Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: ALK positive ALK inhibitor-treated NSCLC
Allocation: NA | Intervention model: PARALLEL
Enrollment: 109
Healthy volunteers: no

Brief summary:
A Phase 2, multi center, open label, dual cohort study to evaluate the efficacy and safety of lorlatinib (PF 06463922) monotherapy in ALK inhibitor treated locally advanced or metastatic ALK positive non small cell lung cancer patients in China

Detailed description:
This is a Phase 2, China only, multi center, open label, dual cohort study, in ALK positive locally advanced or metastatic NSCLC patients will be enrolled to receive lorlatinib monotherapy.

* (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor.
* (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib.

Arms:
arm 1: Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously

Interventions: intervention 1: Lorlatinib
Intervention descriptions: intervention 1: ALK inhibitor-treated ALK-positive NSCL treatment

Protocol document:
Prot_000.pdf: 
L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1
A P H A S E 2, M U L TI -C E N T E R, O P E N -L A B E L, D U A L -C O H O R T S T U D Y T O 
E V A L U A T E T H E E F FI C A C Y A N D S A F E T Y O F L O R L A TI NI B ( P F- 0 6 4 6 3 9 2 2) 
M O N O T H E R A P Y I N A L K I N HI BI T O R -T R E A T E D L O C A L L Y A D V A N C E D O R 
M E T A S T A TI C A L K -P O SI TI V E N O N -S M A L L C E L L L U N G C A N C E R P A TI E N T S 
I N C HI N A
I n vesti g ati o n al Pr o d uct N u m ber:
P F - 0 6 4 6 3 9 2 2
I n vesti g ati o n al Pr o d uct N a me:
L orlati ni b
U nite d St ates ( U S) I n vesti g ati o n al Ne w 
Dr u g (I N D) N u m ber:
E ur o pe a n Cli nic al Tri als D at a b ase 
( E u dr a C T) N u m ber:
N ot a p plica ble ( N/ A)
Pr ot oc ol N u m ber:
B 7 4 6 1 0 2 4
P h ase:
2a
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nts, y o u a gree t o h ol d t his i nf or mati o n i n 
c o nfi de nce a n d n ot c o p y or discl o se it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or 
u na ut h orize d p ur p oses.  I n t he e ve nt of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be 
pr o m ptl y n otifie d.
C CI


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
11 October 2019

Protocol Summary updated for consistency with 
relevant protocol sections.

Schedule of Activities updated for consistency 
with relevant protocol sections.

Schedule of Activities (SOA) modified to allow 
use of available results for assessments 
performed prior to the Informed Consent being 
obtained. Section 7 was updated accordingly.

Time window added for Laboratory test exams 
in SOA: Explanatory notes and clarification for 
Triplicate ECG (electrocardiogram) reported in 
SOA. Section 7.4.4 was updated accordingly.

Time window added for Urinalysis at 
Screening.

Time window added for echocardiogram and 
multigated acquisition scan (MUGA) at 
screening and further assessment.

SOA footnote 14 reworded for clarity. 
Section 5.1 was updated accordingly.

SOA footnote 17 reworded for clarity and for 
consistency with Section 7.

SOA footnote 26 reworded for clarity. 
Section 7 was updated accordingly.

SOA footnote 27 reworded for clarity.

Section 1 background/introduction updated
given the latest information of anaplastic 
lymphoma kinase tyrosine kinase inhibitor 
(ALK TKI) treatment and the update of 
lorlatinib clinical data.

Section 1.2.3.4 Clinical Data updated with the 
Study B7461001 status and safety section 


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revised with regards to the updated list of 
lorlatinib identified risks.

Subject eligibility criteria reworded for clarity. 

Inclusion Criteria #12 revised to allow urine 
pregnancy test at screening and reworded for 
clarity.

Exclusion Criteria #1 revised to define the 
requirement for adjuvant chemotherapy and 
reworded for clarity. 

Exclusion Criteria #4 added to exclude patients 
with epidermal growth factor receptor (EGFR) 
activating mutations and prior therapy with 
EGFR TKI(s).

Exclusion Criteria #9 (#8 in the original 
protocol) revised to exclude prior therapy with 
lorlatinib.

Exclusion Criteria # 11 (#10 in the original 
protocol) revised to exclude patients with 
vascular (both arterial and venous) and 
non-vascular conditions.

Exclusion Criteria #12 (#11 in the original 
protocol) reworded for clarity.

Exclusion Criteria # 14 (#13 in the original 
protocol) revised to clarify that in situ 
malignancies which do not currently require 
treatment are allowed.

Exclusion Criteria #15 (#14 and #15 in the 
original protocol) updated to modify the list of 
cytochromes P450 (CYP) 3A 
inhibitors/inducers per new Food and Drug 
Administration (FDA) (United States)
classification. Section 5.9.1 was updated 
accordingly.

Exclusion Criteria #16 (#16 in the original 
protocol) updated for clarity.


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
Exclusion Criteria #19 (#19 in the original 
protocol) updated per lifestyle guidance 
reported in the new Pfizer protocol template 
and as per contraception requirements of 
updated product labels.

Section 4.3 Lifestyle Requirements. This 
section was updated as per lifestyle guidance 
reported in the new Pfizer protocol template 
and as per contraception requirements of 
updated product labels which was approved.

Section 5.4.1 and Section 7.2 reworded for 
clarity.

A revised list of acceptable statins is provided
(Section 5.5.1) to assist the Investigator in the 
management of patients with elevated lipid 
levels.

Section 5.9 (Concomitant Treatments): Text 
was updated to align the wording with the 
lorlatinib Investigator’s Brochure (IB). The 
record duration was updated for clarity and for 
consistency with lorlatinib asset-level profile. 
SOA footnote 22 was updated accordingly.

Section 5.9.1 (Inhibitors and Inducers of CYP 
Enzymes) updated according to new FDA 
classification.

Section 5.9.3 updated and reworded for clarity.

Clarification provided in Section 7.1 and SOA
for patients continuing treatment beyond 
disease progression.

“Central nervous system (CNS) imaging using 
magnetic resonance imaging (MRI) or brain 
computed tomography (CT) (contrast enhanced)
(unless contraindicated) or” is required at 
baseline in all patients and at every tumor 
assessment” was added in section 7.1 for the 
sake of clarify and for consistency with 
response evaluation criteria in solid tumors
(RECIST) 1.1 & mRECIST 1.1 in the protocol 


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Appendix 3. SOA footnote 17 was updated 
accordingly.

Bone scan frequency in Section 7.1 changed for 
the safety and operational feasibility. SOA 
footnote 17 and footnote 27 were updated 
accordingly.

The frequency of tumor assessment in post 
treatment period in Section 7.1 will be changed 
to be consistent with the frequency in treatment 
period. SOA footnote 17 and footnote 27 were 
updated accordingly.

Brain CT added in Section 7.1 per RECIST 1.1 
and SOA footnote 17 was updated accordingly.

Section 7.4 updated and reworded for 
consistency with SOA.

Clarification provided in SOA footnote 25 and 
Section 7.5 to improve the feasibility and 
precision on pharmacokinetic (PK) sample 
collection.

Section 7.6 reworded to clarify the sample 
disposition process.

Section 7.6.2 revised for consistency with the 
lab manual.

Section 9.1 The following text was added “In 
order to collect more information of anti-tumor 
activity, if patients received study treatment but 
without adequate baseline tumor assessment or 
without post- baseline tumor assessments, 
additional patients may be allowed to be 
enrolled”. 

Section 9.2 reworded as follows: “The per 
protocol analysis set will include all enrolled 
subjects with ALK positive non-small cell lung 
cancer (NSCLC), received a prior ALK 
inhibitor as protocol required, and who received 
at least 1 dose of lorlatinib. In Cohort 1,
received crizotinib as the only ALK inhibitor. 


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In Cohort 2, received one ALK inhibitor other 
than crizotinib, with or without prior crizotinib 
treatment.”

Updates to Appendix 1. Abbreviation.

Updates to Appendix 4 for consistency with 
relevant protocol sections.
Original 
protocol
18 May 2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
LIST OF FIGURES .................................................................................................................11
APPENDICES .........................................................................................................................11
PROTOCOL SUMMARY.......................................................................................................12
SCHEDULE OF ACTIVITIES (SOA)....................................................................................17
1. INTRODUCTION ...............................................................................................................24
1.1. Mechanism of Action/Indication.............................................................................24
1.2. Background and Rationale ......................................................................................24
1.2.1. NSCLC .......................................................................................................24
1.2.2. ALK Alternation and Resistance Mechanism in NSCLC ..........................24
1.2.3. Lorlatinib (PF-06463922)...........................................................................26
1.2.3.1. Preclinical Data .........................................................................27
1.2.3.2. Teratogenicity............................................................................27
1.2.3.3. Pharmacology............................................................................28
1.2.3.4. Clinical Data..............................................................................29
1.2.4. Study Rationale...........................................................................................33
1.2.5. Rationale for Starting Dosing Regimens....................................................33
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................34
3. STUDY DESIGN.................................................................................................................34
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................35
4.1. Inclusion Criteria.....................................................................................................36
4.2. Exclusion Criteria....................................................................................................38
4.3. Lifestyle Requirements ...........................................................................................40
4.3.1. Contraception..............................................................................................40
4.3.1.1. Woman of Childbearing Potential (WOCBP)...........................41
4.3.1.2. Methods of Contraception.........................................................42
4.4. Sponsor’s Qualified Medical Personnel..................................................................43
5. STUDY TREATMENTS.....................................................................................................43
5.1. Allocation to Treatment ..........................................................................................43
5.2. Subject Compliance.................................................................................................44
5.3. Investigational Product Supplies.............................................................................44


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5. 3. 1. D osa ge F or m(s) a n d Pac ka gi n g .................................................................. 4 4
5. 3. 2. Pre parati o n a n d Dis pe nsi n g ........................................................................ 4 5
5. 4. A d mi nistrati o n ......................................................................................................... 4 5
5. 4. 1. Treat me nt d urati o n ...................................................................................... 4 6
5. 5. Rec o m me n de d D ose M o dificati o ns ........................................................................ 4 6
5. 5. 1. H y perli pi de mia ........................................................................................... 5 1
5. 5. 2. P R I nter val Pr ol o n gati o n ............................................................................ 5 1
5. 5. 3. P ne u m o nitis/ P ne u m o n ia............................................................................. 5 2
5. 6. Ma na ge me nt of O ver d ose ....................................................................................... 5 3
5. 7. I n vesti gati o nal Pr o d uct St ora ge ..............................................................................5 3
5. 8. I nvesti gati o nal Pr o d uct Acc o u nta bilit y................................................................... 5 4
5. 8. 1. Destr ucti o n of I n vesti gati o nal Pr o d uct S u p pli es ........................................ 5 4
5. 9. C o nc o mita nt Treat me nt(s) ....................................................................................... 5 4
5. 9. 1. I n hi bit ors a n d I n d ucers of C Y P E nz y mes .................................................. 5 5
5. 9. 2. Ot her A nti -T u m or/ A nti -Ca ncer or E x peri me ntal Dr u gs ............................ 5 6
5. 9. 3. Ot her C o nc o mita nt Me dicati o ns a n d T hera pies ......................................... 5 7
5. 9. 4. He mat o p oietic Gr o wt h Fact ors ................................................................... 5 7
5. 9. 5. C o nc o mita nt S ur ger y .................................................................................. 5 7
5. 9. 6. C o nc o mita nt Ra di ot hera p y ......................................................................... 5 7
6. S T U D Y P R O C E D U R E S ..................................................................................................... 5 8
6. 1. Scree ni n g ................................................................................................................. 5 8
6. 1. 1. Deter mi nati o n of A L K Stat us ..................................................................... 5 8
6. 2. Treat me nt Peri o d ..................................................................................................... 5 9
6. 3. E n d of Treat me nt/ Wit h dra wal a n d P ost -Treat me nt F oll o w -U p .............................. 5 9
6. 4. S u bject Wit h dra wal ................................................................................................. 5 9
6. 5. S ur vi val F oll o w U p Visit ........................................................................................ 6 0
7. A S S E S S M E N T S .................................................................................................................. 6 0
7. 1. T u m or Res p o nse Assess me nts ................................................................................ 6 1
7. 2. E x pe dite d I n de pe n de nt Ce ntral Re vie w of Disease Pr o gr essi o n............................ 6 2
7. 3. Pre g na nc y  Testi n g................................................................................................... 6 2
7. 4. Safet y Assess me nts ................................................................................................. 6 3
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7. 4. 1. A d verse E ve nts ........................................................................................... 6 3
7. 4. 2. L a b orat or y Safety Assess me nt ................................................................... 6 3
7. 4. 3. Vital Si g ns a n d P h ysical E xa mi nati o ns ...................................................... 6 3
7. 4. 4. ( 1 2 -Lea d) Electr ocar di o gra ms .................................................................... 6 3
7. 4. 5. Ec h ocar di o gra ms/ M U G A Sca ns ................................................................. 6 4
7. 4. 6. Assess me nt of M o o d................................ ................................................... 6 4
7. 4. 7. Assess me nt of S uici dal I deati o n a n d Be ha vi or .......................................... 6 5
7. 5. P har mac o ki netics Assess me nts ............................................................................... 6 5
8. A D V E R S E E V E N T R E P O R TI N G ...................................................................................... 6 7
8. 1. Re q uire me nts ........................................................................................................... 6 7
8. 1. 1. A d diti o nal Details o n Rec or di n g A d verse E ve nts o n t he C R F ................... 6 9
8. 1. 2. Eliciti n g A d verse E ve nt I nf or mati o n .......................................................... 6 9
8. 1. 3. Wit h dra wal fr o m t he St u d y D ue t o A d verse E ve nts (see als o t he 
S u bject Wit h dra wal secti o n) ............................................................................ 6 9
8. 1. 4. Ti me Peri o d f or C ollecti n g A E/ S A E I nf or mati o n...................................... 6 9
8. 1. 4. 1. Re p orti n g S A Es t o Pfizer Safet y ............................................... 6 9
8. 1. 4. 2. Rec or di n g N o n -seri o us A Es a n d S A Es o n t he C R F ................. 7 0
8. 1. 5. Ca usalit y  Assess me nt ................................................................................. 7 0
8. 1. 6. S p o n s or’s Re p orti n g Re q uire me nts t o Re g ulat or y A ut h orities .................. 7 0
8. 2. Defi niti o ns ............................................................................................................... 7 1
8. 2. 1. A d verse E ve nts ........................................................................................... 7 1
8. 2. 2. A b n or mal Test Fi n di n gs .............................................................................7 2
8. 2. 3. Seri o us A d vers e E ve nts ..............................................................................7 2
8. 2. 4. H os pitalizati o n ............................................................................................ 7 3
8. 3. Se verit y  Assess me nt................................................................................................ 7 4
8. 4. S pecial Sit uati o ns .................................................................................................... 7 4
8. 4. 1. Pr ot oc ol - S pecifie d Seri o us A d verse E ve nts............................................... 7 4
8. 4. 2. P ote ntial Cas es of Dr u g-I n d uce d Li ver I nj ur y............................................ 7 4
8. 4. 3. E x p os ure t o t he I n vesti gati o nal Pr o d uct D uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure ..................................................... 7 6
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8. 4. 3. 1. E x p os ure D uri n g Pre g na nc y ......................................................7 6
8. 4. 3. 2. E x p os ure D uri n g Breastfee di n g ................................................ 7 8
8. 4. 3. 3. Occ u pati o nal E x p os ure ............................................................. 7 8
8. 4. 4. Me dicati o n Err ors ....................................................................................... 7 8
8. 4. 4. 1. Me dicati o n Err ors ...................................................................... 7 8
9. D A T A A N A L Y SI S/ S T A TI S TI C A L  M E T H O D S...............................................................7 9
9. 1. Sa m ple Size Deter mi nati o n ..................................................................................... 7 9
9. 2. A nal y sis Sets ........................................................................................................... 8 0
9. 3. Efficac y  A nalys is .................................................................................................... 8 1
9. 3. 1. A nal y sis of t he Pri mar y E n d p oi nt...............................................................8 1
9. 3. 2. A nal y sis of Sec o n dar y E n d p oi nts...............................................................8 1
9. 4. A nal y sis of Ot her E n d p oi nts ................................................................................... 8 2
9. 4. 1. A nal y sis of P har mac o ki netics ..................................................................... 8 2
9. 4. 2. P har mac o ki netic a n d E x p os ure -Res p o ns e A nal ysis ................................... 8 3
9. 5. Safet y A nal ys is........................................................................................................ 8 3
9. 5. 1. A d verse E ve nts ........................................................................................... 8 3
9. 5. 2. L a b orat or y A b n or malities........................................................................... 8 4
9. 5. 3. Electr ocar di o gra ms ..................................................................................... 8 4
9. 5. 4. L eft Ve ntric ular Ejecti o n Fracti o n ..............................................................8 4
9. 6. I nteri m A nal ys is...................................................................................................... 8 5
9. 7. Data M o nit ori n g C o m mittee ................................................................................... 8 5
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E ................................................. 8 5
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G ............................................................. 8 5
1 1. 1. Case Re p ort F or ms/ Electr o nic Data Rec or d ......................................................... 8 5
1 1. 2. Rec o r d Rete nti o n................................................................................................... 8 6
1 2. E T HI C S ..............................................................................................................................8 7
1 2. 1. I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee ...................................................... 8 7
1 2. 2. Et hical C o n d uct of t he St u d y ................................................................................ 8 7
1 2. 3. S u bject I nf or mat i o n a n d C o nse nt.......................................................................... 8 7
1 2. 4. Re p orti n g of Safet y I ss ues a n d Seri o us Breac hes of t he Pr ot oc ol or I C H 
G C P ........................................................................................................................... 8 8
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13. DEFINITION OF END OF STUDY.................................................................................88
14. SPONSOR DISCONTINUATION CRITERIA ................................................................89
15. PUBLICATION OF STUDY RESULTS..........................................................................89
15.1. Communication of Results by Pfizer ....................................................................89
15.2. Publications by Investigators ................................................................................90
16. REFERENCES ..................................................................................................................91
LIST OF TABLES
Table 1.
Lorlatinib Dose Levels for Intrapatient Dose Modifications....................46
Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities ............47
Table 3.
PR Interval Prolongation Management ....................................................52
LIST OF FIGURES
Figure 1.
Study B7461024 Design...........................................................................35
APPENDICES
Appendix 1. Abbreviations......................................................................................................94
Appendix 2. Eastern Cooperative Oncology Group (ECOG) Classification of
Performance Status ...................................................................................98
Appendix 3. RECIST Version 1.1 - Modified to Include Assessment of CNS 
Metastases.................................................................................................99
Appendix 4. Required Laboratory Tests................................................................................103
Appendix 5. Medications with Potential PR Interval Prolongation Effect............................104


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PROTOCOL SUMMARY 
BACKGROUND AND RATIONALE
Lung cancer has been the most common cancer in the world for several decades, and by 
2008, there were an estimated 1.61 million new cases, representing 12.7% of all new cancers.  
It was also the most common cause of death from cancer, with 1.38 million deaths (18.2% of 
the total).  Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung
cancer.1  And only 18% of all patients with lung cancer are alive 5 years or more after 
diagnosis.2  In China, lung cancer is also the most common cancer (0.73 million new cases) 
and the leading cause of cancer death (0.61 million) according to a report in 2015.3
In NSCLC patients, there is a clinically relevant molecular subset driven by oncogenic fusion 
gene EML4-ALK that combine portions of the echinoderm microtubule-associated 
protein-like 4 (EML4) gene and anaplastic lymphoma kinase (ALK) gene, which was 
discovered in 2007.4,5
The first approved tyrosine kinase inhibitor (TKI) for ALK-positive NSCLC was crizotinib, 
which has been accepted as standard of care (SOC) for ALK-positive NSCLC patients 
worldwide.  Although most patients with ALK-positive NSCLC derive substantial clinical 
benefit from crizotinib, some ALK-positive NSCLC patients will not derive any benefit 
(intrinsic resistance) while other patients who initially derived benefit may later develop 
resistance (acquired resistance).  Acquired ALK kinase domain mutation and brain metastasis 
are the two major mechanism of refractory or resistance to crizotinib treatment.13,14,15  For 
this group of patients, an alternative ALK-targeted treatment is needed.
The second-generation ALK inhibitors are being developed.  Both ceritinib and alectinib 
showed clinical activity in crizotinib resistance and refractory NSCLC, including those with 
central nervous system (CNS) metastasis.20,23  And in the subsequent Phase 3 studies, both 
these ALK inhibitors also showed great efficacy in treatment-naïve advanced ALK-positive 
NSCLC.22,24  With this evidence, ceritinib and alectinib have both been approved in both 
treatment-naïve and crizotinib-resistance setting in the US by Food and Drug Administration 
(FDA) since 2015. In China, Xalkori® (crizotinib) and ALECENSA® (alectinib) are the 
standard of care (SOC) for patients with ALK-positive advanced NSCLC. For the patients 
previously treated with Xalkori® (crizotinib), the current SOC are ALECENSA® (alectinib) 
and ZYKADIATM (ceritinib) from 2018 in China.
The resistance to ALK inhibitors appears very complex as a greater variety of mutations are 
found in patients.  To date, multiple types of ALK kinase domain mutations have been
identified in crizotinib refractory patients,16,18,19 and account for about one third of resistant 
samples tested.  While ceritinib and alectinib are both approved for ALK-positive advanced 
NSCLC patients, the resistance to both of these inhibitors has also emerged.  In the case of 
ceritinib, relapsed tumors often express the ALK mutant G1202R.25  In the case of alectinib, 
in addition to G1202R, two ALK resistance mutations (V1180L and I1171T) have been 
observed.25 Among these ALK mutations, ALK G1202R conferred high-level resistance to 
almost all of the ALK inhibitors tested.16,18,19 In this situation, targeting on one gene 


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mutation won’t effectively reverse the acquired resistance caused by ALK gene mutation, a 
broader inhibition of variety of mutations is in need for next generation of ALK TKI.
Lorlatinib is a selective, brain-penetrant ALK TKI with potent activity against ALK and ROS 
proto-oncogene 1(ROS1) fusions, including those harboring resistance mutations.  Lorlatinib 
has demonstrated clinically meaningful anti-tumor activity in patients with brain metastases 
after treatment with ALK inhibitors including crizotinib.27 Further, lorlatinib appears to be 
the only ALK TKI active against certain mutations that are the most difficult to inhibit, such 
as the G1202R mutation.25
Lorlatinib has the potential to improve anti-tumor activity in ALK inhibitor resistance and 
ALK-positive advanced NSCLC, based on its greater potency against ALK and its broad 
coverage against all known single point mutations that mediate resistance to crizotinib and 
second generation ALK inhibitors,25 and able to cross the blood brain barrier. Lorlatinib was 
granted breakthrough therapy designation and priority review by FDA, and was approved by 
FDA in November 2018.  Lorlatinib was also approved by Japan and European Union in 
September 2018 and in May 2019, respectively.
STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives

To evaluate the anti-tumor effect of lorlatinib as a single agent as measured by 
objective response rate (ORR) per response evaluation criteria in solid tumors
(RECIST) v1.1 in locally advanced or metastatic ALK-positive NSCLC patients 
whose disease has progressed after crizotinib treatment.
Secondary Objectives

To evaluate the anti-tumor effect of lorlatinib as a single agent as measured by ORR 
per RECIST v1.1 in locally advanced or metastatic ALK-positive NSCLC patients 
whose disease has progressed after ALK inhibitor treatment other than crizotinib.

To evaluate the progression-free survival (PFS) and overall survival (OS) in locally 
advanced or metastatic ALK-positive NSCLC patients whose disease has progressed 
after crizotinib and other ALK inhibitor treatment, respectively.

To evaluate other antitumor activities in locally advanced or metastatic ALK-positive 
NSCLC patients whose disease has progressed after crizotinib and other ALK 
inhibitor treatment, respectively.

To evaluate the safety and tolerability of lorlatinib treatment in locally advanced or 
metastatic ALK+ NSCLC patients whose disease has progressed after crizotinib and 
other ALK inhibitor treatment.

To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic
(PK)/pharmacodynamics relationship for lorlatinib if appropriate.


L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
 
 
Pri m ar y E n d p oi nt

O bjecti ve Res p o nse ( O R) i n patie nts w h ose disease has pr o gresse d after criz oti ni b
( C o h ort 1) as assesse d b y Res p o nse E val uati o n Criteria i n S oli d T u m or ( R E CI S T) 
versi o n 1. 1 per i n de pe n de nt ce ntral ra di ol o g y (I C R) assess me nt.
Sec o n d ar y E n d p oi nts

O R i n patie nts w h ose disease has pr o gress after A L K i n hi bit or treat me nt ot her t ha n 
criz oti ni b ( C o h ort 2) as assesse d b y R E CI S T v 1. 1 per I C R assess me nt.

Pr o gressi o n -free s ur vi val ( P F S) as assesse d b y R E CI S T v 1. 1 per I CR assess me nt a n d 
i n vesti gat or assess me nt, a n d O verall s ur vi val ( O S) i n b ot h C o h orts.

I ntracra nial O bjecti ve Res p o nse (I C-O R) , D ura ti o n of res p o nse ( D o R), D urati o n of 
i ntracra nial res p o nse (I C-D o R), Ti me t o t u m or res p o nse ( T T R) as assesse d b y 
R E CI S T v 1. 1 per I CR assess me nt a n d i n vesti gat or asses s me nt, i n b ot h C o h orts.

Safet y : a d verse e ve nt ( A E ); la b orat or y a b n or malities; electr ocar di og ra p hy ( E C G ), left 
ve ntric ular ejecti o n fracti o n ( L V E F), C N S effects.

P K para meters o n Da y 1 of C y cle 1 a n d at stea d y  state: C ma x ( ma xi m u m ser u m 
c o nce ntrati on), T ma x (ti me t o reac h t he ma xi m u m c o nce ntrati o n), A U Ct (area u n der 
t he plas ma c o nce ntrati o n vers us ti me pr ofile fr o m ti me 0 t o ti me t), A U C ta u (area 
u n der t he plas ma c o nce ntrati o n vers us ti me pr ofile wit hi n a d ose i nter val ) at stea d y 
state.  A U C i nf (area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve t o i nfi nit y ), 
C L / F (oral plas ma cleara nce ), a n d Vz/ F (a p pare nt v ol u me of distri b uti o n ) a n d 
t1/ 2 (ter mi nal eli mi nati o n half-life), Rac (acc u m ulati o n rati o) as data per mit.
 
 
 
C CI
C CI


Lorlatinib (PF-06463922)
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Final Protocol Amendment 1, 11 October 2019
PFIZER CONFIDENTIAL
Page 15
STUDY DESIGN
Study overview
This is a Phase 2, multicenter (at approximately 30 sites), dual-cohort study in China, in 
which approximately 100 patients with locally advanced or metastasis ALK-positive NSCLC 
will be enrolled to receive lorlatinib monotherapy.  In Cohort 1 approximately 66 patients 
whose disease has progressed after crizotinib will be enrolled, and in Cohort 2, 
approximately 34 patients whose disease has progressed after ALK inhibitor other than 
crizotinib.  The study design is illustrated below.
Study Treatments
All the patients enrolled into the study will receive lorlatinib monotherapy at the 
recommended Phase 2 dose (RP2D) of 100 mg QD (quaque die; every day), administered as 
4 x 25 mg oral tablets, continuously. 
The study treatment may continue until disease progression confirmed by independent 
central radiology (ICR) review, global deterioration of health status requiring permanent 
discontinuation per the investigator’s judgement, unacceptable toxicity, pregnancy,
significant protocol violation, patient lost to follow-up, or patient refusal, the study is 
terminated by the sponsor, or the death, whichever comes first.
Statistical Methods
The study will evaluate safety and efficacy for lorlatinib in both Cohort 1 and Cohort 2.  
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.
Sample Size Determination
The primary objective of the study is to evaluate the anti-tumor effect of lorlatinib as a single 
agent as measured by ORR per RECIST v1.1 in locally advanced or metastatic ALK-positive 
NSCLC patients whose disease has progressed after crizotinib treatment, ie, Cohort 1. 


Lorlatinib (PF-06463922)
B7461024
Final Protocol Amendment 1, 11 October 2019
PFIZER CONFIDENTIAL
Page 16
As of the original version date of protocol, given there’s no ALK TKI other than crizotinib 
approved in China currently, chemotherapy is still considered as standard of care for patients 
whose disease have progressed after crizotinib.  Based on the current reported results, the 
ORR of chemotherapy in previous systemic treatment treated patients ranged from 
6.9% - 20%.21,28,29  The ORR was 26.7% even for treatment naive patients.22  Therefore, 
ORR of 30% was chosen as the historical control for Cohort 1.  The Fleming single stage 
design will be used to test the null hypothesis (H0) of ORR 30% with 1-sided 
0.025 significance level.  Assume at least 20% increase of ORR with lorlatinib treatment, 
66 patients will be required to provide 90% power to reject the null hypothesis.  Exact test 
will be performed at the time of the analysis.  If at least 28 or more responses are observed 
among the 66 patients enrolled, then the null hypothesis will be rejected, and it will be 
concluded that the study has demonstrated that the true ORR exceeds 30%.  However, at the 
time of the analysis, the testing will depend on the exact number of patients enrolled. 
Cohort 2 will explore the safety and efficacy of lorlatinib in patients with locally advanced or 
metastasis ALK-positive NSCLC whose disease have progressed after one ALK inhibitor 
treatment other than crizotinib.  As of the original version date of protocol, there was no 
approved ALK inhibitor other than crizotinib in China, therefore, the eligible patients were
very limited and no established standard of care was available.  Considering this limitation, 
Cohort 2 will be exploratory with about 34 patients planned to be enrolled.  No specific 
statistical hypothesis will be tested.  Descriptive analyses will be provided for the endpoints.  
The sample size of 34 patients will provide the estimated ORR with a maximum width of the 
95% CI (confidence interval) of 35%, observed with 17 responses out of 34 patients. In 
order to collect more information of anti-tumor activity, if the patients received study 
treatment but without adequate baseline tumor assessment or without post baseline tumor 
assessments, additional patients may be allowed to be enrolled.
With approximately 66 and approximately 34 patients in Cohort 1 and 2 respectively, this 
study will provide adequate sample size for safety evaluation with a minimal number of 100.


Lorlatinib (PF-06463922)
B7461024
Final Protocol Amendment 1, 11 October 2019
PFIZER CONFIDENTIAL
Page 17
SCHEDULE OF ACTIVITIES (SOA)
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. 
CYCLE 1
21 days
CYCLE 2
21 days
CYCLES 3
(21 days per cycle)
END of TREATMENT (EOT)/ FOLLOW-UP
Visit Identifiera
Screening1
(28 days)
Day 1
Day 5
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal26
Post-Treatment 
Follow- Up27
Survival
Follow-Up28 (every
4 months up to 
3 years, then every 
6 months)
Visit Time Window 
(days)
N/A
3
1
1
2
2
3
7
7
Informed consent2
X
Tumor history, including 
ALK status 
determination
X
Medical/oncological 
history (incl. prior 
medications)
X
Physical examination
(PE)
X
X
X
X
X
X
Baseline signs and 
symptoms3
X
Height
X
Weight
X
X
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
ECOG performance 
status5
X
X
X
X
X
Contraception check6
X
X
X
X
X
X
X
X (at 
30,60,90 days)
Laboratory
Hematology7
X
X
(-7 days)
X
X
X
X
X
X (at 30 and 
60 days)


Lorlatinib (PF-06463922)
B7461024
Final Protocol Amendment 1, 11 October 2019
PFIZER CONFIDENTIAL
Page 18
CYCLE 1
21 days
CYCLE 2
21 days
CYCLES 3
(21 days per cycle)
END of TREATMENT (EOT)/ FOLLOW-UP
Visit Identifiera
Screening1
(28 days)
Day 1
Day 5
Day 8
Day 15
Day 1
Day 1
End of Treatment/
Withdrawal26
Post-Treatment 
Follow- Up27
Survival
Follow-Up28 (every
4 months up to 
3 years, then every 
6 months)
Visit Time Window 
(days)
N/A
3
1
1
2
2
3
7
7
Blood Chemistry8
X
X
(-7 days)
X
X
X
X
X
X (at 30 and 
60 days)
HBV, HCV (if 
applicable)
X
Lipids9
X
X
(-7 days)
X
X
X
X
X
X (at 30 and 
60 days)
Coagulation10
X
X
(-7 days)
X
X (at 30 and 
60 days)
Urinalysis11
X
X
(-7 days)
X (as clinically 
indicated)
X (as clinically 
indicated)
X
X (at 30 and 
60 days)
Pregnancy test12
X
X
X
X
X
X (at 30 and 
60 days)
Triplicate (12-lead) 
ECGs13
X
X
X
X
X
X (single reading, 
pre-dose, on Day 1 
of every other 
cycle)
X
X (at 30 and 
60 days)
LVEF assessment 
(Echocardiogram or 
MUGA scan)15
X
X 
(pre- dose-
not to be 
repeated if 
normal and 
performed
<2 weeks 
prior to 
enrollment)
X (pre dose, Day 1 
of every other cycle; 
a time window of 
1 week prior to 
Day 1 is permitted)
X
X (at 30 and 
60 days)
IRT Registration and 
Study Treatment
IRT Registration14
X
X

Lorlatinib
orally on a continuous QD dosing schedule
Treatment compliance 
check16
X


L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
C Y C L E 1
2 1 d a ys
C Y C L E 2
2 1 d a ys
C Y C L E S 3
( 21 d a ys per c ycle)
E N D of T R E A T M E N T ( E O T)/ F O L L O W- U P
Visit I de ntifiera
Scree ni n g 1
(2 8 d a ys)
D a y 1
D a y 5
D a y 8
D a y 1 5
D a y 1
D a y 1
E n d of Tre at me nt/
Wit h dr a w al
2 6
P ost -Tre at m e nt 
F oll o w - U p 2 7
S ur vi v al
F oll o w -U p 2 8 (e ver y
4 m o nt hs u p t o 
3 ye ars, t he n e ver y 
6 m o nt hs)
Visit Ti me Wi n d o w 
( d a ys)
N/ A
3
1
1
2
2
3
7
7
T u m or Assess me nts
C T or M RI sca n 1 7
X

e ver y 6 wee ks ( ± 1 wee k) f or C T or M RI sca n

e ver y 1 8 wee ks ( ± 1 wee k) f or b o ne sca n (or b o ne M RI if prefer re d b y 
in vesti gat or ) o nl y if e vi de nce of b o ne metastases is o bser ve d at baseli ne
X
X (e ver y 
6 wee ks 
± 1 we e k , u ntil 
I C R P D ; If 
a p plica ble, e very
1 8 wee ks 
( ± 1 wee k) f or 
b o ne sca n (or 
b o ne M RI if 
preferre d b y 
i n vesti gat or)
X (as cli nicall y 
i n dicate d)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI


L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
C Y C L E 1
2 1 d a ys
C Y C L E 2
2 1 d a ys
C Y C L E S 3
( 21 d a ys per c ycle)
E N D of T R E A T M E N T ( E O T)/ F O L L O W- U P
Visit I de ntifiera
Scree ni n g 1
(2 8 d a ys)
D a y 1
D a y 5
D a y 8
D a y 1 5
D a y 1
D a y 1
E n d of Tre at me nt/
Wit h dr a w al
2 6
P ost -Tre at m e nt 
F oll o w - U p 2 7
S ur vi v al
F oll o w -U p 2 8 (e ver y
4 m o nt hs u p t o 
3 ye ars, t he n e ver y 
6 m o nt hs)
Visit Ti me Wi n d o w 
( d a ys)
N/ A
3
1
1
2
2
3
7
7
Ot her Cli nic al 
Assess me nts
Seri o us a n d n o n -seri o us 
a d verse e ve nt 
m o nit ori n g 2 1
X  
X





C o nc o mita nt 
me dicati o ns a n d 
treat me nts2 2
X  
X





X (s u bse q ue nt 
s yste mic 
a ntica ncer 
treat me nt)
M o o d assesse me nt
2 3
X
X  
X ( u p t o C ycle 6 
a n d t he n Da y 1 of 
e ver y ot her c ycle)
X
S uici dal I deati o n a n d 
Be ha vi or 2 4
X
X  
X ( u p t o C ycle 6 
a n d t he n Da y 1 of 
e ver y ot her c ycle)
X
S ur vi val stat us 2 8
X
Ot her S a m ples
P har mac o ki netic 
Sa m pli n g 2 5
See fo ot n ote 2 5
a.
Da y relati ve t o start of st u d y treat me nt ( Da y 1 of C ycle 1 ).
A b bre vi ati o ns: 
= o n g oi n g/c o nti n u o us e ve nt; E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; L V E F = left ve ntric ular ejecti o n fracti o n; 
M U G A =
M ulti gate ac q uisiti o n;
C T = c o m p ute d t o m o gra p h y; M RI = Ma g netic Res o na nce I ma gi n g ; E O R T C = E u r o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer; 
I C R = I n de pe n de nt Ce ntral Ra di ol o g y; P D = Pr o gressi o n of Disease; A L K = a na pla stic l y m p h o ma ki nase; P E = P h ysical e xa mi nati o n; C T C A E = C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts; H B V = He pati tis B Vir us; H C V = He patitis C Vir us; Q D = Q ua q ue Die (e ver y da y); 
 N/ A = N ot a p plica ble.
F o ot n otes: 
Acce p ta b le ti me wi n d o ws f or perf or mi n g eac h assess me nt are descri be d i n t he c ol u m n hea ders.
C CI


L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
1.
Scree ni n g : T o be o btaine d wit h i n 2 8 da ys pri or t o e nr oll me nt (C y cle 1 Da y 1: C 1 D 1 ). A vaila ble res ults f or assess me nts t hat ha ve bee n perf or me d pri or t o i nf or me d c o nse nt 
be in g o btai ne d as part of t he patie nt’s o n -g oi n g r o uti ne sta n dar d of care testi n g (la b orat or y tests or t u m or i magi n g sca ns) ma y be use d t o satisf y patie nt eli gi bilit y
assess me nt , pr o vi de d t he y ha ve bee n perf or me d wit hi n t he re q uire d ti mi ng (t hat is 7 da ys pr ior e nr oll me nt f or la b orat or y tests or 2 8 da ys pri or e nr oll me nt f or t u m or 
i ma gin g or 6 wee ks pri or e nr oll me nt f or b o ne sca n [ or b o ne M RI if preferre d b y i n vesti gat or]) a n d meet t he relate d criteria.
2.
I nf or me d C o nse nt: M ust be o btai ne d pri or t o u n der g oi n g an y st u d y-s pecific pr oce d ures. 
 
3.
B aseli ne Si g ns a n d S y m p t o ms: S u bjects will be as ke d a b o ut a n y si g ns a n d s y m pt o ms e x perie nce d wit hi n t he 1 4 da ys pri or t o Da y 1 of C ycle 1.
4.
Vi t al Si g ns: I ncl u de bl o o d press ure, p ulse rate, b o d y te m perat ure, a n d b o d y wei g ht.  B l o o d press ure a n d p ulse rate t o be rec or ded i n sitti n g p ositi o n after t he su b ject has 
bee n sitti n g q uietl y f or at least 5 mi n utes.  B o d y w ei g ht t o be rec or de d at Da y 1 of eac h c ycle.
5.
Perf or m a nce St at us : acc or di n g t o Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) classificati o n (see A p pe n di x 2 ). 
6.
C o ntr ace pti o n c hec k: Fertile male s u bject s a n d fe male s u bjects w h o are of c hil d beari n g pote ntial wi ll nee d t o f oll o w t he c o ntrace pti o n g ui deli nes i n Secti o n 4. 3. 1 .
7.
He m at ol o g y : Re q uired t ests are liste d i n t he A p pe n di x 4 of t he pr ot oc ol .  Ma y als o be perf or me d w he n cli nicall y i n dicate d (res ults t o be e ntere d i n C R F as u npla n ne d 
visit) .  N o nee d t o re peat o n C 1D 1 if baseli ne assess me nt perf or m e d wit hi n 7 da ys pri or t o t hat date.
8.
Bl o o d C he mis tr y: Re q uire d tests are liste d i n A p pe n di x 4 of t he pr ot oc ol.  Ma y als o be perf or me d w he n cli nicall y i n dicate d (res ults t o be e ntere d i n C R F as u n pla n ne d 
visit) .
No nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys pri or t o t hat date.
9.
L i pi ds: Re q uire d tests are liste d i n t he A p pe n di x 4 of t he pr ot oc ol.  Ma y als o be perf or me d w he n cli nicall y i n dicat e d (res ults t o be e ntere d i n C R F as u n pla n ne d visi t).  N o 
nee d t o re peat o n C 1 D 1 if baseli ne asse ss me nt perf or me d wit hi n 7 da ys pri or t o t hat date.
1 0.
C o a g ul ati o n : Re q uire d tests are liste d i n t he A p pe n di x 4 of t h e p r ot oc ol.  Ma y als o be perf or me d w he n cli nicall y i n dicate d (res ults t o be e ntere d i n C R F as u n pla n ne d 
v isit).  N o nee d t o re peat on C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys pri or t o t hat date.
1 1.
Uri n al ysis: Di ps tic k is acce pta ble.  Micr osc o pic an a l yses if di pstic k a b n or mal a n d/ or if t his is t he l ocal sta n dar d. N ot t o be re peate d at C 1 D 1 if perf or me d wit hi n 7 da ys 
bef ore .
1 2.
Pre g n a nc y Test: F or fe male s u bjects of c hil d beari n g p ote ntial, a ser u m or ur i ne pre g na nc y test, t o be perf or me d o n t w o occasi o n s pri or t o starti n g st u d y t hera p y, o nce at 
t he start of scree ni n g an d o nce at t he baseli ne visit, w h ose res ults m ust be a vaila ble bef ore i n vesti gati o nal pr o d uct a d mi nistrati o n.  Pre g na nc y test s also r o uti n el y re peate d 
at e ver y c ycle d uri n g t he acti ve tr eat me nt peri o d, at t he e n d of st u d y t hera p y a n d a d diti o nall y w he ne ver o ne me nstr ual c ycle is misse d or w he n p ote ntial pre g na nc y is 
ot her wise s us pecte d.  A d diti o nal pre g na nc y tests if re q ueste d b y I R B/ I E Cs or b y l ocal re g ulati o ns. 
1 3.
Tri plic ate 1 2 -le a d E C Gs: At eac h ti me p oi nt, 3 c o nsec uti ve 1 2 -lea d E C Gs perf or me d a p pr o xi mately 2 mi n utes a part ( or wit hi n 1 0 mi n utes, w hic he ver is a p pr o priate ) to 
deter mi ne P R i nter val a n d mea n Q Tc i nter val.  T he E C G m ust occ ur pr i or t o a n y bl o o d sa m ple c ollecti o ns or ve ni p u nct u ri ng if c o n d ucte d o n t he sa me da y, e xce pt f or t he 
s pecific re q uire me nt i n t he pr ot oc ol.  E C Gs are t o be c ollecte d at pre d ose a n d 1- 4 h o urs p ost -d ose o n C ycle 1 Da y 1.  E C Gs will als o be c ollecte d at 1- 4 h o ur s p ost-d ose o n 
C y cle 1 Da y 8 a n d Da y 1 5, a n d o n C y cle 2 Da y 1.   Si n gle rea di n g E C G are t o be c ollec te d pre-d ose o n Da y 1 of C ycle 3 a n d e ver y ot her c ycle t hereafter .  E C Gs at later 
c ycles are t o be c ollecte d as cli n icall y i n dicate d.  At E n d of Treat me nt/ Wit h dra wal, tri plicate E C Gs are t o be c ollecte d.  Ad di ti o nal E C G ti me p oi nts may be perf or me d 
base d o n t he e mer gi n g data.
1 4.
I R T re gistr ati o n: St u d y treat me nt s h o ul d be i nitiate d prefera bl y o n t he ra n d o mizati o n da y b ut n o later t ha n 1 da ys after ra n d o mizati o n.
1 5.
L eft ve ntric ul ar ejecti o n fr acti o n (L V E F ) Asses sme nt: Ec h ocar di o gra m ( E C H O) or m ul ti gate d ac q uisiti o n sca n ( M U G A) t o be perf or me d at Scree ni n g, at pre- d ose, o n 
C y cle 1 Da y 1 a n d e ver y ot her c ycles t hereafter, a n d at t he E O T visi t.  T he sa me met h o d s h o ul d be use d at eac h ti me p oi nt. If t he scree ni n g E C H O or M U G A is n or mal 
a n d has bee n perf or me d wit hi n 2 wee ks pri or t o ra n d o mizati o n, t here is n o nee d t o re peat t his assess me nt at Da y 1 of C ycle 1. At s u bse q ue nt visits a ti me wi n d o w o f 
1 wee k pri or t o Da y 1 of s u bse q ue nt c ycles will be per mitte d f or t he E C H O / M U G A assess me nt.
C CI


L orlati n i b ( P F-0 6 4 6 3 9 2 2 )
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
1 6.
Tre at me nt c o m pli a nce c hec k : T he st u d y site m ust f oll o w u p (f or e xa m ple, via a tele p h o ne call) wit h eac h s u bject o n C ycle 1 Da y 5 ( ± 3 da ys) t o c o nfir m t hat t he s u b ject 
u n dersta n ds a n d is i n c o m plia nce wit h l orlati ni b d osi n g i nstr ucti o n s.
1 7.
T u m or Assess me nts: t o i ncl u de all k n o w n or s uspecte d d isease sites.  I ma gi n g t o i ncl u de c hest, a b d o me n, a n d pel vis C T or M RI sca ns; brai n M RI; b o ne sca n (or b o ne 
M RI if preferre d b y i n v esti gat or).  Brai n M RI ( Ga d oli ni u m c o ntrast e n ha nce d) or brai n C T ( co n trast e n ha nce d) t o be use d f or assess me nt of C N S lesi o ns (e ve n if brai n 
metastases n ot s us pecte d), wit h c o nti n ge nt slices of 1 m m f or lesi o ns wit h a mi ni m u m size of 5 m m – 1 0 m m i n size, 5 m m f or lesi o ns greater t ha n 1 0 m m .  C N S i ma gi n g 
usi n g M RI or C T (c o ntrast e n ha nce d is preferre d u nless c o ntrai n dic ate d) is re q uired at baseli ne i n all patie nts a n d at e ver y t u m or assess me nt . B o ne sca ns ( or b o ne M RI if 
preferre d b y i n vesti gat or) t o be perf or me d at baseli ne f or all s u bjects a n d re peate d e ver y 1 8 wee ks ± 1 w ee k o n st u d y o nl y if e vi de nce of b o ne met astases is o bser ve d at 
baseli ne.  F or all t u m or assess me nts, t he met h o d of assess m e nt t hat was use d at baseli ne s h o ul d be t he sa me met h o d u se d t hr o u g h o ut t he st u d y.  C T or M RI sca ns t o be 
d o ne at e ver y 6 wee ks ± 1 we e k starti n g fr o m t he first d ose of the i n ves ti gati o nal pr o d uct w hile o n treat me nt d uri n g p ost -treat me nt f oll o w-u p peri o d u ntil d oc u me nte d 
pr o gressi o n of disease b y I C R. D uri n g p ost -treat me nt f oll o w-u p peri o d, if a p plica ble, b o ne sca n ( or b o ne M RI if preferre d b y i n vesti gat o r) t o be perf or me d e ver y 1 8 wee ks
± 1 wee k u ntil d oc u me nte d pr o gressi o n of disease b y I C R .  T he res p o nses will be re q ui re d t o be c o nfir me d ≥4 wee ks after t he i nitial res p o nse is o bser ve d.  T u m or 
assess me nt s h o ul d be re peate d at t he E O T visit if m ore t ha n 6 wee ks ha ve passe d si nce t he last e va l uati o n.  T u m or assess me nts m ust c o nti n ue u ntil d oc u me nte d 
pr o gressi o n of disease b y i n de pe n de nt ce ntr al ra di ol o g y re vie w.  S u bjects w h o disc o nti n ue treat me nt wit h o ut P D s h o ul d be f oll o we d u ntil P D c o nfir me d b y i n de pe n de nt 
ce ntral ra di ol o g y re vie w re gar dle ss of s u bse q ue nt a nti-ca ncer treat me nts.  Assess me nt of res p o nse will be ma de usi ng R E CI S T v. 1. 1.  Ass ess me nt of res p o nse of 
meas ura ble i ntracra nial disease will be ma de usi n g a m o difie d versi o n of R E CI S T v. 1. 1.
3 1 Refer t o Secti o n 7. 1 f or t he m ore details.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
2 1.
A d verse E ve nt ( A E) Asses s me nts: A Es s h o ul d be d oc u me nte d a n d rec or de d at eac h visit usi n g t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( N CI C T C A E) versi o n 4. 0 3.  T he ti me peri o d f or acti vel y eliciti n g a n d c ollecti n g A Es a n d Seri o us A d verse E ve nts ( S A Es ) (“acti ve c ollecti o n peri o d”) f or eac h 
s u bject be gi ns fr o m t he ti me t he s u bject pr o vi des i nf or me d c o nse nt, w hic h is o btai ne d bef ore t he s u bject’s partici pati o n i n t he st u d y (ie, bef ore u n der g oi n g a n y 
st u d y-relate d pr oce d ure a n d/ or recei vi n g i n vesti gati o nal pr o d uct), t hr ou g h a n d i ncl u di n g a mi ni m u m of 2 8 cale n d ar da ys after t he last a d mi nistrati o n of t he i n vesti gati o nal 
pr o d uct.  D uri n g t he acti ve c ollecti o n peri o d, b ot h n o n -seri o us A Es an d S A Es are rec or de d o n t he case re p ort f or m ( C R F ).  If a s u bject be gi ns a ne w a ntica ncer t hera p y, t he 
A E re p orti n g peri o d f or n o n- seri o us A Es e n ds at t he ti me t he ne w treat me nt is starte d; h o we ver, S A Es m ust c o nti n ue t o be rec or de d o n t he C R F d uri n g t he a b o ve -i n dicate d 
acti ve c ollecti o n peri o d. 
C CI


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22. Concomitant Medications and treatments: All concomitant medications and treatments will be recorded in the CRF from 28 days prior to enrollment and up to 28 days 
after the last dose of study treatment. 
23. Mood Assessment: An assessment of mood via the Beck Depression Inventory II (BDI II) scale will be administered to subjects prior to the first day of lorlatinib dosing 
(ie, Cycle 1 Day 1) 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.
24. Suicidal Ideation and Behavior: An assessment of suicidal ideation and behavior via the Columbia Suicide Severity Rating Scale (C-SSRS) will be administered to
subjects prior to the first day of lorlatinib dosing (ie, Cycle 1 Day 1) 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.
25. Pharmacokinetics Sampling: Blood samples will be collected at pre-dose and 1-2 hours post-dose in on Day 1 of Cycles 2 to 5 in all subjects.  Additionally, in up to 
16 subjects (to acquire no less than 12 evaluable PK profiles), blood samples will be collected on Day 1 and Day 15 of Cycle 1 at the following time points: Pre-dose, 0.5, 
1, 2, 3, 4, 6, 8, 9, and 24 hours.  Note: 1) When collecting the serial PK sample at 8 hour and 9 hour, if the actual collection time of the 8 hour sample is nearing the 9 hour 
nominal time (within the 10% window of the 9 hour collection time), the 9 hour sample should still be collected after the 8 hour sample and as close to the 9 hour nominal 
time as possible. 2) In the event of any dose interruption in 15 day time period prior to Day 15 of Cycle 1, the planned intensive PK sampling schedule on C1D15 is 
suggested to be extended to the Day 1 of next cycle.
26. End of Treatment (EOT) Visit: Obtain these assessments if not completed in the last 7 days (last 6 weeks for tumor assessments). EOT visit should be performed no later 
than 4 weeks (+1w) from the last dose of investigational product or when decision taken to provide alternative anti-cancer therapy, whichever is sooner. Subjects 
continuing treatment after disease progression confirmed by independent central radiology review will continue to perform safety assessment required in the treatment 
period, until treatment discontinue, and tumor assessment will be in need when clinically indicated.
27. Post-Treatment Follow-Up Visits: Subjects continuing to experience toxicity at this point will continue to be followed (the test/examination related to continuing adverse 
event(s) will be followed) at least every 4 weeks (except for the tumor assessment which will be performed every 6 weeks ±1 week, if applicable) until resolution or 
determination, in the clinical judgment of the investigator, that no further improvement is expected.  Subjects discontinuing treatment for reasons other than progression of 
disease will continue to perform tumor assessments every 6 weeks ±1 week [if applicable, bone scan (or bone MRI if preferred by investigator) to be performed every 
18 weeks ±1 week] until PD documented by ICR, regardless of subsequent anti-cancer treatments. 
28. Survival Follow-Up: After discontinuation of study treatment, information on post-study survival status and subsequent systemic anti-cancer treatment (including 
administration dates, reason for treatment discontinuation and date of progression, if applicable) will be collected every 4 months up to 3 years, then every 6 months until 
death, or subject withdrawal of consent or study closure (as defined in the SAP), whichever occurs first (telephone contact is acceptable for subjects refusing/unable to go 
back to the site).  


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Lorlatinib (PF-06463922) is an anaplastic lymphoma kinase (ALK) and c-ROS oncogene-1
(ROS1) receptor tyrosine kinase inhibitor that is currently being investigated in patients 
previously treated with ALK inhibitors advanced ALK-positive non-small cell lung cancer 
(NSCLC).
The mechanism of action of lorlatinib is described in Section 1.2.3.
1.2. Background and Rationale
1.2.1. NSCLC
Lung cancer has been the most common cancer in the world for several decades, and by 2008, 
there were an estimated 1.61 million new cases, representing 12.7% of all new cancers.  It 
was also the most common cause of death from cancer, with 1.38 million deaths (18.2% of
the total).  Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung
cancer.1 And only 18% of all patients with lung cancer are alive 5 years or more after 
diagnosis.2  In China, lung cancer is also the most common cancer (0.73 million new cases) 
and the leading causes of cancer death (0.61 million) according to report in 2015.3
In NSCLC patients, there is a clinically relevant molecular subset is driven by oncogenic 
fusion gene EML4-ALK that combine portions of the echinoderm microtubule-associated 
protein-like 4 (EML4) gene and anaplastic lymphoma kinase (ALK) gene, which was 
discovered in 2007.4,5
The first approved tyrosine kinase inhibitor (TKI) for ALK-positive NSCLS was crizotinib, 
which has been accepted as standard of care (SOC) for ALK-positive NSCLC patients 
worldwide.  Although most patients with ALK-positive NSCLC derive substantial clinical 
benefit from crizotinib, some ALK-positive NSCLC patients will not derive any benefit 
(intrinsic resistance), while other patients who initially derive benefit will develop resistance 
(acquired resistance).  In the case of crizotinib-resistant ALK-positive NSCLC, the rate of 
resistance due to mutations in the ALK kinase domain is typically reported in the range of 
35-40%.6
1.2.2. ALK Alternation and Resistance Mechanism in NSCLC
Since the discovery of ALK-EML-4 fusion gene within chromosome 2p, a subsequent series 
of studies have described 9 fusion variants of EML4-ALK plus additional but less common 
fusion partners with ALK.7  Currently, there are at least 27 different ALK fusion variants 
reported in the literature, while the majority of the isoforms involve EML4-ALK fusion gene, 
which is reported to be 3%-5% in all NSCLC patients, who tend to be young (average age 
50 years at diagnosis), and light or never smokers.8 In China, the proportion of EML4-ALK 
fusion in NSCLC is found to be 5.6% which is similar to that of western patient population.9


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Oncogenic fusions of ALK and ROS1 define 2 distinct subsets of human lung
adenocarcinomas4,10 and play essential roles in regulation of tumor cell survival, growth, and
metastasis.  Targeting ALK or ROS1 in these cancers provides a novel opportunity to
selectively target cancer cells bearing ALK or ROS1 fusions that are implicated as causative
oncogenic driver events in these patients’ tumors.11,12
Crizotinib, as the first-generation selective adenosine triphosphate (ATP)-competitive 
small-molecule inhibitor of ALK, ROS1,c-MET receptor tyrosine kinase and their oncogenic
variants, demonstrated significant clinical benefit in ALK and ROS1 fusion-positive lung 
cancers.11,12  This clinical benefit led to the approval of the US approval in August 2011 of 
Xalkori(crizotinib) in advanced ALK-positive NSCLC patients.  And subsequently, 
Xalkoriwas approved in European Union (EU) and Japan.  In 2013, Xalkorireceived 
approval by China Food and Drug Administration (CFDA) in treatment of ALK-positive 
advanced NSCLC in China. 
Although most patients with ALK-positive NSCLC derive substantial clinical benefit from
crizotinib, some ALK-positive NSCLC patients will not derive any benefit (intrinsic 
resistance) while other patients who initially derived benefit may later develop resistance 
(acquired resistance).  Acquired ALK kinase domain mutation and brain metastasis are the 
two major mechanism of refractory or resistance to crizotinib treatment13,14,15 for this group.
The resistance to ALK inhibitors appears much more complex as a greater variety of
mutations are found in patients along with the activation of bypass resistance
mechanisms.16,17  To date, multiple types of ALK kinase domain mutations have been
identified in crizotinib refractory patients including ALKG1269A, ALKL1196M, ALKC1156Y,
ALKL1152R, ALKF1174L, ALK G1202R, ALKS1206Y, ALK1151Tins and ALK gene
amplification,16,18,19 and account for about one third of resistant samples tested.  Among these 
ALK mutations, ALKG1202R conferred high-level resistance to almost all of the ALK 
inhibitors tested.16,18,19 In the case of crizotinib resistant ALK-positive NSCLC patients, the 
rate of resistance due to mutations in the ALK kinase domain is typically reported in the 
range of 35-40%.16  While other mechanisms of resistance (independent of ALK mutation) 
are active, the tumor cell may still remain dependent upon ALK signaling.  It was also 
reported that the brain was the most common single site of disease progression
(>30%) following initial crizotinib treatment.14,15  It is unknown if this is due to the 
formation of resistance mutations or the intact blood brain barrier (BBB) creates a sanctuary 
site preventing the passage of crizotinib.  Finally another roughly 5% of patients acquire 
resistance through amplification of the EML4-ALK fusion gene.16
To fulfill this treatment need in ALK-positive advanced NSCLC patients, second-generation 
of ALK inhibitors have been developed and showed treatment activity. 
Ceritinib (Zykadia) is the first second-generation ALK inhibitor to show clinical activity.20  
Results from a global Phase 1 study led to the drug’s accelerated approval for the treatment 
of NSCLC patients who progressed or were intolerant to crizotinib in US and Europe, based 
on tumor response and duration of response.  Subsequently, in global Phase 3 studies, 
Ceritinib showed superior efficacy compared to chemotherapy in both treatment naïve and 


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crizotinib refractory advanced ALK-positive NSCLC patients, and gain approval in all 
ALK-positive metastatic NSCLC patients in 2017.21,22
Alectinib (Alecensa) is a selective ATP-competitive ALK inhibitor, and has showed clinical 
activity in patients previously treated with crizotinib, including those with CNS metastasis.  
In this study, among 35 patients with baseline measurable CNS lesion, the CNS ORR was 
57%.23 Basing on this result, alectinib received accelerated approval by FDA in the US in 
2015.  In further, in a Phase 3 study of alectinib compared to crizotinib in treatment-naïve
advanced NSCLC, alectinib show superior efficacy, with a significantly longer PFS,24 which 
lead to approval of alectinib for treatment-naïve ALK-positive advanced NSCLC.
While ceritinib and alectinib are both approved for ALK-positive advanced NSCLC patients, 
the resistance to both of these inhibitors has also emerged.  In the case of ceritinib, relapsed 
tumors often express the ALK mutant G1202R.25  In the case of alectinib, in addition to 
G1202R, two ALK resistance mutations (V1180L and I1171T) have been observed.25  Some 
ALK mutants such as G1202R confer high-level resistance to all clinically available ALK 
inhibitors.  Both ceritinib and alectinib have demonstrated activity in brain metastases of 
crizotinib-relapsed patients.  A Phase 1/2 clinical trial of alectinib showed a CNS response 
rate of 52%. Despite the observed CNS activity with these agents, it remains common for 
patients to relapse with CNS progression.25
Currently in China, there are several ALK inhibitors being developed in different stages in 
both treatment-naïve and crizotinib-resistant ALK-positive advanced NSCLC settings, such 
as alectinib (NCT02838420), ceritinib (NCT02040870), ensartinib (NCT02959619), X-396 
(NCT03215693), PLB1003 (NCT03130881), CT-707 (NCT02695550) etc. Xalkori®
(crizotinib) and ALECENSA® (alectinib) are the SOC for ALK-positive advanced NSCLC
patients. For the patients previously treated with Xalkori® (crizotinib), the SOC are 
ALECENSA® (alectinib) and ZYKADIATM (ceritinib) from 2018 in China.
1.2.3. Lorlatinib (PF-06463922)
The lorlatinib program was initiated with the aim to develop a next-generation ALK inhibitor
that is more potent than crizotinib, capable of inhibiting the catalytic activity of ALK
resistant mutants, and able to cross the blood-brain barrier.25
Lorlatinib is a potent and selective, macrocyclic, ATP competitive small molecule inhibitor
of ALK and ROS1 receptor tyrosine kinases.  It is orally available, brain penetrating, and
able to inhibit all clinically reported ALK kinase domain mutations responsible for resistance
to crizotinib.27 Lorlatinib was granted breakthrough therapy designation and priority review 
by FDA, and was approved by FDA in in November 2018. Lorlatinib was also approved by 
Japan and European Union in September 2018 and in May 2019, respectively.
This drug is currently in clinical development and is being investigated for the treatment of
ALK-positive or ROS1-positive advanced NSCLC.  Lorlatinib has so far had substantial
efficacy results which are described in more detail in Section 1.2.3.4.


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Additional information for this compound may be found in the single reference safety
document (SRSD), which for this study is the lorlatinib Investigator's Brochure (IB).
1.2.3.1. Preclinical Data
Lorlatinib has been studied in a variety of in vitro and in vivo model systems to determine
potency for inhibition of ALK or ROS1 tyrosine kinase activity, kinase selectivity, antitumor
efficacy, pharmacokinetic (PK)/pharmacodynamic relationships, and mechanism of action.
In vitro, lorlatinib demonstrated potent, concentration-dependent inhibition of catalytic
activities of ALK, ALK mutants, and ROS1 kinases in recombinant enzyme and cell-base
assays.  Lorlatinib also inhibited ALK and ROS1 dependent oncogenic functions in human 
NSCLC cell lines, and demonstrated potent and selective growth inhibitory activity and 
induced apoptosis in tumor cell lines exhibiting either non-mutant ALK and ROS1 fusion 
variants or mutant ALK fusions that are resistant to crizotinib treatment.
In vivo, lorlatinib demonstrated marked cytoreductive activity in mice bearing tumor
xenografts that express ALK or ROS1 fusion variants, including the crizotinib-resistant
EML4-ALKL1196M or EML4-ALKG1269A mutations.  Lorlatinib treatment significantly
reduced tumor size and prolonged animal survival in the orthotopic brain models 
(EML4- ALK and EML4-ALKL1196M) in mice.  The antitumor efficacy of lorlatinib was 
dose dependent and demonstrated a strong correlation to inhibition of ALK or ROS1
phosphorylation.
Detailed information on PK/pharmacodynamics modeling, ADME (Absorption, Distribution, 
Metabolism and Elimination), and cytochromes P450 (CYP) enzymes inhibition can be 
found in Section 1.2.3.3 and the lorlatinib IB.
As described in the lorlatinib IB, the nonclinical safety profile of lorlatinib has been
adequately characterized to support continued clinical trials in advanced cancer indications.
1.2.3.2. Teratogenicity
Preliminary developmental toxicity studies using lorlatinib have been completed in rats and
rabbits.  Embryonic and fetal toxicity (including embryo lethality, fewer and smaller viable
fetuses with some external and visceral malformations) was observed in both species at all
doses, where the low dose was projected to yield similar exposure as the RP2D of 100 mg
once daily.  Based on the study results, lorlatinib induces embryonic and fetal toxicity in
animals, and the current safety measures in the clinical development program for lorlatinib to
prevent pregnancy should remain in place.
Additional information may be found in the IB.


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1.2.3.3. Pharmacology
1.2.3.3.1. Metabolism
Lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways.  
Oxidative metabolism of lorlatinib is primarily mediated by CYP3A4 with minor 
contributions from CYP2C19, CYP2C8, and CYP3A5.  Glucuronidation of lorlatinib is 
mediated primarily by uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4, with minor 
contribution from UGT1A3.
1.2.3.3.2. Clinical Drug-Drug Interaction
In vitro, lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A4/5 and 
activates the human pregnane X receptor (hPXR), with a net induction effect on CYP3A4/5
in vivo.  Coadministration of lorlatinib and midazolam (MDZ) in patients resulted in 
decreased mean oral MDZ (a CYP3A4 substrate) AUC and Cmax after 25 mg and 150 mg QD 
lorlatinib dosing, compared with those for MDZ alone.  Coadministration of lorlatinib with
CYP3A4/5 substrates with narrow therapeutic indices should be avoided.
Coadministration of 200 mg daily doses of itraconazole (a strong CYP3A4/5 inhibitor) with a 
single 100 mg of lorlatinib increased lorlatinib AUCinf by 42% and Cmax by 24%.  An 
alternative concomitant medicinal product with less potential to inhibit CYP3A4 should be 
considered.  If a strong CYP3A4/5 inhibitor must be coadministered, a dose reduction of 
lorlatinib from the starting dose of 100 mg QD to 75 mg QD is recommended.
Coadministration of 600 mg daily doses of rifampin (a strong CYP3A4/5 inducer) with a
single 100 mg dose of lorlatinib decreased lorlatinib AUCinf by 85% and Cmax by 76%.  
Concomitant administration of lorlatinib and rifampin led to elevated AST and ALT levels in 
all subjects.  Use of strong CYP3A4/5 inducers with lorlatinib is contraindicated.  Avoid 
concomitant use with moderate CYP3A4/5 inducers if possible, as they may also reduce 
lorlatinib plasma concentrations.
1.2.3.3.3. Exposure-Response Relationship
No exposure response (E-R) relationship was observed between lorlatinib plasma exposure 
and efficacy endpoints (objective response rate [ORR], intracranial objective response rate 
[IC-ORR]) in patients who received 1 or 2 prior ALK inhibitors.
A statistically significant E-R relationship of safety was observed for Grade 3 
HYPERCHOLESTEROLEMIA and any Grade 3 treatment-emergent all-causality adverse 
events (AEs), with higher probability of the occurrence of these events with increasing 
lorlatinib plasma exposure.
An itraconazole drug interaction study (Study B7461012) was conducted as an alternative to 
a thorough QT (TQT) study.  E-R analyses for Holter Monitoring data from this study 
indicate that there was no relationship between lorlatinib plasma concentration and the RR
interval and no evidence of Corrected QT Interval (QTc) prolongation associated with 
lorlatinib plasma concentrations.  Increase in lorlatinib plasma concentrations was associated 


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with prolongation of the PR interval, however, the probability of PR interval 200 msec at
the clinical dose of 100 mg QD was predicted to be low.
1.2.3.4. Clinical Data
Study B7461001 is a Phase 1/2, dose-escalation, safety, PK, pharmacodynamics, and 
anticancer efficacy exploration study of lorlatinib as a single-agent in patients with advanced 
ALK-positive and advanced ROS1 positive NSCLC.  This clinical study consists of 2 parts: 
both parts - Phase 1 and Phase 2 portion - have completed the enrollment (329 patients have 
been enrolled, 54 in the Phase 1 portion and 275 in the Phase 2). The Phase 1 portion of the 
study was designed to estimate the MTD for lorlatinib as a single-agent with advanced 
ALK-positive or advanced ROS1-positive NSCLC with or without asymptomatic CNS 
metastases, and to determine recommended Phase 2 dose (RP2D).  Enrollment in the Phase 1 
part of the study was completed and 54 patients were treated.  The Phase 2 portion of the 
study was designed to evaluate the anti-cancer activity of single-agent lorlatinib administered 
at the dose of 100 mg QD in different cohorts of patients with advanced ALK-positive or 
with advanced ROS1-positive NSCLC.  Enrollment in the Phase 2 part of the study was 
completed and 275 patients were treated.  Additionally, to evaluate the safety and tolerability 
of lorlatinib in Japanese patients, lead-in cohort (LIC) was to evaluate lorlatinib safety and 
PK in patients treated at a previously tested dose in Phase 1.
As of the data cutoff date of 15 September 2017, lorlatinib has been administered to a total of 
54 patients in Phase 1 across 7 QD doses of 10, 25, 50, 75, 100, 150, and 200 mg and 
3 twice-a-day (BID) doses of 35, 75, and 100 mg; and to 275 patients in Phase 2 at 
100 mg QD, and to 3 patients at 100 mg in the Japan LIC.
Note, the leading designation included in a Pfizer sponsored lorlatinib study protocol number 
(ie, “B746”) will be omitted in the text (but not in tables or figures) for simplicity.  For 
example, study protocol number B7461001 will be referred to in the text as Study 1001.
Maximum Tolerated Dose (MTD) Determination
The Phase 1 portion of the study was designed to estimate the maximum tolerated dose
(MTD) for lorlatinib as a single agent in patients with advanced ALK-positive or advanced
ROS1-positive NSCLC with or without asymptomatic CNS metastases.  As part of this study, 
the food effect was also tested in a limited subset of patients, as well as the midazolam (MDZ) 
drug-drug interaction (DDI), given at the steady-state of lorlatinib, to evaluate the effect of
lorlatinib on CYP3A inhibition/induction.
The MTD estimate was defined as the highest dose level associated with 33% of patients
experiencing a dose-limiting toxicity (DLT).  Due to the discreteness of the dose levels and
in the interest of patient safety, the estimated MTD was defined as the highest dose level with
a DLT rate <0.33.  The primary endpoint of first-cycle DLTs was defined with pre-specified
severity based upon predicted target organ toxicity in hematologic and non-hematologic
system organ classes.  Additionally, the inability to obtain sufficient drug administration due
to treatment-related toxicities (but not of DLT severity) was also considered a DLT.


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One (1) DLT was reported in a Phase 1 patient enrolled at the 200 mg QD dose level who
received <16 out of 21 planned doses in Cycle 1 due to toxicities attributed to lorlatinib,
which met the protocol definition of a DLT.  This patient experienced Grade 1 and Grade 2
CNS effects during Cycle 1, including Grade 2 aphasia and cognitive disorder, and Grade 1
visual impairment and abnormal dreams.  As a result, lorlatinib was temporarily discontinued 
and the patient did not receive at least 16 of the planned 21 doses in Cycle 1.
Although the continual reassessment method (CRM) model used in Phase 1 recommended 
dose escalation above 200 mg QD, the CNS effects observed at this dose and at the 
150 mg QD dose were considered intolerable to some patients and the majority had 
treatment-related AEs resulting in dose interruption and/or dose reduction.  As a result, it was 
agreed upon by the sponsor and the Phase 1 investigators to evaluate doses lower than 
200 mg QD and consider an alternative dosing regimen.  BID dosing was evaluated to 
potentially modulate these AEs, but the patients did not tolerate the 75 mg or 100 mg BID 
dosing.
Overall, 100 mg QD was a well-tolerated dose in Phase 1.  Additionally, based on the PK
data observed in Phase 1, simulated patient exposure suggested that the 100 mg QD dose was
the lowest dose that would exceed the lorlatinib minimum effective concentration (Ceff) of 
150 ng/mL, to inhibit ALK G1202, during the majority of the 24-hour dosing interval, once 
steady-state was reached.
Therefore, while the MTD was not formally identified, 100 mg QD was chosen as the RP2D
based on the entirety of the safety, efficacy, and clinical pharmacology data.
Safety
Lorlatinib was generally tolerable and, when needed, AEs were manageable through dosing
interruption, dose reduction, and/or standard supportive medical therapy.
As of the data cutoff date of 15 September 2017, there were 295 patients in the safety 
analysis data set received lorlatinib treatment at 100 mg dose, with 143 patients still in 
treatment.  There were also 37 patients in Phase 1 portion received lorlatinib at doses other 
than the RP2D of 100 mg QD.
The 100-mg Pooled Group of study 1001 includes all patients who received lorlatinib 
100 mg QD (RP2D).  This group consisted of 17 patients from the Phase 1 portion, 
275 patients from the Phase 2 portion, and 3 patients from the Japan Lead-in Cohort (LIC).  
In total, this group consisted of 295 patients.
In the 100-mg pooled group of study 1001, the most frequent (>20%) treatment-related AEs 
were hypercholesterolemia (83.7%), hypertriglyceridemia (65.8%), edema (44.4%), 
peripheral neuropathy (33.6%), cognitive effects (21.7%) and weight increased (20.7%).  
Grade 3 and Grade 4 treatment-related AEs were reported in 115 (39.0%) and 18 (6.1%)
patients, respectively.  The most frequently reported (>10%) treatment-related Grade 3 AEs 
were hypercholesterolemia (14.6%) and hypertriglyceridemia (13.9%).  The most frequently 
reported (>2%) treatment-related Grade 4 AE was hypertriglyceridemia (2.4%).  


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Twenty-three (23) (7.8%) patients had treatment-related Serious Adverse Events (SAEs).  
The most frequent (>1 patient) treatment-related SAE was cognitive effects (3 patients, 
1.0%).  Grade 3 treatment-related SAEs were reported in 4.4% patients and Grade 4 
treatment-related SAEs were reported in 1.4% of patients.
Lorlatinib toxicity was generally manageable through temporary discontinuations of dosing
with or without dose reduction, as permanent discontinuation due to an AE was not
commonly reported in the 100-mg pooled group of Study 1001 (7.8%).  Temporary
discontinuations of dose, dose reductions, and/or standard medical therapy allowed most
patients treated with lorlatinib to remain in the study and continue receiving treatment.  
Altogether, 22.7% of patients had AEs associated with dose reductions, 31.9% had AEs 
associated with temporary discontinuations of dose, and 2.7% of patients discontinued 
lorlatinib in association with treatment-related AEs, in the 100-mg pooled group of 
Study 1001.
CNS effects could be categorized into 3 different categories including cognitive effects, 
mood effects and speech effects, which have been reported separately.  The treatment related 
including cognitive effects, mood effects and speech effects have been observed in 21.7%, 
15.3%, 8.1% patients in the 100-mg pooled group of Study 1001.  The most common 
treatment related AEs in each category are memory impairment and irritability, slow speech, 
each occurring in 9.5%, 5.8% and 3.4% patients. 
The CNS effects reported in both Phase 1 and Phase 2 portions have been generally 
considered mild (Grade 1 and Grade 2) in severity and transient, and improved upon dose 
delay and/or dose reduction.  No Grade 4 or 5 CNS effects have been reported in the Phase 1 
or Phase 2 portions. A more detailed evaluation of CNS effects is ongoing in the Phase 2 
portion by routine assessment of cognition, mood, and suicidality through a computerized 
test (using laptops provided by Cogstate).  Based on the preliminary results observed, the
assessments in this Phase 2 study will be limited to mood and suicidality.
Changes in QTc and PR prolongation have also been observed in the study.  QT interval 
prolongation was reported as treatment related AE in 5.4% patients in the 100-mg pooled 
group of Study 1001.  And no Grade 3, Grade 4, Grade 5 treatment related AE have been 
reported.  There were no atrioventricular block events in Phase 1, Grade 1 atrioventricular 
block was reported in 2 patients in Phase 2 as treatment related AE.  No Grade 2 and above 
treatment related atrioventricular block have been reported.  Basing on the preliminary
evidence, the assessment of ECG and heart function will be conducted in this Phase 2 study. 
In the 100-mg pooled group of Study 1001, 11.3% patients had a maximum decrease from 
baseline in LVEF 20%.  The mechanism for the LVEF decreases is currently unclear, and it 
will need be further explored.  Thus, the decrease of LVEF will also be evaluated in this 
study.


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Peripheral neuropathy, mood disorders, cognitive disorders, speech disorders, vision 
disorders, diarrhoea, constipation, arthralgia, oedema, fatigue, weight increased are identified 
risks associated with lorlatinib administration, for which dose delay and/or dose reduction 
have been effective.
For complete details of the nonclinical/clinical studies, refer to lorlatinib current 
investigator’s brochure
Efficacy
As of the data cutoff date of 15 March 2017, among the 53 patients who were evaluable for 
efficacy in Phase 1 as of the data cutoff date, the independently assessed objective response 
rate (ORR) was 41.5% (95% CI: 28.1, 55.9) and included 1 (1.9%) confirmed complete 
responses (CR) and 21 (39.6%) confirmed partial responses (PR).  Eleven (11 [20.8%]) 
patients had stable disease (SD) as their best overall response.
Forty-two (42) Phase 1 patients had CNS metastases at study entry.  Of the 42 patients
evaluable for intracranial response at the time of the data cutoff, 13 (31.0%) patients had an
independently confirmed CR and 5 (11.9%) patients had a confirmed PR, resulting in an
intracranial ORR of 42.9% (95% CI: 27.7, 59.0).  Further, 8 (19.0%) patients had SD as their 
best overall response.
Among the 274 patients who were evaluable for efficacy in Phase 2 as of the data cutoff date,
the independently assessed ORR was 50% (95% CI: 43.9, 56.1) and included 7 (2.6%) 
confirmed CRs and 130 (47.4%) confirmed PRs.  Eighty-two (82 [29.9%]) patients had 
stable disease (SD) as their best overall response.
One hundred and sixty-five (165) Phase 2 patients had CNS metastases at study entry.  Of the
165 patients evaluable for intracranial response at the time of the data cutoff, 48 (29.1%)
patients had an independently confirmed CR and 42 (25.5%) patients had a confirmed PR,
resulting in an intra-cranial ORR of 54.5% (95% CI: 46.6, 62.3).  Further, 49 (29.7%) 
patients had SD as their best overall response.
Overall Results
Basing on the data from study B7461001, 100 mg QD dose of lorlatinib monotherapy, was 
chosen as the RP2D, based on the entirety of the safety, efficacy, and clinical pharmacology 
data.  Lorlatinib conferred a clinically meaningful benefit in patients with advanced
ALK-positive NSCLC across a range of treatment with prior ALK inhibitors and/or 
chemotherapies, including in treatment settings such as crizotinib treated or 
second-generation of ALK inhibitor treated disease.  Lorlatinib was generally tolerable, as 
AEs were primarily mild to moderate in severity, and manageable as rates of permanent 
discontinuations due to AEs were low and could be managed by dosing interruption, dose 
reduction, and/or standard supportive medical therapy.


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Basing on the result from B7461001 study, FDA granted a breakthrough therapy designation 
to lorlatinib for patients with ALK-positive metastatic NSCLC who have previously received 
1 or more ALK inhibitors in 2016, as well as a priority review to a new drug application 
(NDA) for lorlatinib in the same indication.
1.2.4. Study Rationale
Since 2013, after receiving approval by China Food and Drug Administration (CFDA) in 
treatment of ALK-positive advanced NSCLC in China, Xalkorihas become the standard of 
care for ALK-positive advanced NSCLC patients.  Consequently, the treatment resistance to 
crizotinib becomes common in these patients.  Acquired ALK kinase domain mutation and 
brain metastasis are the two major mechanism of refractory or resistance to crizotinib 
treatment.13,14,15
To fulfill this treatment need in ALK-positive advanced NSCLC patients, second-generation 
of ALK inhibitors have been developed and showed treatment activity.  In the near future, 
the second generation ALK inhibitors will be increasingly used in both crizotinib resistant 
and treatment naïve patients, and eventually, the resistance to 2nd gen ALK inhibitor will be 
more and more common.
The resistance to ALK inhibitors appears much more complex as a greater variety of
mutations are found in crizotinib resistant patients.  And in ceritinib or alectinib resistant
patients, ALK mutation G1202R, V1180L and I1171T have all been observed.
Lorlatinib is a selective, brain-penetrant ALK TKI with potent activity against ALK and
ROS1 fusions, including those harboring resistance mutations.  Lorlatinib has demonstrated
clinically meaningful anti-tumor activity in patients with brain metastases after treatment
with ALK inhibitors including crizotinib.27 Further, lorlatinib appears to be the only ALK
TKI active against certain mutations that are the most difficult to inhibit after 
second-generation ALK inhibitor resistance, such as the G1202R mutation.25
Lorlatinib has the potential to improve anti-tumor activity in ALK inhibitor resistance and 
refractory ALK-positive advanced NSCLC, based on its greater potency against ALK and its 
broad coverage against all known single point mutations that mediate resistance to crizotinib 
and second generation ALK inhibitors,25 and able to cross the blood brain barrier.  This study 
will evaluate the antitumor activities of lorlatinib in ALK inhibitor treated patients, which 
include both crizotinib treated and ALK inhibitors other than crizotinib treated patients.
1.2.5. Rationale for Starting Dosing Regimens
Lorlatinib starting dosing regimen will be 100 mg QD which was chosen as the RP2D based 
on the entirety of the safety, efficacy, and clinical pharmacology data available in B7461001 
study.
Additional information may be found in IB.


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
2. S T U D Y O B J E C TI V E S A N D E N D P OI N T S
Pri m ar y O bjecti ve(s):
Pri m ar y E n d p oi nt(s):

T o e val uate t he a nti -t um or effect of l orlat i ni b as a 
si n gle a ge nt as meas ure d b y O R R per R E CI S T v 1. 1 i n 
l ocall y a d va nce d or metastatic A L K- p ositi ve N S C L C
patie nt s w h ose disease has pr o gresse d after criz oti ni b 
treat me nt.

O bjecti ve Res p o nse ( O R) i n patie nts w h ose disease 
h a s pr o gr esse d after criz oti n i b ( C o h ort 1) b y 
i n de pe n de nt ce ntral ra di ol o g y (I C R) assess me nt per 
R E CI S T v 1. 1 ( A p pe n di x 3 ).
Sec o n d ar y O bjecti ve(s):
Sec o n d ar y E n d p oi nt(s):

T o e val uate t he a nti -t u m or effect of l orlati ni b as a 
si n gle a ge nt as meas ure d b y O R R per R E CI S T v 1. 1 i n 
l ocall y a d va nce d or metastatic A L K- p ositi ve N S C L C 
patie nts w h ose disease h as pr o gresse d after A L K 
i n hi bit or treat me nt ot her t ha n criz oti ni b .

O R i n patie nts w h ose disease ha s pr o gress after A L K 
i n hi bitor treat me nt ot her t ha n criz oti ni b ( C o h ort 2) as 
assesse d b y R E CI S T v 1. 1 per I C R assess me nt.

T o e val uate t he P F S a n d O S i n l ocally a d va nc e d or 
metastatic A L K -p ositi ve N S C L C patie nts w h ose 
disease has pr o gresse d after criz oti ni b a n d ot her A L K 
i n hi bit or treat me n t, res pecti vel y.

Pr o gressi o n-free s ur vi val ( P F S ) as assesse d b y 
R E CI S T v 1. 1 per I C R assess me nt a n d i n vesti gat or 
assess me nt a n d O veral l s ur vi val ( O S) i n b ot h 
C o h orts .

T o e val uate ot her a ntit u m or acti vit ies i n l ocall y 
a d va nce d or metastatic A L K-p ositi ve N S C L C patie nts 
w h o se disease has pr o gresse d after criz oti ni b a n d 
ot her A L K i n hi bit or treat me nt, res pecti vel y.

I ntracra nial o bje cti ve res p o nse (I C-O R) , D urati o n of 
res p o nse (D o R ), D urati o n of i ntracra nial res p o nse 
(I C-D o R ), Ti me t o t u m or res p o nse ( T T R) as assesse d 
b y R E CI S T v 1. 1 per I C R assess me nt a n d i n vesti gat or 
assess me nt i n b ot h C o h orts.

T o e val uate t he safet y a n d t olera bilit y of l orl ati ni b 
treat me nt i n l ocall y a d va nce d or metastatic A L K + 
N S C L C patie nts w h ose disease has pr o gresse d after 
criz oti ni b an d ot her A L K i n hi bit o r treat me nt.

Safet y: A E; la b orat or y a b n or malities; E C G, L V E F,
C N S effects .

T o e val uate t he p har mac o ki netics ( PK) of l orlati ni b 
a n d p ote ntial p har mac o ki netic ( P K)
/ p har mac o d y na mics relati o ns hi p f or l orlati ni b if
a p pr o priate.

P K : para meters o n Da y 1 of C ycl e 1 a n d at stea d y 
state: C ma x, Tma x , A U Ct, A U Ct a u at stea d y state, 
A U C i nf, C L/ F, Vz/ F , t1/ 2 a n d R ac as data per mit.
 
 
 
 
 
 
 
3. S T U D Y D E SI G N
T his is a P ha se 2, C hi na o nl y , m ulti -ce nter (at a p pr o xi matel y 3 0 sites), o pe n-la bel, 
d ual -c o h ort st u d y, i n w hic h ap pr o xi ma tel y 1 0 0 A L K -p ositi ve l ocall y  a d va nce d or metastatic 
N S C L C patie nts will be e nr olle d t o recei ve l orlati ni b m o n ot hera p y acc or di n g t o t he st u d y 
desi g n s h o w n i n Fi g ure 1 .  The patie nt s s h o ul d ha ve (als o see Secti o n 4. 1 ).
C CI


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
(in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor.  
Approximately 66 patients will be enrolled to this cohort.

(in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib.  
Approximately 34 patients will be enrolled to this cohort.
Figure 1.
Study B7461024 Design
A cycle duration will be 3 weeks (21 days) and will always be considered 3 weeks
irrespective of any dose delays/dosing interruptions or missed doses which may affect
nominal days of each cycle.
Study treatment may continue until confirmed disease progression assessed by ICR, subject
refusal, subject lost to follow-up, unacceptable toxicity, or the study is terminated by the
sponsor, whichever comes first (see Section 6.4 Subject Withdrawal).
Subjects who develop radiological disease progression confirmed by ICR assessment but are 
otherwise continuing to derive clinical benefit from study treatment will be eligible to
continue with the treatment they have been assigned to, provided that the treating physician
has determined that the benefit/risk for doing so is favorable.  See Section 7.2 for details on
expedited ICR assessment of disease progression.
Details of the study treatment forms and packaging and recommendations for dose
modifications are included in the Study Treatment Section 5 of the protocol.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol. 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 


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4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced 
or metastatic ALK-positive NSCLC where ALK status has been previously 
established by the Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis 
ALK Break Apart FISH Probe Kit (Abbott Molecular), or the EML4-ALK Fusion 
Gene Detection Kit (AmoyDx).
2. Subject should have:
a.
(in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;
b. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, 
with or without prior crizotinib.
3. Prior treatment with an ALK inhibitor must have completed 5 half-lives prior to 
study entry.
4. All Subjects must have at least 1 measurable extracranial target lesion according to 
RECIST v1.1 that has not been previously irradiated.  CNS metastases are allowed if:
a.
Asymptomatic: either not currently requiring corticosteroid treatment, or on a 
stable or decreasing dose of 10 mg QD prednisone or equivalent; or
b. Previously diagnosed and treatment has been completed with full recovery from 
the acute effects of radiation therapy or surgery prior to enrollment, and if 
corticosteroid treatment for these metastases has been withdrawn for at least 
4 weeks with neurological stability. 
5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2. 
6. Age 18 years (or 20 years as required by local regulation).
7. Adequate bone marrow functions:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL.


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8. Adequate pancreatic function:
a.
Serum total amylase 1.5 x upper limit of normal (ULN);*
b. Serum lipase 1.5 x ULN.
*if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then subject 
may be enrolled.
9. Adequate renal function:
a.
Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as 
calculated using the method standard for the institution.
10. Adequate liver function:
a.
Total serum bilirubin 1.5 x ULN; 
b. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 
2.5 x ULN (5.0 x ULN in case of liver metastases).
11. Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or 
to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 except for AEs that in the investigator’s judgment do not
constitute a safety risk for the subject.
12. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.  Female subjects of non-childbearing potential must meet at least 1 of the 
following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or
physiological cause (which may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state if appropriate;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
13. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.


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14. Willing and able to comply with the study scheduled visits, treatment plans, 
laboratory tests, and other procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic
setting.
If disease recurred/relapsed within the adjuvant chemotherapy treatment or 6 
months after the completion of the adjuvant chemotherapy, then the adjuvant 
chemotherapy is considered as the first line systemic chemotherapy to the disease.
2. Systemic anti-cancer therapy completed within a minimum of 5 half-lives of study 
enrollment.
3. Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or 
immune checkpoint pathways, including, but not limited to, anti-programmed cell 
death protein 1 (anti-PD-1), anti- programmed cell death protein ligand 
1 (anti-PD-L1), anti-PD-L2, anti-cluster of differentiation 137 (anti-CD137), or 
anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
4. Known epidermal growth factor receptor (EGFR) activating mutations; known prior 
therapy with EGFR TKI(s) (the prior treatment with brigatinib is allowed as an ALK 
TKI). 
5. 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.
6. Radiation therapy within 2 weeks prior to enrollment.  Palliative radiation must have 
been completed at least 48 hours prior to enrollment.  Stereotactic or partial brain 
irradiation must have completed at least 2 weeks prior to enrollment.  Whole brain 
irradiation must have completed at least 4 weeks prior to enrollment.
7. Spinal cord compression unless the subject has good pain control attained through 
therapy, and there is complete recovery of neurological function for the 4 weeks prior 
to enrollment.
8. 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.


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9. Known prior or suspected severe hypersensitivity to lorlatinib or any component in 
the formulation; known prior therapy with lorlatinib.
10. Active and clinically significant bacterial, fungal, or viral infection including 
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
11. Clinically significant cardiovascular disease (both arterial and venous) and 
non-vascular cardiac conditions, (active or within 3 months prior to enrollment, 
which may include, but not are limited to: 

Arterial disease such as cerebral vascular accident/stroke (including transient 
ischemic attack -TIA), myocardial infarction, unstable angina;

Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary 
embolism;

Nonvascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥II), second- degree or third-degree 
atrioventricular block (unless paced) or any AV block with PR interval
>220 msec; or

Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial 
fibrillation of any grade, bradycardia defined as <50 bpm (unless subject is 
otherwise healthy such as long-distance runners, etc.), machine-read 
electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome.
12. Subject with predisposing characteristics for acute pancreatitis according to 
investigator judgment, including but not limited to uncontrolled hyperglycemia, 
current gallstone disease, in the last month prior to enrollment. 
13. 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. 
14. Evidence of active malignancy (other than NSCLC, non-melanoma skin cancer, or 
localized and presumed cured prostate cancer or any in situ cancer which does not 
currently require treatment) within the last 3 years prior to enrollment. 
15. 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 administration of lorlatinib: 


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a.
Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or 
grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], 
boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, 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). The topical use of these medications 
(if applicable), such as 2% ketoconazole cream, is allowed;
b. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, 
terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, 
alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, 
dihydroergotamine) (*withdrawn from US market);
c.
Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort);
d. Known P-glycoprotein (P-gp) substrates with a narrow therapeutic index 
(eg, digoxin). 
16. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator and/or the sponsor, would make 
the subject inappropriate for entry into this study.
17. Subject who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members, 
directly involved in the conduct of the study.
18. Participation in other studies involving investigational drug(s) within 2 weeks prior to 
study entry and/or during study participation.
19. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects 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 
investigational product.
4.3. Lifestyle Requirements
4.3.1. Contraception
Lorlatinib is 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 these study drugs is mandatory.


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The investigator or his or her designee, in consultation with the participant, will confirm that 
the patient has selected a highly effective method of contraception for the individual patient 
and his or her partner(s) from the permitted list of contraception methods (see below) and 
will confirm that the participant has been instructed in its consistent and correct use. At time 
points indicated in the schedule of activities, the investigator or designee will inform the 
patient 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 patient’s 
chart (patients need to affirm their consistent and correct use of at least one of the appropriate 
methods of contraception).
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.
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).
All sexually active male patients must agree to prevent potential transfer to and exposure of 
pregnant partner(s) and fetus to drug through ejaculate by using a condom consistently and 
correctly, beginning with the first dose of lorlatinib and continuing for at least 97 days after 
the last dose of lorlatinib.
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. Woman 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:


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1. 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.
2. 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. Methods of Contraception
1. 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.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4. Male condom must be used in association with a female highly effective method of 
contraception.
5. Male sterilization with absence of sperm in the postvasectomy ejaculate.


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NOTE: For patients 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 methods of contraception for the individual patient and his/her 
partner(s) from the list of permitted contraception methods.
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 manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International 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 (PF-06463922).
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.


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A subject must sign an informed consent document (ICD) before being evaluated for study 
entry.  Once a subject who has met inclusion and exclusion criteria has provided a signed 
ICD, allocation of subjects to lorlatinib treatment will proceed through the use of an 
interactive response technology (IRT) system (interactive Web-based response [IWR]).  The 
site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number assigned.  The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
Qualified subjects will be enrolled to the study to receive lorlatinib monotherapy at the RP2D 
of 100 mg QD, administered as 4×25 mg oral tablets, continuously. Study treatment should 
be initiated preferably on the randomization day but no later than 1 day after randomization.
5.2. Subject Compliance
For self-administration of lorlatinib at home, compliance will be captured and completed by 
the subject.
A patient diary will be provided to the subjects to aid in lorlatinib compliance.  The diary will 
be maintained by the subject to include unchanged, missed, or changed doses.
Subject will be required to return to the investigational site all bottles of lorlatinib at the end 
of each 21-day cycle during the planned visit at the site.  The number of lorlatinib tablets
remaining will be documented and recorded at each clinic visit.
The study site must follow up (for example, via a telephone call) with each subject on
Cycle 1 Day 5 (3 days) to confirm that the subject understands and is in compliance with
lorlatinib dosing instructions.  If needed, the subject will be re-trained.  The same follow- up 
process will be applied in case the dose of lorlatinib is modified during the treatment period.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
Lorlatinib will be supplied for oral administration as 25 mg tablets in High-Density
Polyethylene (HDPE) bottles with desiccant and labeled according to local regulatory
requirements.


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5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of investigational agents.  Investigational product should be prepared and dispensed 
by an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) 
as allowed by local, state, and institutional guidance.
Lorlatinib will be dispensed at the beginning of every 21-day cycle (or as otherwise 
indicated) using an IRT drug management system.  Subjects should be instructed to keep 
their medication in the bottles provided and not transfer it to any other container.  Lorlatinib 
will be provided in bottles containing 25 mg tablets.  Site personnel must ensure that subjects 
clearly understand the directions for self-medication.  Subjects should be given sufficient 
supply to last until their next study visit.  Subjects will be provided with Drug Administration 
Cards and Patient Diaries.  In addition, administration instructions will be detailed for site 
personnel in the Investigational Product (IP) Manual.
5.4. Administration
All study 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.  Subjects will swallow the investigational product whole, and will not manipulate or 
chew the investigational product prior to swallowing.  A dosing card will be provided to the 
subjects to provide guidance for the correct use of lorlatinib.  Subjects 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 dose, otherwise it should 
be skipped and dosing resumed with subsequent doses as prescribed.  The subject 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).
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. 
Since no clinically meaningful effect of food on the PK of lorlatinib has been observed,
lorlatinib can be administered with or without food.


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5.4.1. Treatment duration
The study treatment may continue until disease progression confirmed by independent 
central radiology (ICR) review, unacceptable toxicity, subject lost to follow-up, or subject 
refusal, or the study is terminated by the sponsor, whichever comes first.
If the subject has documented PD by ICR, subjects should be discontinued from study 
treatment.  However, if according to the investigator’s clinical judgment and after discussion
between the investigator and Pfizer, if a subject with evidence of PD is still experiencing 
clinical benefit, the subject may be eligible for continued lorlatinib treatment.  The 
investigator’s judgment should be based on the overall benefit/risk assessment and the 
subject’s clinical condition, including ECOG performance status, clinical symptoms, adverse 
events and laboratory data.
5.5. Recommended Dose Modifications
Every effort should be made to administer investigational products 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.  Subjects are to be instructed to notify their investigators at the
first occurrence of any adverse event.
If a dosing interruption longer than 4 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
subject may resume treatment after a lapse of greater than 4 weeks.
In case of adverse events, investigators are encouraged to employ best supportive care
according to local institutional clinical practices or follow the guidance for selected adverse 
events provided in Table 2.  Subjects will be monitored closely for toxicity, and the dose of 
lorlatinib may be adjusted as indicated in Table 1 below.  All dose modifications will be 
reported in the Case Report Form (CRF).
Table 1.
Lorlatinib Dose Levels for Intrapatient Dose Modifications
Dose Levels
Lorlatinib dose
0
100 mg QD
-1
75 mg QD
-2
50 mg QD
Dose reductions below dose level -2 are not allowed.
Intrapatient dose reduction by 1 and, if needed, 2 dose levels will be allowed depending on
the type and severity of toxicity encountered (Dose Level -1 is 75 mg QD; Dose Level -2 is
50 mg QD).  It is recommended that in case of lorlatinib dose decrease, the subject is 
assigned new drug rather than using less tablets from the bottle assigned at previous visit.


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If a subject has a significant toxicity from lorlatinib treatment which fails to recover within
28 days (4 weeks) or, in the opinion of the investigator, requires permanent discontinuation
of the treatment based on the severity of the adverse event, then this subject should not be
further treated with lorlatinib but should remain in the study with ongoing tumor assessments
until RECIST-defined disease progression by the ICR.
Recommendations for lorlatinib dose modification for treatment-related non-hematological
and hematological toxicity, as well as for treatment-related toxicity of special interest, are
provided in Table 2 below.
Re-escalation is not allowed except if discussed with and approved by the sponsor’s medical
contact.
Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
Non-Hematologic Toxicities
Pancreatitis
NA
If elevated enzymes (both 
amylase and lipase are 
Grade 2) are observed in 
the absence of radiological 
findings of pancreatitis:
continue lorlatinib at the 
same dose level without dose 
hold.  Repeat lipase and 
amylase and obtain 
pancreatic isoenzyme if
possible.
If radiologically confirmed
pancreatitis: withhold 
lorlatinib dose.  Repeat 
radiology and lipase and 
amylase weekly and obtain
pancreatic isoenzyme.  If 
appropriate, resume lorlatinib 
treatment at one dose level 
lower if radiology has 
returned to baseline and 
lipase and amylase are 
Grade 2.
Permanently
discontinue 
lorlatinib
Permanently
discontinue lorlatinib


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Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
Pneumonitis (in the
absence of disease
progression,
pulmonary
embolism, positive
cultures or 
radiation effect)
section
Asymptomatic,
radiographic 
findings only: No 
need for lorlatinib 
dose adjustment.  
Initiate
appropriate 
monitoring.
Withhold current lorlatinib 
dose until toxicity has 
returned to baseline.  Rule 
out infection and consider 
initiating treatment with
corticosteroids.  Then resume 
lorlatinib treatment at one 
dose level lower.  
Discontinue lorlatinib 
permanently if pneumonitis 
recurs or if failure to recover 
after 6 weeks of study 
treatment hold and steroid 
treatment.
Permanently
discontinue 
lorlatinib
Permanently
discontinue lorlatinib
Electrocardiogram
QTc prolongation
(see Section 5.5.2)
Assess 
electrolytes and
concomitant 
medications
Correct any 
electrolyte
abnormalities, or 
hypoxia
Continue 
lorlatinib at the
same dose level
Assess electrolytes and 
concomitant medications
Correct any electrolyte 
abnormalities, or hypoxia
Continue lorlatinib at the 
same dose level
Withhold 
lorlatinib dose
Assess 
electrolytes and
concomitant
medications
Correct any 
electrolyte
abnormalities, or
hypoxia.
Upon recovery to
Grade 1 resume
lorlatinib 
treatment at one 
dose level lower.
Permanently
discontinue lorlatinib
LV Dysfunction
CTCAE v4.03 
does not report 
Grade 1.
CTCAE v 4.03 does not 
report Grade 2
Permanently
discontinue 
lorlatinib
Permanently
discontinue lorlatinib
Non-Hematologic
General
Continue 
lorlatinib at the
same dose level 
Continue lorlatinib at the
same dose level 
Withhold 
lorlatinib dose
until toxicity is
Grade 1 (or has
returned to 
baseline) then 
reduce the dose by
1 level or 
rechallenge at the 
same dose*
Withhold dose until 
toxicity is Grade 1 
(or has returned to
baseline), then reduce 
the dose by 1 level* 
or discontinue at the
discretion of the
investigator 


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Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
* Subjects who develop asymptomatic Grade 4 hyperuricemia or Grade 3 hypophosphatemia may continue lorlatinib 
without dose modification at the discretion of the investigator.  Nausea, vomiting or diarrhea must persist at Grade 3 or 4 
despite maximal medical therapy to require lorlatinib dose modification. 
** In cases where no specific dose adjustments for Grade 1 or Grade 2 treatment-related toxicity are provided, 
investigators should always manage their patients according to their medical judgment which may include dose reduction 
or interruption based on the particular clinical circumstances.
Section If a subject has a potential diagnosis of pneumonitis or drug-related lung injury the same evaluations/procedures 
provided in Section 5.5.3 should be considered to assist or exclude the diagnosis of pneumonitis during this period.
Hematologic Toxicities
Hematologic
General
Continue 
lorlatinib at the
same dose level 
Continue lorlatinib at the
same dose level 
Withhold 
lorlatinib dose 
until toxicity is 
Grade 1 (or has
returned to 
baseline), then
rechallenge at the 
same dose or
reduce the dose by 
1 dose level 
Withhold lorlatinib 
dose until toxicity is
Grade 1 (or has
returned to baseline), 
then rechallenge at the 
same dose or reduce 
the dose by 1 dose 
level 
Lymphopenia
Continue 
lorlatinib at the
same dose level 
Continue lorlatinib at the
same dose level 
If no evidence of 
infection or other
clinically
significant 
toxicity, continue 
lorlatinib at the 
same dose; 
otherwise, 
withhold dose
until toxicity is 
Grade 1 (or
baseline) then 
rechallenge at the
same dose or 
reduce by 1 level
If no evidence of 
infection or other
clinically significant 
toxicity, continue 
lorlatinib at the same
dose; otherwise, 
withhold dose until 
toxicity is Grade 1 
(or baseline) then 
rechallenge at the
same dose or reduce 
by 1 level 


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Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
Lipid Elevation Toxicitiesα
Cholesterol
Continue 
lorlatinib at the 
same dose 
Consider 
introducing use of 
a statin or other
lipid lowering 
agent as
appropriate based 
on investigator’s 
medical judgment 
Introduce the use of a statin 
or other lipid lowering agent 
as appropriate, and continue
lorlatinib at the same dose 
Introduce the use 
of a statin or other 
lipid-lowering
agent as
appropriate, or 
increase the dose 
of the statin/lipid
lowering agent or 
change to a new 
agent. Continue 
lorlatinib at the
same dose without
interruption 
Increase the dose of 
the statin or other 
lipid-lowering agent, 
or change to a new 
statin/lipid lowering 
agent. Withhold
lorlatinib dose until 
toxicity is Grade 2
Re-challenge at same 
dose while 
maximizing lipid 
lowering therapy in 
accordance with 
respective prescribing 
information 
If Grade 3
hypercholesterolaemi
a recurs despite 
maximal lipid 
lowering therapy in 
accordance with 
respective prescribing 
information, reduce 
lorlatinib by 1 dose 
level 
Triglycerides
Continue 
lorlatinib at the 
same dose 
Consider 
introducing use of 
a statin or other
lipid lowering 
agent as
appropriate based 
on investigator’s 
medical judgment 
Introduce the use of a statin 
or other lipid lowering agent 
as appropriate, and continue
lorlatinib at the same dose 
Introduce the use 
of a statin or other 
lipid-lowering
agent as
appropriate, or 
increase the dose 
of the statin/lipid
lowering agent or 
change to a new 
agent. Continue 
lorlatinib at the
same dose without
interruption
Increase the dose of 
the statin or other 
lipid-lowering agent, 
or change to a new 
statin/lipid lowering 
agent. Withhold
lorlatinib dose until 
toxicity is Grade 2
Re-challenge at same 
dose while 
maximizing lipid 
lowering therapy in 
accordance with 
respective prescribing 
information 
If Grade 3 
hypertriglyceridaemia 
recurs despite 
maximal lipid 
lowering therapy in 
accordance with 
respective prescribing 
information, reduce 
lorlatinib by 1 dose 
level 


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Table 2.
Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities
Toxicity
Grade 1**
Grade 2**
Grade 3
Grade 4
α See also instructions provided in Section 5.5.1 Hyperlipidemia
CNS Toxicities
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
CNS effectsβ
Continue 
lorlatinib at the 
same dose or
withhold dose 
until recovery to 
baseline.  Then 
resume at the 
same dose or 
reduce by 1 dose 
level 
Withhold dose until toxicity 
is less than or equal to 
Grade 1.  Then resume at 
1 reduced dose level 
Withhold dose 
until toxicity is 
less than or equal 
to Grade 1.  Then 
resume at 
1 reduced dose 
level
Permanently
discontinue lorlatinib 
β Examples of CNS effects could include changes in speech, memory, sleep, cognition, or vision.
5.5.1. Hyperlipidemia
In the lorlatinib Phase 1 Study B7461001, hypercholesterolemia was the most common AE
reported.  Elevations in lipids usually begin in the first few cycles and, if statins are not
introduced, can rise to Grade 3 levels by the next treatment cycle.  Therefore, the suggested
management is to begin a statin for Grade 1 elevations in either cholesterol or triglycerides
and to increase the statin dose if adequate control is not obtained, as outlined in Table 2. 
Members of the statin class of agents are differentially sensitive to CYP3A4, and caution 
should be exercised when selecting statin for management of elevated lipid levels.
Pitavastatin and rosuvastatin can be used during lorlatinib treatment without dose adjustment 
since there is no CYP3A4 involvement in their elimination. Pravastatin, fluvastatin and 
atorvastatin should be used with caution during lorlatinib treatment, and a dose adjustment of 
these statins may be necessary (increasing dose may be considered). Lovastatin and 
simvastatin are not recommended for use during lorlatinib treatment.
5.5.2. PR Interval Prolongation
Analysis of ECG data from ongoing and completed human studies with lorlatinib has
identified a subset of subjects who exhibited ECG evidence of PR interval prolongation.  The
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 lorlatinib IB.
Guidance for management of PR interval prolongation is provided in Table 3 below and
examples of drug with potential PR interval prolongation effect can be found in Appendix 5.


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Table 3.
PR Interval Prolongation Management
Toxicity
No symptomatic
Symptomatic
1st-Degree Heart Block (PR 
interval >200 msec)
No dose hold or reduction
needed. Assess concomitant 
medications and electrolyte 
imbalance that may prolong PR 
interval. Monitor ECG/symptoms 
potentially related to AV block 
closely 
Withhold dose.  Assess 
concomitant medications and 
electrolyte imbalance that may 
prolong PR interval.  Monitor 
ECG/symptoms potentially 
related to AV block closely.  If 
symptoms resolve, resume at 
same dose or at 1 reduced dose 
level 
2nd-Degree Heart Block
Withhold dose.  Assess 
concomitant medications and 
electrolyte imbalance that may 
prolong PR interval.  Monitor
ECG/symptoms potentially related 
to AV block closely.  If subsequent 
ECG does not show second degree 
block, resume at same dose or 
1 reduced dose level 
Withhold dose.  Assess 
concomitant medications and 
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 block resolve 
or if subjects revert to 
asymptomatic first degree AV
block, resume at 1 reduced dose 
level 
Complete Heart Block
Withhold dose.  Assess concomitant medications and electrolyte 
imbalance that may prolong PR interval.  Refer for cardiac observation 
and monitoring.  Temporary 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, may resume at full dose.  If no pacemaker placed, 
resume at 1 reduced dose level only when symptoms resolve AND PR 
interval is less than 200 msec.
5.5.3. Pneumonitis/Pneumonia
Investigators must evaluate thoroughly subjects who demonstrate potential signs/symptoms 
of pneumonitis/pneumonia.  If a subject has a potential diagnosis of pneumonitis or 
drug-related lung injury, then the following evaluations/procedures should be considered to 
confirm or exclude the diagnosis of pneumonitis during this period in the absence of disease 
progression, other pulmonary disease, infection, or radiation effects:

A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and mycobacteria.

Blood culture should be performed in febrile subjects.  Consider appropriate 
serologies (mycoplasma, legionella, cytomegalovirus, other viruses, etc).

Thoracentesis if pleural fluid is present (culture, microbiology, cytology).


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
Bronchoscopy with bronchoalveolar lavage if appropriate.  The bronchoalveolar 
lavage fluid should be sent for culture, microbiology, and cytology (same pathogens 
as above).

Lung biopsy (eg, open or thorascopic preferable, bronchoscopy with transbronchial 
biopsy) if appropriate.

A plasma sample for BNP (B-type natriuretic peptide) to evaluate for evidence of 
congestive heart failure.

For Asian countries based subjects, a blood sample for -D glucan to evaluate for the 
presence of fungal pneumonia (eg, Pneumocystis jirovecii).
If clinically appropriate, high-dose corticosteroid treatment should be initiated.  Should the 
event be fatal an autopsy is highly recommended to confirm/exclude the diagnosis. 
5.6. Management of Overdose
An overdose is defined as any dose of lorlatinib >100 mg QD.  Any overdose must be 
recorded in the study drug section of the CRF. If an extra dose is taken during a day, the next 
dose should not be taken.
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.
5.7. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 


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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, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.8. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
All bottles of study drug must be returned to the investigator by the subject at the end of each 
cycle and at the end of the study.  The sponsor will provide instructions as to the process for 
drug accountability in the monitoring plan.
5.8.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.9. Concomitant Treatment(s)
Concomitant treatment considered necessary for the subject’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).


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Medications intended solely for supportive care (eg, antiemetics, analgesics, megestrol 
acetate for anorexia, bisphosphonates or receptor activator of nuclear factor kappa-Β
(RANK)-ligands for metastatic bone disease or osteoporosis) are allowed. In case the patient 
is already on treatment with RANK-ligands (like denosumab) before study entry, the therapy 
should be at a stable dose prior to randomization.
There are no prohibited therapies during the Post-Treatment Follow-Up Phase.
5.9.1. Inhibitors and Inducers of CYP Enzymes
The list of food and drugs to be avoided provided below may not be fully exhaustive.  
Consult the sponsor when in doubt whether a food or a drug falls into any of the categories
below.
The 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 CYP 3A and also an inducer of
CYP3A and CYP2B6.  At substantially higher concentrations than those observed clinically, 
lorlatinib also inhibited CYP2C9 in in vitro studies.
To protect subject 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, itraconazole, ketoconazole, 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.  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.


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
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 lorlatinib is permanently discontinued.  In addition, use 
with moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil) 
should be avoided due to the potential reduction in lorlatinib exposure.

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
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-glycoprotein (P-gp) (in vitro) so concurrent use of drugs which 
are P-gp substrates with a narrow therapeutic index (NTI) may have increased effect.  
The concurrent use of drugs which are NTI P-gp substrates, 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.
Any questions regarding the use of alternative medications should be directed to the sponsor 
for guidance.
5.9.2. Other Anti-Tumor/Anti-Cancer or Experimental Drugs
No additional concurrent anti-tumor treatment will be permitted while subjects are receiving 
study treatment, which includes but not limited to anti-cancer systemic chemotherapy and 
biological therapy.  


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5.9.3. Other 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 Section 5.9.6).

Other experimental pharmaceutical products.

Herbal remedies with anticancer properties or known to potentially interfere with 
major organ function or study drug metabolism (eg, hypericin).
5.9.4. Hematopoietic Growth Factors 
Use of granulocyte colony stimulating factors should follow the current American Society of
Clinical Oncology (ASCO) guidelines.30  Subjects who enter the study on stable doses of
erythropoietin or darbepoetin may continue this treatment, and subjects may start either drug
during the study at the discretion of the investigator.
5.9.5. Concomitant 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, but resumed no sooner than 48 hours 
after surgery.
5.9.6. Concomitant Radiotherapy
Radiation therapy during the treatment phase is not allowed, with the exception described as 
below.
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.
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.


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
6. S T U D Y P R O C E D U R E S 
A s a p plica ble, all visi ts m ust occ ur wit hi n t he pre defi ne d wi n d o ws o utli ne d i n t his pr ot oc ol.
6. 1. Scree ni n g
I nf or me d C o nse nt m ust be o btai ne d pri or t o u n der g oi n g a ny st u d y s pecific pr oce d ures.  
 
F or scree ni n g pr oce d ures see t he S C H E D U L E O F A C TI VI TI E S a n d A S S E S S M E N T S
secti o n.
6. 1. 1. Det er mi n ati o n of A L K St at us
E vi de nce of p ositi ve A L K stat us as pre vi o usl y deter mi ne d t hr o u g h use of t he Ve nta na A L K 
( D 5 F 3) C D x Assa y ( R oc he Dia g n ostics), t he V ysis A L K Brea k A part FI S H Pr o be Kit 
( A b b ott M olec ular), or t he E M L 4-A L K F usi o n Ge ne Det ecti o n Kit ( A m o y D x), m ust be 
a vailable at scree ni n g sta ge bef ore e nr oll me nt.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
 
 
 
 
 
6. 2. Tre at me nt Peri o d
F or treat me nt peri o d pr oced ures, see S C H E D U L E O F A C TI VI TI E S a n d A S S E S S M E N T S
secti o n. 
6. 3. E n d of Tre at me nt/ Wit h dr a w al a n d P ost -Tre at me nt F oll o w -U p 
F or treat me nt peri o d pr oce d ures, see S C H E D U L E O F A C TI VI TI E S a n d A S S E S S M E N T S
sectio n.
6. 4. S u bject Wit h dr a w al 
S u bjects ma y wit h dra w fr o m t he st u d y  at a n y ti me at t heir o w n re q uest, or t he y m a y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or o r s p o ns or f or safet y (see als o t he 
Wit h dra wal
Fr o m t he St u d y D ue t o A d verse E ve nts secti o n) or be ha vi oral reas o ns, or t he 
i na bilit y of t he s u bject t o c o m pl y wit h t he pr ot oc ol-re q uire d sc he dule of st u d y  visits or 
pr o ce d ures at a gi ve n st u d y site. 
Reas o ns f or wit h dra wal of st u d y  treat me nt ma y i ncl u de:

O bjecti ve disease pr o gressi o n.  H o we ver, s u bjects wit h disease pr o gressi o n w h o are 
c o nti n ui n g t o deri ve cli nical be nefit fr o m t he st u d y  treat ment per t he i n vesti gat or wi ll 
be eli gi ble t o c o nti n ue wit h l orlati ni b as si n gle a ge nt, pr o vi de d t hat t he treati n g
p h y sicia n has deter mi ne d t hat t he be nefit/ris k f or d oi n g s o is fa v ora ble a n d disc usse d 
wit h t he s p o ns or;

Gl o bal deteri orati o n o f healt h stat us re q uiri n g per ma ne nt disc o n ti n uati o n per t he 
i n vesti gat or’s j u d ge me nt;

U nacce pta ble t o xicit y ;

Pre g na nc y ;

Si g nifica nt pr ot oc ol vi olati o n;

L ost t o f oll o w - u p;

S u bject ref use d f urt her treat me nt (f oll o w u p per mitte d b y  s u bject);
C CI


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
Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow up may include:

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
6.5. Survival Follow Up Visit
For survival follow up procedures see SCHEDULE OF ACTIVITIES table and 
ASSESSMENTS section.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
products, request that the subject return for a final visit, if applicable, and follow up with the 
subject regarding any unresolved adverse events (AEs).
If the subject refuses further visits, the subject should continue to be followed for survival
unless the subject withdraws from the study, and also withdraws consent for disclosure of 
future information. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
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 subject.  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.


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Available results for assessments that have been performed prior to informed consent being 
obtained as part of the patient’s on-going routine standard of care testing (laboratory tests or 
tumor imaging scans) may be used to satisfy patient eligibility assessment, provided they 
have been performed within the required timing (that is 7 days prior enrollment for 
laboratory tests or 28 days prior enrollment for tumor imaging or 6 weeks prior enrollment 
for bone scan [or bone MRI if preferred by investigator] ) and meet the related criteria.
End of treatment (EOT) visit should be performed no later than 4 weeks (+1w) from the last 
dose of investigational product or when decision taken to provide alternative anti-cancer 
therapy, whichever is sooner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Tumor Response Assessments
Tumor Assessments need to include all known or suspected disease sites.  Imaging to include 
chest, abdomen, and pelvis computed tomography (CT) or magnetic resonance imaging
(MRI) scans (contrast enhanced CT/MRI is preferred unless contraindicated).  Brain MRI 
(Gadolinium contrast enhanced) or brain CT (contrast enhanced) to be used for assessment of 
CNS lesions (even if brain metastases not suspected), with contingent slices of 1 mm for 
lesions 5 mm – 10 mm in size, 5 mm for lesions greater than 10 mm (target intracranial 
lesions need to be suitable for accurate measurements with a minimum size of 5 mm by MRI 
or CT or no less than double the slice thickness, whichever is largest).  CNS imaging using
MRI/CT (contrast enhanced is preferred unless contraindicated) is required at baseline in all 
patients and at every tumor assessment. Bone scans (or bone MRI if preferred by 
investigator) to be performed at baseline for all subjects and repeated every 18 ±1 weeks on 
study only if evidence of bone metastases is observed at baseline. 
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.  Exception to this 
rule is in the presence of CNS metastases 5 mm in diameter assessed by gadolinium 
contrasted MRI with slices of 1 mm; up to 5 CNS lesions will be permitted in addition to 
5 extracranial lesions previously noted, assessed by a modified version of RECIST v1.1
(Appendix 3).
For all tumor assessments, the method of assessment that was used at baseline should be the 
same method used throughout the study.  CT or MRI scans to be done at every 6 weeks 
±1 week starting from the first dose of the investigational product while on treatment and 
during post-treatment follow-up period, until documented progression of disease by ICR; 
During post-treatment follow-up period, if applicable, bone scan (or bone MRI if preferred 
by investigator) to be performed every 18 weeks ±1 week until documented progression of 
disease by ICR.  The responses will have to be confirmed ≥4 weeks after the initial response 
is observed. If the disease progression is suspected during the study, an unscheduled tumor 
assessment may be conducted before the regular tumor assessment visit, if applicable.


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Tumor assessment should be repeated at the end of treatment (EOT) visit if more than 
6 weeks have passed since the last evaluation.  Tumor assessments must continue until 
documented progression of disease by ICR.  Subjects who discontinue treatment without PD 
should be followed until PD confirmed by ICR, regardless of subsequent anti-cancer 
treatments.  For subjects continue lorlatinib treatment after disease progression by ICR 
(based on the investigator’s judgement of clinical benefit in spite of confirmed disease 
progression), tumor assessment is in need when clinically indicated.
Assessment of response will be made using RECIST v.1.1.  Assessment of response of 
measurable intracranial disease will be made using a modified version of RECIST v.1.1,31
see Appendix 3.
All subjects’ files and radiologic images must be available for independent central radiology 
review.  Instructions for submission of these images will be provided in the Study Reference 
Manual.  Specific imaging sequences, step-by-step and storage of images will be defined in a 
separate Imaging Charter developed by the imaging vendor. 
Management of incidental findings 
An incidental finding is one unknown to the subject that has potential health or reproductive 
importance, which is discovered unexpectedly in the course of a research study, but is 
unrelated to the purpose and beyond the aims of the study.
Radiologic images will be reviewed by a central review facility.  The purpose of this review 
is to evaluate images for tumor response assessment.  Central image review is not a complete 
medical review of the subject and no incidental findings will be shared with the principal 
investigator, site staff, or the subject.  All safety reviews will be the sole responsibility of site 
staff.
7.2. Expedited Independent Central Review of Disease Progression
An expedited ICR review will be performed for investigator-assessed disease progression.  
Upon investigator-assessed disease progression, all radiographic images collected for a
subject from baseline onwards will be submitted to the ICR for expedited review (see the
Study Manual for process details and maximum allowable time).  Every effort should be
made to keep the subject on study treatment and have all the assessments performed as per 
Schedule of Activities until the ICR has completed the radiographic image review, unless 
contraindicated by the investigator.
7.3. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting administration of study treatment-once at the start of screening 
and once at the baseline visit, immediately before starting lorlatinib treatment.  Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit before the 
subject may receive lorlatinib treatment.  Pregnancy tests will be repeated at every treatment


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cycle during the active treatment period, at the end of study treatment, and additionally 
whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken 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 subject will be withdrawn from administration of 
investigational product but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review
Board (IRBs)/ECs or if required by local regulations.
7.4. Safety Assessments
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, 12-lead ECGs, echocardiogram/multigated acquisition (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).  
7.4.1. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03) 
timing, seriousness, and relatedness.
7.4.2. Laboratory Safety Assessment
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the SCHEDULE OF ACTIVITIES table and analyzed at local laboratories.  They may also
be performed when clinically indicated and relevant results reported in the CRF as
‘unplanned visits’.  The required laboratory tests are listed in Appendix 4.
7.4.3. Vital Signs and Physical Examinations
Subjects will have a physical examination to include major body systems, body weight, 
blood pressure, pulse rate, body temperature, assessment of ECOG performance status, and 
height (height will be measured at screening only) at the time points described in the SOA.  
Blood pressure and pulse rate should be taken with the subject in the seated position after the 
subject has been sitting quietly for at least 5 minutes. 
7.4.4. (12-Lead) Electrocardiograms
A triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all
electrocardiograms (ECG) assessments, except for ECG at Day 1 of Cycle ≥3, which will be 
single readings according to Schedule of Activities.


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All subjects require a triplicate ECG measurement at screening.  On treatment ECGs will be 
performed as outlined in the SOA table.  At each time point which requires a triplicate 
reading per SOA, 3 consecutive 12-lead ECGs (triplicates) will be performed approximately 
2 minutes apart (or within 10 minutes, whichever is appropriate) to determine PR interval 
and mean QTc (average of triplicates). The ECG must occur prior to any blood sample 
collections or venipuncturing if conducted on the same day, except for the specific 
requirement in the protocol (SOA & Section 7.5).
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 subject 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.
If a subject experiences PR interval prolongation >200 msec or second-degree or third-degree 
AV block, while on treatment with lorlatinib, refer to Section 5.5.2. 
If subject 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 and 
relevant results reported in the CRF as ‘unplanned visits’ if applicable. 
7.4.5. Echocardiograms/MUGA Scans
In order to monitor left ventricular ejection fraction (LVEF), 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.
7.4.6. Assessment of Mood
An assessment of mood will be administered to subjects via the Beck Depression 
Inventory-II scale at the time points described in the SCHEDULE OF ACTIVITIES table.  
This is a 21- item self-report scale, with each item rated by subjects on a 4 point scale 
(ranging from 0-3).  The scale includes items capturing mood (loss of pleasure, sadness,
irritability), suicidal ideation, and cognitive signs (punitive thoughts, self- criticism, 
self-dislike, pessimism poor concentration) as well as somatic signs (appetite, sleep, fatigue, 
libido).


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7.4.7. Assessment of Suicidal Ideation and Behavior 
To assess suicidal ideation behaviors, the Columbia Suicide Severity Rating Scale
(C-SSRS)32 will be administered to subjects 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.
For C-SSRS rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study.  The minimum qualifications a rater must meet for this assessment is:

Educational level: Medical Doctor or Registered Nurse.

Prior clinical experience: at least 1 year experience with clinical trial.

Prior scale experience: Prior training with C-SSRS within the past two years with 
valid documented certification will exempt rater from having to retake C-SSRS 
training.  Upon 2 year expiration of documented certification, raters will be required 
either to retake C-SSRS training or resubmit valid, current documented certification.  
Should the two years lapse during the course of the study, retraining updated training 
and a renewed certificate will be required.
Proposed raters who do not meet specific criteria but who may be qualified based on unique 
circumstances may be individually reviewed by the study clinical team to determine whether 
or not a waiver may be issued.  The rater must become certified to perform selected study 
assessments before he or she can participate in the conduct of the study.  For specifically 
defined assessments, rater training and standardization exercises may be conducted, and 
written and signed documentation will be provided by the site for each rater’s certification.  
In return, each site will be provided written and signed documentation outlining each rater’s 
certification for specific study assessments.  Recertification may be required at periodic 
intervals during the study.  The raters who administer specific study assessments will be 
documented in a centralized location and all site staffs who administer ratings will be verified 
in the site study documentation during the conduct of the study.
7.5. Pharmacokinetics Assessments
All efforts will be made to obtain the PK samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and the data collection 
tool (eg, CRF).  During the study, actual collection times may change but the number of 
samples will remain the same. 


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Plasma samples will be assayed for lorlatinib using a validated analytical method(s) in 
compliance with Pfizer standard operating procedures.  Details regarding the storage and 
shipping of plasma samples will be provided in the Study Manual.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
potential qualitative and/or quantitative metabolite analyses and/or evaluation of the 
bioanalytical methods for lorlatinib and its metabolites (if possible).  The results of such 
analyses may not be included in the clinical report.
Plasma samples for determination of plasma concentrations of lorlatinib will be collected at 
time 0 (pre-dose), and any time between 1 to 2 hours after the lorlatinib dose on Days 1 of 
Cycle 2 to 5 in all subjects.  In order to obtain 12 evaluable full PK profiles, in up to 
16 subjects, Plasma samples will be collected at time 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 9, and 
24 hours on Day 1 and Day 15 of Cycle 1.  Note: 1) When collecting the serial PK sample at 
8 hour and 9 hour, if the actual collection time of the 8 hour sample is nearing the 9 hour 
nominal time (within the 10% window of the 9 hour collection time), the 9 hour sample 
should still be collected after the 8 hour sample and as close to the 9 hour nominal time as 
possible. 2) In the event of any dose interruption in 15 day time period prior to Day 15 of 
Cycle 1, the planned intensive PK sampling schedule on C1D15 is suggested to be extended 
to the Day 1 of next cycle.
Additional plasma samples may be requested from subjects experiencing unexpected or 
serious adverse events.
During all study periods, blood samples (about 3.0 mL) to provide approximately 1.2 mL 
plasma for pharmacokinetic analysis of lorlatinib will be collected into appropriately labeled 
tubes containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) at times specified in 
the Section 6 of the protocol.
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.

Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the laboratory manual.

Lorlatinib plasma samples will be analyzed using a validated analytical method in 
compliance with Pfizer standard operating procedures.

The PK samples must be processed and shipped as indicated to maintain sample 
integrity. Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the sponsor.  On a case-by-case basis, the 
sponsor may make a determination as to whether sample integrity has been 
compromised.  Any sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation.


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7
T he s hi p me nt a d dress a n d assa y  la b orat or y c o ntact i nf or mati o n will be pr o vi de d t o t he 
i n vesti gat or site prior t o i nitiati o n of t he st u d y .
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. A D V E R S E E V E N T R E P O R T I N G
8. 1. Re q uire me nts
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g safet y e ve nts o n t he C R F a n d f or 
re p ortin g safet y e ve nts o n t he Cli nical Trial ( C T) Seri o us A d verse E ve nt ( S A E) Re p ort F or m 
t o Pfizer Safet y .  T hese re q uire me nts are deli neate d f or 3 t ypes of e ve nts : ( 1) S A Es; 
( 2) n o n- seri o us a d verse e ve nts ( A Es); a n d ( 3) e x p os ure t o t he i n vesti gati o nal pr o d uct u n der 
st ud y  d uri n g pre g na nc y or breastfee di n g, a n d occ u pati o nal e x p os ure. 
C CI
C CI


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


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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 subject/legally acceptable representative.  In addition, each study 
subject/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.


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SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a subject 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.
If a subject 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 the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to:

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
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.


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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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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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.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);


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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;

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.
8.3. Severity Assessment
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed below.
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
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 


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(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in 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.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. 


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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
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.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).


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
A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 


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subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. 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.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.


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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The primary objective of the study is to evaluate the anti-tumor effect of lorlatinib as a single 
agent as measured by ORR per RECIST v1.1 in locally advanced or metastatic ALK-positive 
NSCLC patients whose disease has progressed after crizotinib treatment, ie, Cohort 1. 
As of the original version date of protocol, given there’s no ALK inhibitor other than 
crizotinib approved in China currently, chemotherapy is still considered as standard of care 
for patients progressed after crizotinib.  Based on the current reported results, the ORR of
chemotherapy in previous systemic treatment treated patients ranged from 6.9% - 20%.21,28,29  
The ORR was 26.7% even for treatment naive patients.22  Therefore, ORR of 30% was 
chosen as the historical control for Cohort 1.  The Fleming single stage design will be used to 
test the null hypothesis (H0) as of ORR 30% with 1-sided 0.025 significance level.  
Assuming at least a 20% increase of ORR with lorlatinib treatment, 66 patients will be 
required to provide 90% power to reject the null hypothesis.  Exact test will be performed at 
the time of the analysis.  If at least 28 responses are observed among the 66 patients enrolled, 
then the null hypothesis will be rejected, and it will be concluded that the study has 
demonstrated that the true ORR exceeds 30%.  However, at the time of the analysis, the 
testing will depend on the exact number of patients enrolled. 
Cohort 2 will explore the safety and efficacy of lorlatinib in patients with locally advanced or 
metastasis ALK-positive NSCLC whose disease have progressed after one ALK inhibitor
treatment other than crizotinib.  As of the original version date of protocol, there was no 
approved ALK inhibitor other than crizotinib in China, therefore, the eligible patients were
very limited and no established standard of care was available.  Considering this limitation, 
Cohort 2 will be exploratory with about 34 patients planned to be enrolled.  No specific 
statistical hypothesis will be tested.  Descriptive analyses will be provided for the endpoints.  


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
T he sa m ple siz e of 3 4 patie nts will pr o vi de t he esti mate d O R R wit h a ma xi m u m wi dt h of t he 
9 5 % CI  of 3 5 %, o bser ve d wit h 1 7 resp o nses o u t of 3 4 p atie nts.  I n or der t o c ollect m ore 
i nf or mati o n of a nti -t u m or acti vit y, if t he patie nts recei ve d st u d y treat me nt b ut wit h o ut 
a de quate baseli ne t u m or assess me nt or wit h o ut p ost baseli ne t u m or assess me nts, a dditi o nal
patie nts ma y  be all o we d t o be e nrolle d .
Wi t h a p pr o xi matel y 6 6 a n d a p pr o xi matel y 3 4 i n C o h ort 1 a n d 2 res pecti vel y , t his st u d y will 
pr o vi de a de q uate sa m ple s ize f or safety e val uati o n wit h a mi ni mal n u m ber of 1 0 0.
9. 2. A n al ysis Sets

F ull A nal ys is Set:
T h e f ull a nal ys is ( F A) set will i ncl u de all s u bjects w h o are e nr olle d, re gar dless of 
w het her or n ot treat me nt was recei ve d .

Per pr ot oc ol ( P P) a nal ys is set:
T he per pr o t oc ol a nalys is set will i ncl u de all e nr olle d s u bjects wit h A L K p ositi ve 
N S C L C, recei ve d a pri or A L K i n hi bit or as pr ot oc ol re q uire d, a n d w h o re cei ve d at 
least 1 d ose of l orlati ni b:

I n Co h ort 1, recei ve d criz oti ni b as t he o nl y  A L K i n hi bit or.

I n C o h ort 2, recei ve d o ne A LK i n hi bit or ot her t ha n criz oti ni b, wit h or wit h o ut 
pri or criz oti ni b treat me nt.

Safet y  A nalys is ( S A) Set:
T he saf et y a nal y sis set incl u des all e nr olle d s u bjects w h o recei ve at least o ne d ose of
l orlati ni b.

P K A nal y sis Set:
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all e nr olle d s u bjects w h o recei ve 
at least o ne d ose of st u dy m e dicati o n a n d ha ve s ufficie nt i nf or mati o n t o esti mate at 
least 1 of t he P K para meters of i nterest.
 
C
C
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9.3. Efficacy Analysis
All efficacy analyses will be performed by Cohort on the SA set. 
Radiographic images and clinical information collected on study will be reviewed by an ICR.  
ICR assessment will be used for the primary analysis of OR and for all secondary endpoints 
based on radiological assessments of tumor burden (ie, IC-OR, DoR, IC-DoR, TTR and
PFS).  These endpoints will also be derived using the local radiologist’s/investigator’s 
assessment. 
9.3.1. Analysis of the Primary Endpoint 
The primary endpoint is Objective Response (OR) in Cohort 1 per RECIST version 1.1.  OR 
is defined as a complete response (CR) or partial response (PR) recorded from enrollment 
until disease progression or start of new anti-cancer therapy.  Both CR and PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.  A subject will be considered to have achieved an OR if the subject 
has a sustained CR or PR according to RECIST version 1.1 definitions. Otherwise, the 
subject will be considered as a non-responder in the objective response rate (ORR) analysis.  
Additionally, subjects with inadequate data for tumor assessment (eg, no baseline assessment 
or no follow-up assessments) will be considered as non-responders in the ORR analysis. 
The ORR is defined as the percent of subjects with confirmed OR (CR or PR) relative to the 
SA set.  The corresponding exact 2-sided 95% CI will be provided.  The exact test will be 
performed to test the null hypothesis H0: ORR 30%.  One-sided p-value will be provided. 
Sensitivity analyses will be conducted calculating the same ORRs relative to the FA set and 
PP set, if applicable.
9.3.2. Analysis of Secondary Endpoints

OR in Cohort 2: The estimated ORR and corresponding exact 2-sided 95% CI will be 
provided.

Intracranial objective response (IC-OR): IC-OR is defined the same as OR, but 
limited to Intra Cranial lesions only on subjects with CNS metastases (ie, Best 
Overall Intracranial Response as confirmed CR or confirmed PR considering only the 
lesions having disease site as Brain).  Intracranial ORR is defined as the percent of 
subjects with IC-OR relative to subjects with brain lesions at study entry in the SA 
set.  The estimated IC-ORR and corresponding exact 2-sided 95% CI will be 
provided.

Duration of Response (DoR): 
DoR is defined as the time from the first documentation of CR or PR to the first 
documentation of disease progression or death due to any cause, whichever occurs 
first. 


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DoR will only be calculated for the subgroup of subjects with a confirmed objective 
tumor response.  DoR will be summarized in this subgroup using Kaplan-Meier 
methods and will be displayed graphically where appropriate.  The median event time 
(if applicable) and 2-sided 95% CI for the median will be provided.  If the number of 
subjects with a confirmed CR or PR is small and the use of Kaplan-Meier methods 
may be limited, the DoR will be listed. 
The above analyses will be repeated also for the IC-DoR in the subgroup of subjects 
with IC-OR. 

Time to Tumor Response (TTR):
TTR is defined as the time from first dose to first documentation of objective tumor 
response (CR or PR).  TTR will only be summarized for the subgroup of subjects 
with an objective response.  Descriptive statistics mean, median and range will be 
provided. 

Progression-free Survival (PFS):
PFS is defined as the time from first dose to first documentation of objective disease 
progression or to death due to any cause, whichever comes first. 
PFS will be summarized using the Kaplan-Meier method and displayed graphically 
where appropriate.  The median event time (if applicable) and 2-sided 95% CI for the 
median will be reported. 

Overall Survival (OS)
OS is defined as the time from first dose to the date of death due to any cause. 
OS will be summarized using the Kaplan-Meier method and displayed graphically 
where appropriate.  The median OS (if applicable) and 2-sided 95% CI for the median 
will be reported. 
9.4. Analysis of Other Endpoints
9.4.1. Analysis of Pharmacokinetics
Plasma pharmacokinetic parameters of lorlatinib on day 1 of cycle 1 (C1D1) and at steady 
state including the maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax), area under the plasma concentration versus time profile from time 0 to 
time t (AUCt) and area under the plasma concentration versus time profile within a dose 
interval (AUCtau) for lorlatinib will be estimated using non-compartmental analysis.  If data 
permit or if considered appropriate, area under the plasma concentration versus time curve to 
infinity (AUCinf), terminal elimination half-life (t1/2), oral plasma clearance (CL/F), apparent 
volume of distribution (Vz/F) and accumulation ratio (Rac) will be also estimated.  The C1D1 
and steady-state PK parameters will be summarized descriptively by cycle and day.


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
F or l orlati ni b, c o nce ntrati o ns will be s u m marize d descri pti vel y ( n, mea n, sta n dar d de viati o n, 
C V (coefficie nt of variati o n ), me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its 
ass ociate d C V) by d ose, c y cle, da y a n d no mi nal ti me. I ndi vi d ual s u bject a n d me dia n pr ofiles 
of t he c o nce ntrati o n -ti me data will be pl otte d b y  c ycle a n d da y ( C 1 D 1 a n d stea d y-state) usi n g 
n o mi nal ti mes.  Me dia n pr ofiles will be prese nte d o n b ot h li near -li near a n d l o g-li near scales.
T he o bser ve d a cc u m ulatio n r ati o will be s u m marize d descri pti vel y .  Eac h will be a nalyz e d 
after nat ural l o g tra nsf or mati o n usi n g a o ne -wa y  a nalys is of varia nce wit h a si n gle ter m f or 
d ose.  T he mea ns a n d 9 0 % c o nfi de nce i nter vals ( CI s) o btai ne d fr o m t he m o del will be 
bac k -tra nsf orme d t o pro vi de mea ns a n d 9 0 % CIs f or t he acc u m ulati o n rati o.
Tr o u g h c o nce ntrati o ns will be pl otte d usi n g a b o x -w his ker pl ot b y c ycle a n d da y wit hi n c ycle 
i n or der t o assess t he attai n me nt a n d mai ntai ni n g of stea d y-state.
9. 4. 2. P h ar m ac o ki netic a n d E x p os u re-Res p o n se An al ys is
P har mac o ki netic a n d p har mac o d y na mics data fr o m t his st u d y  ma y be a nal yze d usi n g 
c o m part me ntal or mi xe d- effect m o deli n g a p pr oac hes a n d ma y als o be p o ole d wit h ot her 
st u d y res ults.  P K/ phar mac o d y na mics m o deli n g ma y  be atte m pte d t o i n vesti gate a ny ca usal 
relati o ns hi p bet wee n l orlati ni b e x p os ure a n d efficac y,
 or si g nifica nt safet y 
e n d p oi nts.  T he res ults of t hese a nal ys es, if perf or me d, will be re p orte d se paratel y.
 
 
 
9. 5. S afet y A n al ysis
T he S A set will be t he pri mar y  p o p ulati o n f or safet y e val uati o ns.  S u m maries of A Es a n d 
ot her safet y para meters will be pr o vi de d, b y C o h ort a n d T otal .
9. 5. 1. A d verse E ve nts
A d verse e ve nts will be classif ie d usi n g the me dica l dicti o nar y f or re g ulat or y acti vities 
( Me d D R A) classificati o n s yste m.  T he se verity of t he t o xicities will be gra de d acc or di n g t o 
t he N CI C T C A E v 4. 0 3 w he ne ver p ossi ble ( htt p://cte p.i nf o. ni h. g o v/re p ortin g/ ctc. ht ml).
T he f oc us of A E s u m m aries will be o n Tre at me nt E mer ge nt A d verse E ve nts ( T E A E), t h ose 
wit h i nitial o nset or i ncreasi n g i n se verit y after t he first d ose of st u d y  me dicati o n.  T E A E will 
be s u m marize d b y  w orst N CI C T C A E v 4. 0 3 se verit y gra de a n d relate d ness t o st u d y 
treat me nt c orres p o n di n g t o s yste m or ga n class a n d Me d D R A preferre d ter m . T he n u m ber 
a n d fre q ue nc y of s u bjects w h o e x perie nce d a n y A E, seri o us A E ( S A E), treat me nt-relate d A E 
a n d treat me nt -relate d S A E will be re p orte d.
C CI
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Adverse events leading to death or discontinuation of study treatment, events classified as 
NCI CTCAE v4.03 Grade 3, study drug-related events, and serious adverse events will be 
considered with special attention. 
Detailed information collected for each adverse event will be listed with a description of the 
event, duration, whether the adverse event was serious, intensity, relationship to study 
treatment, action taken, and clinical outcome.
9.5.2. Laboratory Abnormalities
Laboratory test results will be graded according to NCI CTCAE v4.03.  The frequency of 
subjects with laboratory test abnormalities will be summarized according to the worst grade 
for each laboratory test result. 
For laboratory tests without an NCI CTCAE grade definition, results will be categorized as 
normal (within normal ranges), abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory abnormalities.
9.5.3. Electrocardiograms
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged, and all summary statistics and data presentations will use the triplicate averaged 
data.  Any data obtained from ECGs repeated for safety reasons after the nominal time points 
will not be averaged along with the preceding triplicates.
QT intervals will be corrected for heart rate (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, HR, RR, PR, QRS, QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) of 
corrected QT interval and other ECG parameters will be used to summarize absolute values 
and changes from baseline on treatment.  Categorical analysis will be conducted for the 
maximum change from baseline in corrected QT, PR, and QRS and the maximum 
post-baseline corrected QT interval. 
9.5.4. Left Ventricular Ejection Fraction
For subjects with MUGA scans or echocardiograms, individual LVEF proportion (%) and its 
changes from baseline will be summarized by time point.  The number of subjects and the 
percentage whose maximum relative decrease from baseline in LVEF is greater than 
20% will be calculated.  The number and percentage for subjects whose LVEF proportion 
falls below lower limit of normal (LLN) and/or maximum relative decrease from baseline is 
greater than 10% will also be summarized.


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9.6. Interim Analysis 
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating pharmacokinetic (PK)/pharmacodynamic modeling, and/or to support clinical 
development.  
9.7. Data Monitoring Committee 
This study will not use a data monitoring committee. 
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.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.


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A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and paper form and will be 
password protected or secured in a locked room 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 subject 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.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
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 the 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 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.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable law. 
The personal data will be stored at the study site in encrypted electronic and paper form and 
will be password protected or secured in a locked room to ensure that only authorized study 
staffs 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, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined 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 subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.


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The informed consent documents and any subject recruitment materials must be in 
compliance with ICH Good Clinical Practice (GCP), local regulatory requirements, and legal 
requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study subject, 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 subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’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 subject or the subject's legally acceptable representative, before any 
study-specific activity is performed. The investigator will retain the original of each subject's 
signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF STUDY
End of study is defined as last subject last visit (LSLV).


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
lorlatinib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within one month.  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. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.


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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report 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.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1. American Cancer Society. Global Cancer Facts and Figures; 2nd Edition 2008. Available
at:http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docu
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2. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER 
Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD,
https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, 
posted to the SEER web site, April 2017.
3. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA: a cancer 
journal for clinicians 2016; 66(2): 115-32.
4. Soda M et al Identification of the transforming EML4-ALK fusion gene in non-smallcell
lung cancer. Nature 2007; 448:561-566.
5. Rivoka K, Global survey of phosphotyrosine signaling identifies oncogenic kinases in
lung cancer. Cell 2007; 131: 1190-1203.
6. Camidge DR, Pao W and Sequist LV. Acquired resistance to TKIs in solid tumours:
learning from lung cancer. Nat Rev Clin Onc. 2014; 11: 473-481.
7. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4 ALK fusion gene and efficacy of an 
ALK kinase inhibitor in lung cancer. Clin Canc Res. 2008; 14: 4275 4283.
8. Ou S H I, Bartlett CH, Mino Kenudson M, Cui J, Iafrate AJ. Crizotinib for the Treatment 
of ALK Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the 
Second Decade of Molecular Targeted Therapy in Oncology. The Oncologist. 2012; 
17(11):1351 1375.
9. Gou LY, Wu YL. Prevalence of driver mutations in non-small-cell lung cancers in the 
People's Republic of China. Lung Cancer (Auckland, NZ) 2014; 5: 1-9.
10. Bergethon K et al ROS 1 Rearrangement define a unique molecular class of lung cancer. 
J Clinical Oncology 2012; 30: 863 870.
11. Kwak E et al Anaplastic Lymphoma Kinase Inhibition in Non-Smal Cell Lung Cancer. N 
Engl J Med 2010; 363:1693 1703.
12. Kim D.W. et al. Results of a global phase II study with crizotinib in advanced ALK
positive non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr 7533).
13. Shaw A.T. and Engelman J.A. ALK in Lung Cancer: Past, Present, and Future. J Clin.
Oncol. 2013; 31 (8):1105-11.


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14. Otterson G.A.Clinical characteristics of ALK+ NSCLC patients treated with crizotinib
beyond disease progression (PD): Potential implication for management. J Clin Oncol
2012; suppl: abstr 7600.
15. Camidge, D.R. Taking Aim at ALK Across the Blood Brain Barrier. J Thorac Oncol.
2013; 8 (4):389 90.
16. Doebele R et al. Mechanisms of resistance to crizotinib in patients with ALK gene
rearranged Non Small Cel Lung Cancer. Clin Cancer Research 2012; 18(5):1472-82.
17. Yamada T et al. Paracrine receptor activation by microenvironment triggers by pass
survival signals and ALK inhibitor- resistance in EML4-ALK lung cancer. Clin Cancer
Research 2012; 18(13): 3592-3602.
18. Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., et al.
EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors. N
Engl J Med 2010; 363(18):1734-39.
19. Katayama, R et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung 
cancers. Sci.Transl. Med. 2012; 3: 120ra17.
20. Shaw A.T., Kim D.W., Mehra R,, et al: Ceritinib in ALK-rearranged non-small-cell lung 
cancer. N Engl J Med 2014,370: 1189-1197.
21. Shaw AT, Kim TM, Crino L, et al. Ceritinib versus chemotherapy in patients with ALK-
rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib 
(ASCEND-5): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology 
2017; 18(7): 874-86.
22. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based 
chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a 
randomised, open-label, phase 3 study. Lancet (London, England) 2017; 389(10072): 
917-29.
23. Ou SH, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged 
Non-Small-Cell Lung Cancer: A Phase II Global Study. Journal of clinical oncology: 
official journal of the American Society of Clinical Oncology 2016; 34(7): 661-8.
24. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-
Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 2017; 
377(9): 829-38.
25. Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and 
Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer discovery 
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26. Zou, H et al. PF 06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and
second generation ALK inhibitors in preclinical models. Cancer Cell 28: 70 81, 2015.
27. Bauer, TM, Clinical Activity and Safety of the ALK /ROS1 TK Inhibitor PF 06463922 in 
Advanced NSCLC Oral Presentation 33.07, World Conference on Lung Cancer, Denver, 
Colorado, September 2015.
28. Novello, S et al. Primary results from the phase III ALUR study of alectinib versus 
chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC). Abstract 
#1299O, 2017 ESMO Congress.
29. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. The New England journal of medicine 2013; 368(25): 
2385-94.
30. Smith,TJ et al. Recommendations for the Use of WBC Growth Factors: American
Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol, 2015;33.
31. Long G et al. Dabrafenib in patients with Val600GLu or Val600Lys BRAF-mutant
melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, Phase 2 trial. 
Lancet Oncology 2012; 13:1087-1095.
32. Posner K, Brown GK, et al. The Columbia–Suicide Severity Rating Scale: Initial Validity 
and Internal Consistency Findings from Three Multisite Studies with Adolescents and 
Adults. Am J Psychiatry 2011; 168: 1266-1277.
33. Nada A et al. The evaluation and management of drug effects on cardiac conduction (PR 
and QRS Intervals) in clinical development. Am Heart J 2013;165:489-500.


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
A p pe n di x 1. A b bre vi ati o ns
T his f oll o wi n g is a list of a b bre viati o ns t hat ma y  be use d i n t he pr ot oc ol. 
A b bre vi ati o n
Ter m
A D M E
A bs or pti o n, Distri b ut i o n, Meta b olis m a n d Eli minati o n
A E
a dvers e e ve nt
A L K
a na plastic l y m p h o ma ki nase
A L T
ala ni ne a mi n otra nsferase
A N C
A bs ol ute ne utr o p hils c o u nt
P D - 1
pr o gra m me d cell deat h pr otei n 1
P D -L 1
pr o gra m me d cell deat h pr otei n li ga n d 1
AI D S
ac q uire d i m m u n o deficie nc y  sy n dr o me
A S C O
A meric a n S ociet y of Cli nical O nc ol o g y
A S T
as partate a mi n otra nsferase
A U C
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve
A U Ci nf
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve t o i nfi nit y
A U Ct
area u n der t he plas ma c o nce ntrati o n vers us ti me pr ofile fr o m
ti me 0 t o time t
A U Cta u
area u n der t he plas ma c o nce ntrati o n vers us ti me pr ofile wit hi n a 
d ose i nter val
B B B
bl o o d brai n barrier
BI D
bis i n die (t wice dail y)
B N P
B- t ype natri uretic pe pti de
C 1 D 1
c yc le 1, da y 1
C D x
C o m pa n i o n Dia g n ostics
C ma x
ma xi m u m plas ma c o nce ntrati o n
C tr o u g h
tr o u g h plas ma c o nce ntrati o n
C B R
Cli nical Be nefit Res p o nse
C D
cl uster of differe ntiati o n
C D S
C ore data s heet
Ceff
effecti ve c o nce ntrati o n
C F D A
C hi na F o o d a n d Dr u g A d mi nistrati o n
CI
c o nfi de nce i nter val
C K
creati ne ki nase
C L / F
oral plas ma cleara nce
C N S
ce ntral ner v o us s ys te m
C R
C o m plete res p o nse
C R F
case re p ort f or m
C R M
c o nti n ual reassess me nt met h o d
C S A
cli nical st u d y a gree me nt
C CI
C CI
C CI


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
A b bre vi ati o n
Ter m
C S F
cerebr os pi nal fl ui d
C- S S R S
C ol u m bia S uici de Se verit y  Rati n g Scale
C S R
cli nical st u d y re p ort
C T
C o m p ute d t o m o gra p h y
C T A
cli nical trial a p plicati o n
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C T L A- 4
c yt ot oxic T l y m p h oc y te ass ociate d a nti ge n 4
C V
C oefficie nt of variati o n
C Y P
c yt oc hr o mes P 4 5 0
D DI
Dr u g - dr u g i nteracti o n
DI LI
dr u g -i n d uce d li ver i nj ur y
D L T
d ose -li miti n g t o xicit y
D M C
data m o nit ori n g c o m mittee
D o R
d urati o n of res p onse
D U
dis pe nsa ble u nit
E- R
e x p os ure res p o nse
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E C H O
ec h ocar di o gra m
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us
E D T A
e detic aci d (et h yl e ne dia mi netetraacetic aci d)
E D P
e x p os ure d uri n g p re g na nc y
E G F R
e pi der mal gr o wt h fact or rece pt or
E M L 4
ec hi n o der m micr ot u b ule-ass ociate d pr otei n -li ke 4
E O T
e n d of treat me nt
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F D A
F o o d a n d Dr u g A d mi nistrati o n ( U nite d States)
F F P E
f or mali n fi xed para ffi n e mbe d de d
F N A
fi ne nee dle as pirati o n
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G G T
Ga m ma -gl uta m yl  tra nsferase
H 0
n ull h y p ot hesis 
H B V
he patitis B vir us
H C V
he patitis C vir us
H D P E
Hi g h De nsit y  P olyet h yl e ne
HI V
h u ma n i m m u n o def icie nc y vir us
H D L
h i g h de nsit y li p o pr otei n
h P X R
h u ma n p re g na ne X rece pt or
H R
hazar d rati o
H R Q L
healt h -relate d q ualit y of life
C CI


L orlati ni b ( P F -0 6 4 6 3 9 2 2)
B 7 4 6 1 0 2 4
Fi nal Pr ot oc ol A me n d m e nt 1 , 1 1 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
A b bre vi ati o n
Ter m
H R T
h or m o ne re place me nt t hera p y
I B
I n vesti gat or’s Br oc h ure
I C- D oR
D urati o n of I ntracra nial Res p o nse
I CF
I nf or me d c o nse nt for m
I CH
I nter nati o nal C o nfere nce o n Har m onisati o n
I C-O R
I ntracra nial O bjecti ve Res p o nse
I C-O R R
I ntracra nial O bjecti ve Res p o nse Rate
I C D
i nf or me d c o nse nt d oc u me nt
I C R
I n de pe n de nt Ce ntral Ra di ol o g y
I D
i de ntificati o n
I L D
i nterstitial l u n g disease
I ND
i n vesti gati o nal ne w dr u g a p plicati o n
I N R
i nter nati o nal n or malize d rati o
I P
i n vesti gati o nal pr o d uct
I RB
i nstit uti o nal re vie w b oar d
I R C
i nter nal re vie w c o m mittee
I R T
i nteracti ve res p o nse tec h n ol o g y
I UD
i ntra uteri ne de vice
I W R
i nteracti ve we b res p o nse
K 2E D T A
di p otass i u m et h yle ne dia mi netetraacetic aci d
K R A S
Kirste n rat sarc o ma vir us
L D L
lo w de nsit y  pr otei n
L F T
li ver f u ncti o n test
LI C
lea d-i n c o h ort
L L N
l o wer li mit of n or mal
L S L V
last s u bject last visit 
L V E F
left ve ntricular ejecti o n fracti o n
Me d D R A
me dical dic ti o nar y for re g ulat or y  acti vities
M D Z
mi daz ola m
M RI
m a g netic res o na nce i ma gi n g
M T D
ma xi m u m t olerate d d ose
M U G A
m ulti gate d ac q uisiti o n (sca n)
N/ A
n ot a p plica ble
N CI
Nati o n al Ca ncer I ns tit ute
N D A
ne w dr u g a p pl icati o n
N G S
ne xt ge nerati o n se q ue nci n g
N S C L C
n o n- s mall cell l u n g ca ncer
N TI
n arr o w t hera pe utic i n de x
O R
O bjecti ve Res p o nse
O R R
O bjecti ve Res p o nse Rate
O S
O verall S ur vi val
P C D
pri mar y  c o m pleti o n date
C CI


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Abbreviation
Term
PD
Progression Disease
PE
physical examination
PFS
Progression-Free Survival
P-gp
Permeability glycoprotein
PI
principal investigator
PK
pharmacokinetic
PP
per protocol
PR
Partial response
PRO
Patient-Reported Outcome
PT
prothrombin time
QD
quaque die (every day)
QTc
Corrected QT Interval
Rac
accumulation ratio
RANK
receptor activator of nuclear factor kappa-Β
RECIST
response evaluation criteria in solid tumors
RNA
ribonucleic acid
ROS1
ROS proto-oncogene 1
RP2D
recommended phase 2 dose
SA
safety analysis
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
Stable disease
SIB
suicidal ideation and behavior
SOA
Schedule of Activities
SOC
Standard of care
SOP
standard operating procedure
SRSD
single reference safety document
t1/2
half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
Tmax
time to reach Cmax
TQT
thorough QT
TTP
Time to Tumor Progression
TTR
Time to Tumor Response
ULN
upper limit of normal
UGT
uridine 5'-diphospho-glucuronosyltransferase
US
United States
VAS
Visual Analogue Scale
Vz/F
apparent volume of distribution
WOCBP
Women of Childbearing Potential


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


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Appendix 3. RECIST Version 1.1 - Modified to Include Assessment of CNS Metastases
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);

5 mm for CNS lesions provided gadolinium contrast enhanced MRI is performed with
contingent slices of 1 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 to 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 the baseline and at the stipulated intervals during treatment. Exception to this 
rule is in the presence of CNS metastases 5 mm in diameter assessed by gadolinium 
contrasted MRI with slices of 1 mm (MRI slices of 1 mm for CNS lesions with a minimum 
size of 5 mm – 10 mm in size, MRI slices of 5 mm for CNS lesions greater than 10 mm); up 
to 5 CNS lesions will be permitted in addition to 5 extracranial lesions previously 


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noted.31 Target lesions should be selected on the basis of the size (lesions with the longest 
diameters) and their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically).  Target intracranial lesions need to be suitable for accurate 
measurements with a minimum size of 5 mm by brain MRI or CT or no less than double the 
slice thickness, whichever is largest.
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.


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Page 101
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.

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 6 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 evaluated
No
PR
SD
Non-PD or Not 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.


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Page 102
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 6 weeks.
NOTE: Patients with a global deterioration of health status requiring permanent
discontinuation of treatment per the investigator’s judgement 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.


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Appendix 4. Required Laboratory Tests
Hematology
Chemistry Panel
Urinalysis§
Coagulation Tests
Hemoglobin
ALT1
Protein, glucose and 
blood
Urine dipstick for urine 
protein: If positive, and 
clinically indicated, 
collect 24-hour and 
microscopic urinalyses 
(Reflex Testing)
Urine dipstick for urine 
blood: If positive, 
collect microscopic 
urinalysis (Reflex 
Testing)
PT or INR
Platelets
AST1
aPTT
WBC
Alkaline Phosphatase
Absolute Neutrophils2
Sodium
Absolute 
Lymphocytes2
Potassium
Absolute Monocytes2
Magnesium
Absolute Eosinophils2
Chloride
Absolute Basophils2
Calcium
Total Bilirubin1
BUN or Urea1
Creatinine1
Glucose1
Phosphorus or Phosphate
Albumin1
Lipids1
Total Protein1
Pregnancy Tests
Total Cholesterol1
Uric Acid1
For female patients of 
childbearing potential, 
serum or urine 
LDL1
Amylase^1
HDL1
Gamma glutamyl 
transferase (GGT)
Triglycerides1
Lactate dehydrogenase 
(LDH)
Lipase1
Infections
HBV, HCV (Screening
only and if clinically
indicated in case
infection status is
unknown)
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, total bile acids, alkaline phosphatase, and acetaminophen levels 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.  
1.
The laboratory results in fasted condition are suggested as applicable per CTCAE version 4.03 guidelines.
2.
If absolute values are not reported as per local laboratory standard practice, percentages (%) are acceptable.
ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, GGT=gamma-glutamyltransferase, HDL=High density lipoprotein,
INR=international normalized ratio, LDH=lactate dehydrogenase, LDL=Low density protein, WBC=white 
blood cell.


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Appendix 5. Medications with Potential PR Interval Prolongation Effect
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)33
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
Disopyarmide
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 interval prolongation/AVB contained with Warning 
or Precautions sections of drug labels. 
PSVT, Paroxysmal supraventricular tachycardia.

SAP_001.pdf: 
Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 1
Pr ot oc ol B 7 4 6 1 0 2 4
A P H A S E 2, M U L TI -C E N T E R, O P E N -L A B E L, D U A L -C O H O R T S T U D Y T O 
E V A L U A T E T H E E F FI C A C Y A N D S A F E T Y O F L O R L A TI NI B( P F- 0 6 4 6 3 9 2 2) 
M O N O T H E R A P Y I N A L K
I N HI BI T O R-T R E A T E D L O C A L L Y A D V A N C E D O R 
M E T A S T A TI C A L K -P O SI TI V E N O N -S M A L L C E L L L U N G C A N C E R P A TI E N T S 
I N C HI N A
Statistical A nal y sis Pla n 
( S A P)
Versi o n :
2. 0
D ate:
1 1 - Se p- 2 0 2 0


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ..................................................................................................................... 4
LI S T O F FI G U R E S ................................................................................................................... 5
1. V E R SI O N HI S T O R Y ............................................................................................................ 6
2. I N T R O D U C TI O N ................................................................................................................. 7
2. 1. St u d y  O bjecti ves ....................................................................................................... 8
2. 2. St u d y  Desi g n............................................................................................................. 8
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI N I TI O N S A N D 
C O N V E N TI O N S .................................................................................................................. 9
3. 1. Pri mar y  E n d p oi nt(s).................................................................................................. 9
3. 2. Sec o n dar y  E n d p oi nt(s).............................................................................................. 9
3. 4. Baseli ne Varia bles ................................................................................................... 1 0
3. 5. Safet y E n d p oi nts ..................................................................................................... 1 1
3. 5. 1. A d ver se E ve nts ........................................................................................... 1 1
3. 5. 2. A d verse E ve nts of S pecial I nterest ( A E SI) ................................................ 1 1
3. 5. 3. L a b orat or y Data.......................................................................................... 1 1
4. A N A L Y SI S S E T S ............................................................................................................... 1 2
4. 1. F ull A nal ys is Set ..................................................................................................... 1 2
4. 2. Per Pr ot oc ol ( P P) A nal y sis Set ................................................................................ 1 2
4. 3. Safet y A nal ys is( S A) Set.......................................................................................... 1 2
4. 4. Ot her A nal ys is Sets................................................................................................. 1 2
4. 4. 1. P har mac o ki netics A nal y sis Set ................................................................... 1 2
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S .................................................... 1 2
5. 1. H y p ot heses a n d Decisi o n R ules .............................................................................. 1 2
5. 1. 1. H y p ot heses a n d Sa m ple Size Secti o n ......................................................... 1 2
5. 1. 2. Decisi o n R ules ............................................................................................ 1 3
5. 2. Ge neral Met h o ds ..................................................................................................... 1 3
5. 2. 1. Data Ha n dli n g after t he C ut - off Date ......................................................... 1 3
5. 2. 2. P o oli n g of Data b y Ce nter .......................................................................... 1 3
5. 2. 3. Defi niti o n of St u d y  D a y.............................................................................. 1 4
5. 2. 4. Defi niti o n of C y cle a n d C ycle Da y ............................................................ 1 4
C CI
C CI


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 3
5. 2. 5. Defi niti o n of Start of Ne w A nti -ca ncer Dr u g T hera p y............................... 1 4
5. 2. 6. Defi niti o n of Start of Ne w A nti -ca ncer T hera p y ........................................ 1 5
5. 2. 7. Date of Last C o ntact ................................................................................... 1 5
5. 2. 8. Meas ura ble Disease.................................................................................... 1 6
5. 2. 9. T u m or Assess me nt Date ............................................................................. 1 6
5. 2. 1 0. S u m of L esi o n Dia meters ......................................................................... 1 7
5. 2. 1 1. A de q uate Baseli ne.................................................................................... 1 7
5. 2. 1 2. A de q uate P ost Baseli ne T u m or Assess me nt ............................................. 1 7
5. 2. 1 3. U nsc he d ule d Assess me nts ........................................................................ 1 7
5. 2. 1 4. Sta n dar d Deri vati o ns a n d Re p orti n g C o n ve nti o ns ................................... 1 7
5. 2. 1 5. A nal y ses f or C o nti n u o us Data .................................................................. 1 8
5. 2. 1 6. A nal y ses f or Cate g orical Data .................................................................. 1 8
5. 2. 1 7. A nal y ses f or Ti me t o E ve nt Data..............................................................1 8
5. 3. Met h o ds t o Ma na ge Missi n g Data
.......................................................................... 1 8
5. 3. 1. Missi n g Dates
............................................................................................. 1 8
5. 3. 2. Missi n g T o xicit y  Gra de of A d verse E ve nts................................................ 2 1
5. 3. 3. Missi n g P har mac o ki netic ( P K) data ........................................................... 2 2
5. 3. 4. Missi n g E C G Data ...................................................................................... 2 3
6. A N A L Y S E S A N D S U M M A R I ES ...................................................................................... 2 3
6. 1. Pri mar y  E n d p oi nt(s): O bjecti ve Res p o nse i n C o h ort 1........................................... 2 3
6. 1. 1. Se nsiti vit y / R o b ust ness A nalys es (if nee de d) .............................................. 2 5
6. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................ 2 5
6. 2. 1. O R i n C o h ort 2 ............................................................................................ 2 5
6. 2. 2. I ntracra nial O bjecti ve Res p o nse (I C- O R) i n B ot h C o h orts ........................2 5
6. 2. 3. D urati o n of Res p o nse ( D o R) i n B ot h C o h orts............................................2 6
6. 2. 4. D urati o n of I ntracra nial Res p o nse (I C -D o R) i n B ot h C o h orts................... 2 6
6. 2. 5. Ti me t o T u m or Res p o nse ( T T R) i n B ot h C o h orts...................................... 2 6
6. 2. 6. Pr o gressi o n -free S ur vi val ( P F S) i n B ot h C o h orts ...................................... 2 6
6. 2. 7. O verall S ur vi val ( O S) i n B ot h C o h orts ...................................................... 3 0
6. 2. 8. P har mac o ki netics ........................................................................................ 3 1
6. 3. Ot her E n d p oi nt(s) .................................................................................................... 3 2
C CI
C CI


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 4
6. 4. Baseli ne a n d Ot her S u m maries ............................................................................... 3 3
6. 4. 1. Baseli ne S u m maries .................................................................................... 3 3
6. 4. 2. St u d y  C o n d uct a n d S u bject Dis p ositi o n..................................................... 3 4
6. 4. 2. 1. Patie nt Dis p ositi o n .................................................................... 3 4
6. 4. 2. 2. Pr ot oc ol De viati o ns ...................................................................3 5
6. 4. 3. St u d y  Treat me nt E x p os ure ......................................................................... 3 5
6. 4. 3. 1. E x p os ure t o l orlati ni b ................................................................ 3 5
6. 4. 3. 2. D ose Re d ucti o ns, I nterr u pti o ns, a n d Dela y s ............................. 3 6
6. 4. 4. C o nc o mita nt Me dicati o ns a n d N o n -Dr u g Treat me nts ................................ 3 6
6. 4. 5. S u bse q ue nt A nti -Ca ncer T hera pies/ Pr oce d ures ......................................... 3 7
6. 5. Safet y S u m maries a n d A nal yses ............................................................................. 3 7
6. 5. 1. A d verse E ve nts ........................................................................................... 3 7
6. 5. 1. 1. A d verse E ve nts of S pecial I nterest ............................................ 3 9
6. 5. 2. Deat hs ......................................................................................................... 3 9
6. 5. 3. La b orat or y  Data.......................................................................................... 3 9
6. 5. 4. Vital Si g ns .................................................................................................. 4 2
6. 5. 5. Elect r ocar di o gra m....................................................................................... 4 3
6. 5. 6. P h y sical E xa mi nati o n ................................................................................. 4 5
6. 5. 7. L eft Ve ntric ular Ejecti o n Fracti o n ( L V E F) ................................................ 4 5
6. 5. 8. Perf or ma nce Stat us ..................................................................................... 4 5
6. 5. 9. M o o d a n d S uici dal I deati o n a n d Be ha vi or A nal y ses.................................. 4 5
7. I N T E RI M A N A L Y S E S ....................................................................................................... 4 6
8. C O N SI D E R A TI O N O N C O VI D -1 9 I M P A C T ................................................................... 4 6
9. R E F E R E N C E S .................................................................................................................... 4 7
LI S T O F T A B L E S
Ta ble 1.
S u m mar y  of Maj or C ha n ges i n S A P A me n d me nts....................................6
Ta ble 2.
O utc o me a n d e ve nt dates f or P F S a nal ys es ..............................................2 8
Ta ble 3.
Ce ns ori n g Reas o ns a n d Hierarc h y................................ ............................2 9
C CI
C CI


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
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LI S T O F FI G U R E S
Fi g ure 1 .
St u d y  B 7 4 6 1 0 2 4 Desi g n............................................................................. 9
A P P E N DI C E S
A p pe n di x 1. Deri ve d O bjecti ve Res p o nse per m R E CI S T v 1. 1 base d o n I C R Data ................4 8


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
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1. V E R SI O N HI S T O R Y
T his Statistical A nal y sis Pla n ( S A P) f or st u d y B 7 4 6 1 0 2 4 is base d o n t he pr ot oc ol a me n d me nt 
date d 1 1 Oct o ber 2 0 1 9.   
T a ble 1 .
S u m m ar y of M aj or C h a n ges i n S A P A me n d me nts
S A P 
Versi o n
D ate
C h a n ge
R ati o n ale
1. 0 
6- J u n- 2 0 1 8
Ori gi nal S A P 
N ot A p plica ble
2. 0 
1 1- Se p - 2 0 2 0
T he P C D ti me has bee n m o difie d 
fr o m 1 2 m o nt hs after last s u bject 
e nr olle d i n C o h ort 1 t o 8 m o nt hs after 
last s u bject first d ose i n st u d y 
B 7 4 6 1 0 2 4 .
U p date d t he defi niti o n of 
o n -treat me nt a n d a d di n g ne w -a nti 
ca ncer t hera p y i n Secti o n 3. 5.
U p date d t he defi niti o n of treat me nt 
e mer ge nt a d verse e ve nts( T E A E) i n 
S ecti o n 3. 5. 1.
U p date d Per Pr ot oc ol A nal y sis Set 
i n S ecti o n 4. 2.
U p date d C o h ort 2 i n S ecti o n 5. 1. 1.
A d de d defi niti o n of start of ne w 
a nti-ca ncer dr u g t hera p y a n d 
defi niti o n of start of ne w a nti -ca nc er 
t hera py i n Secti o n 5. 2. 5 a n d 
Secti o n 5. 2. 6 . 
U p date d a de q uate baseli ne i n 
Secti o n 5. 2. 1 1 (c orres p o n di n g t o 
S ecti o n 5. 2. 9 i n t he 1 st versi o n S A P).
U p date d Se nsiti vit y / R o b ust ness 
a nal ys is i n S ecti o n 6. 1. 1.
Re m o ve d t he u n necessar y a nal ys is i n 
Secti o n 6. 2. 2. a n d Secti o n 6. 2. 4.
T he rati o nale f or t his 
c ha n ge is per pr ot oc ol 
a me n d me nt a n d st u d y 
re q uire me nt


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
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U p date d ce ns ori n g met h o d f or 
a nti-ca ncer t hera pies i n Secti o n 6. 2. 6.
U p date d t he P har mac o ki netics 
a nal ys is i n Secti o n 6. 2. 8.
Re m o ve d t he s u m mar y  of relati ve 
d ose( %) i n S ecti o n 6.4 . 3. 1 a n d 
a d di n g descri pti o ns of d ose 
i nterr u pti o n i n t he case of m ulti ple 
d ose i nterr u pti o ns S ecti o n 6.4. 3. 2.
U p date d A d verse E ve nts s u m mar y  i n 
S ecti o n 6. 5. 1.
Re m o ve d u n necessar y  w or di n gs a n d 
a nal ys is i n S ecti o n 6. 5. 3.
Re m o ve d t he u n necessar y a nal ys is 
f or Vital Si g ns i n Secti o n 6. 5. 4.
C orrecte d Fri dericia’s c orrecti o n 
( Q Tc F) f or m ula a n d re m o ve d 
u n necessar y  a nalys is i n 
Secti o n 6. 5. 5.
M o difie d t he s u m mar y  of L V E F % i n 
Secti o n 6. 5. 7.
Re m o ve t he u n necessar y  a nalys is i n 
S ecti o n 6. 5. 9 .
A d de d c o nsi derati o n o n c o vi d- 1 9 
i m pact i n Secti o n 8 .
A d de d se nsiti vit y  a nal ysis f or 
pri mar y  e n d p oi nt O R R b y 
i n de pe n de nt ce ntral ra di ol o g y(I C R) 
re vie w i n A p pe n di x 1.  
2. I N T R O D U C TI O N
T his S A P pr o vi des t he detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nal yses of t he data 
c ollecte d i n st u d y B 7 4 6 1 0 2 4 . T his a nal y sis pla n is mea nt t o s u p ple me nt t he st u d y pr ot oc ol. 
A n y  de viati o ns fr o m t his a nalys is pla n will be descri be d i n t he Cli nical St u d y Re p ort. 


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
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T he pri mar y  a nalys is will i ncl u de all data u p t o a data c ut off date w hic h will be deter mi ne d 
b y  t he data mat urity a n d is c urre ntl y esti mate d t o be ar o u n d 8 m o nt hs after last s u bject first 
d ose i n st u d y  B 7 4 6 1 0 2 4. All s u m maries a n d a nal yses will i ncl u de all data pertai ni n g t o 
visits/assess me nts perf or me d u p t o a n d i ncl u di n g t he data c ut off date.
2. 1. St u d y O bjecti ves
Pri mar y  O bjecti ve(s):

T o e val uate t he a nti -t u m or effect of l orlati ni b as a si n gle a ge nt as meas ure d b y 
o bjecti ve res p o nse rate ( O R R ) per R E CI S T v 1. 1 i n l ocall y  a d va nce d or metastatic 
A L K -p ositi ve N S C L C patie nts w h ose disease has pr o gresse d after criz oti ni b 
treat me nt.
Sec o n dar y  O bjecti ve(s):

T o e val uate t he a nti -t u m or effect of l orlati ni b as a si n gle a ge nt as meas ure d b y  O R R 
per R E CI S T v 1. 1 i n l ocall y  a d va nce d or metastatic A L K-p ositi ve N S C L C patie nts 
w h ose disease has pr o gresse d after A L K i n hi bit or treat me nt ot her t ha n criz oti ni b.

T o e val uate t he pr o gressi o n- free s ur vi val ( P F S) a n d o verall s ur vi val ( O S) i n l ocall y 
a d va nce d or metastatic A L K -p ositi ve N S C L C patie nts w h ose disease has pr o gresse d 
after criz oti ni b a n d ot her A L K i n hi bit or treat me nt, res pecti vel y.

T o e val uate ot her a ntit u m or acti vit ies i n l ocall y a d va nce d or metastatic A L K-p ositi ve 
N S C L C patie nts w h ose disease has pr o gresse d after criz oti ni b a n d ot her A L K 
i n hi bit or treat me nt, res pecti vel y.

T o e val uate t he safet y a n d t olera bilit y of l orlati ni b treat me nt i n l ocally a d va nce d or 
metastatic A L K + N S C L C patie nts w h ose disease has pr o gresse d after criz oti ni b a n d 
ot her A L K i n hi bit or treat me nt .

T o e val uate t he p har mac o ki netics of l orlati ni b a n d p ote ntial 
p har mac o ki netic/ p har mac o d y na mics relati o ns hi p f or l orlati ni b if a p pr o priate.
 
 
2. 2. St u d y Desi g n
T his is a n o pe n -la bel, m ulti -ce nter, P hase 2, d ual -c o h ort st u d y of e val uat i n g t he efficac y a n d 
safety of P F - 0 6 4 6 3 9 2 2 as a m o n ot hera p y i n patie nts wit h A L K- p ositi ve l ocall y  a d va nce d or 
metastatic N S C L C.
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A p pr o xi matel y  1 0 0 patie nts wit h l ocall y a d va nce d or metastasis A L K-p ositi ve N S C L C will 
be e nr olle d t o recei ve l orlati ni b m o n ot hera p y . I n C o h ort 1 a p pr o xi matel y 6 6 patie nts w h ose 
disease has pr o gresse d after criz oti ni b will be e nr olle d, a n d i n C o h ort 2, a p pr o xi matel y  
3 4 patie nts w h ose disease has pr o gresse d after A L K i n hi bit or ot her t ha n criz oti ni b.
A c ycle d urati o n will be 3 wee ks ( 2 1 d a ys) a n d will al wa ys be c o nsi dere d 3 wee ks
irres pecti ve of a ny d ose dela y s/ d osi n g i nterr u pti o ns or misse d d oses w hic h ma y affect
n o mi nal da y s of eac h c ycle.
T he st u d y  desi g n is ill ustrate d i n Fi g ure 1 bel o w.
Fi g ure 1 .
St u d y B 7 4 6 1 0 2 4 Desi g n
St u d y  treat me nt ma y c o nti n ue u ntil c o nfir me d disease pr o gressi o n assesse d b y I C R, s u bject
ref usal, s u bject l ost t o f oll o w-u p, u nacce pta ble t o xicit y , or t he st u dy is ter mi nate d b y t he
s p o ns or, w hic he ver c o mes first. Su bject s w h o de vel o p ra di ol o gical disease pr o gressi o n 
c o nfir me d b y I C R assess me nt b ut are ot her wise c o nti n ui n g t o deri ve cli nical be nefit fr o m 
st ud y  treat me nt will be eli gi ble t o c o nti n ue wit h t he treat me nt t he y ha ve bee n assi g ne d t o, 
pr o vi de d t hat t he treati n g p h y sicia n has deter mi ne d t hat t he be nefit/ris k f or d oi n g s o is 
fa v ora ble. 
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D 
C O N V E N TI O N S
3. 1. Pri m ar y E n d p oi nt(s)

O bjecti ve Res p o nse ( O R) i n patie nts w h ose disease ha ve pr o gresse d after criz oti ni b 
( C o h ort 1) b y i n de pe n de nt ce ntral ra di ol o g y (IC R) assess me nt per R E CI S T v 1. 1 . O R 
is defi ne d as a c o m plete res p o nse ( C R) or partial res p o nse ( P R) rec or de d fr o m 
e nr oll me nt u ntil disease pr o gressi o n or start of ne w a nti- ca ncer t hera p y.  B ot h C R a n d 
P R m ust be c o nfir me d b y re peat assess me nts perf or me d n o less t ha n 4 wee ks after t he 
criteri a f or res p o nse are first met.
3. 2. Sec o n d ar y E n d p oi nt(s)

O R i n patie nts w h ose disease ha ve pr o gress after A L K i n hi bit or treat me nt ot her t ha n 
criz oti ni b (C o h ort 2 ) as assesse d b y R E CI S T v 1. 1 per I C R assess me nt.


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
Pr o gressi o n -free s ur vi val ( P F S) base d o n I C R assessme n t a n d i n vesti gat or assess me nt
b y  R E CI S T v. 1. 1 is defi ne d as t he ti me fr o m first d ose t o first d oc u me ntati o n of 
o bjecti ve disease pr o gressi o n or t o deat h d ue t o a n y ca use, w hic he ver c o mes first i n 
b ot h C o h ort 1 a n d C o h ort 2 .

O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m first d ose t o t he date of deat h d ue t o 
a n y ca use. 

I ntracra nial o bjecti ve res p o nse(I C- O R)
I C-O R is defi ne d t he sa me as O R, b ut li mite d t o I ntra Cra nial lesi o ns o nl y  o n patie nts 
wit h C N S metastases (ie, Best O verall I ntracra nia l Res p o nse as c o nfir me d C R or 
c o nfir me d P R c o nsi deri n g o nl y t he lesi o ns ha vi n g disease site as Brai n).

D urati o n of res p o nse ( D o R )
D o R is defi ne d as t he ti me fr o m t he first d oc u me ntati o n of C R or P R t o t he first 
d oc u me ntati o n of disease pr o gressi o n or deat h d ue t o a n y  ca use, w hic he ver occ urs 
first. 

D urati o n of i ntracra nial res p o nse (I C-D o R)
I C-D o R is defi ne d t he sa me as D o R , b ut li mite d t o Intra Cra nial lesi o ns o nl y  o n 
patie nts wit h C N S metastases (ie, Best O verall I ntracra nial Res p o nse as c o nfir me d 
C R or c o nfir me d P R c o nsi deri n g o nl y t he lesi o ns ha vi n g disease site as Brai n).

Ti me t o t u m or res p o nse ( T T R)
T T R is defi ne d as t he ti me fr o m first d ose t o first d oc u me ntati o n of o bjecti ve t u m or 
res p o nse ( C R or P R).

P K: para meters o n da y  1 of c ycle 1 a n d at stea d y s tate: Cma x , Tma x , A U Ct, A U Cta u at 
stea d y state, A U C
i nf ,C L / F, Vz/ F, t1/ 2 a n d R ac as data per mit .
 
3. 4. B aseli ne V ari a bles
A n y  de viati o ns fr o m t he pr ot oc ol s pecifie d wi n d o w will be d oc u m e nte d as pr ot oc ol 
de viati o ns.  A se parate defi niti o n of a de q uate baseli ne will be pr o vi de d f or t u m or assess me nt 
relate d efficac y e n d p oi nts. 
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F or efficac y  a nal yses, safet y (i ncl u di n g Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
perf or ma nce stat us) a n d baseli ne c haracteristics ass oc iate d wit h t u m or assess me nts 
(e g, n u m ber of sites of disease at baseli ne), t he last assess me nt pri or t o first d ose will ser ve as 
t he baseli ne assess me nt.  
Tri plicate E C Gs are c ollecte d; t heref or e t he baseli ne f or eac h E C G meas ure me nt is t he 
a vera ge of t he pre-d ose meas ure me nts o n t he baseli ne da y .  U nsc he d ule d assess me nts will 
n ot be i ncl u de d i n t he calc ulati o n of t he a vera ge.  M ost of t he E C G para meters will n ot be 
deri ve d as t he y  are pr o vi de d by sites o n t he C R F. Q Tc F ( Fri dericia’s c orrecti o n) a n d Q Tc B 
( Bazett’s c orrecti o n) will be deri ve d base d o n R R a n d Q T.  T he a vera ge of t he re plicate 
meas ure me nts will be deter mi ne d after t he deri vati o n of t he i n di vi d ua l para meters at eac h 
ti me p oi nt.
3. 5. S afet y E n d p oi nts
Safet y  e n d p oi nts will be s u m marize d base d o n t he o n-treat me nt peri o d u nless ot her wise 
s pecifie d.
O n -treat me nt is defi ne d as t he ti me fr o m t he first d ose of st u d y treat me nt t hr o u g h t he e n d of 
st u d y f oll o w-u p (i nfi nite la g) or start of ne w a nti-cancer dr u g t hera p y, w hic he ver occ urs first.
A d verse e ve nts occ urri n g o n t he sa me da y  as t he first d ose of st u d y treat me nt will be 
c o nsi dere d t o ha ve occ urre d d uri n g t he o n -treat me nt peri o d. All ot her assess me nts w hic h 
occ ur o n t he sa me da y  as t he first d ose of st u d y treat me nt will be c o nsi dere d baseli ne 
assess me nts (see S ecti o n 3. 4 f or t he defi niti o n of baseli ne).
Safet y  data c ollecte d o utsi de t he o n -treat me nt peri o d as descri be d a b o ve will be liste d b ut n ot 
s u m marize d.
3. 5. 1. A d verse E ve nts
A n a d verse e ve nt is c o nsi dere d treat me nt e mer ge nt ( T E A E) if t he e ve nt occ urs d uri n g t he
o n -treat me nt peri o d.
3. 5. 2. A d verse E ve nts of S peci al I nterest ( A E SI) 
A E SI s i ncl u de e ve nts s uc h as C N S ( m o o d, s peec h, c o g niti o n) e ve nts. T hese e ve nts will be 
defi ne d base d o n a list of Me d D R A Preferre d Ter ms s pecifie d i n t he Safet y Re vie w Pla n f or 
l orlati ni b. A fi nal list will be pr o vi de d t o pr o gra m mi n g pri or t o data base release.
3. 5. 3. L a b or at or y D at a
He mat ol o g y , c he mistr y, li pi ds , coa g ulati o n a n d uri nal y sis res ult will be pr o gra m matically 
gra de d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3 f or rele va nt para meters.  A s hift s u m mar y 
of baseli ne gra de b y ma xi m u m p ost -baseli ne gra de will be prese nte d.  Para meters w hic h 
ca n n ot be gra de d will be s u m marize d relati ve t o t he n or mal ra n ge (ie, n or mal ra n ge hi g h or 
n or mal ra n ge l o w).  A d diti o nal details are pr o vi de d i n S ecti o n 6. 5. 3 .


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4. A N A L Y SI S S E T S
Data f or all s u bjects will be assesse d t o deter mi ne if s u bjects meet t he criteria f or i ncl usi o n i n 
eac h a nal ys is p o p ulati o n pri or t o releasi n g t he data base a n d classificati o ns will be 
d oc u me nte d per sta n dar d o perati n g pr oce d ures.
4. 1. F ull A n al ysis Set
T he f ull a nal ys is ( F A) set will i ncl u de all patie nts w h o are e nr olle d, re gar dless of w het her or 
n ot treat me nt wa s recei ve d.
4. 2. P er P r ot oc ol ( P P) A n al ysis Set 
T he per pr ot oc ol a nal ys is set will i ncl u de all e nr olle d s u bjects wit h A L K p ositi ve N S C L C, 
recei ve d a pri or A L K i n hi bit or as pr ot oc ol re q uire d, a n d w h o recei ve d at least 1 d ose of 
l orlati ni b:

I n C o h ort 1, recei ve d criz oti ni b as t he o nl y A L K i n hi bit or.

I n C o h ort 2, recei ve d o ne A L K i n hi bit or ot her t ha n criz oti ni b, wit h or wit h o ut pri or 
criz oti ni b treat me nt.
4. 3. S afet y A n al ysis ( S A) Set
T he safet y a nal ys is set i ncl u des all e nr olle d patie nts w h o recei ve at least o ne d ose of 
l orlati ni b.
4. 4. Ot her A n al ysis Sets
4. 4. 1. P h ar m ac o ki netics A n al ysis Set
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all e nr olle d patie nts w h o recei ve at least 
o ne d ose of st u d y me dicati o n a n d ha ve s ufficie nt i nf or mati o n t o esti mate at l east 1 of t he P K 
para meters of i nterest.
 
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S
5. 1. H y p ot heses a n d Decisi o n R ules
5. 1. 1. H y p ot heses a n d S a m ple Size Secti o n
C o h ort 1:
T he pri mar y  o bjecti ve of t he st u d y  is t o e val uate t he a nti-t u m or effect of l orlati ni b as a si n gle 
a ge nt as meas ure d b y O R R per R E CI S T v 1. 1 i n l ocall y a d va nce d or metastatic A L K-p ositi ve 
N S C L C patie nts w h ose disease has pr o gresse d after criz oti ni b treat me nt , ie, C o h ort 1. 
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T he st u d y  is desi g ne d t o test t he n ull h y p ot hesis H 0: O R R < = 3 0 % vs. H A : O R R > 5 0 %. 
Ass u mi n g at least a 2 0 % i ncrease of O R R wit h l orlati ni b treat me nt, 6 6 patie nts will be 
re q uire d t o pr o vi de 9 0 % p o wer t o reject t he n ull h yp ot hesis at a si g nifica nce le vel of 
0. 0 2 5 ( o ne-si de d).
C o h ort 2 :
N o f or mal statistical h y p ot hesis testi n g is plan ne d f or C o h ort 2. T his c o h ort will e x pl ore t he 
safety a n d efficac y of l orlati ni b after o ne A L K i n hiti b or treat me nt ot her t ha n criz oti ni b wit h 
3 4 patie nts pla n ne d t o be e nr olle d.
T he sa m ple size of 3 4 patie nts will pr o vi de t he esti mate d O R R wit h a ma xi m u m wi dt h of t he 
9 5 % CI  of 3 5 %, o bser ve d wit h 1 7 res p o nses o ut of 3 4 patie nts. I n or der t o c ollect m ore
i nf or mati o n of a nti-t u m or acti vit y, if t he patie nts recei ve d st u d y treat me nt b ut wit h o ut
a de q uate baseli ne t u m or assess me nt or wit h o ut p ost baseli n e t u m or assess me nts, a d diti o nal
patie nts ma y  be all o we d t o be e nr olle d.
Wit h
a p pr o xi matel y 6 6 a n d 3 4 patie nts i n C o h ort 1 a n d 2 res pecti vely, t his st u d y will pr o vi de 
a de q uate sa m ple size f or safet y e val uati o n wit h a mi ni mal n u m ber of 1 0 0.
5. 1. 2. Decisi o n R ules
C o h ort 1 wi ll test t he n ull h yp ot hesis H 0 : O R R < = 3 0 %. 
If at least 2 8 res p o nses are o bser ve d a m o n g t he 6 6 patie nts e nr olle d, t he n t he n ull h yp ot hesis 
will be rejecte d, a n d it will be c o ncl u de d t hat t he st u d y  has de m o nstrate d t hat t he tr ue O R R 
e xcee ds 3 0 %.
H o w e ver, if t he act ual n u m ber of patie nts is n ot e q ual t o 6 6 at t he ti me of fi nal a nal ys is of 
O R R i n C o h ort 1, t he testi n g will de pe n d o n t he e xact n u m ber of patie nts e nr olle d. If t he 
p -val ue of t he test < 0. 0 2 5, t he n t he n ull h y p ot hesis will be rejecte d.
5. 2. Ge ner al Met h o ds 
U nless ot her wise s pecifie d, baseli ne data will be s u m marize d b y  C o h ort .  Dis p ositi o n, 
efficac y, e x p os ure (i ncl u di n g c o nc o mita nt t hera pies), a n d safety data will als o be 
s u m marize d b y C o h ort a n d T otal .
5. 2. 1. D at a H a n dli n g after t he C ut -off D ate 
Data after t he c ut-off date ma y  n ot u n der g o t he clea ni n g pr ocess a n d will n ot be dis pla ye d i n  
a n y listi n gs or use d f or s u m mar y statistics, statistical a nalys es or i m p utati o ns.
5. 2. 2. P o oli n g of D at a b y C e nter 
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss ce nters.  
T he ‘ce nter’ fact or will n ot be c o nsi dere d i n statistical m o dels or f or s u bset a nal ys es d ue t o 
t he hi g h n u m ber of partici pati n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of 
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5. 2. 3. Defi niti o n of S t u d y D a y
Start da y  of st u d y treat me nt is t he da y of t he first d ose of st u d y treat me nt.
T he st u d y  d a y f or assess me nts occ urri n g o n or after t he first d ose of st u d y treat me nt 
(e g, a d verse e ve nt o nset, la b orat or y date, t u m or meas ure me nt) will be calc ulate d as:
St u d y  d a y = Date of t he assess me nt/e ve nt - start date of st u d y treat me nt + 1. 
T he st u d y  d a y f or assess me nts occ urri n g pri or t o t he first d ose of st u dy treat me nt 
(e g, baseli ne c haracteristics, me dical hist or y ) will be ne gati ve a n d calc ulate d as:
St u d y  d a y = Date of t he assess me nt/e ve nt – start date of st u d y treat me nt.
T he st u d y  d a y will be dis pla ye d i n all rele va nt data listi n gs.
5. 2. 4. Defi niti o n of C ycle a n d C ycle D a y 
C y cle start a n d e n d dates are deri ve d per patie nt. 
L orlati ni b is a d mi nistere d e ver y 3 wee ks i n a c ycle; t heref ore t he n o mi nal c ycle le n gt h is 
2 1 da y s.
F or C ycle X, t he act ual c ycle start date f or eac h s u bject is t he earliest start date of d osi n g
( d ose > 0 at t hat visit ) i n C ycle X visit C R F e x p os ure pa ge. 

F or all b ut t he last c y cle;

A ct ual c ycle st o p date is calc ulate d as t he start date of t he ne xt c y cle mi n us o ne da y. 

A ct ual c ycle d urati o n is calc ulate d fr o m Da y 1 of a c ycle t o t he da y pri or t o Da y 1 of 
t he ne xt c ycle, as f oll o ws: 
Act ual C ycle D urati o n ( wee ks) = (c y cle st o p date – c ycle start date + 1) / 7 

F or t he last c y cle, act ual c ycle d urati o n is calc ulate d as f oll o ws: 
Act ual C y cle D urati o n ( wee ks) = (last date of st u d y  treat me nt– c ycle start 
date + 1) / 7 
T he c y cle da y will be calc ulate d as:
C y cle da y = Date of t he assess me nt/e ve nt – c ycle start date + 1. 
5. 2. 5. Defi niti o n of St art of Ne w A nti-c a ncer Dr u g T her a p y
Start date of ne w a nti -ca ncer dr u g t hera p y is use d t o deter mi ne t he e n d of t he o n -treat me nt 
peri o d (see Secti o n 3. 5 ).


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T he start date of ne w a nti -ca ncer dr u g t hera p y is t he earliest start date of a nti -ca ncer dr u g 
t hera py rec or de d i n t he ‘F oll o w -u p Ca ncer T hera p y ’ e C R F pa ges t hat is after t he first d ose of 
st u d y treat me nt. W he n start date of a nti- ca ncer dr u g t hera p y is missi n g or partiall y missi n g, 
t he i m p utati o n r ules descri be d i n Secti o n 5. 3. 4 s h o ul d be a p plie d usi n g o nl y data fr o m t he 
‘F oll o w -u p Ca ncer T hera p y ’ e C R F pa ges.
5. 2. 6. Defi niti o n of St art of Ne w A nti- c a ncer T her a p y
Start date of ne w a nti -ca ncer t hera p y ( dr u g, ra diati o n, s ur ger y) is use d f or ce ns ori n g i n
efficac y a nalys es (see Secti o n 6. 2. 6 ).
T he start date of ne w a nti -ca ncer t hera p y is t he earliest date after first d ose a m o n gst t he 
f oll o wi n g:

Start date of a nti -ca ncer dr u g t hera p y rec or de d i n t he ‘F oll o w -u p Ca ncer T hera p y’
e C R F pa ges .

Start date of ra diati o n t hera p y rec or de d i n ‘C o nc o mita nt Ra diati o n T hera p y ’, a n d 
‘F oll o w -u p Ra diati o n T hera p y ’ e C R F pa ges wit h ‘Treat me nt I nte nt’ = ‘ C urati ve i n 
i nte nt’.

S ur ger y  date rec or de d i n ‘C o nc o mita nt S ur ger y ’, a n d ‘F oll o w -u p S ur ger y ’ e C R F 
pa ges w he n ‘S ur ger y  O utc o me’ = ‘ Resecte d’ or ‘Partiall y  Resecte d’. 
W he n start date of a nti -ca ncer t hera p y is missi n g or partiall y missi n g, t he i m p utati o n r ules 
descri be d i n Secti o n 5. 3. 1 s h o ul d be ap plie d usi n g ‘F oll o w -u p Ca ncer T hera p y ’, 
‘C o nc o mita nt Ra diati o n T hera p y’, ‘ F oll o w -u p Ra diati o n T hera p y ’, ‘C o nc o mita nt S ur ger y ’, 
a n d ‘F oll o w -u p S ur ger y ’ e C R F pa ges.
5. 2. 7. D ate of L ast C o nt act 
T he date of last c o ntact will be deri ve d f or patie nts n ot k n o w n t o ha v e die d at t he data c ut off 
date us i n g t he latest c o m plete date (ie, i m p ute d dates will n ot be use d i n t he deri vati o n) 
a m o n g t he f oll o wi n g:

All patie nt assess me nt dates (e g, bl o o d dra ws (la b orat or y , P har mac o ki netics ( P K)), 
vital si g ns, p h y sical e xa m, perf or ma nce stat us, E C G, Ec h ocar di o gra ms 
( E C H O)/ m ulti gate d ac q uisiti o n ( MU G A) sca ns, t u m or assess me nts , M o o d a n d 
S uici dal I deati o n assess me nt );

Start a n d st o p dates of c o nc o mita nt t hera pies i ncl u di n g n o n -dr u g treat me nts or 
pr oce d ures ;

Start a n d e n d dates of a nti-ca ncer t hera pies a d mi nistere d after st u dy treat me nt 
disc o nti n uati o n i ncl u di n g s y ste mic t hera p y, ra diati o n, a n d s ur geries;

A E start a n d e n d dates;


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
Last date of c o ntact c ollecte d o n t he ‘ S ur vi val F oll o w- u p’ C R F ( d o n ot use date of 
s ur vi val f oll o w-u p ass ess me nt u nless stat us is ‘ali ve’);

St u d y treat me nt start a n d e n d dates;

Date of disc o nti n uati o n o n dis p ositi o n C R F pa ges ( d o n ot use if reas o n f or 
disc o nti n uati o n is l ost t o f oll o w -u p or deat h).
O nl y  dates ass ociate d wit h act ual e xa mi nati o ns of t he patie nt will be use d i n t he deri vati o n.  
Dates ass ociate d wit h a tec h nical o perati o n u nrelate d t o patie nt stat us s uc h as t he date a 
bl o o d sa m ple was pr ocesse d or dates w he n data were e ntere d i nt o t he C R F will n ot be use d. 
Assess me nt dates after t he data c ut off date will n ot be a p plie d t o deri ve t he last c o ntact date.
5. 2. 8. Me as ur a ble Dise ase 
A patie nt will be c o nsi dere d t o ha ve meas urea ble disease if t here is at least o ne tar get lesi o n 
i de ntifie d at baseli ne meeti n g t he f oll o wi n g criteria: 

N o n l y m p h n o de lesi o ns wit h l o n gest dia meter ≥1 0 m m b y  C T sca n;

N o n l y m p h n o de lesi o ns wit h l o n gest dia meter ≥1 0 m m cali per meas ure me nt b y  
cli nical e xa m (lesi o ns w hic h ca n n ot be acc urately meas ure d wit h cali pers s h o ul d be 
rec or de d as n o n-meas ura ble) ;

C N S lesi o ns wit h l o n gest dia meter ≥5 m m pr o vi de d b y  ga d oli ni u m c o ntrast e n ha nce d 
M RI ;

L y m p h n o des wit h s h ort a xis ≥1 5 m m w he n assesse d b y C T. 
5. 2. 9. T u m or Assess me nt D ate
T u m or assess me nt dates will be assi g ne d differe ntl y  f or I CR assess me nt a n d f or 
i n vesti gat or’s assess me nt of t u m or data.
F or a nal y ses of I C R assess me nts, t he date of t u m or assess me nt will be deter mi ne base d o n 
t he ra di ol o gist assess me nts at eac h n o mi nal ti me p oi nt a n d will be pr o vi de d o n listi n gs as t he 
ass ociate d d ate of res p o nse/ pr o gressi o n at n o mi nal ti me p oi nts.  T hese dates will als o be use d 
f or ce ns ori n g i n ti me t o e ve nt a nalys es; h o we ver, t he date of pr o gressi o n a n d res p o nse as 
pr o vi de d b y t he i n de pe n de nt ra di ol o gist will be use d i n ti me t o e ve nt e n d p oi nt a nal y ses as t he 
i n de pe n de nt ra di ol o gist pr o vi de d a n o verall assess me nt of best res p o nse a n d date of 
pr o gressi o n base d o n a re vie w of eac h n o mi nal ti me p oi nt a n d a d diti o nal cli nical i nf or mati o n 
a vaila ble f or t he deter mi nati o n of t he date of res p o nse/ pr o gressi o n .
F or a nal y ses base d o n i n vesti gat or’s assess me nt w he n res p o nse/ pr o gressi o n are deri ve d 
pr o gra m maticall y fr o m t he tar get lesi o ns meas ure me nts, n o n -tar get lesi o ns stat us, a n d ne w 
lesi o ns rec or de d o n t he C R F, t he date of t u m or assess me nt s h o ul d be deri ve d as t he earliest 
sca n/assess me nt date. Si nce t u m or assess me nts are ca pt ure d o n a l o g C R F pa ge, a cl usteri n g 
al g orit h m f or gr o u pi n g sca ns will be use d: 


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Eac h cl uster re prese nts a n act ual visit. F or eac h patie nt, t he n u m ber of cl usters is e q ual t o t he 
ma xi m u m n u m ber of assess me nts a vaila ble a m o n g all tar get a n d n o n -tar get lesi o ns. S A S 
pr oce d ure, Pr oc Fastcl us, is a p plie d t o a varia ble t hat re prese nts t he da y s fr o m t he date of 
first d ose t o t he date of t he sca n f or eac h tar get a n d n o n-tar get lesi o n ( date of sca n – date of 
first d ose + 1). T he n t he assess me nts of tar get a n d n o n -tar get lesi o ns t hat occ urre d cl ose t o 
eac h ot her i n ti me will be assi g ne d t o t he sa me cl uster.
5. 2. 1 0. S u m of Lesi o n Di a meters
F or lesi o ns t hat are assesse d as ‘t o o s mall t o meas ure’, 5 m m will be i m p ute d a n d use d i n t he 
calc ulati o n of t he s u m of t he lesi o n dia meters. 
5. 2. 1 1. A de q u ate B aseli ne
A de q uate baseli ne f or t u m or data is defi ne d usi n g t he f oll o wi n g criteria:

All baseli ne assess me nts m ust be wit hi n 2 8 da y s pri or t o dat e of first d ose .

All d oc u me nte d lesi o ns m ust ha ve n o n - missi n g assess me nts (ie, n o n missi n g 
meas ure me nts f or tar get lesi o ns a n d n o n missi n g lesi o ns stat us at baseli ne f or 
n o n -tar get lesi o ns).
5. 2. 1 2. A de q u ate P ost B aseli ne T u m or Assess me nt 
A n a de q uate assess me nt is defi ne d as a n assess me nt w here a res p o nse of C R, P R, Sta ble 
Disease ( S D), n o n -C R/ n o n -P D, or P D has bee n pr o vi de d b y t he i n vesti gat or or I C R f or t he 
a nal ys es b y i n vesti gat or or I C R res pecti vel y.  Ti me p oi nts w here t he re s p o nse is n ot e val ua ble 
or n o assess me nt was perf or me d will n ot be use d f or deter mi ni n g t he ce ns ori n g date. 
5. 2. 1 3. U nsc he d ule d Assess me nts
U nless ot her wise s pecifie d, u nsc he d ule d assess me nts will n ot be dis pla y e d i n s u m mar y ta bles 
b y  n o mi nal visit/ti me p oi nt. U n sc he d ule d assess me nts will be use d w he n deri vi n g baseli ne 
a n d w orst case o n-treat me nt f or safety a nal ys es. A d diti o nall y , u nsc he d ule d t u m or 
assess me nts will b e use d f or efficac y a nalys es (e g, defi ni n g date of pr o gressi o n/ce ns ori n g, 
best o verall res p o nse, d ate of last c o ntact).
5. 2. 1 4. St a n d ar d Deri v ati o ns a n d Re p orti n g C o n ve nti o ns
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da y s i nt o wee ks, m o nt hs or years: 
1 wee k = 7 da y s, 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.
Perce nta ges will be re p orte d t o o ne deci mal place. T he r o u n di n g will be perf or me d t o cl osest 
i nte ger/first deci mal usi n g t he c o m m o n mi d-p oi nt bet wee n t he t w o c o nsec uti ve val ues.  
E g , 5. 1 t o 5. 4 will be r o u n de d t o a n i nte ger of 5, a n d 5. 5 t o 5. 9 will be r o u n de d t o a n 
i nte ger of 6.


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5. 2. 1 5. A n al yses f or C o nti n u o us D at a
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics ie , n u m ber of 
n o n- missi n g val ues a n d n u m ber of missi n g val ues [ie , n ( missi n g)], mea n, me dia n, sta n dar d 
de viati o n ( S D), mi ni m u m, ma xi m u m a n d first a n d t hir d q uartile ( Q 1 a n d Q 3 ). 
 
 P K s u m maries will als o i ncl u de c oefficie nt of variati o n perce nt ( % C V).
I n case t he a nalys is refers o nl y t o certai n visits, perce nta ges will be base d o n t he n u m ber of 
patie nts wit h a n assess me nt at t hat vis it, u nless ot her wise s pecifie d.
5. 2. 1 6. A n al yses f or C ate g oric al D at a
Q ualitati ve varia bles will be s u m marize d b y  fre q ue nc y c o u nts a n d perce nta ges. U nless 
ot her wise s pecifie d, t he calc ulati o n of pr o p orti o ns will i ncl u de t he missi n g cate g or y .
T heref ore c o u nts of missi n g o bser va ti o ns will be i ncl u de d i n t he de n o mi nat or a n d prese nte d 
as a se parate cate g or y. 
I n case t he a nalys is refers o nl y t o certai n visits, perce nta ges will be base d o n t he n u m ber of 
patie nts wit h a n assess me nt at t hat visit, u nless ot her wise s pecifie d.
5. 2. 1 7. A n al yses f or Ti me t o E ve nt D at a
Ti me t o e ve nt e n d p oi nts will be s u m marize d usi n g t he Ka pla n -Meier met h o d a n d esti mate d 
s ur vi val c ur ves will be dis pla ye d gra p hicall y  w he n a p pr o priate.  Gra p hs will descri be t he 
n u m ber of patie nts at ris k o ver ti me. T he me dia n, first a n d t hir d q uartiles, a n d pr o ba bilities 
of a n e ve nt at partic ular p oi nts i n ti me will be esti mate d b y  t he Ka pla n-Meier met h o d.  
C o nfi de nce i nter vals f or me dia ns a n d q uartiles are base d o n t he Br o o k me y er- Cr o wley 1
met h o d .  C o nfi de nce i nter vals f or t he esti mate d pr o ba bilit y of e ve nt at a partic ular ti mep oi nt 
will be ge nerate d usi n g t he l o g( -l o g) met h o d wit h bac k tra nsf or mati o n t o a c o nfi de nce 
i nter val on t he u ntra nsf or me d scale. S u m maries of t he n u m ber a n d perce nta ges of patie nts 
wit h a n e ve nt will als o be pr o vi de d o n s u m mar y  ta bles a n d/ or fi g ures.
5. 3.
Met h o ds t o M a n a ge Missi n g D at a
U nless ot her wise s pecifie d, all data will be e val uate d as o bser ve d, a n d n o i m p utati o n met h o d 
f or missi n g val ues will be use d.
A n y  i m p utati o ns will occ ur at t he a nalys is dataset le vel.  A d diti o nall y, i n all patie nt data 
listi n gs i m p ute d val ues will be prese nte d a n d fla g ge d as i m p ute d.
Missi n g statistics, e g,
w he n t he y  ca n n ot be calc ulate d, s h o ul d be prese nte d as ‘ N D’ f or n ot 
d o ne, ‘ N R’ f or n ot reac he d or ‘ N A’ f or n ot a p plica ble.  F or e xa m ple, if N = 1, t he meas ure of 
varia bilit y  ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as ‘ N D’ or ‘ N A’. 
5. 3. 1. Missi n g D ates
F or p ur p oses of data listi n gs, dates will reflect o nl y  t he i nf or mati o n pr o vi de d b y t he 
i n vesti gat or o n t he C R F.
C CI


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If start dates f or a d verse e ve nts or c o nc o mita nt me dicati o ns are c o m pletel y missi n g a w orst 
case a p pr oac h will be ta ke n w here b y t he e ve nts will be c o ns i dere d treat me nt e mer ge nt a n d 
t he me dicati o ns will be c o nsi dere d c o nc o mita nt.  If o nl y partial i nf or mati o n are a vaila ble 
(e g, o nl y  a m o nt h a n d year or o nl y a ye ar) a n d t he partial i nf or mati o n pr o vi de s ufficie nt 
i nf or mati o n t o i n dicate t he dates are pri or to t he start of st u d y treat me nt (e g, m o nt h/ y ear less 
t ha n m o nt h/ year of first d ose) t he n t hese will be c o nsi dere d t o ha ve starte d pri or t o treat me nt; 
ot her wise a si milar w orst case a p pr oac h will a p pl y a n d t hese will be c o nsi dere d t o ha ve 
starte d after treatme nt.
D ate of L ast D ose of St u d y Tre at me nt
N o i m p utati o n will be d o ne f or first d ose date.  Date of last d ose of st u d y  treat me nt, if 
u n k n o w n or partiall y u n k n o w n, will be i m p ute d as f oll o ws:

If t he last date of st u d y treat me nt is c o m pletely missi n g a n d t he re is n o E n d of 
Treat me nt ( E O T) C R F pa ge a n d n o deat h date, t he patie nt s h o ul d be c o nsi dere d t o be 
o n g oi n g a n d use t he data c ut off date f or t he a nal ys is as t he last d osi n g date; or

If t he last date of st u d y treat me nt is c o m pletely or partiall y missi n g a n d t here is 
EI T H E R a n E O T C R F pa ge O R a deat h date a vaila ble ( o n or pri or t o t he data c ut off 
date), t he n i m p ute t his date as t he last d ose date:
= 3 1 D E C Y Y Y Y, if o nl y Year is a vaila ble a n d Year < Year of mi n ( E O T date, deat h 
date),
= Last da y  of t he m o nt h, if b ot h Year a n d M o nt h are a vaila ble a n d Year = Year of 
mi n ( E O T date, deat h date) a n d M o nt h < t he m o nt h of mi n ( E O T date, deat h date), or
= mi n ( E O T date, deat h date), f or all ot her cases.
Missi n g or P arti al De at h D ates
Missi n g or partial deat h dates will be
i m p ute d base d o n t he last c o ntact date:

If t he e ntire date is missi n g it will be i m p ute d as t he da y after t he date of last c o ntact 
(see deri vati o n of date of last c o ntact i n Secti o n 5. 2. 7 ); or
If t he da y or m o nt h is missi n g, deat h will be i m p ute d t o t he ma xi m u m of t he f ull ( n o n-
i m p ute d) da y after t he date of last c o ntact a n d t he f oll o wi n g:
Missi n g da y :
1st da y  of t he m o nt h a n d year of deat h, or
Missi n g da y a n d m o nt h: Ja n uar y  1st of t he ye ar of deat h.


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D ate of St art of Ne w A nti- c a ncer T her a p y
I nc o m plete dates f or ne w a nti -ca ncer t hera p y will be i m p ute d as f oll o ws a n d will be use d t o 
deter mi ne ce ns ori n g dates f or efficac y a nalys es:

T he e n d date of ne w a nti -ca ncer t hera p y will be i ncl u de d i n t he i m p utati o n f or start 
date of ne w a nti -ca ncer t hera p y.  If t he e n d data of ne w a nti -ca ncer t hera p y is:

C o m pletel y  missi n g t he n it will be i g n ore d i n t he i m p utati o ns bel o w, 

P artiall y missi n g wit h o nl y year a vaila ble t he n t he i m p utati o ns bel o w will 
c o nsi der 3 1 D E C Y Y Y Y as t he e n d date of t he ne w a nti- ca ncer t hera p y, or

P artiall y missi n g wit h o nl y m o nt h a n d year a vaila ble t he n t he i m p utati o ns bel o w 
will c o nsi der t he last da y of t he m o nt h f or M M M Y Y Y Y as t he e n d date of t he 
ne w a nti -ca ncer t hera p y.

F or patie nts w h o ha ve n ot disc o nti n ue d st u d y  treat me nt at t he ti me of t he data c ut off 
date, last d ose of st u d y treat me nt is set t o t he data c ut off date i n t he i m p utati o ns 
bel o w.

If t he start date of ne w a nti-ca ncer t hera p y is c o m pletel y or partiall y missi n g t he n t he 
i m p ute d start date of ne w a nti-ca ncer t hera p y is:
= 3 1 D E C Y Y Y Y, if o nl y Year is a vaila ble a n d Year < Year of mi n [ ma x ( P D date + 1, 
last d ose of st u d y treat me nt + 1), e n d date of ne w a nti -ca ncer t hera p y]
= Last da y  of t he m o nt h, if b ot h Year a n d M o nt h are a vaila ble a n d 
Year = Year of mi n [ ma x ( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d date of 
ne w a nti -ca ncer t hera p y] 
M o nt h < M o nt h of mi n [ ma x ( P D date + 1 da y , last d ose of st u d y treat me nt + 1 da y), 
e n d date of ne w a nti -ca ncer t hera p y]
= mi n [ ma x ( P D date + 1, last d ose of st u d y treat me nt + 1), e n d date of ne w 
a nti-ca ncer t hera p y] , f or all ot her cases.
A E O nset D ate:
T he f oll o wi n g i m p utati o n r ules a p ply if t he e v e nt is u ni q ue f or a patie nt or it is t he first of a 
series of si milar e ve nts; ot her wise, t he A E O nset Date will n ot be i m p ute d:

If t he A E C ollecti o n Date is n ot missi n g, is less t ha n t he Date of First E x p os ure t o 
Treat me nt, a n d is less t ha n t he A E St o p Dat e, t he n A E O nset Date is set t o t he Date of 
A E C ollecti o n.

If t he Pre vi o us Visit Date is greater t ha n t he Date of First E x p os ure t o Treat me nt a n d 
less t ha n t he A E St o p Date, t he A E Start Date is set t o t he pre vi o us visit date.


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
If t he Date of First E x p os ure t o Treat me nt is greater t ha n t he pre vi o us visit date a n d 
less t ha n t he A E St o p Date, t he A E O nset Date is set t o t he Date of First E x p os ure t o 
Treat me nt.

Ot her wise A E O nset date is set t o t he A E St o p date.
A E St o p D ate:
O n g oi n g e ve nts will ha ve t he A E St o p Date set t o o ne of t he f oll o wi n g val ues:

Date of Deat h, if t he patie nt die d a n d a date of deat h e xists.

Ma xi m u m of ( Patie nt Wit h dra w date, A E O nset Date, A E C ollecti o n Date) if t he 
patie nt wit h dre w fr o m t he st u d y  a n d a date of wit h dra w e xists.

Ma xi m u m of ( A E O nset Date, S u bject S u m mar y  C ollecti o n Date, A E C ollecti o n 
Date) if t he Dis p ositi o n C R F pa ge e xists b ut a date of wit h dra w d oes n ot e xists.

Ma xi m u m of ( Last Treat me nt Date, A E O nset Date) if n o Dis p ositi o n pa ge e xits.
I m p utati o n will o nl y occ ur if e ve nt is u ni q ue f or t he patie nt, or it is t he last of a series of 
si milar e ve nts; ot her wise t he St o p Date will n ot be i m p ute d.  A d verse E ve nts are dee me d 
si milar if t he y ha ve t he sa me ver bati m ter m.
Res ol ve d e ve nts will ha ve t he A E St o p Date set t o t he ma xi m u m of t he A E c ollecti o n date 
a n d t he A E O nset date.
Ot her Missi n g or P arti al D ates
I m p utati o n met h o ds f or ot her partial dates as f oll o ws: 

If t he da y of t he m o nt h is missi n g f or a start date use d i n a calc ulati o n, t he first da y of 
t he m o nt h will be use d t o re place t he missi n g date. 

If b ot h t he da y a n d m o nt h are missi n g, t he first da y of t he year is use d. 

F or st o p dates, t he last da y  of t he m o nt h, or last da y of t he year is use d if t he da y or 
da y  a n d m o nt h are missi n g, res pecti vely. 

If t he date is c o m pletel y missi n g, n o i m p utati o n will be perf or me d.
5. 3. 2.
Missi n g T o xicit y Gr a de of A d verse E ve nts
Pri or t o St u d y  Treat me nt: If n o t o xicit y gra de is a vaila ble or t he gra de is re p orte d as 
u n k n o w n f or a n a d verse e ve nt pri or t o t he first st u d y treat me nt, t he n Gra de 1 will be ass u me d 
f or p ur p oses of defi ni n g a baseli ne gra de f or assessi n g if f urt her occ urre nces are treat me nt 
e mer ge nt. H o we ver, if t he patie nt e x perie nces m ulti ple e pis o des of t he sa me A E pri or t o 


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st u d y treat me nt, t he n t he ma xi m u m t o xicit y gra de o bser ve d pri or t o st u dy treat me nt will be 
utilize d i n assessi n g if f urt her occ urre nces are treat me nt e mer ge nt. 
D uri n g St u d y Treat me nt: If n o t o xicit y gra de is a vaila ble or t he gra de is re p orte d as u n k n o w n 
f or a n a d verse e ve nt d uri n g t he st u dy treat me nt, t he n t he e ve nt will be c o nsi dere d treat me nt 
e mer ge nt u nless a baseli ne e ve nt was re p orte d as Gra de 4. 
I n s u m maries w hic h prese nt ma xi m u m t o xicit y gra de, t he ma xi m u m of n o n-missi n g gra des 
will be dis pla y e d.  Missi n g gra de will o nl y be dis pla ye d f or cases w her e a patie nt re p orte d 
o nl y  o ne e ve nt a n d t he gra de is missi n g.
5. 3. 3. Missi n g P h ar m ac o ki netic ( P K) d at a
C o nce ntr ati o ns bel o w t he li mit of q u a ntific ati o n
F or all calc ulati o ns, fi g ures, a n d esti mati o n of i n di vi d ual p har mac o ki netic para meters, all 
c o nce ntrati o ns as s a ye d as bel o w t he le vel of q ua ntificati o n ( B L Q) will be set t o zer o. I n 
l o g-li near pl ots t hese val ues will n ot be re prese nte d.  T he B L Q val ues will be e xcl u de d fr o m 
calc ulati o ns of ge o metric mea ns a n d t heir c o nfi de nce i nter vals. A state me nt si milar t o ‘ All 
val ues re p orte d as B L Q ha ve bee n re place d wit h zer o’ s h o ul d be i ncl u de d as a f o ot n ote t o t he 
a p pr o priate ta bles a n d fi g ures.  I n listi n gs B L Q val ues will be re p orte d as bel o w li mit of 
q ua ntificati o n (“ < L L O Q”), w here L L O Q will be re place d wit h t he c orre s p o n di n g val ue fr o m 
t he a nalyt ical assa y use d.
De vi ati o ns, Missi n g C o nce ntr ati o ns a n d A n o m al o us V al ues
I n s u m mar y ta bles a n d pl ots of me dia n pr ofiles, c o nce ntrati o ns will be set t o missi n g if o ne 
of t he f oll o wi n g cases is tr ue:

A c o nce ntrati o n has bee n re p orte d as N D (ie, n ot d o ne) or N S (ie, n o sa m ple);

A de viati o n i n sa m pli n g ti me is of s ufficie nt c o ncer n or a c o nce ntrati o n has bee n 
fla g ge d as a n o mal o us b y t he cli nical p har mac ol o gist.
S u m mar y  statistics will n ot be prese nte d at a partic ular ti me p oi nt if more t ha n 5 0 % of t he 
data are missi n g.  F or a nal y sis of p har mac o ki netic c o nce ntrati o ns, n o val ues will be i m p ute d 
f or missi n g data.
Act ual P K sa m pli n g ti mes will be use d i n t he deri vati o n of P K para meters.  If a P K 
para meter ca n n ot be deri ve d fr o m t he c o nce ntrati o n data, t he para meter will be c o de d as N C 
(ie, n ot calc ulate d). N C val ues will n ot be ge nerate d be y o n d t he da y  t hat a patie nt 
disc o nti n ues.
I n s u m mar y ta bles of c o nce ntrati o n-ti me pr ofiles or P K para meters, statistics will be 
calc ulate d b y s etti n g N C val ues t o missi n g; a n d statistics will n ot be prese nte d f or t he
treat me nt if m ore t ha n 5 0 % of t he data are n ot c ollecte d, n ot calc ulate d, or bel ow L L O Q.  F or 
statistical a nal yses (ie, a nal ysis of varia nce), P K para meters c o de d as N C will als o be set t o 
missi n g.


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
If a n i n di vi d ual patie nt has a k n o w n biase d esti mate of a P K para meter ( d ue f or e xa m ple t o a 
de viati o n f or t he assi g ne d d ose le vel), t his will be f o ot n ote d i n s u m mar y  ta bles a n d will n ot 
be i ncl u de d i n t he calc ulati o n of s u m mar y statistics or statistical a nal ys es.
5. 3. 4. Missi n g E C G D at a
F or E C G a nal ys es, n o val ues will be i m p ute d f or missi n g data (e xce pt R R val ues t hat ca n be 
deri ve d fr o m H R val ues, if prese nt. If b ot h R R a n d H R val ues are missi n g Q Tc B will n ot be 
de ter mi ne d). I n case of missi n g R R val ue, R R ( msec) will be deri ve d as ( 6 0/ H R ( b p m)) * 
1 0 0 0, if H R is c ollecte d. 
If o ne or t w o of t he tri plicate meas ure me nts f or a n E C G para meter are misse d, t he a vera ge of 
t he re mai ni n g t w o meas ure me nts or t he si n gle meas ure me nt ca n be use d i n t he a nalys es. If 
all tri plicate meas ure me nts are missi n g at a ti me p oi nt f or a n E C G para meter, n o val ues will 
be i m p ute d f or t his ti me p oi nt. If t he tri plicate nee ds t o be re peate d beca use of a n artifact, 
t he n t he re peate d tri plicate will be re p orte d o n a n u nsc he d ule d C R F pa ge. Base d o n a re vie w 
of t he data t hese u nsc he d ule d assess me nts ma y  be use d i n place of t he assess me nts at t he 
n o mi nal ti me. Data re vie w a n d c o ns ultati o n wit h t he st u d y tea m is re q uire d t o fla g t hese 
cases.
 
6. A N A L Y S E S A N D S U M M A RI E S
All efficac y  a nal yses will be perf or me d b y  C o h ort o n t he S A set. 
Ra di o gra p hic i ma ges a n d cli nical i nf or mati o n c ollecte d o n st u dy will be re vie we d b y a n I CR.  
I C R assess me nt will be use d f or t he pri mar y a nalysis of O R a n d f or all sec o n dar y e n d p oi nts 
base d o n ra di ol o gical assess me nts of t u m or b ur de n (ie, I C-O R , D oR, I C-D o R, T T R a n d
P F S ).  T hese e n d p oi nts will als o be deri ve d usi n g t he l ocal ra di ol o gist’s/i n vesti gat or’s 
assess me nt.  
6. 1. Pri m ar y E n d p oi nt (s): O bjecti ve Res p o nse i n C o h ort 1
T he pri mar y  efficac y a nal ysis will e val uate t he a nti-t u m or effect of l orlati ni b as a si n gle 
a ge nt as me as ure d b y O R per R E CI S T v 1. 1 i n l ocall y  a d va nce d or metastatic A L K-p ositi ve 
N S C L C patie nts w h ose disease has pr o gresse d after criz oti ni b treat me nt.
O R is defi ne d as a c o m plete res p o nse ( C R) or partial res p o nse ( P R) rec or de d fr o m 
e nr oll me nt u ntil disease pr o gressi o n or start of ne w a nti- ca ncer t hera p y.  B ot h C R a n d P R 
m ust be c o nfir me d b y re peat assess me nts perf or me d n o less t ha n 4 wee ks after t he criteria f or 
res p o nse are first met.  
C CI


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
O bjecti ve Res p o nse R ate ( O R R) is defi ne d as t he perce nta ge of patie nts wit h a best o verall 
c o nfir me d res p o nse of C R or P R acc or di n g t o R E CI S T v 1. 1 relati ve t o t he t otal patie nts i n 
t he a nalys is p o p ulati o n.  Patie nts wit h o ut d oc u me nte d C R or P R will be c o nsi dere d as 
n o n -res p o n ders. A d diti o nall y , patie nts wit h i na de q uate data f or t u m or assess me nt (e g, n o 
baseli ne assess me nt or n o f oll o w- u p assess me nts) will be c o nsi dere d as n o n- res p o n ders. T he 
pri mar y  e val uati o n of O R R will be base d o n IC R ’s re vie w relati ve t o t he S A set.  
T he e xact test will be perf or me d t o test t he n ull h y p ot hesis H 0: O R R < = 3 0 %.  O ne -si de d 
p -val ue will be pr o vi de d t o get her wit h t he esti mate of O R R a n d t he c orres p o n di n g e xact 
9 5 % CI .
Best o ver all res p o nse ( B O R) will be assesse d base d o n re p orte d o verall res p o nses at 
differe nt e val uati o n ti me p oi nts b y  t he i n de pe n de nt ra di ol o gist a n d b y  t he i n vesti gat or fr o m 
t he date of first d ose u ntil d oc u me nte d disease pr o gressi o n or start of ne w a nti -ca ncer 
t hera py, acc or di n g t o t he f oll o wi n g r ules:

C R = at least t w o deter m i nati o ns of C R at least 4 wee ks a part a n d d oc u me nte d bef ore 
pr o gressi o n a n d start of ne w a nti- ca ncer t hera p y.

P R = at least t w o deter mi nati o ns of P R or better (a n d n ot q ualif y i n g f or a C R) at least 
4 wee ks a part a n d bef ore pr o gressi o n a n d start of ne w a nti- ca ncer.

S D (f or patie nts wit h at least o ne meas ura ble lesi o n at baseli ne) = at least o ne S D 
assess me nt ( or better a n d n ot q ualif y i n g f or C R or P R) ≥6 wee ks after date of first 
d ose a n d bef ore pr o gressi o n a n d t he start of ne w a nti -ca ncer t hera p y.

N o n -C R/ N o n -P D (f or patie nts wit h o nl y  n o n-tar get disease at baseli ne) = at least o ne 
N o n -C R/ N o n - P D assess me nt ( or better a n d n ot q ualif y i n g f or C R or P R) ≥6 wee ks 
after date of first d ose a n d bef ore pr o gressi o n a n d t he start of ne w a nti- ca ncer 
t hera py.

P D = pr o g ressi o n ≤1 4 wee ks after date of first d ose a n d n ot q ualif y i n g f or C R, P R or 
S D .

N ot E val ua ble ( N E) = all ot her cases.
Cli nical deteri orati o n will n ot be c o nsi dere d as d oc u me nte d disease pr o gressi o n.
Patie nts wit h B O R of N E will be s u m marize d b y  reas o n f or ha vi n g N E stat us. T he f oll o wi n g 
reas o ns will be use d:

Earl y deat h defi ne d as deat h pri or t o 6 wee ks after date of first d ose ;

N o p ost -baseli ne assess me nts, f or reas o ns ot her t ha n earl y deat h ;

All p ost -baseli ne assess me nts ha ve o verall res p o nse N E;

Ne w a nti -ca ncer t hera p y starte d bef ore first p ost-baseli ne assess me nt ;


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5

S D of i ns ufficie nt d urati o n ( < 6 wee ks after first d ose);

P D t o o late ( > 1 4 wee ks after first d ose).
S pecial a n d rare cases w here B O R is N E d ue t o b o t h early S D a n d late P D will be classifie d 
as ‘ S D of i ns ufficie nt d urati o n’.
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h B O R of C R, P R, S D, P D, 
n o n -C R/ n o n -P D (a p plica ble o nl y  t o patie nts wit h n o n-meas ura ble disease at baseli ne), a n d 
N E ( n ot -e val ua ble) will be ta b ulate d.  
Waterfall pl ots dis pla y i n g t he best perce nta ge c ha n ge fr o m baseli ne i n t u m or size will be
prese nte d. T he best perce nt c ha n ge fr o m baseli ne will be calc ulate d fr o m start of st u d y  
treat me nt u p t o first visit wit h disease pr o gressi o n or t o t he last visit a vaila ble pri or t o t he 
start of ne w a nti-t u m or t hera py (f or patie nts w h o start ne w a nti -t u m or t hera p y pri or t o 
pr o gressi o n or w h o are pr o gressi o n -free patie nts at t he ti me of a nalys is).
A s pi der pl ot dis pla y i n g t he % c ha n ge fr o m baseli ne acr o ss visits i n t u m or size will be 
prese nte d. T he % c ha n ge fr o m baseli ne will be calc ulate d f r o m start of st u d y treat me nt t o 
eac h visit u p t o first visit wit h disease pr o gressi o n or t o t he la st visit a vaila ble pri or t o t he 
start of ne w a nti-t u m or t hera py (f or patie nts w h o start ne w a nti- t u m or t hera p y pri or t o 
pr o gressi o n or w h o are pr o gressi o n free patie nts at t he ti me of a nalys is).
6. 1. 1. Se nsiti vit y / R o b ust ness A n al yses (if nee de d)
T he Disa gree me nt Rate bet wee n i n vesti gat or’s assess me nt a n d I C R’s assess me nt f or O R will 
be calc ulate d i n C o h ort 1 i n t he safety a nal ysis p o p ulati o n.
Deri ve d O R R per m R E CI S T v 1. 1 base d o n t u m or assess me nt per I C R will be calc ulate d i n 
C o h ort 1 i n t he safet y a nal ysis p o p ulati o n( details ca n be f o u n d i n A p pe n di x 1 ).
Se nsiti vit y  a nal yses ma y be c o n d ucte d calc ulati n g t he sa me O R Rs relati ve t o t he P P set, if 
a p plica ble.
6. 2. Sec o n d ar y E n d p oi nt(s)
6. 2. 1. O R i n C o h ort 2
T he O R i n C o h ort 2, will be s u m marize d i n a si milar wa y  as O R i n C o h ort 1.
The esti mate 
of O R R a n d t he c orres p o n di n g 9 5 % CI will be pr o vi de d. T he fre q ue nc y  ( n u m ber a n d 
perce nta ge) of patie nts wit h B O R of C R, P R, S D, P D, n o n -C R/ n o n -P D (a p plica ble o nl y  t o 
patie nts wit h n o n - meas ura ble disease at baseli ne), a n d N E ( n ot-e val ua ble) will be ta b ulate d.   
T he waterfall pl ot a n d s pi der pl ot will be prese nte d. 
6. 2. 2. I ntr acr a ni al O bjecti ve Res p o nse (I C- O R) i n B ot h C o h or ts
T he I C-O R, will be s u m marize d si milar t o O R as descri be d a b o ve i n t he s u bset of t he S A 
p o p ulati o n wit h at least 1 i ntracra nial lesi o n.


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
I ntracra nial O R R is defi ne d as t he perce nt of patie nts wit h i ntracra nial res p o nse (ie, Best
O verall I ntracra nial Res p o nse as c o nfir me d C R or c o nfir me d P R c o nsi deri n g o nl y t he 
Lesi o ns ha vi n g Disease Site = Brai n) relati ve t o patie nts wit h Brai n lesi o ns at st u d y e ntr y, a n d 
will be pr o vi de d al o n g wit h t he c orres p o n di n g 9 5 % c o nfi de nce i nter val. T his i ncl u des 
patie nts f or w h o m t he brai n lesi o ns ha ve bee n c h o ose n as R E CI S T tar get lesi o ns or n ot.
S ur ger y  or ra di ot hera py of e xtracra nial lesi o ns will n ot affect t he deter mi nati o n of I C- O R.
6. 2. 3. D ur ati o n of Res p o nse ( D o R) i n B ot h C o h orts
D o R is defi ne d as t he ti me fr o m t he first d oc u me ntati o n of C R or P R t o t he first 
d oc u me ntati o n of disease pr o gressi o n or deat h d ue t o a n y ca use, w hic he ver occ urs first. 
D o R will o nl y  be calc ulate d f or t he s u b gr o u p of patie nts wit h a c o nfir me d o bjecti ve t u m or
res p o nse.  D o R will be s u m marize d i n t his s u b gr o u p usi n g Ka pla n-Meier met h o ds a n d will 
be dis pla y e d gra p hicall y w here a p pr o priate.  T he me dia n e ve nt ti me (if a p plica ble) a n d 
2 -si de d 9 5 % CI f or t he me dia n will be calc ulate d acc or di n g t o Br o o k me yer a n d Cr o wl e y.2  If 
t he n u m ber of patie nts wit h a c o nfir me d C R or P R is s mall a n d t he use of Ka pla n-Meier 
met h o ds ma y  be li mite d, t he D o R will be liste d.
I n case t he n u m ber of patie nts wit h Pr o gressi ve Disease after a c o nfir me d C R or P R is s mall, 
t he use of Ka pla n-Meier met h o d ma y  be li mite d s o t he D R a n d I C -D R will be s u m marize d 
usi n g N u m ber ( %) of S u bjects Ce ns ore d wit h D R less t ha n 6 m o nt hs, ≥6 - < 9 , ≥9- < 1 2, 
≥1 2 -< 1 5, ≥1 5- < 1 8, ≥1 8- < 2 1, ≥2 1- < 2 4, > = 2 4 m o nt hs.
6. 2. 4. D ur ati o n of Intr acr a ni al R es p o nse (I C-D o R) i n B ot h C o h orts
T he I C- D o R , will be s u m marize d si milar t o D o R as descri be d a b o ve i n t he s u bset of t he S A 
p o p ulati o n wit h at least 1 i ntracra nial lesi o n. S ur ger y  or ra di ot hera py of e xtracra nial lesi o ns 
will n ot affect t he deter mi nati o n of I C- D o R.
6. 2. 5. Ti me t o T u m or Res p o nse ( T T R) i n B ot h C o h orts
T T R is defi ne d as t he ti me fr o m first d ose t o first d oc u me ntati o n of o bjecti ve t u m or res p o nse 
( C R or P R).  T T R will onl y  be s u m marize d f or t he s u b gr o u p of patie nts wit h a n o bjecti ve 
res p o nse.  Descri pti ve statistics mea n, me dia n a n d ra n ge will be pr o vi de d. 
6. 2. 6. Pr o gressi o n -free S ur vi v al ( P F S) i n B ot h C o h orts
Pr o gressi o n -Free S ur vi val ( P F S) is defi ne d as t he ti me fr o m date of first d ose t o t he date of 
t he first d oc u me ntati o n P D per R E CIS T v 1. 1 as assesse d b y  t he i n de pe n de nt o nc ol o gist a n d 
i n vesti gat or or deat h d ue t o a n y ca use, w hic he ver occ urs first a n d will be s u m marize d i n 
m o nt hs:
P F S ( m o nt hs) = [ date of e ve nt or ce ns ori n g – date of first d ose + 1]/ 3 0. 4 3 7 5
P F S data will be ce ns ore d as f oll o ws:


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7

F or patie nts w h o start a ne w a nti -ca ncer t hera p y (as defi ne d i n Secti o n 5. 2. 6 ) pri or t o 
a n e ve nt, ce ns ori n g will be at t he last a de q uate t u m or assess me nt (see Secti o n 5. 2 ) 
pri or t o t he start of ne w a nti -ca ncer t hera p y.  N ote: if date of pr o gressi o n occ urs o n 
t he sa me date as t he start of ne w a nti-ca ncer t hera p y, t he pr o gressi o n will be c o u nte d 
as a n e ve nt.

F or patie nts wit h d oc u me nte d pr o gressi o n or deat h after t w o or m ore missi n g t u m or 
assess me nts, ce ns ori n g will occ ur at t he last a de q uate t u m or assess me nt pri or t o t he 
missi n g assess me nts.  I n t his st u d y  a ntit u m or acti vit y will be assesse d t hr o u g h 
ra di ol o gical t u m or assess me nts c o n d ucte d at scree ni n g a n d e ver y 6 wee ks u ntil 
disease pr o gressi o n re gar dless of i nitiati o n of s u bse q ue nt a nti -ca ncer t hera p y.  T he 
all o wa ble ti me wi n d o w f or disease assess me nts is ± 7 da y s w hile o n treat me nt a n d 
w he ne ver diseas e pr o gressi o n is s us pecte d (e g , sy m pt o matic deteri orati o n). 
T heref ore ti me wit h o ut a de q uate assess me nt is defi ne d as 9 8 d a y s ( 1 2 wee ks pl us 
2 wee ks ). 

F or patie nts w h o d o n ot ha ve a n a de q uate baseli ne t u m or assess me nt or w h o d o n ot 
ha ve a n y p ost -baseli ne t u m or asses s me nts, ce ns ori n g will occ ur o n t he date of first 
d ose u nless deat h occ urre d o n or bef ore t he ti me of t he sec o n d pla n ne d t u m or 
assess me nt (ie, o n or bef ore D a y 9 8 ) i n w hic h case t he deat h will be c o nsi dere d a n 
e ve nt.  N ote f or patie nts w h o die d wit h o ut a n y p ost baseli ne assess me nts a n d meet t he 
defi niti o n of t w o or m ore missi n g assess me nt t he reas o n f or ce ns ori n g will be 
d oc u me nte d as t w o or m ore misse d assess me nts a n d ce ns ori n g will occ ur o n t he date 
of first d ose .

All ot her patie nts ali ve wit h o ut o bjecti ve pr o gressi o n will be ce ns ore d o n t he date of 
t he last a de q uate t u m or assess me nt.
T he date of t u m or res p o nse at eac h n o mi nal ti me p oi nt base d o n t he i n de pe n de nt ra di ol o gist 
assess me nts will be use d f or deter mi ni n g t he dates of last a de q uate f or ce ns ori n g.  
T he date of t u m or res p o nse at eac h n o mi nal ti me p oi nt base d o n t he i n de pe n de nt ra di ol o gist 
assess me nts will be use d f or deter mi ni n g t he dates of last a de q uate assess me nt f or ce ns ori n g 
p ur p oses. 
T he ce ns ori n g a n d e ve nt date o pti o ns t o be c o nsi dere d f or t he P F S anal y sis are prese nte d i n 
Ta ble 2 .


Pr ot oc ol B 7 4 6 1 0 2 4 ( P F-0 6 4 6 3 9 2 2) Statistical A nal ysis Pla n
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
T a ble 2.  
O utc o me a n d e ve nt d ates f or P F S a n al yses
Sce n ari o
D ate of e ve nt/ce ns ori n g
O utc o me
N o a de q uate baseli ne assess me nt
Date of first d ose
Ce ns ore d a
Pr o gressi o n or deat h ≤9 8 da y s after 
last a de q uate t u m or assess me nt or 
9 8 da y s after  date of first d ose
Date of pr o gressi o n or 
deat h
E ve nt
Pr o gressi o n or deat h > 9 8 da y s after 
t he last a de q uate t u m or assess me ntb
Date of last a de q uate 
assess me nt b d oc u me nti n g 
n o P D pri or t o a nti -ca ncer 
t hera py or misse d 
assess me nts
Ce ns ore d
N o pr o gressi o n
Ne w a nti -ca ncer t hera p y gi ve n pri or 
t o P D
a.
If t he patie nt dies ≤9 8 da ys after date of first d ose t he deat h is a n e ve nt o n t he deat h date .
b.
If t here are n o a de q uate p ost-baseli ne assess me nts pri or t o P D or deat h, t he n t he ti me wit h o ut a de q uate 
assess me nt s h o ul d be meas ure d fr o m t he date of first d ose; if t he criteria were met t he ce ns ori n g will be 
o n t he start date.
Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d by C o h ort t o get her wit h 
a s u m mar y of ass ociate d statistics i ncl u di n g t he me dia n P F S ti me wit h t w o-si de d 9 5 % CIs.  
T he P F S rate at cli nical mea ni n gf ul ti me p oi nts will be esti mate d wit h c orres p o n di n g 
t w o-si de d 9 5 % CIs. T he CI s f or t he me dia n will be calc ulate d acc or di n g t o Br o o k me y er a n d 
Cr o wle y 2 a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d a b o ve will 
be deri ve d usi n g t he l o g( -l o g) met h o d acc or di n g t o Kal bfleisc h a n d Pre ntice 3
(c o nfty pe =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T). T he esti mate of t he sta n dar d err or 
will be c o m p ute d usi n g Gree n w o o d’s f or m ula. 
Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h e ve nt t ype ( P D or deat h) a n d 
ce ns ori n g reas o ns will be prese nte d b y  C o h ort al o n g wit h t he o verall e ve nt a n d ce ns or rates.
Reas o ns f or ce ns ori n g s h o ul d be s u m marize d acc or di n g t o t he cate g ories i n Ta ble 3 .  If a 
patie nt meets m ulti ple defi niti o ns f or ce ns ori n g t he list will be use d t o defi ne t he hierarc h y.  


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Pa ge 2 9
T a ble 3.
Ce ns ori n g Re as o ns a n d Hier arc h y
Hier arc h y
C o n diti o n
Ce ns ori n g Re as o n
1
N o a de q uate baseli ne assess me nt
N o a de q uate baseli ne 
assess me nt
2
Start of ne w a nti -ca ncer t hera p y bef ore 
e ve nt. 
Start of ne w a nti -ca ncer 
t hera py
3 
E ve nt m ore t ha n 9 8 d a y s fr o m last 
a de q uate p ost -baseli ne t u m or 
assess me nt/start date
E ve nt after missi n g 
assess me nts a
4
N o e ve nt a n d [ wit h dra wal of c o nse nt 
date ≥ start date O R E n d of st u d y  
( E O S) = S u bject ref use d f urt her 
f oll o w-u p] 
Wit h dra wal of c o nse nt
5
N o e ve nt a n d l ost t o f oll o w -u p i n a n y 
dis p ositi o n pa ge 
L ost t o f oll o w - u p
6
N o e ve nt a n d [ E O S prese nt O R 
dis p ositi o n pa ge f or a n y E P O C H after 
scree ni n g sa ys patie nt will n ot c o nti n ue 
i nt o a n y s u bse q ue nt p hase of t he st u d y] 
a n d n o a de q uate p ost -baseli ne t u m or 
assess me nt 
N o a de q uate p ost -baseli ne 
t u m or assess me nt
7 
N o e ve nt a n d n o ne of t he c o n diti o ns i n 
t he pri or hierarc hy are met 
O n g oi n g wit h o ut a n e ve nt
a m o re t ha n 9 8 d a y s after last a de q uate t u m or assess me nt. 
T he P F S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g.
Ti me of F oll o w -U p f or P F S
A Ka pla n -Meier s u m mar y  ta ble f or P F S f oll o w-u p d urati o n will als o be ge nerate d t o assess 
t he f oll o w-u p ti me i n t he treat me nt ar ms re versi n g t he P F S ce ns ori n g a n d e ve nt i n dicat ors.
 
 
 
 
C CI


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6. 2. 7. O ver all S ur vi v al ( O S) i n B ot h C o h orts
O verall s ur vi val ( O S) is defi ne d as t he ti me fr o m date of first d ose t o t he date of deat h d ue t o 
a n y ca use. Patie nts last k n o w n t o be ali ve will be ce ns ore d at date of last c o ntact (see 
Secti o n 5. 2. 7 ). O S will be s u m marize d i n m o nt hs: 
O S ( m o nt hs) = [ date of deat h or ce ns ori n g – start date + 1]/ 3 0. 4 3 7 5 
C CI
C CI
C CI


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O S ti me ass ociate d wit h C o h ort will be s u m marize d usi n g t he Ka pla n - Meier met h o d 
( pr o d uct-li mit esti mates) a n d dis pla ye d gra p hicall y w here a p pr o priate. CIs f or t he 2 5t h, 5 0t h, 
a n d 7 5 t h perce ntiles will be re p orte d. 
T he O S rate at cli nical mea ni n gf ul ti mep oi nts will be esti mate d wit h c orres p o n di n g 
t w o-si de d 9 5 % CIs. T he CI s f or t he me dia n will be calc ulate d acc or di n g t o Br o o k me y er a n d 
Cr o wle y 2 a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d a b o ve will 
be deri ve d usi n g t he l o g( -l o g) met h o d acc or di n g t o Kal bfleisc h a n d Pre ntice 3
(c o nfty pe =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T). T he esti mate of t he sta n dar d err or 
will be c o m p u te d usi n g Gree n w o o d’s f or m ula. 
Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h a n e ve nt ( deat h) a n d ce ns ori n g reas o ns 
will be prese nte d b y treat me nt ar m. Ce ns ori n g reas o ns are as f oll o ws: 

Ali ve ;

Wit h dra wal of c o nse nt ;

L ost t o f oll o w - u p.
T he O S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g.
Ti me of F oll o w -U p f or O S 
A Ka pla n -Meier s u m mar y ta ble f or O S f oll o w -u p d urati o n will als o be ge nerate d t o assess t he 
f oll o w-u p ti me i n C o h ort re versi n g t he O S ce ns ori n g a n d e ve nt i n dicat ors.
6. 2. 8. P h ar m ac o ki netics
F or l orlati ni b, c o nce ntrati o ns will be s u m marize d descri pti vel y ( n, mea n, S D, C V, me dia n, 
mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d C V) b y c o h ort, c ycle, da y a n d 
n o mi nal ti me. I ndi vi d ual patie nt a n d me dia n pr ofiles of t he c o nce ntrati o n- ti me data will be 
pl otte d b y  c o h ort c o h ort c ycle a n d da y (si n gle d ose a n d stea d y-state). F or i n di vi d ual patie nt 
pl ots b y  ti me, t he act ual P K sa m pli n g ti me will be use d. F or s u m mar y  statistics a n d 
mea n/ me dia n pl ots b y  sa m pli n g ti me, t he n o mi nal P K sa m pli n g ti me will be use d. 
M e dia nMe dia n pr ofiles will be prese nte d o n b ot h li near- li near a n d l o g-li near scales.
Prese ntati o ns f or c o nce ntrati o ns will i ncl u de b ut n ot be li mite d t o:

Listi n g of all c o nce ntrati o ns of l orlati ni b s orte d b y c o h ort, da y of assess me nt, patie nt
I D a n d n o mi nal ti me p ost d ose. T he listi n g of c o nce ntrati o ns will i ncl u de t he act ual 
ti mes. De viati o ns fr o m t he n o mi nal ti me will be gi ve n i n a se parate listi n g.

S u m mar y  of c o nce ntrati o ns b y c o h ort, d a y  of assess me nt a n d n o mi nal ti me p ost d ose,
w here t he set of statistics will i ncl u de n, mea n, sta n dar d de viati o n, c oefficie nt of 
variati o n ( C V), me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d 
C V a n d t he n u m ber of c o nce ntrati o ns a b o ve t he l o wer li mit of q ua ntificati o n.


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
Li near a n d se mi-l o g pl ots of me dia n c o nce ntrati o ns a gai nst n o mi nal ti me p ost d ose b y  
c o h ort, d a y  of assess me nt ( base d o n t he s u m mar y of c o nce ntrati o ns b y d a y of 
assess me nt a n d ti me p ost d ose). 

Li near pl ots of i n di vi d ual c o nce ntrati o ns a gai nst act ual ti me p ost d ose b y c o h ort a n d
da y  of assess me nt.

Tr o u g h c o nce ntrati o ns will be pl otte d usi n g a b o x- w his ker pl ot b y c o h ort, c ycle a n d
da y  i n or der t o assess t he attai n me nt a n d mai ntai ni n g of stea d y-state.
Plas ma p har mac o ki netic para meters of l orlati ni b o n D a y 1 of C ycle 1 ( C 1 D 1) a n d at stead y 
state i ncl u di n g t he ma xi m u m plas ma c o nce ntrati o n ( C ma x ), ti me t o ma xi m u m plas ma 
c o nce ntrati o n ( T ma x ), area u n der t he plas ma c o nce ntrati o n vers us ti me pr ofile fr o m ti me 0 t o 
ti me t (A U C t) a n d area u n der t he plas ma c o nce ntrati o n vers us ti me pr ofile wit hi n a d ose 
i nter val (A U C ta u) f or l orlati ni b will be esti mate d usi n g n o n-c o m part me ntal a nal ys is.  If data 
per mit or if c o nsi dere d a p pr o priate, area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve t o 
i nfi nit y ( A U Ci nf), ter mi nal eli mi nati o n half-life (t1/ 2), oral plas ma cleara nce ( C L/ F), a p pare nt 
v ol u me of distri b uti o n ( V z/ F) a n d acc u m ulati o n rati o ( R ac) will be als o esti mate d.  T he C 1 D 1 
a n d stea d y-state P K para meters will be s u m marize d descri pti vel y b y c yc le a n d da y a n d will 
i ncl u de t he set of s u m mar y statistics as s pecifie d i n t he ta ble bel o w:
P ar a meter
S u m m ar y S t atistics
A U C last, A U Ci nf*, A U C ta u, Cma x , 
C L / F *, Vz/ F *,
N, arit h metic mea n, me dia n, c v %, sta n dar d
de viati o n, mi ni m u m, ma xi m u m, ge o metric
mea n, ge o metric c v %.
T ma x
N, me dia n, mi ni m u m, ma xi m u m.
t1/ 2, Rac *
N, arit h metic mea n, me dia n, c v %, sta n dar d
de viati o n, mi ni m u m, ma xi m u m.
* if data per mits .
P h ar m ac o ki netic a n d E x p os ure -Res p o nse A n al ysis
P har mac o ki netic a n d p har mac o d y na mics data fr o m t his st u d y  ma y be a nal yze d usi n g 
c o m part me ntal or mi xe d -effect m o deli n g a p pr oac hes a n d ma y als o be p o ole d wit h ot her 
st u d y res ults.  P K/ P D m o deli n g ma y be atte m pte d t o i n vesti gate a n y ca usal 
relati o ns hi p bet wee n l orlati ni b e x p os ure a n d efficac y,  
 or si g nifica nt safet y 
e n d p oi nts. T he res ults of t hese a nalys es, if perf or me d, will be re p orte d se paratel y.
 
 
 
C CI
C CI


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6. 4. B aseli ne a n d Ot her S u m m aries
6. 4. 1. B aseli ne S u m m aries

De m o gr a p hic a n d P h ysic al C h ar acteristics 
T he f oll o wi n g de m o gra p hic a n d baseli n e c haracteristics will be s u m marize d b y  
n u m ber a n d perce nta ge:

Ge n der( male, fe male) ;

A ge < ( 1 8-< 4 5; 4 5 - < 6 5; ≥6 5) >;

Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce stat us;

S m o ki n g classificati o n ( ne ver s m o ker, f or mer s m o ker, s m o ker) .
A ge (c o nti n u o us), hei g ht (c m), wei g ht ( k g) will be s u m marize d wit h descri pti ve statistics 
( mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m).

Dise ase C h ar acteristics 
T he f oll o wi n g baseli ne disease c haracteristics will be s u m marize d b y  n u m ber a n d 
perce nt a ge:

Hist o pat h ol o gical Classificati o n T M N sta ge at i nitial dia g n osis a n d c urre nt sta ge ;

E xte nt of disease (l ocall y /a d va nce d, metastatic);

Meas ura ble disease at baseli ne ( y es/ n o) (see Secti o n 5. 2. 8 );

A de q uate baseli ne assess me nt ( y es/ n o) (see Secti o n 5. 2. 1 1 );

I n v ol ve d t u m or sites at baseli ne.
Ti me si nce dia g n osis ( m o nt hs), defi ne d as ( date of first d ose – date of dia g n osis)/ 3 0. 4 3 7 5, 
will be s u m marize d b y  descri pti ve statistics (mea n, me dia n, sta n dar d de vi ati o n, mi ni m u m, 
a n d ma xi m u m).  
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I n v ol ve d t u m or sites at baseli ne will be deri ve d fr o m tar get a n d n o n tar get lesi o ns at baseli ne.  
Eac h patie nt will be c o u nte d o nce per or ga n.
Si milarl y , n u m ber of sites of disease at baseli ne 
will be deri ve d b y c o u nti n g t he n u m ber of u ni q ue or ga n sites fr o m tar get a n d n o n tar get 
lesi o ns at baseli ne.  “ Ot her” will be c o u nte d as o ne or ga n site.

Me dic al Hist or y 

Me dical hist or y  will be c o de d usi n g t he m ost c urre nt versi o n of Me d D R A a n d 
s u m marize d b y Me d D R A’s S yste m Or ga n Class ( S O C) a n d P T.  Eac h patie nt will 
be c o u nte d o nl y o nce wit hi n eac h P T or S O C.  S u m maries will be or dere d b y 
pri mar y  S O C a n d P T i n desce n di n g or der of fre q ue nc y  b y C o h ort .  Se parate 
s u m maries will be pr o vi de d f or past a n d prese nt c o n diti o ns. 

Pri or A nti -C a ncer Tre at me nts 
Pri or a nti -ca ncer treat me nts i ncl u de s y ste mic t hera p y, ra diati o n, a n d s ur ger y.
T he n u m ber a n d perce nta ge of patie nts i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y 
cate g ories will be ta b ulate d:

Patie nts wit h at least o ne t y pe of pri or a nti -ca ncer treat me nt; Patie nts wit h 
differe nt t y pe of pre vi o us A L K i n hi bit or;

Patie nts wit h at least o ne pri or a nti -ca ncer dr u g t hera p y;

Patie nts wit h at least o ne pri or a nti -ca ncer ra di ot hera p y;

Patie nts wit h at least o ne pri or a nti -ca ncer s ur ger y.
Pri or a nti -ca ncer dr u g t hera p y will be s u m marize d as f oll o ws base d o n t he n u m ber 
a n d perce nta ge of patie nts: 

N u m ber of pri or a nti -ca ncer t hera p y re gi me ns: 0/ 1 / > 1; 

I nte nt of T hera py:  Ne o-A dj u va nt/ A dj u va nt/ A d va nce d – Metastatic .
6. 4. 2. St u d y C o n d uct a n d S u bject Dis p ositi o n
T he f oll o wi n g a nal ys es will be base d o n t he F A p o p ulati o n o verall a n d se paratel y b y C o h ort.
6. 4. 2. 1. P atie nt Dis p ositi o n
A s u m mar y  of t he n u m ber of patie nts e nr olle d by s ite will be pr o vi de d b y C o h ort as well as 
o verall f or t he F A p o p ulati o n.
Disc o nti n uati o ns fr o m st u d y  treat me nt will be s u m marize d usi n g t he S A set . 


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Disc o nti n uati o ns fr o m st u d y  treat me nt d ue t o a d verse e ve nts will be i de ntifie d as eit her 
relate d or n ot relate d t o st u d y treat me nt. If ca usalit y is missi n g t he e ve nt will be c o nsi dere d 
relate d t o treat me nt.  If m ulti ple e ve nts lea d t o st u d y treat me nt disco nti n uati o n a n d at least 
o ne was c o nsi dere d relate d, disc o nti n uati o n will be re p orte d as relate d t o st u d y  treat me nt. 
6. 4. 2. 2. Pr ot oc ol De vi ati o ns
Pr ot oc ol de viati o ns will be c o m pile d pri or t o data base cl os ure a n d will be liste d a n d 
s u m marized b y  cate g or y ( n( %)) f or t he F A set b y  C o h ort.  Cate g ories will be assi g ne d by t he 
st u d y Cli nicia n.
6. 4. 3. St u d y Tre at me nt E x p os ure
T he f oll o wi n g a nal ys es will be base d o n t he S A p o p ulati o n. 
6. 4. 3. 1. E x p os ure t o l orl ati ni b 
T he s u m mar y  of treat me nt e x p os ure f or l orlati ni b will i ncl u de t he f ollo wi n g i nf or mati o n: 

Treat me nt d urati o n ( wee ks) ;

C u m ulati ve d ose ( m g) ;

D ose i nte nsit y  ( m g/ wee k);

Relati ve d ose i nte nsit y  ( %);
T he d urati o n of l orlati ni b (i n wee ks) is defi ne d as:
Treat me nt d urati o n ( wee ks) = (last d ose date – first d ose date + 1)/ 7
T he c u m ulati ve d ose ( m g) of l orlati ni b is t he s u m of t he act ual d ose le vels t hat t he patie nt 
recei ve d (ie, total d ose a d mi nistere d ( m g)).  L orlati ni b is gi ve n o nce dail y, a d mi nistere d as 
4 x 2 5 m g oral ta blets, c o nti n u o usl y ; t heref ore if all d oses (e g, d mg/ da y ) were recei ve d i n a 
wee k t he c u m ulati ve d ose w o ul d be 7 × 1 0 0 m g.
T he d ose i nte nsit y  ( DI) a n d t he relati ve d ose i nte nsit y ( R DI) of l orlati ni b will be calc ulate d 
f or eac h patie nt d uri n g t he st u d y. T he DI ( m g/ wee k) of l orlati ni b d uri n g t he st u d y  is defi ne d 
as 
DI  ( m g/ wee k) = [c u m ulati ve d ose ( m g)]/[treat me nt d urati o n ( wee ks)] 
T he R DI of l orlati ni b is defi ne d as t he rati o of t he DI a n d pla n ne d d ose i nte nsit y  a n d 
e x presse d i n % 
R DI  ( %) = 1 0 0 × [ DI ( m g/ wee k]/[ 7 × 1 0 0 ( m g/ wee k)].   


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6. 4. 3. 2. D ose Re d ucti o ns, I nterr u pti o ns, a n d Del a ys
A d ose re d ucti o n is defi ne d as a n o n-zer o d ose t hat is less t ha n t he pri or d ose.
T he n u m ber a n d perce nta ge of patie nts wit h at least o ne d ose re d ucti o n as well as a 
brea k d o w n of d ose re d ucti o ns ( 1/ 2/ 3) will be s u m m arize d b y C o h ort.  
Reas o ns f or d ose re d ucti o ns will als o be s u m marize d.  Patie nts ca n c o ntri b ute t o m ore t ha n 
o ne reas o n if m ulti ple d ose re d ucti o ns occ urre d f or differe nt reas o ns, b ut will o nl y  be 
c o u nte d o nce per reas o n.  Perce nta ges will be calc ulate d base d o n t he t otal n u m ber of 
patie nts i n S A set.
A n i nterr u pti o n is defi ne d a 0 m g d ose a d mi nistere d f or m ore t ha n 1 d a y . T he n u m ber a n d 
perce nta ge of patie nts wit h d ose i nterr u pti o ns a n d t he c orres p o n di n g reas o ns will be 
s u m marize d b y C o h ort. Patie nts ca n c o ntri b ute t o m ore t ha n o ne reas o n if m ulti ple d ose 
i nterr u pti o ns occ urre d f or differe nt reas o ns, b ut will o nl y be c o u nte d o nce per reas o n. 
Perce nta ges will be calc ulate d base d o n t he t otal n u m ber of patie nts i n t he S A set.
W hat f oll o ws defi n es h o w d ose i nterr u pti o ns will be c o u nte d i n t he case of co nsi derati os f or 
m ulti ple d ose i nterr u pti o ns:

If a n i nterr u pti o n occ urs c o nsec uti vely f or at least t w o da y s d ue t o t he sa me reas o n, 
t he n it will be c o u nte d o nl y o nce.

If a n i nterr u pti o n occ urs c o nsec uti vel y f or at least t w o da y s d ue t o differe nt reas o ns,
t he n it will be c o u nte d f or eac h reas o n.

If a n i nterr u pti o n occ urs f or m ore t ha n o ne da y d ue t o t he sa me reas o n, b ut t he da ys 
are n ot c o nsec uti ve, ie, t here is at least o ne d osi n g da y i n bet wee n, t hen eac h d ose 
i nterr u pti o n will be c o u nte d as a differe nt occ urre nce. 
6. 4. 4. C o nc o mit a nt Me dic ati o ns a n d N o n -Dr u g T re at me nts
C o nc o mita nt me dicati o ns a n d n o n- dr u g treat me nts recei ve d b y  patie nts d uri n g t he st u d y will 
be s u m marize d f or t he S A set b y  C o h ort. 
C o nc o mi ta nt me dicati o ns refer t o all me dicati o ns w hic h starte d pri or t o first d ose of st u d y 
treat me nt a n d c o nti n ue d d uri n g t he o n-treat me nt peri o d (see Secti o n 5. 2 ) as well as t h ose 
starte d d uri n g t he o n-treat me nt peri o d. C o nc o mita nt me dicati o ns will be c o de d i n t he W H O 
Dr u g c o di n g dicti o nar y  a n d will be ta b ulate d b y A nat o mical T hera pe utic C he mical ( A T C) 
Classificati o n le vel 2 a n d preferre d ter m i n desce n di n g or der of fre q ue nc y  i n t he l orlati ni b 
ar m. I n case of e q ual fre q ue nc y re gar di n g dr u g class (res pecti vely dr u g na me), al p ha betical 
or der will be use d. A patie nt will be c o u nte d o nl y  o nce wit hi n a give n dr u g class a n d wit hi n 
a gi ve n dr u g na me, e ve n if he/s he recei ve d t he sa me me dicati o n at differe nt ti mes. Preferre d 
Ter ms will be re p orte d u n der eac h A T C class t hat it is i ncl u de d u n der wit hi n W H O Dr u g ( n o 
pri mar y  pat h is a vaila ble i n W H O Dr u g).


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C o nc o mita nt n o n -dr u g treat me nts refer t o all n o n -dr u g treat me nts a d mi nistere d d uri n g t he 
o n -treat me nt peri o d. N o n -dr u g treat me nts will be c o de d wit h t he m ost c urre nt versi o n of 
Me d D R A a n d will be s u m marize d b y  Me d D R A’s S O C a n d P T i n desce n di n g or der of 
fre q ue nc y i n t he l orlati ni b ar m. Patie nts will be c o u nte d o nl y  o nce per P T e ve n if he/s he 
recei ve d t he sa me treat me nt m ulti ple ti mes. 
A n y  me dicati o ns or n o n- dr u g treat me nts, asi de fr o m a nti-ca ncer treat me nts descri be d i n 
Secti o n 6. 4. 1 w hic h were o nl y  a d mi nistere d pri or t o treat me nt start will be liste d b ut n ot 
s u m marize d.
6. 4. 5. S u bse q ue nt A nti -C a ncer T her a pies/ Pr oce d ures
S u bse q ue nt A nti- Ca ncer T her a pies a n d Pr oce d ures are defi ne d as t hera pies e ntere d o n t he 
‘ F oll o w-u p Ca ncer T hera p y ’, ‘ F oll o w-u p Ra diati o n T hera p y ’, a n d ‘ F oll o w-u p S ur ger y ’ C R F 
pa ges. T he n u m ber a n d perce nta ge of patie nts wit hi n eac h cate g or y  ( me dicati o n t hera py, 
ra diati o n t hera py, a n d s ur geries) will be pr o vi de d b y  C o h ort. 
Me dicati o ns will be c o de d usi n g t he W H O Dr u g c o di n g dicti o nar y  a n d will be ta b ulate d b y 
preferre d ter m i n desce n di n g or der of fre q ue nc y  o n t he st u d y treat me nt. 
A nal y ses will be base d o n t he F A p o p ulati o n b y C o h ort .
6. 5. S afet y S u m m aries a n d A n al yses
U nless ot her wise s pecifie d, s u m maries of A Es a n d ot her safet y para meters will be base d o n 
t he safety a nal ys is set b y  C o h ort a n d T otal . 
6. 5. 1. A d verse E ve nts
All a nal y ses will be base d o n treat me nt e mer ge nt e ve nts u nless ot her wise s pecifie d.  
Treat me nt e mer ge nt is defi ne d i n Secti o n 3. 5. 1 .  A Es n ot c o nsi dere d treat me nt e mer ge nt will 
be fla g ge d i n data listi n gs.
A hi g h le vel s u m mar y  of a d verse e ve nts will i ncl u de t he n u m ber a n d perce nt of patie nts 
wit h:

A n y  A d verse E ve nt;

Seri o us A E;

A d verse E ve nts wit h C T C A E Gra de 3 - 4;

Gra de 5 e ve nts;

A Es lea di n g t o d ose i nterr u pti o ns;

A Es lea di n g t o d ose re d ucti o ns;

A Es lea di n g t o wit h dra w .


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A d diti o nall y , t he n u m ber of a n y A E will be pr o vi de d.  Eac h u ni q ue a d verse e ve nt at t he P T 
le vel i n eac h C o h ort of t he st u d y  f or a patie nt is i ncl u de d i n t he c o u nt. 
Seri o u s ness, t o xicit y gra de, acti o n ta ke n (i nterr u pti o n, re d ucti o n, a n d wit h dra w) are as 
re p orte d by t he i n vesti gat or o n t he a d verse e ve nt C R F.
S u m maries b y  C o h ort, S O C a n d P T i n decreasi n g fre q ue nc y base d o n t he fre q ue ncies 
o bser ve d i n eac h C o h ort will be pr o vi de d f or:

Treat me nt E mer ge nt E ve nts b y  Ma xi m u m T o xicit y Gra de ( All Ca usalit y);

Treat me nt E mer ge nt E ve nts b y  Ma xi m u m T o xicit y Gra de ( Treat me nt Relate d);

Seri o us Treat me nt E mer ge nt E ve nts ( All Ca usalit y );

Seri o us Treat me nt E mer ge nt E ve nts ( Treat me nt Rela te d).
A n e ve nt will be c o nsi dere d treat me nt relate d if t he i n vesti gat or c o nsi dere d t he e ve nt relate d 
t o t he st u d y dr u g or t his i nf or mati o n is u n k n o w n.
T he f oll o wi n g s u m maries will be pr o vi de d b y  C o h ort a n d P T /cl usters of A Es (ie, s u m maries 
will n ot i ncl u d e S O C) i n decreasi n g fre q ue nc y base d o n t he fre q ue ncies o bser ve d i n t he st u d y 
treat me nt f or:

Treat me nt E mer ge nt E ve nts ( All Ca usalit y ) by Preferre d Ter m (i ncl u di n g Cl usters of 
Preferre d Ter m) a n d Ma xi m u m T o xicit y Gra de; 

Treat me nt E mer ge nt E ve nts ( Treat me nt Relate d ) b y Preferre d Ter m(i ncl u di n g 
Cl usters of Preferre d Ter m)   a n d Ma xi m u m T o xicit y Gra de; 

Treat me nt E mer ge nt Gra de 3- 5 E ve nts ( All Ca usalit y ) by Preferre d Ter m (i ncl u di n g 
Cl usters of Preferre d Ter m)   a n d Ma xi m u m T o xicit y Gra de; 

Treat me nt E mer ge nt A d verse E ve nts Lea di n g t o D ose I nterr u pti o ns b y Ma xi m u m 
T o xicit y  Gra de ( All Ca usalit y); 

Treat me nt E mer ge nt A d verse E ve nts Lea di n g t o D ose Re d ucti o ns b y  Ma xi m u m 
T o xicit y  Gra de ( All Ca usalit y); 

Treat me nt E mer ge nt A d verse E ve nts Lea di n g t o Per ma ne nt Wit h dra w b y Ma xi m u m 
T o xicit y  Gra de ( All Ca usalit y); 

Seri o us Treat me nt E mer ge nt E ve nts ( All Ca usalit y ). 

Seri o us Treat me nt E mer ge nt E ve nts ( Treat me nt Relate d ). 
Eac h patie nt will be c o u nte d o nl y  o nce wit hi n eac h P T. 


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As descri be d i n Secti o n 5. 3 i n case a patie nt has e ve nts wit h missi n g a n d n o n missi n g 
t o xicit y gra des, t he ma xi m u m of t he n o n-mis si n g gra de will be dis pla ye d.  Missi n g gra de will 
o nl y  be dis pla ye d i n t he e ve nt t hat o nl y o ne e ve nt has bee n re p orte d f or a patie nt a n d t he 
gra de is missi n g.
6. 5. 1. 1. A d verse E ve nts of S peci al I nterest
T hese a nal y ses will be perf or me d f or treat me nt e mer ge nt A Es of s pecial i nterest as s pecifie d 
i n Secti o n 3. 5. 2 . 

Ti me t o A E O nset (i n da ys) is defi ne d as t he ti me fr o m t he date of t he first d ose t o 
t he o nset date of t he A E, re gar dless of gra de. If a patie nt has m ulti ple e pis o des of a n 
A E, t he date of t he first occ urre nce is use d. Ti me t o A E o nset (i n da y s) will be 
calc ulate d as ( A E start date – first d ose date + 1). Ti me t o o nset is calc ulate d f or t he 
s u b gr o u p of patie nts w h o ha d t he s pecific A E 

Ti me t o Gr a de 3 or 4 A E O nset (i n da ys) is defi ne d si milarl y as ti me t o A E o nset 
f or Gra de 3 or 4 A Es. 

D ur ati o n of A E (i n da ys) is defi ne d as t he c u m ulati ve d urati o n acr oss e pis o des of t he 
A E, re gar dless of gra de, w here d urati o n f or eac h e pis o de is t he ti me fr o m t he A E start 
date t o t he A E e n d date. F or o ne e pis o de, d urati o n (i n da ys) = A E e n d date – A E start 
date + 1. If a patie nt has m ulti ple e pis o des of a n A E, c u m ulati ve d urati o n acr oss all 
e pis o des will be use d a dj usti n g f or a n y o verla p. If a patie nt has a n A E t hat was 
o n g oi n g at t he ti me of a nal y sis, the ti me is ce ns ore d at t he last a vaila ble o n treat me nt 
visit date. D urati o n is calc ulate d f or t he s u b gr o u p of patie nts w h o ha d t he s pecifie d 
A E. 
Descri pti ve statistics will be prese nte d f or ti me t o A E o nset ( da y s), ti me t o Gra de 3 or 4 A E 
o nset, a n d d ura ti o n of A Es f or t he s u b gr o u p of patie nts wit h t he A E.
6. 5. 2. De at hs
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts i n t he safety a nal ys is set w h o die d a n d 
w h o die d wit hi n 2 8 da y s after last d ose of st u d y treat me nt as well as t he pri mar y reas o n f or 
deat h, will be ta b ulate d base d o n i nf or mati o n fr o m t he ‘ N otice of Deat h’ a n d ‘ S ur vi val 
F oll o w -U p’ C R Fs, b y C o h ort .  
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts i n t he safety a nal ys is set w h o die d d uri n g 
f oll o w-u p peri o d after 2 8 da y s after t he last d ose of st u d y t reat me nt will als o be pr o vi de d.
Date a n d ca use of deat h will be pr o vi de d i n i n di vi d ual patie nt data listi n g t o get her wit h 
selecte d d osi n g i nf or mati o n (st u d y treat me nt recei ve d, date of first/last a d mi nistrati o n, d ose).
6. 5. 3. L a b or at or y D at a
La b orat or y  res ults will be c o n verte d t o I nter nati o nal S y ste m of U nits ( Sys tè me I nter nati o nal 
d' u nités, SI) u nits w hic h will be use d f or a p pl yi n g t o xicit y  gra des a n d f or all s u m maries. 


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As descri be d i n Secti o n 3. 4 , baseli ne will defi ne d as t he last assess me nt perf or me d o n or 
pri or t o date of t he first d ose of st u d y treat me nt.  If t here are m ulti ple assess me nts t hat meet 
t he baseli ne defi niti o n o n t he sa me da y wit h o ut t he a bilit y t o deter mi ne w hic h was tr uly last, 
t he n t he w orst gra de will be assi g ne d as t he baseli ne gra de.  Si nce a fe w C T C A E ter ms 
(i ncl u di n g H yp o/ H y percalce mia a n d Acti vate d Partial T hr o m b o plasti n) ca n be deri ve d usi n g 
se veral la b orat or y tests (a nalyt es) refer t o t he secti o n 2. 3. 7 of t he “ Pfizer O nc ol o g y  C T C A E 
Gra di n g I m ple me ntati o n G ui da nce f or La b orat or y  Data” f or deter mi nati o n of baseli ne 
C T C A E gra de i n t his sit uati o n. 
A d diti o nall y , la b orat or y res ults will be pr o gra m maticall y classifie d acc or di n g t o 
N CI -C T C A E versi o n 4. 0 3 gra de.  N o n -n u merical q ualifiers will n ot be ta ke n i nt o 
c o nsi derati o n i n t he deri vati o n of gra de (e g, h y p o kale mia Gra de 1 a n d Gra de 2 are o nl y 
disti n g uis he d b y  a n o n-n u merical q ualifier a n d t heref ore Gra de 2 will n ot be deri ve d). I n 
s u m mar y statistics t he n u m ber a n d perce nta ge of patie nts c orres p o n di n g t o gra des t hat o nly 
i ncl u de n o n- q ua ntitati ve criteria will be dis pla ye d as a bla n k or N A ( n ot assesse d) rat her 
t ha n 0.  If t here is a n y o verla p bet wee n gra de criteria (e g, C T C A E gra di n g criteria f or 
Creati ni ne I ncrease d - a val ue ca n fall i nt o o ne ra n ge base d o n c o m paris o n t o U L N a n d 
a n ot her ra n ge base d o n c o m paris o n t o baseli ne), t he hi g hest ( w orst) gra de w o ul d be assi g ne d 
t o t hat rec or d. Gra de 5 is defi ne d i n t he C T C A E criteria g ui da nce as a n e ve nt wit h a n 
o utc o me of deat h. Si nce la b orat or y  data d oes n ot c ollect a n o utc o me, Gra de 5 is n ot use d 
w he n pr o gr a m maticall y gra di n g la b orat or y  data.
Gra de 0 or O utsi de T o xicit y  Refere nce ( O T R) is n ot defi ne d s pecifically b y i n t he C T C A E 
g ui da nce. H o we ver, pr o gra m maticall y t his is use d as a cate g or y t o re prese nt t h ose patie nts 
w h o di d n ot meet a n y of t he Gra des 1 t o 4 criteria.  If t he la b orat or y  val ue is e val ua ble f or 
C T C A E criteria gra di n g ( n u meric val ue is prese nt, vali d u nits a n d ra n ges are prese nt as 
re q uire d t o all o w c o n versi o n t o sta n dar d u nits a n d gra di n g), a n d d oes n ot q ualif y f or a ny of 
t he Gra de 1-4 criter ia f or a gi ve n la b test, t he n t he val ue is assi g ne d as Gra de 0 or O T R.
A b n or malities will be descri be d usi n g t he w orst gra de b y sc he d ule d ti me p oi nt a n d o verall.  
W orst gra de b y s c he d ule d ti me p oi nt will be deter mi ne d usi n g o nl y  ce ntral la b orat or y res ults.  
W orst case o verall will be deter mi ne d usi n g b ot h ce ntral a n d l ocal la b orat or y  res ults fr o m 
sc he d ule d a n d u nsc he d ule d visits.  Se veral la b orat or y tests ha ve bi- directi o nal gra di n g 
criteria defi ne d s o t hat b ot h l o w ( h y p o) a n d hi g h ( h y per) val ues ca n be gra de d se paratel y.  
Eac h criteri o n will be s u m marize d se paratel y.  I n t he cases w here a val ue is gra de d as a 
Gra de 1, 2, 3, or 4 f or o ne of t he directi o ns, t hat val ue will als o be assi g ne d as a Gra de 0 f or 
t he o p p osite directi o n f or t hat test.  F or e xa m ple, a val ue meeti n g t he criteria f or Gra de 3 
H y percalce mia will be classifie d as a Gra de 0 H y p ocalce mia. F or C T C A E ter ms t hat ca n be 
deri ve d usi n g o ne of se veral la b orat or y  tests, t he ma xi m u m p ost-baseli ne gra de f or a gi ve n 
patie nt a n d C T C A E ter m will be t he ma x i m u m acr oss all p ossi ble la b orat or y tests.
F or W B C differe nti al c o u nts
(t otal ne utr o p hil [i ncl u di n g ba n ds], l ym p h oc y te, m o n oc yte, 
e osi n o p hil, a n d bas o p hil c o u nts), t he a bs ol ute val ue will be use d w he n re p orte d b y  t he la b. 
W he n o nl y  perce nta ges are a vaila ble (t his is mai nl y a p plica ble f or ne utr o p hils a n d 
l ym p h oc y tes, beca use t he C T C A E gra di n g is base d o n t he a bs ol ute c o u nts), t he a bs ol ute 
val ue is deri ve d as f oll o ws: 


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Deri ve d differe ntial a bs ol ute c o u nt = ( W B C c o u nt) × ( Diff ere ntial % val ue/ 1 0 0) 
If t he i n vesti gat or re p orts b ot h t he a bs ol ute a n d % val ue f or Ne utr o p hils or L ym p h oc y tes 
fr o m t he sa me la b orat or y sa m ple date a n d patie nt, O N L Y t he a bs ol ute val ue will be gra de d. 
T he % val ue will n ot be gra de d i n t his sce nari o. 
If t he % val ue is c o n verte d t o t he differe ntial a bs ol ute c o u nt f or gra di n g a n d t he L L N f or t he 
differe ntial a bs ol ute c o u nt is n ot a vaila ble ( o nl y  L L N f or % is a vaila ble) t he n Gra de 1 will be 
assi g ne d if t he f oll o wi n g c o n diti o ns are met:

L y m p h oc y te c o u nt decrease d: 

deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d 

% val ue < % L L N val ue, a n d 

deri ve d a bs ol ute c o u nt ≥8 0 0/ m m 3.

Ne utr o p hil c o u nt decrease d :

deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d 

% val ue < % L L N val ue, a n d 

deri ve d a bs ol ute c o u nt ≥1 5 0 0/ m m 3.
F or c alci u m, C T C A E gra di n g is base d o n C orrecte d Calci u m a n d I o nize d Calci u m. 
C orrecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws: 

C orrecte d Calci u m ( m g/ d L) = Calci u m ( m g/ d L) – 0. 8 [ Al b u mi n ( g/ d L )-4]. 
La b orat or y t o xicities will be ta b ulate d usi n g descri pti ve statistics ( n u m ber of patie nts a n d 
perce nta ges): 

S hift ta ble will s u m marize baseli ne C T C A E gra de vers us t he w orst p ost -baseli ne 
C T C A E gra de. 
Li ver f u ncti o n tests : Ala ni ne a mi n otra nsferase ( A LT), as partate a mi n otra nsferase ( A S T), 
Al kali ne P h os p hatase ( A L P), a n d t otal bilir u bi n ( T BI LI) are use d t o assess p ossi ble dr u g 
i n d uce d li ver t o xicit y. T he rati os of test res ult o ver t he U L N will be calc ulate d a n d classifie d 
f or t hese t hree para meters d uri n g t he o n-treat me nt peri o d. 
S u m mar y  of li ver f u ncti o n tests will i ncl u de t he f oll o wi n g cate g ories.  T he n u m ber a n d 
perce nta ge of patie nts wit h eac h of t he f oll o wi n g d uri n g t he o n -treat me nt peri o d will be 
s u m marize d b y treat me nt ar m:

A L T ≥3 × U L N, A L T ≥5 x U L N, A L T ≥1 0 × U L N, A L T ≥2 0 × U L N ;


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
A S T ≥3 × U L N, A S T ≥5 x U L N, A S T ≥1 0 × U L N, A S T ≥2 0 × U L N ;

( A L T or A S T) ≥3 × U L N, ( A L T or A S T) ≥5 × U L N, ( A L T or A S T) ≥1 0 × U L N, 
( A L T or A S T) ≥2 0 × U L N ;

T BI LI ≥2 × U L N ;

C o nc urre nt A L T ≥3 × U L N a n d T BI LI ≥2 × U L N ;

C o nc urre nt A S T ≥3 × U L N a n d T BI LI ≥2 × U L N ;

C o nc urre nt ( A L T or A S T) ≥3 × U L N a n d T BI LI ≥2 × U L N ;

C o nc urre nt ( A L T or A S T) ≥3 × U L N a n d T BI LI ≥2 × U L N a n d A L P > 2 × U L N ;

C o nc urre nt ( A L T or A S T ) ≥3 × U L N a n d T BI LI ≥2 × U L N a n d A L P ≤2 × U L N or 
missi n g .
C o nc urre nt meas ure me nts are t h ose occ urri n g o n t he sa me date.
Cate g ories will be c u m ulati ve, ie , a patie nt wit h a n ele vati o n of A S T ≥1 0 × U L N will als o 
a p pear i n t he cate g ories ≥5 × U L N a n d ≥3 × U L N. Li ver f u ncti o n ele vati o n a n d p ossi ble H y ’s 
La w cases will be s u m marize d usi n g fre q ue nc y  c o u nts a n d perce nta ges. 
A n e val uati o n of Dr u g -I nd uce d Seri o us He pat ot o xicit y  (e DI S H) pl ot will als o be create d, 
wit h differe nt s y m b ols f or differe nt treat me nt ar ms, b y  gra p hically dis pla y i n g:

P ea k ser u m A L T(/ U L N) vs pea k t otal bilir u bi n (/ U L N) i ncl u di n g refere nce li nes at 
A L T = 3 × U L N a n d t ota l bilir u bi n = 2 × U L N. 

P ea k ser u m A S T(/ U L N) vs pea k t otal bilir u bi n (/ U L N) i ncl u di n g refere nce li nes at
A S T = 3 × U L N a n d t otal bilir u bi n = 2 × U L N. 
I n a d diti o n, a listi n g of all T BI LI, A L T, A S T a n d A LP val ues f or patie nts wit h a 
p ost -baseli ne T BI LI ≥2 × U L N, A L T ≥3 × U L N o r A S T ≥3 × U L N will be pr o vi de d.
6. 5. 4. Vit al Si g ns
Vital si g ns data i ncl u des wei g ht, p ulse, s ys t olic bl o o d press ure, a n d diast olic bl o o d press ure. 
Meas ure me nts were o nl y t o be pr o vi de d o nce per ti me p oi nt. 
If m ulti ple assess me nts are 
pr o vi de d per ti me p oi nt, t h e ma xi m u m val ue will be use d f or re p orti n g.
T he n u m ber a n d perce nt of patie nts i n eac h of t he f oll o wi n g mi ni m u m a n d ma xi m u m bl o o d 
press ure, b o d y wei g ht, a n d p ulse cate g ories will be prese nte d:

I ncrease i n S yst olic Bl o o d Press ure ≥4 0 m m H g ;

Decrea se i n Sys t olic Bl o o d Press ure ≥4 0 m m H g ;


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
I ncrease i n Diast olic Bl o o d Press ure ≥2 0 m m H g ;

Decrease i n Diast olic Bl o o d Press ure ≥2 0 m m H g ;

I ncrease i n Diast olic Bl o o d Press ure ≥6 0 m m H g ;

Decrease i n B o d y Wei g ht ≥1 0 %;

I ncrease i n Bo d y  W ei g ht bet wee n 1 0 % a n d 2 0 %;

I ncrease i n B o d y  Wei g ht (i ncrease) ≥2 0 %;

Ma xi m u m P ulse Rate > 1 2 0 b p m;

Mi ni m u m P ulse Rate < 5 0 b p m;

M a xi m u m i ncrease i n p ulse rate ≥3 0 b p m;

M a xi m u m decrease i n p ulse rate ≥3 0 b p m.
All assess me nts, i ncl u di n g u nsc he d ule d assess me nts will be c o nsi dere d.  A patie nt ca n be 
i ncl u de d i n m ulti ple cate g ories if differe nt criteria are met at differe nt ti me p oi nts. 
6. 5. 5. Electr oc ar di o gr a m
Tri plicate E C Gs were re q uire d at eac h assess me nt.  A mea n sc ore is calc ulate d f or a n y 
re plicate meas ure me nts ha vi n g t he sa me n o mi nal visit. T he mea n meas ure me nt is re p orte d. 
E C G s u m maries will i ncl u de all E C G assess me nts fr o m t he o n- treat me nt peri o d.  All E C G 
assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n- treat me nt peri o d will be fla g ge d 
i n t he listi n g.  
T he a nal ys is of Q T data is c o m plicate d b y t he fact t hat t he Q T i nter val is hi g hly c orrelate d 
wit h heart rate.  Beca use of t his c orrelati o n, f or m ulas are r o uti nel y use d t o o btai n a c orrecte d 
val ue, de n ote d Q Tc, w hic h is i n de pe n de nt of heart rate. T his Q Tc i nter val is i nte n de d t o 
re prese nt t he Q T i nter val at a sta n dar dize d heart rate. 
Fri dericia’s c orrecti o n ( Q Tc F) will be pr o gra m maticall y  deri ve d usi n g t he f oll o wi n g f or m ula:
Q Tc F (m s ec) = Q T ( m s ec) /    (   )
a n d Bazett’s c orrecti o n ( Q Tc B) will be pr o gra m mat icall y deri ve d usi n g t he f oll o wi n g 
f or m ula:
(sec)
sec)
(
sec)
(
R R
m
Q T
m
Q Tc B

,
w here R R re prese nts t he R R i nter val of t he E C G, i n sec o n ds.  


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R R use d i n t he a b o ve f or m ula will be deri ve d by ( 6 0/ H R ( b p m)) if H R is c ollecte d. 
Ot her wise, R R will be directl y use d f or calc ulati o n .
A d diti o nall y Q Tc B a n d Q Tc F (a n d Q Tc S if a p plica ble) will be s u m marize d b y  ma xi m u m 
o n -treat me nt val ues usi n g t he f oll o wi n g cate g ories:

≤4 5 0 msec ;

> 4 5 0 msec b ut ≤4 8 0 msec; 

> 4 8 0 msec b ut ≤5 0 0 msec; 

> 5 0 0 msec.
U nsc he d ule d assess me nts will be utilize d i n a d diti o n t o pla n ne d assess me nts.  
S hift ta bles will be pr o vi de d f or baseli ne val ue vers us w orst o n -treat me nt val ue.  
A d diti o nall y  ma xi m u m i ncreases fr o m baseli ne (i ncl u di n g sc he d ule d a n d u nsc he d ule d 
assess me nts) will be s u m marize d ba se d o n t he f oll o wi n g cate g ories:

C ha n ge > 6 0 msec;

C ha n ge > 3 0 msec b ut ≤6 0 msec;

C ha n ge ≤3 0 msec .
I n t he e ve nt t hat neit her Fri dericia’s n or Bazett’s c orrecti o n a de q uatel y a dj usts f or heart rate, 
a n a d diti o nal c orrecti o n s uc h as a p o p ulati o n or patie nt -specific baseli ne c orrecti o n c o ul d be 
use d a n d s h o ul d be f ull y j ustifie d. 
F or P R a n d Q R S ma xi m u m i ncreases fr o m baseli ne, t he f oll o wi n g cate g ories will be a p plie d: 

P R c ha n ge ≥5 0 % if a bs ol ute baseli ne val ue was < 2 0 0 msec;

P R c ha n ge ≥2 5 % if a bs ol ute baseli ne val ue was ≥2 0 0 msec; 

Q R S c ha n ge ≥5 0 % if a bs ol ute baseli ne val ue was < 1 0 0 msec, 

Q R S c ha n ge ≥2 5 % if a bs ol ute baseli ne val ue was ≥1 0 0 msec .
If m ore t ha n o ne E C G is meas ure d at a n o mi nal ti me p ost- d ose (e g, tri plicate E C Gs wit hi n 
2 - 4 mi n utes), t he mea n will be use d t o re prese nt a si n gle o bser vati o n per patie nt a n d ti me 
p ost -d ose. If a ny of t he t hree i n di vi d ual E C Gs res ults i n a Q Tc ≥5 0 0 msec a n d t he mea n is 
n ot ≥5 0 0 msec, t he n t hat patie nt’s data will be descri be d i n t he safet y sect i o n i n t he st u d y 
re p ort i n or der t o place t he ≥5 0 0 msec val ue i n a p pr o priate cli nical c o nte xt. O n t he ot her 
ha n d, s uc h i n di vi d ual ≥5 0 0 msec val ue wit hi n a tri plicate will n ot be i ncl u de d i n t he 
cate g orical a nal ys is u nless t he a vera ge fr o m t hat tri plicate is als o ≥5 0 0 msec. Data listi n gs 


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will c o ntai n t he mea ns fr o m a tri plicate as well as t he para meters fr o m eac h of t he t hree 
E C Gs. N ote t hat usi n g t he mea n val ue ma y  res ult i n a patie nt ha vi n g a meas ure me nt t hat is 
n ot re prese nte d b y a n act ual E C G. 
6. 5. 6. P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n fi n di n gs will o nl y be liste d.
6. 5. 7. Left Ve ntric ul ar Ejecti o n Fr acti o n ( L V E F)
L V E F % will be s u m marize d as fre q ue nc y ( n u m ber a n d perce nta ge) of patie nts wit h:

A s hift fr o m baseli ne n or mal t o at least o ne res ult bel o w t he i nstit uti o nal l o wer li mit 
of n or mal d uri n g t he o n -treat me nt peri o d;

≥2 0 -p oi nt decrease fr o m baseli ne i n L V E F %. 
A patie nt will be i ncl u de d i n t he cate g ories a b o ve if a n y  p ost-baseli ne assess me nt (i ncl u di n g 
u nsc he d ule d assess me nts) meet t he criteria; h o we ver o nl y p ost - baseli ne assess me nts w hic h
use t he sa me met h o d of assess me nt ( E C H O or M U G A) as baseli ne will be c o nsi dere d.
6. 5. 8. Perf or m a nce St at us 
T he E C O G s hift fr o m baseli ne t o t he hi g hest sc ore d uri n g t he p ost - baseli ne peri o d will be 
s u m marize d b y C o h ort.
6. 5. 9. M o o d a n d S uici d al I de ati o n a n d Be h a vi or A n al yses 

T he Bec k De pressi o n I n ve nt or y -II ( B DI-II) - Assess me nt of M o o d 
A n assess me nt of m o o d will be a d mi nistere d t o patie nts via t he Bec k De pressi o n I n ve nt or y -II 
( B DI-II) scale at t he ti me p oi nts descri be d i n t he Sc he d ule of Acti vities of t he St u d y Pr ot oc ol.  
T his is a 2 1 ite m self -re p orte d scale, wit h eac h ite m rate d by patie nts o n a 4 p oi nt scale 
(ra n gi n g fr o m 0-3.). T he scale i ncl u des ite ms ca pt uri n g m o o d, (l oss of pleas ure, sa d ness, a n d 
irrita bilit y), s uici dal i deati o n, a n d c o g niti ve si g ns ( p u niti ve t h o u g hts, self- criticis m, 
self- disli ke pessi mis m, p o or c o nce ntrati o n) as well as s o matic si g ns (a p petite, slee p, fati g ue, 
li bi d o). 
Sc ores are o btai ne d b y a d di n g u p t he t otal p oi nts fr o m t he series of a ns wers. Hi g her t otal 
sc ores i n dicate m ore se vere de pressi ve sy m pt o ms. T he sta n dar dize d c ut offs are as f oll o ws: 

0 – 1 3: mi ni mal de pressi o n ;

1 4 – 1 9: mil d de pressi o n ;

2 0 – 2 8: m o derate de pressi o n ;

2 9 – 6 3: se ver e de pressi o n. 


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T he f oll o wi n g descri pti ve statistics will be pr o vi de d: n, arit h metic mea n a n d S D. 
Fre q ue ncies a n d perce nta ges will be dis pla y e d o n ite ms ca pt uri n g m o o d, (l oss of pleas ure, 
sa d ness, irrita bilit y), s uici dal i deati o n, a n d c o g niti ve si g ns ( p u niti ve t h o u g hts, self- criticis m, 
self- disli ke, pessi mis m, p o or c o nce ntrati o n) as well as s o matic si g ns (a p petite, slee p, fati g ue, 
li bi d o) o n t he B DI-II scale will be s u m marize d. 

C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C - S S R S) 
Fre q ue ncies a n d perce nta ges will be dis pla y e d f or patie nts wit h s uici dal i deati o n, s uici dal 
be ha vi or, a n d self -i nj uri o us be ha vi or wit h o ut s uici dal i nte nt base d o n t he C-S S R S d uri n g 
treat me nt.
7. I N T E RI M A N A L Y S E S
N o f or mal i nteri m a nal ys is will be c o n d ucte d f or t his st u d y. H o we ver, as t his is a n 
o pe n -la bel st u d y, t he s p o ns or c o n d uct u n bli n de d re vie ws of t he data d uri n g t he c o urse of t he 
st u d y f or t he p ur p ose of safet y assess me nt, facilitati n g p har mac o ki netic/ p har mac o d y na mic 
m o deli n g, a n d/ or t o s u p p ort cli nical de vel o p me nt.
8. C O N SI D E R A TI O N O N C O V I D-1 9 I M P A C T
D uri n g t he st u d y , C O VI D-1 9 e mer ge nc y  starte d a n d m a y  ha ve i m pacte d st u d y c o n d uct.  The 
f oll o wi n g a nal ysis will be c o n d ucte d t o assess t he i m pact d ue t o C O VI D-1 9.  
Pr ot oc ol de viati o ns d ue t o C O VI D -1 9 will be s u m marie d. 
A listi n g of patie nts i m pacte d b y C O VI D -1 9 will be pr o vi de d. 
If t here are deat hs d ue t o C O VI D-1 9,  se nsiti viet y a nal ys is f or P F S a n d O S ma y be 
c o nsi der d.


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9. R E F E R E N C E S 
1.  
A mit O, et al.  Bli n de d i n de pe n de nt ce ntral re vie w of pr o gressi o n i n ca ncer cli nical 
trials: Res ults fr o m a meta-a nal ys is a n d rec o m me n dati o n fr o m a P h R M A w or ki n g 
gr o u p. E ur o pea n J o ur nal of Ca ncer 4 7: 1 7 7 2 -1 7 7 8, 2 0 1 1.
2.
Br o o k me yer R a n d Cr o wle y  J.  A c o nfi de nce i nter val f or t he me dia n s ur vi val ti me. 
Bi o metrics 3 8: 2 9 -4 1, 1 9 8 2 .
3.
Kal bfleisc h J D, Pre nt ice, R L. Statistical A nalys is of Fail ure Ti me Data, 2 n d 
E diti o n. H o b o ke n, Wile y  Interscie nce .


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A p pe n di x 1. Deri ve d O bjecti ve Res p o nse per m R E CI S T v 1. 1 b ase d o n I C R D at a
T he pri mar y  e n d p oi nt is O bjecti ve Res p o nse ( O R) i n patie nts w h ose disease has pr o gresse d 
after criz oti ni b ( C o h ort 1) b y  i n de pe n de nt ce ntral ra di ol o g y (IC R) assess me nt per m R E CI S T 
v 1. 1 s pecifie d i n pr ot oc ol A p pe n di x 3.
Per pr ot oc ol A p pe n di x 3, u p t o 5 C N S lesi o ns were per mitte d t o be i de ntifie d as tar get lesi o n 
i n a d diti o n t o 5 e xtracra nial lesi o ns ( u p to 2 lesi o ns per or ga n) at baseli ne.  F urt her m ore, it 
was e x pecte d sa me set of brai n lesi o ns were use d f or b ot h o verall a n d i ntracra nial assess me nt 
per R E CI S T v 1. 1 ( Pr ot oc ol A p pe n di x 3) .  
H o we ver, per I CR (P A R E X E L  ) o perati o nal pr oce d ure, o verall assess me nt a n d i ntracra nial 
assess me nt are perf or me d i n de pe n de ntl y f or st u d y B 7 4 6 1 0 2 4; O verall assess me nt was base d 
o n R E CI S T 1. 1 wit h u p t o 2 C N S lesi o ns a n d 5 lesi o ns i n t otal were per mitte d t o be 
i de ntifie d as tar get lesi o n at baseli ne.  W hile i ntracra nial assess me nt was base d o n m o difie d 
R E CI S T 1. 1 t hat all o ws u p t o 5 meas ura ble C N S lesi o ns. He nce t he brai n lesi o ns i n t he 
o verall assess me nt a n d i ntracra nial assess me nt ma y be differe nt.  A n d t he o verall assess me nt 
was c o n d ucte d i n a differe nt wa y  as s pecifie d i n pr ot oc ol A p pe n di x 3. 
T o miti ga te t he p ote ntial ris k d ue t o t he differe nce bet wee n I C R’s pr oce d ure a n d t hat defi ne d 
i n pr ot oc ol A p pe n di x 3 , pr o gra m mi n g deri ve d o verall assess me nt per m o difie d R E CIS T v 1. 1 
base d o n I C R t u m or lesi o n data will be c o n d ucte d t o s u p p ort t he efficac y a nal ysis.
Gi ve n t he I C R data pr o vi de d b y  P A R E X E L, f or eac h patie nt, t he e xtracra nial lesi o ns 
i de ntifie d i n t he o verall assess me nt will be c o m bi ne d wit h t he i ntracra nial lesi o n i de ntifie d i n 
t he i ntracra nial assess me nt. T he t u m or res p o nse will t he n be deri ve d base d o n t u m or 
meas ure me nt/assess me nt per R E CI S T v 1. 1.  
As t here will be 2 ra di ol o gist t o re vie w eac h patie nt,  f or t he deri ve d res p o nse, o nl y t he 
rea di n gs fr o m t he rea der a gree d by t he a dj u dicat or will be use d f or t he deri vati o n.  If t here’s 
n o a dj u dicati o n, w hic h mea ns t hat t here’s n o discre pa nc y  i n t he t w o rea ders’ assess me nt f or 
eac h ti me p oi nt, t he rea der wit h m ore re prese ntati ve e xtracra n ial lesi o n selecte d at baseli ne 
will be use d f or t he deri vati o n.  T he selecti o n will f oll o w t he bel o w r ule:

If b ot h t he e xtracra nial assess me nt a n d i ntracra nial assess me nt ha ve a dj u dicat ors, t he 
a dj u dicat or’s assess me nt will be a p plie d , n o matter w het her th e e xtracra nial 
assess me nt a n d i ntracra nial assess me nt ha ve c h ose n t he sa me re vie wer’s rea di n gs.

If o nl y t he e xtracra nial assess me nt or o nl y  i ntracra nial assess me nt ha ve a dj u dicat or 
b ut n ot b ot h of t he m, b ot h of t he e xtracra nial assess me nt a n d i ntracra nial assess me nt 
base d o n t he e xist a dj u dicat or’s decisi o n will be a p plie d.

If n o a dj u dicat or a p peare d f or b ot h of e xtracra nial a n d i ntracra nial assess me nt, t he 
selecti o n will f oll ow t he bel o w r ule:

T he o ne wit h m ore e xtracra nial tar get lesi o n at baseli ne i n o v erall assess me nt will 
be use d if t here was n o a dj u dicati o n ;

If t he t w o rea ders i de ntifie d t he sa me n u m ber of e xtracra nial tar get lesi o n, t he o ne 
wit h t he lar ger S O D of e xtracra nial tar get lesi o n will be c h ose n.