s)

Type, incidence, severity, seriousness, and relationship to study medications of 
adverse events (AE) and any laboratory abnormalities.

Objective response rate (ORR).

Duration of response (DR).

Plasma PK parameters of lorlatinib, if possible: AUClast, Tlast, and Tmax after single 
dose; Cmin, AUClast, Tlast, and CL/F at steady-state.

Plasma PK parameters for metabolite(s) if possible: AUC24, AUClast, Cmax, Tmax, Tlast
MRAUC24, MRAUClast, and MRCmax
3.3. Baseline Variables
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
the study drug.  The date of last dose of study treatment is the latest date of non-zero dosing 
of the study drug.
No windowing will be applied when defining baseline.  Any deviations from the protocol 
specified window will be documented as protocol deviations. 
For efficacy analyses the last assessment prior to randomization will serve as the baseline 
assessment. 
For safety (including Eastern Cooperative Oncology Group (ECOG) performance status) the 
last assessment performed on or prior to date of the first dose of study treatment will serve as 
the baseline assessment.  If there are no observations meeting these criteria, then baseline is 
considered missing. 
Triplicate ECGs are collected; therefore the baseline for each ECG measurement is the 
average of the pre-dose measurements on the baseline day.  Unscheduled assessments will 
not be included in the calculation of the average. 
3.4. Analysis Sets
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.


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3.4.1. Full Analysis Set
The full analysis set includes all enrolled patients, regardless of whether or not treatment was 
received.
3.4.2. PK analysis sets
3.4.2.1. PK Concentration Analysis Set
The PK concentration analysis set is defined as all enrolled patients who are treated and 
have at least 1 analyte concentration.
3.4.2.2. PK Parameter Analysis Set
The PK parameter analysis set is defined as all enrolled patients treated who have sufficient 
information to estimate at least 1 of the PK parameters of interest.
3.4.2.3. PK evaluable Analysis set
The PK evaluable analysis set is defined as all patients in the PK parameter analysis 
population who have (1) completed Cycle 2 Day 1 PK collection; (2) received lorlatinib dose 
on Cycle 2 day 1; (3) received at least 80% of total dose within 14 days prior to Cycle 2 
Day 1; (4) no dose reduction in the first cycle.
3.4.3. Safety Analysis Set
The safety analysis (SA) population will include all enrolled patients who receive at least one 
dose of lorlatinib on Cycle 1, Day 1. The safety analysis population will be the primary 
population for evaluating patient characteristics, treatment administration, and safety. 
3.4.4. Response Evaluable Analysis Set
The response evaluable analysis set includes all patients in the safety analysis population 
who have an adequate baseline tumor assessment. 
4. GENERAL METHODOLOGY AND CONVENTIONS
Once all the patients complete their planned PK collection, data collection for the primary 
objective of the study will be accomplished.  After data collection for the primary objective 
has been completed, the sponsor could generate a study report including all PK data and 
other data.
4.1. Hypotheses and Decision Rules
The study is not powered to detect treatment difference in PK parameters.  No formal 
statistical hypothesis testing is planned, and no decisions will be made to the conduct of the 
study. 
The sample size for this study is determined empirically based on feasibility and regulatory 
recommendation.  Sufficient numbers of patients will be enrolled and dosed to obtain 
approximately 38 PK evaluable subjects (approximately 16 subjects in normal group, 
8 patients each in mild and moderate groups, and 6 in severe group).  Subjects may be 
replaced if not PK evaluable.


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4.2. General Methods 
4.2.1. Analyses for Binary Data
The point estimates of the rate will be provided along with the corresponding exact 2-sided 
95% confidence intervals using the exact Clopper-Pearson method based on the 
F-distribution.2
4.2.2. Analyses for Continuous Data
For continuous variables, summaries will include N, Mean, S.D., CV%, 25th quartile, median, 
and 75th quartile, min and max.  One-way analysis of variance (ANOVA) will be used to test 
for difference between treatment groups. 
4.2.3. Analyses for Categorical Data
The number and percentage of patients in each category will be provided for categorical
variables.
4.2.4. Analyses for Time to Event Data
Time-to-event endpoint will be summarized using the Kaplan-Meier method3 and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence interval for 
each median will be provided (Brookmeyer R and Crowley JJ).4
4.3. Methods to Manage Missing Data
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of resolution cannot be prior to date 
of onset; if replacing resolution date with the 1st of the month results in a negative duration, 
the resolution date will be set to the onset date.).  In this case, the date resulting in 0 time 
duration will be used.  Pfizer standards are also used if both month and day are missing 
(Jan 1 unless negative time duration). 
For the analysis of safety endpoints, the Pfizer data standard rules for imputation will be 
applied.
4.3.1. Pharmacokinetic Concentrations
4.3.1.1. 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.)
4.3.1.2. 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),


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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.
4.3.2. 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 not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing.
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 drug is 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.
4.3.3. Efficacy Endpoints
For duration of response (DR), if calculation based on conventions result in a negative value, 
durations will be reset to 1 day.
For efficacy analyses no values will be imputed for missing data, except as specified in 
Section 5.2.2, where for time to event endpoint DR, non-event observations will be censored, 
and for ORR, patients with no post-baseline tumor evaluations will be counted as 
non-responders. 
4.3.4. ECG Parameters
For analyses of ECG parameters, no values will be imputed for missing data.  If one or two 
of the triplicate measurements for an ECG parameter are missing, the average of the 
remaining two measurements or the single measurement can be used in the analyses.  If all 
triplicate measurements are missing at a time point for an ECG parameter, no values will be 
imputed for this time point and no analyses related to this time point will be performed. 
5. ANALYSES AND SUMMARIES
All summaries will be provided by hepatic function group.  Patients treated on different dose 
levels within the same hepatic function group will be categorized by dose level (eg, Group C 
split into Group C1 and C2). 


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5.1. Primary Endpoint(s)
5.1.1. Pharmacokinetic Analysis
5.1.1.1. Pharmacokinetic Parameter Analysis Methods
Pharmacokinetic parameters will be derived from the lorlatinib and its metabolite(s) 
concentration-time profile as described in Table 3.
Table 3.
Pharmacokinetic Parameter Derivation
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from 
time zero to the time of the last 
quantifiable concentration 
(Clast)
linear-log trapezoidal method
AUC24
Area under the plasma 
concentration-time profile 
during one dosing interval 
(24 hours)
linear-log trapezoidal method
Cmax
Maximum plasma concentration
Observed directly from data
Cmin
Minimum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
CL/F
Apparent clearance
Dose/AUC24 at steady-state
MRAUClast
Metabolite ratio for AUClast
(AUClast/MW)metabolite/(AUClast/MW)lorlatinib
MRAUC24
Metabolite ratio for AUC24
(AUC24/MW)metabolite /(AUC24/MW)lorlatinib
MRCmax
Metabolite ratio for Cmax
(Cmax/MW)metabolite /(Cmax/MW)lorlatinib
MW= molecular weight; F= oral bioavailiability
Actual PK sampling times will be used in the derivation of PK parameters.  In the case that 
actual PK sampling times are not available, nominal PK sampling times will be used in the 
derivation of PK parameters. 
The effect of the hepatic impairment on PK parameters will be assessed by constructing 
90% confidence intervals around the estimated difference between each of the Test and the 
Reference using a one-way ANOVA model based on natural log transformed data.
One-way analysis of variance (ANOVA) will be used to compare the natural log transformed 
AUC24, AUClast and Cmax of lorlatinib at steady state for each of the hepatic impairment 
groups (Test) to the corresponding normal hepatic function group with the same dosing 
schedule (Reference).  Group B (Test) will be compared to Group A1 (Reference) and Group 
C (Test) will be compared with Group A2 (Reference).  If a decision has been made to use 
the same dose for severe and moderate patients, the half of the control Group A2 will be 
matching Group C and half will be matching Group D (test), and the corresponding pairwise 
comparisons will be made.  Additionally, Group D will be compared to Group A1 
(Reference), and Group C will be compared with A1.  Estimates of the mean differences 
(Test-Reference) and corresponding 90% confidence intervals will be obtained from the 


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model.  The mean differences and 90% confidence intervals for the differences will be 
exponentiated to provide estimates of the ratio of geometric means (Test/Reference) and 
90% confidence intervals for the ratios.
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 descriptively by analyte, hepatic function
group and at C1D1 and C2D1for lorlatinib and its metabolites. 
Parameter
Summary statistics
AUC24,  AUClast, Cmax, 
Cmin, CL/F, MRAUC24,
MRAUClast , MRCmax
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean.
Tmax
N, median, minimum, maximum.
Box and whisker plots for individual subject parameters (lorlatinib AUC 24, AUClast and Cmax) 
will be presented against hepatic function group by analyte and overlaid with geometric 
means.
PK parameter analysis set will be used for performing the analysis. 
5.1.1.2. Pharmacokinetic Concentration Analysis Methods
Presentations for lorlatinib and its metabolites concentrations will include:

listings of all plasma concentrations sorted by analyte, hepatic function group (present 
in heading),  cycle, subject id and nominal time postdose.  The listing of plasma 
concentrations will include the actual times.  Deviations from the nominal time will 
be given in a separate listing.

summaries of plasma concentrations by analyte, hepatic function group,  cycle and 
nominal time, where the set of statistics will include n, mean, median, standard 
deviation, geometric mean, coefficient of variation (cv), minimum, maximum and the 
number of concentrations above the lower limit of quantification.


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
median plasma concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by analyte, hepatic function group and cycle (all cycles on the 
same plot for each hepatic function group per scale per analyte, based on the 
summary of plasma concentrations by analyte, hepatic function group, cycle and time 
postdose). 

mean plasma concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by analyte, hepatic function group and cycle with one side up 
standard deviation (all cycles on the same plot for each hepatic function group per 
scale per analyte, based on the summary of plasma concentrations by analyte, hepatic 
function group,  cycle and time postdose). 

individual plasma concentration time plots against actual time postdose by analyte, 
hepatic function group and cycle (on both linear and semi-log scales), (there will be 
separate spaghetti plots for each hepatic function group per scale and will be different 
lines for each cycle on the same individual plots).

median plots of the predose concentrations against day (including day 1 of cycle 2 as 
Day 29 on the same x-axis) by analyte and hepatic function group in order to assess 
the attainment of steady-state (all hepatic function group on the same plot),

individual plots of the predose concentrations against day (including day 1 of cycle 2 
as Day 29 on the same x-axis) by analyte and hepatic function group.
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.
PK concentration analysis set will be used for performing the analysis. 
5.2. Efficacy Analyses
5.2.1. Best Overall Response 
The frequency (number and percentage) of patients with BOR of CR, PR, SD, PD , non 
CR/non PD, and NE (not evaluable) will be provided along with a summary of the objective 
response rate (ORR) and the corresponding exact 95% 2-sided confidence interval using 
standard methods based on the binomial distribution, by hepatic function group.  ORR is 
defined as the percent of patients with complete response (CR) or partial response (PR), that 
is subsequently confirmed, based on investigator evaluation, according to RECIST v1.1 
(Appendix 1), relative to the response-evaluable population.  Confirmed responses are those 
that persist on repeat imaging study at least 4 weeks after the initial documentation of 
response.  Designation of best response of SD requires the criteria to be met at least once 
after the first dose of medication, at a minimum interval of 6 weeks. Since efficacy is a 
secondary objective in this study, tumor response derivation will not be performed 
programmatically and the investigator overall tumor assessment (IOTA) of best response will 
be used. 


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5.2.2. Duration of Response
Duration of response (DR) is defined as the time (in weeks) from the first documentation of 
objective tumor response (CR or PR) that is subsequently confirmed, to the first 
documentation of objective tumor progression or death on study due to any cause, whichever 
occurs first.  If tumor progression data include more than 1 date, the first date will be used.  
DR (in weeks) will be calculated as (first date of PD or death - first date of CR or 
PR +1)/7.02.  DR will be calculated based on RE population for the subgroup of patients 
with a confirmed objective tumor response.  The censoring rules for DR are presented as 
below.
Patients with inadequate baseline disease assessment are censored at the start date.
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every odd-numbered cyles (6 weeks) until disease progression.  
while on treatment and whenever disease progression is suspected (eg, symptomatic 
deterioration).  The allowable time window for disease assessments is 1 week.  Therefore 
time without adequate assessment is defined as 14 weeks (12 weeks +2 weeks). Patients 
lacking an evaluation of tumor response after treatment start or for whom the first on-study 
disease assessment occurs after Week 14 and shows progression, will also have their event 
time censored on the date of treatment start unless death occurs within (and including) 
Week 14 (in which case the death is an event).
If patients have at least 1 on-study disease assessment, PFS data will be censored on the date 
of the last evaluable on-study tumor assessment documenting absence of progressive disease 
for patients:

Who are alive, on study, have not started anti-tumor treatment other than study 
medication and progression free at the time of the analysis;  

Who are given anti-tumor treatment other than the study medication and prior to 
documented disease progression or death on study.  In this case, the last evaluable
assessment prior to start of the anti-tumor treatment will be used. 
For patients who have at least 1 on-study disease assessment and who have documentation of 
disease progression or death on study after 2, consecutive missed tumor assessments 
(ie, >14 weeks after last on-study tumor assessment), the date of censoring will be the last 
assessment documenting no progression prior to the missed assessments.
DR will be summarized by hepatic function group using the Kaplan-Meier method.3 The 
median event time (if appropriate) and 2-sided 95% CI for the median4 will be provided.  
Since the number of patients in each hepatic function group is small, and number of CR or 
PR would be even smaller, the use of Kaplan-Meier method may be limited and the DR will 
be also summarized using descriptive statistics. 
5.3. Subset Analyses 
None


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5.4. Baseline and Other Summaries and Analyses
5.4.1. Baseline Summaries
Summaries of baseline variables, patient and disease characteristics and prior anti-cancer 
treatments will be provided on the safety analysis set.  The summaries will be presented 
overall, by hepatic group and by tumor type (as appropriate).  All data collected as part of 
screening will be listed.
The following demographic and baseline characteristics will be summarized by number and 
percentage:

Gender(male, female).

Age (<18, 18-44; 45-64, 65).

Race (white, black, asian, other).

Eastern Cooperative Oncology Group (ECOG) Performance status.
Age (continuous), height (cm), weight (kg), Body Mass Index (BMI) (kg/m2), will be 
summarized with descriptive statistics (mean, standard deviation, minimum, and maximum). 
BMI (kg/m2) is computed as weight (kg) /(height (cm)*0.01)**2
Patient characteristics at study entry such as diagnosis, and medical history will be 
summarized in frequency tables, and descriptive statistics will be provided for quantitative 
variables. 
The number and percentage of patients in each of the following prior anti-cancer therapy 
categories will be tabulated:

Patients with at least one prior non-drug treatment/surgeries;

Patients with at least one prior radiotherapy;

Patients with at least one prior systemic therapy.
5.4.2. Study Conduct and Subject Disposition
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, efficacy, as well as for safety (adverse events 
and laboratory data).  Frequency counts (numbers and percentages) will be supplied for 
subject discontinuation(s) by hepatic function group. 
5.4.2.1. Patient Disposition
Discontinuation from study will be summarized using full analysis set.  Discontinuation from 
study treatment will be summarized using safety analysis set.  Patients not completing the 
study will be listed along with the reason for their discontinuation. 


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Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment.  If causality is missing the event will be considered 
related to treatment.  If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment. 
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by hepatic function group.
5.4.2.2. 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.
5.4.3. Study Treatment Exposure
Drug administration of PF-06463922 will be described on the Safety Analysis set in terms of:

Duration of Treatment in months (Last Treatment Date – C1D1 date + 1)/30.44.

Days on drug in months (duration of treatment in days– days of interruption)/30.44.

Overall relative dose of PF-06463922.  Details for calculation of relative dose are 
provided in Appendix 1.
The mean, median and range will be provided for these variables by hepatic function group. 
Number and percentage of patients having dose reductions /interruptions will be provided by 
hepatic function group.  An interruption is defined as a 0 mg dose administered for more than 
1 day. 
5.4.4. Concomitant Medications and Non-Drug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
5.4.5. Columbia Suicide Severity Rating Scale (C- SSRS)
Individual patient data will be presented in patient data listings. 
5.5. Safety Summaries and Analyses
Summaries and analyses of safety parameters will be provided based on the on-treatment 
period unless otherwise specified, by hepatic function group for the Safety Analysis Set. For 
all safety analyses, only descriptive methods will be used without any formal statistical 
testing.


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The on-treatment period is defined as the time from the first dose of study treatment through 
and including 28 days after last dose or start of new anti-cancer drug therapy, whichever 
occurs first [minimum (28 days + last dose of study treatment, start day of new anti-cancer drug 
therapy – 1 day)].  Adverse events occurring on the same day as the first dose of study 
treatment will be considered to have occurred during the on-treatment period.  All other 
safety assessments which occur on the same day as the first dose of study treatment will be 
considered baseline assessments.
Safety data collected outside the on-treatment period as described above will be listed but not 
summarized.
5.5.1. Adverse Events
An adverse event is considered treatment emergent if:

the event occurs for the first time during the on-treatment period and was not seen 
prior to the start of treatment (Cycle 1 Day 1), or

the event was seen prior to the start of treatment but increased in severity during the 
on-treatment period.
Adverse Events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of study medication.  The number and percentage of patients who 
experienced any AE, serious AE (SAE), treatment related AE, and treatment related SAE 
will be summarized according to worst toxicity grades.  The summaries will be presented by 
hepatic function group, by system organ class and preferred term. 
Patients who withdraw from study treatment because of an AE will be listed.  Patient 
discontinuation will be determined from the end of treatment (EOT) evaluation (where 
reason for termination is “Adverse Event”) and the specific AE(s) will be determined from 
the AE CRF page (where action taken is “Withdrawn from Study” or action taken for study 
drug is “Permanently Discontinued”).
Adverse events associated with permanent discontinuation of the study drug or with 
temporary discontinuation/dose reduction will also be summarized (taking into consideration 
the action taken from the CRF AE page).
Clustered adverse events will be summarized by maximum CTCAE grade and causality 
(all-causality and treatment-related) together with other adverse events.  Adverse Events 
pertaining to each cluster will be summarized separately, by cluster.  The clustered events are 
described in a list in the product’s Safety Narrative Plan maintained by the Sponsor.


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All causality and treatment-related SAEs will be summarized by MedDRA SOC, preferred 
term and maximum CTCAE grade.  Patients who experienced a SAE during the SAE 
reporting period will be listed for all the patients in the safety analysis set.  A summary of 
SAEs by preferred term, maximum CTCAE grade will be presented. 
Deaths will be summarized by time period (on treatment vs. during follow-up) and cause of 
death.  Deaths that occurred on or after first dose of study medication and within 28 days 
after the last dose of study medication are defined as on-treatment deaths.  A listing of death 
data will also be provided and it will include all deaths that occurred during the reporting 
period for deaths which starts from the signing of the informed consent to the end of the 
follow up period for death.
5.5.2. Laboratory Data
Hematology, biochemistry, and lipid results will be programmatically graded according to 
the NCI CTCAE Version 4.03. 
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed on treatment for each lab assay.  
Worst case is defined as the maximum post-baseline CTCAE grade using scheduled and 
unscheduled visits.  The analyses will summarize laboratory tests on the entire study period.  
Shift tables of baseline grade by maximum post-baseline CTCAE grade will also be 
presented.
Patients who developed Grade 3 toxicity will be listed.
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, by 
graphically displaying post-baseline:

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin=2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a 
post-baseline TBILI 2×ULN, ALT 3×ULN or AST 3×ULN will be provided.
5.5.3. Vital Signs
Baseline values and change from baseline values will be summarized with descriptive 
statistics by hepatic group and for each nominal visit over time. 
The number and percent of patients in each of the following minimum and maximum blood 
pressure, body weight and pulse rate categories will be presented,


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Vital Sign
Category
Blood Pressure
Maximum Change from baseline (increase) in SBP of 40 mmHg
Maximum Change from baseline (decrease) in SBP of 40 mmHg
Maximum Change from baseline (increase) in SBP of 60 mmHg
Maximum Change from baseline (decrease) in SBP of 60 mmHg
Maximum Change from baseline in DBP (increase) of 20 mmHg
Maximum Change from baseline in DBP (decrease) of 20 mmHg
Maximum Change from baseline in DBP (increase) of 40 mmHg
Maximum Change from baseline in DBP (decrease) of 40 mmHg
Body Weight
Maximum change from baseline body weight (increase) 20%
Maximum change from baseline body weight (decrease) 10%
Pulse Rate
Minimum Pulse Rate <50 bpm
Maximum Pulse Rate >120 bpm
5.5.4. Electrocardiogram
A triplicate 12-lead will be used for all ECG assessments.
All patients require a triplicate ECG measurement at screening and at each scheduled time 
point during treatment.  A mean score is calculated for the replicate measurements having the 
same nominal visit, and will be reported.
QT, RR, HR, PR, QRS, QTcF (Fridericia correction), and QTcB (Bazett’s correction) data 
will be provided by sites on the ECG page of the CRF. 
The analysis of ECG results will be provided for safety analysis set patients with baseline 
and on-treatment ECG data by hepatic group and for each nominal visit over time.  ECG 
measurements collected closest prior to the first dose of study drug will be used as the 
baseline ECG for analysis. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis as individual values obtained at unscheduled time points.


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Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute value and changes from baseline in QT, QTcF, QTcB, HR, 
RR, PR, QRS after treatment by hepatic group and nominal visit.
The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated: 
Absolute Value (msec)
450 -<480
480 -<500
500
Absolute Change (msec)
30-<60
60
The number (%) of subjects with maximum post-dose PR interval values and maximum 
increases from baseline in the following categories will be tabulated: 
Absolute Value (msec)
<160
160 - <180
180 - <200
200 - <220
220 - <240
240 - <260
260
Absolute Change (msec)
40-<60
60-<80
80
Relative Change from baseline
>25%
Shift tables will be provided for baseline vs worst on study PR using the categories in the 
above table.  The effect of drug concentrations on QTc change (and PR interval) from 
baseline will be explored graphically.
5.5.5. Left Ventricular Ejection Fraction
LVEF% will be summarized using simple descriptive statistics (mean, SD, median, Q1, Q3,
minimum, and maximum) of actual values and changes from baseline for each nominal visit
over time.  In addition, LVEF% will be summarized as frequency (number and percentage)
of patients with:

a shift from baseline normal to at least one result below the institutional lower limit of
normal during the on-treatment period;

20-point decrease from baseline in LVEF%.
A patient will be included in the categories above if any post-baseline assessment (including 
unscheduled assessments) meet the criteria; however only post-baseline assessments which 
use the same method of assessment (ECHO or MUGA) as baseline will be considered.


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5.5.6. Physical Examination
Individual patient data will be listed. 
5.5.7. ECOG Performance Status
The ECOG shift from baseline to the highest score during the post-baseline period will be
summarized by hepatic function group.
6. INTERIM ANALYSES
No formal interim analysis is planned.  However, an interim PK and safety analysis will be 
done when 3 PK evaluable patients have been enrolled in group C1 to determine the dose 
regimen for groups C2 and D.  Final analyses of PK and all other endpoints will follow the 
official database release at the end of the study. In case an early reporting of PK results is 
necessary, the study database will be released for final reporting of PK, safety and efficacy 
data after PK collection in all patients is completed.  Then, a supplement report will be 
generated to only include additional safety and efficacy data after all patients completed the
study.


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7. REFERENCES 
1. National Cancer Institute Phase 1 Organ Dysfunction – Hepatic Template Version 3.0, 
http://ctep.cancer.gov/protocolDevelopment/docs/hepatic_dysfunction_v3.doc. 
2. Clopper, C., Pearson, E. S. "The use of confidence or fiducial limits illustrated in the case 
of the binomial". 1934; Biometrika 26: 404–413. 
3. Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am 
Stat Assoc 1958; 53:457-481.
4. Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  
Biometrics 1982; 38:29-41.


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8. APPENDICES
Appendix 1. Relative Dose
Overall exposure will be summarized as dose received relative to intended dose (relative 
dose [RD]). 
Actual total dose in a cycle or overall is the sum of the actual doses of PF-06463922 
received in a cycle or overall, respectively. 
Relative dose [RD]: The basic intent is to evaluate dose per day factoring in dose reductions 
or interruptions.  
Overall RD (%) = 100 × [overall actual total dose] / [intended total dose per day × number of 
days from C1D1 to last dose of PF-06463922]. 
Note:

The Intended total daily dose of PF-06463922 remains constant; the intended dose 
level is fixed at the start of treatment for each hepatic group;

What is described above remains the same for the calculations even if the intended 
dose level changes, per protocol, during the study. 


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Appendix 2. SAS Code for Analyses
An example of the PROC MIXED code for PK parameter analysis is provided below:
proc mixed data=tab.pk;
class group;
model l&var=group/s cl alpha=0.1 ddfm=KR;
lsmeans group;
estimate 'Moderate vs Normal' group 0 -1 0 1 /cl alpha=0.1;
estimate 'Mild   vs Normal' group  -1 0 1 0 /cl alpha=0.1;
ods output lsmeans=lms;
ods output solutionf=fixedcoef;
run;
/* Letter assignments for group within the estimate statement above are as follows;
Group A1 = Normal (Reference)
Group B = Mild (Test)
Group A2 = Normal (Reference)
Group C = Moderate (Test)
Note: Group B (Test) will be compared to Group A1 (Reference) and Group C (Test) will be 
compared with Group A2 (Reference)
  */;