Clinical trial NCT03672643
Conditions: ALK or ROS1-positive NSCLC
Keywords: NSCLC
Sponsor: Pfizer
Start date: 2019-01-28; Completion date: 2023-09-28
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is to allow access to crizotinib who were treated in previous Pfizer-sponsored studies in China.

Detailed description:
This study is a phase 4 study, to continually access Xalkori to Chinese patients who were recruited in previous studies of Crizotinib in China, and only collect the safety data.

Arms: arm 1: Crizotinib
Interventions: intervention 1: Crizotinib
Intervention descriptions: intervention 1: receive crizotinib orally

Protocol documents:
Prot_000.pdf: 
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AN OPEN-LABEL, SINGLE-ARM STUDY OF THE LONG-TERM SAFETY OF 
XALKORI® IN PATIENTS FROM CHINA WITH ADVANCED NON-SMALL CELL 
LUNG CANCER (NSCLC) HARBORING A TRANSLOCATION OR INVERSION 
EVENT INVOLVING THE ANAPLASTIC LYMPHOMA KINASE (ALK) OR 
ROS1 LOCUS WHO HAVE PREVIOUSLY BEEN TREATED ON A STUDY OF 
XALKORI®
Investigational Product Number:
PF-02341066
Investigational Product Name:
Crizotinib
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
A8081067
Phase:
4
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
02 August 2019
Extended the study treatment duration until 
disease progression, unacceptable toxicity, 
consent withdrawal, or death, whichever 
came first, to provide longer treatment
access to the patients.
Updated the AE and SAE collection and 
recording requirements to remove 
inconsistencies and to provide further 
clarifications.
Clarified that scans outside the screening 
window may be used in this study.
Updated “End of Trial” definition.
Added “all AEs leading to permanent 
treatment discontinuation” into the 
endpoint.
Original protocol
22-March-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.....................................................................................................................6
APPENDICES ...........................................................................................................................6
PROTOCOL SUMMARY.........................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................9
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................16
3. STUDY DESIGN.................................................................................................................16
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................17
4.3. Registration Criteria ................................................................................................18
4.4. Lifestyle Requirements ...........................................................................................18
4.4.1. Contraception..............................................................................................18
4.4.2. Sunlight Exposure.......................................................................................19
4.5. Sponsor’s Qualified Medical Personnel..................................................................19
5. STUDY TREATMENTS.....................................................................................................20
5.1. Allocation to Treatment ..........................................................................................20
5.2. Patient Compliance .................................................................................................20
5.3. Investigational Product Supplies.............................................................................21
5.3.1. Dosage Form(s) and Packaging..................................................................21
5.3.2. Preparation and Dispensing........................................................................21
5.4. Administration.........................................................................................................21
5.5. Investigational Product Storage ..............................................................................21
5.6. Investigational Product Accountability...................................................................22
5.6.1. Destruction of Investigational Product Supplies ........................................22
5.7. Management of Selected Crizotinib-Related Adverse Events ................................22
5.7.1. Nausea and Emesis .....................................................................................22
5.7.2. Diarrhea ......................................................................................................22
5.7.3. Bradycardia.................................................................................................23


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5.7.4. Pneumonitis ................................................................................................23
5.8. Dose Modifications .................................................................................................24
5.9. Concomitant Treatment(s).......................................................................................29
5.9.1. Concomitant Radiotherapy or Surgery.......................................................29
6. STUDY PROCEDURES .....................................................................................................29
6.1. Screening.................................................................................................................29
6.2. Study Period ............................................................................................................29
6.2.1. Follow-up Contact ......................................................................................30
6.3. Patient Withdrawal..................................................................................................30
7. ASSESSMENTS..................................................................................................................31
7.1. Safety Assessment...................................................................................................31
7.1.1. Laboratory Safety Assessments..................................................................31
7.1.2. Physical Examination .................................................................................32
7.1.3. Electrocardiogram (ECG) Measurements...................................................32
7.1.4. Pregnancy Test............................................................................................32
7.2. Tumor Assessments.................................................................................................33
8. ADVERSE EVENT REPORTING......................................................................................33
8.1. Requirements...........................................................................................................33
8.1.1. Additional Details On Recording Adverse Events on the CRF..................35
8.1.2. Eliciting Adverse Event Information..........................................................35
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal Section) ............................................................................35
8.1.4. Time Period for Collecting AE/SAE Information......................................36
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................36
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................36
8.1.5. Causality Assessment .................................................................................37
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................37
8.2. Definitions...............................................................................................................38
8.2.1. Adverse Events...........................................................................................38
8.2.2. Abnormal Test Findings .............................................................................39
8.2.3. Serious Adverse Events ..............................................................................39
8.2.4. Hospitalization............................................................................................40


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8.3. Severity Assessment................................................................................................41
8.4. Special Situations ....................................................................................................42
8.4.1. Protocol-Specified Serious Adverse Events...............................................42
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................42
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................43
8.4.3.1. Exposure During Pregnancy......................................................44
8.4.3.2. Exposure During Breastfeeding ................................................45
8.4.3.3. Occupational Exposure .............................................................45
8.4.4. Medication Errors .......................................................................................45
8.4.4.1. Medication Errors......................................................................46
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................46
9.1. Sample Size Determination.....................................................................................46
9.2. Efficacy Analysis ....................................................................................................46
9.3. Analysis of Other Endpoints ...................................................................................46
9.4. Safety Analysis........................................................................................................47
9.5. Data Monitoring Committee ...................................................................................47
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................47
11. DATA HANDLING AND RECORD KEEPING .............................................................48
11.1. Case Report Forms/Electronic Data Record .........................................................48
11.2. Record Retention...................................................................................................48
12. ETHICS..............................................................................................................................49
12.1. Institutional Review Board/Ethics Committee......................................................49
12.2. Ethical Conduct of the Study ................................................................................49
12.3. Patient Information and Consent...........................................................................49
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................50
13. DEFINITION OF END OF TRIAL...................................................................................50
13.1. End of Trial ...........................................................................................................50
14. SPONSOR DISCONTINUATION CRITERIA ................................................................51
15. PUBLICATION OF STUDY RESULTS..........................................................................51
15.1. Communication of Results by Pfizer ....................................................................51
15.2. Publications by Investigators ................................................................................52


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16. REFERENCES ..................................................................................................................53
LIST OF TABLES
Table 1.
Schedule of Activities.................................................................................9
Table 2.
Schedule of Activities For Patients who are pending for Crossover 
Treatment in Study A8081014 or A8081029 ...........................................12
Table 3.
Available Study Medication Dose Levels ................................................24
Table 4.
Crizotinib Dose Modifications for Treatment-Related Toxicity ..............25
APPENDICES
Appendix 1. Laboratory Safety Assessments ..........................................................................54
Appendix 2. Abbreviations......................................................................................................55


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PROTOCOL SUMMARY
Background and Rationale: 
On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved XALKORI®
(crizotinib) for the treatment of locally advanced or metastatic non-small cell lung cancer 
(NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an 
FDA-approved test.1 Crizotinib received approvals for the treatment of ALK-positive 
advanced NSCLC in China in January 2013 and was approved for the treatment of c-ROS 
oncogene 1 (ROS1)-positive advanced NSCLC in China in September 2017.
This protocol permits continued access to crizotinib for patients with advanced NSCLC 
harboring translocation or inversion event involving the ALK or ROS1 gene locus who were 
enrolled and treated in Studies A8081005, A8081007, A8081014, A8081029, or 
A8081063 and are still receiving crizotinib treatment at the time of enrollment into this 
study.  In addition, patients randomized to the chemotherapy arm in Studies A8081014 or 
A8081029 who have not yet crossed over to receive crizotinib treatment at the time of 
enrollment into this study are eligible to enroll into this study after investigator-assessed 
disease progression.  This clinical trial is only open to patients in China.  Patients will follow 
a schedule of visits and data collection for safety monitoring.
Additional information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the XALKORI® local product document (LPD).
Objectives: 
To evaluate the long-term safety of crizotinib in patients with advanced NSCLC harboring a 
translocation or inversion of the ALK gene or ROS1 gene locus.
Endpoints:
All Grade 3-5 adverse events (AEs), all AEs leading to permanent treatment discontinuation,
and all serious adverse events (SAEs) as assessed by National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). 
Study Design: 
This is a multi-center, open-label study in China only.  Eligible patients include those with 
advanced NSCLC harboring a translocation or inversion of the ALK gene or ROS1 gene 
locus who were enrolled and treated in Studies A8081005, A8081007, A8081014, 
A8081029, or A8081063 and are still receiving crizotinib treatment at the time of enrollment 
into this study. In addition, patients, randomized to the chemotherapy arm in 
Studies A8081014 or A8081029 and have not yet crossed over to receive crizotinib treatment 
at the time of enrollment into this study are eligible to enroll into this study after 
investigator-assessed disease progression.  Dose reductions and re-escalations are allowed 
based on tolerability.


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Study Treatments:
Patients, who were receiving crizotinib prior to enrolling into this study, will continue to 
receive their current crizotinib dosing regimen.  Patients in Study A8081014 or A8081029, 
who have not started crizotinib treatment prior to enrollment in this study, will receive the 
standard starting dose of crizotinib at 250 mg Twice Daily (BID) orally after 
investigator-assessed disease progression.  Crizotinib will be supplied by the Sponsor.
Patients will continue single-agent crizotinib treatment on this study until disease 
progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.  
Patients may continue crizotinib treatment as assigned beyond the time of Response 
Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression at the discretion 
of the investigator if the patient is still experiencing clinical benefit.
Statistical Methods:
Due to the nature of this rollover study, the number of patients to be enrolled is not 
predefined.  However, it is expected that approximately 75 patients will be enrolled. 
No statistical methods will be employed to test a specific hypothesis in this study.  Only 
descriptive summaries of safety and demographic characteristics will be provided, and no 
inferential analyses are planned.






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h.
On study tumor assessments should be performed according to site standard of care imaging modality.  The most recent tumor assessment available may be 
utilized for tumor assessment at baseline, even if conducted more than 28 days prior to Cycle 1 Day 1. Abdominal scans should include complete 
visualization of both kidneys.  The interval for monitoring disease status and for progression of disease should not be longer than every 6 months.
i.
Hematology and Chemistry: Required tests are listed in Appendix 1 of the protocol. Hematology and Chemistry is performed on Day 1 of each treatment 
cycle and may be additionally performed as clinically indicated. Blood chemistry and hematology does not need to be repeated if acceptable screening 
assessment is performed within 7 days prior to Cycle 1 Day 1.
j.
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days after the last administration of the investigational product to 
capture any potential adverse events (see the Time Period for Collecting AE/SAE Information section) and to confirm appropriate contraception usage (see 
the Contraception section).  Contact with the patient may be done via a phone call.






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h.
On-study tumor assessments should be performed according to site standard-of-care imaging modality.  The most recent tumor assessment available may be 
utilized for tumor assessment at baseline, even if conducted more than 28 days prior to Cycle 1 Day 1.  Abdominal scans should include complete 
visualization of both kidneys.  The interval for monitoring disease status and for progression of disease should not be longer than every 6 months.
i.
Hematology and Chemistry: Required tests are listed in Appendix 1 of the protocol. Hematology and Chemistry is performed on Day 1 of each treatment 
cycle and may be additionally performed as clinically indicated.  Blood chemistry and hematology does not need to be repeated if acceptable screening 
assessment is performed within 7 days prior to Cycle 1 Day 1.  For the first 2 cycles, hematology and chemistry should be repeated on Day 8, 15, 22
(±1 day). 
j.
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days after the last administration of the investigational product to 
capture any potential adverse events (see the Time Period for Collecting AE/SAE Information section) and to confirm appropriate contraception usage (see 
the Contraception section).  Contact with the patient may be done via a phone call.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Crizotinib (PF-02341066) is a selective adenosine triphosphate (ATP)-competitive small 
molecule oral inhibitor of the anaplastic lymphoma kinase (ALK), c-Met/hepatocyte growth 
factor receptor (HGFR), Recepteur d’Origine Nantais (RON), and ROS1 receptor tyrosine 
kinases and their oncogenic variants (eg, c-Met/HGFR mutations and ALK or ROS1 fusion 
proteins). Consistent with this mechanism of action, crizotinib inhibited phosphorylation of 
c-Met/HGFR, selected ALK fusion or mutant variants and ROS1 fusion variants in tumor 
cells both in vitro and in vivo, and RON in vitro. Crizotinib exhibited potent and selective 
growth inhibitory activity against tumor cells exhibiting translocation/inversion or selected 
mutations involving the ALK gene or ROS1 gene locus (ie, echinoderm 
microtubule-associated protein-like-4 [EML4]-ALK or nucleophosmin [NPM]-ALK fusion 
variants), exhibiting translocation of the ROS1 gene locus, or amplification of the 
c-Met/HGFR gene locus.
The results from single arm clinical Studies A8081001 and A8081005 supported accelerated 
marketing approval of crizotinib in the United States (US) in August 2011 for the treatment 
of patients with locally advanced or metastatic NSCLC that is ALK positive as detected by a 
Food and Drug Administration (FDA)-approved test. In March 2016, FDA approved 
crizotinib for a new indication for the treatment of patients with metastatic non-small cell 
lung cancer whose tumors are ROS-1 positive, which is based on Study A8081001 results in 
ROS1 positive patients.
1.2. Background and Rationale
Crizotinib received approval for the treatment of ALK-positive advanced NSCLC in China in 
January 2013 and was approved for the treatment of ROS1-positive advanced NSCLC in 
China in September 2017.
This protocol permits continued access to crizotinib for patients with advanced NSCLC 
harboring translocation or inversion event involving the ALK gene or ROS1 gene locus who 
had received crizotinib treatment in another Pfizer-sponsored clinical study 
(Studies A8081005, A8081007 and A8081014) and are still receiving crizotinib treatment at 
the time of enrollment into this study or currently receiving crizotinib treatment in Studies
A8081029 and A8081063. In addition, patients in Studies A8081014 or A8081029 who 
were randomized to the chemotherapy treatment and do not cross over to receive crizotinib 
treatment at the time of enrollment into this study, will have the opportunity to receive 
crizotinib treatment in this study after investigator-assessed disease progression.  This 
clinical trial is only open to patients in China.
Patients will follow Table 1 or Table 2, as appropriate, for the schedule of visits and data 
collection for safety monitoring.
Additional information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the XALKORI® LPD.


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):

To evaluate the long-term safety of crizotinib in 
patients with advanced NSCLC harboring a 
translocation or inversion of the ALK gene or 
ROS1 gene locus.

All Grade 3-5 AEs, all AEs leading to 
permanent treatment discontinuation, and all 
SAEs as assessed by National Cancer Institute 
Common Terminology Criteria for Adverse 
Events version 4.03 (NCI CTCAE v4.03).
3. STUDY DESIGN
This is a multi-center, open-label study in China only.  Eligible patients include those with 
advanced NSCLC harboring translocation or inversion event involving the ALK gene or 
ROS1 gene locus, who were enrolled in Studies A8081005, A8081007, A8081014, 
A8081029 and A8081063 and are still receiving crizotinib treatment at the time of 
enrollment into this study.  In addition, patients, randomized to the chemotherapy arm in 
Studies A8081014 and A8081029 and have not yet crossed over to receive crizotinib 
treatment at the time of enrollment into this study, are eligible to enroll into this study after 
investigator-assessed disease progression. Approximately 75 patients will be enrolled into 
this study. Dose reductions and re-escalations are allowed based on tolerability.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Patients who were enrolled and treated in Studies A8081005, A8081007, A8081014, 
A8081029, or A8081063 and are still receiving crizotinib treatment at the time of 
enrollment into this study.  
OR
Patients randomized to the chemotherapy arm in Studies A8081014 or A8081029
who have experienced investigator-assessed disease progression and have not yet 
crossed over to receive crizotinib treatment.
2. No ongoing NCI CTCAE Grade ≥3 or intolerable Grade 2 adverse events considered 
to be related to crizotinib treatment.


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3. Eastern Cooperative Oncology Group (ECOG) performance status 0-3.
4. Adequate organ function as defined by the following criteria:

Hepatic function: Serum aspartate aminotransferase (AST) and serum alanine 
aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN), or AST and ALT 
≤5 × ULN if liver function abnormalities were due to underlying malignancy; 
total serum bilirubin ≤1.5 × ULN (except patients with documented Gilbert’s 
syndrome);

Bone marrow function: absolute neutrophil count ≥1000/µL, platelets 
≥50,000/µL; hemoglobin ≥8.0 g/dL;

Renal function: Serum creatinine ≤2.0 × ULN.
5. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
6. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study prior to enrollment. 
7. Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Use of any anticancer drug subsequent to crizotinib prior to study entry.
2. Use of drugs or foods that are known potent Cytochrome P450 (CYP)3A4 inhibitors 
including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin, voriconazole, and grapefruit or grapefruit juice.  The topical use of 
these medications (if applicable), such as 2% ketoconazole cream, is allowed.


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3. Use of drugs that are known potent CYP3A4 inducers including but not limited to 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort.
4. Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, 
associated with life-threatening arrhythmias, including but not limited to 
dihydroergotamine, ergotamine, and pimozide.
5. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
6. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
7. 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 90 days after the last dose of investigational product.
4.3. Registration Criteria
The Sponsor must approve the enrollment of each patient. Patients will be registered into the 
study provided that they have satisfied all patient selection criteria and have withdrawn from 
their original crizotinib clinical study prior to enrollment in this study.
4.4. Lifestyle Requirements 
4.4.1. Contraception
All fertile male subjects and female patients who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for 90 days after the last dose of crizotinib.  
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient from 
the permitted list of contraception methods (see below) and will confirm that the patient 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 highly 
effective contraception consistently and correctly and document the conversation and the 
patient’s affirmation in the patient’s chart (patients need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception).  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 patient or the partner. 


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the patient.
All sexually active male patients must agree to prevent potential transfer of and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of crizotinib and continuing for 90 days after the last dose of 
investigational product.
Contraceptive checks will not be recorded on the Case Report Form (CRF), but all 
information will need to be available from the patient’s medical record upon request by the 
Sponsor.
4.4.2. Sunlight Exposure
Patients treated with crizotinib should avoid sunbathing, prolonged unprotected sun exposure, 
or tanning for the duration of the study period.
4.5. 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 supporting study documentation. 


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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational product is crizotinib. 
5.1. Allocation to Treatment
Patients who were receiving crizotinib prior to enrolling into this study will continue to 
receive their current crizotinib dosing regimen.  Patients, who were enrolled into the 
chemotherapy arms of Studies A8081014 or A8081029 and had not crossed over to crizotinib 
treatment prior to enrollment into this study will receive the standard starting dose of 
crizotinib (ie, 250 mg BID) orally after investigator-assessed disease progression.  Available 
crizotinib dosing regimens are 250 mg BID, 200 mg BID, or 250 mg Once Daily (QD).  
Crizotinib will be supplied by the Sponsor.
Treatment will be administered orally in continuous fashion.  For purposes of scheduling 
visits and assessments, treatment cycles are 4 weeks (28 days) in length.
5.2. Patient Compliance
Patients will be required to return all containers of study medication before dispensing 
crizotinib for new cycles. All drug returned will be documented on the drug accountability 
log.  Patient compliance information will not be recorded on the CRF, but will need to be 
available from the patient’s medical record upon request by the Sponsor.


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5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
Crizotinib will be provided by the Sponsor as capsules 250 mg and 200 mg of oral study 
medication and will be packaged in High-Density Polyethylene (HDPE) bottles and labeled 
according to local regulatory requirements.
5.3.2. Preparation and Dispensing
Crizotinib will be dispensed at the beginning of each treatment cycle (or as otherwise 
indicated).  Patients should be instructed to keep their medication in the bottles provided and 
not transfer it to any other container.
5.4. Administration
Patients who were receiving crizotinib prior to enrolling into this study will continue to 
receive their current dose of crizotinib.  Patients who were enrolled into the chemotherapy 
arms of Studies A8081014 or A8081029 and have not started crizotinib treatment prior to 
enrollment into this study will receive the standard starting dose of crizotinib (ie, 250 mg 
BID).  Patients will continue single-agent crizotinib treatment on this study until disease 
progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.  
Patients may continue crizotinib treatment as assigned beyond the time of RECIST-defined 
disease progression at the discretion of the investigator if the patient is still experiencing 
clinical benefit.
Subjects will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing.
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that crizotinib is 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
Crizotinib should be stored in its original container and in accordance with the drug label. 
Storage conditions stated in the single reference safety document (SRSD) (ie, LPD) 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 crizotinib receipt throughout study.  Even for continuous 
monitoring systems, a log or site procedure which ensures active evaluation for excursions 
should be available.  The intent is to ensure that the minimum and maximum temperature is 
checked each business day to confirm that no excursion occurred since the last evaluation 
and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order. 


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Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Pfizer provides permission to use crizotinib.  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 patients on the proper storage requirements for take home 
investigational product including how to report temperature excursions.
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  All containers must be returned to the 
investigator by the patient at every visit and at the end of the trial. 
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Management of Selected Crizotinib-Related Adverse Events
5.7.1. Nausea and Emesis
Standard anti-emetics such as prochlorperazine or ondansetron may be used for the treatment 
of vomiting.  Taking the medication with food may reduce nausea. Prophylactic anti-emetics 
may be used.
5.7.2. Diarrhea
CTCAE Grade 1: Symptomatic care such as loperamide (Imodium) or no intervention per 
investigator judgment. 
CTCAE Grade 2: Loperamide (4 mg at first onset, then 2 mg every 2-4 hours until symptom 
free for 12 hours).  No dose modification unless patient is intolerant or symptom is recurrent. 
CTCAE Grade ≥3 (despite use of loperamide): Withhold treatment until recovery to 
Grade ≤1.


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5.7.3. Bradycardia
Avoid using crizotinib in combination with other bradycardic agents (eg, beta-blockers, 
non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, 
digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia 
(syncope, dizziness, hypotension).  Heart rate and blood pressure should be monitored 
regularly.  Dose modification is not required in cases of asymptomatic bradycardia.  In cases 
of symptomatic bradycardia, crizotinib should be held and the use of concomitant 
medications should be re-evaluated.  For management of patients who develop symptomatic 
bradycardia, see Table 4.  The dosage of any medication known to be associated with 
bradycardia, eg, beta blockers, should be adjusted accordingly.  It is important to counsel 
patients about the risk of bradycardia and inform them of what symptoms and signs to be 
aware of and actions to take.
5.7.4. Pneumonitis
Investigators must evaluate thoroughly patients who demonstrate potential signs/symptoms 
of pneumonitis/pneumonia.  If a patient has a potential diagnosis of pneumonitis or drug 
related lung injury the following evaluations/procedures should be considered to assist or 
exclude the diagnosis of pneumonitis during this period.

A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and mycobacteria. 

Blood culture should be performed in febrile patients.

Thoracentesis if pleural fluid is present (examined for same pathogens as sputum).

Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate.  The BAL fluid 
should be sent for culture and cytology (same pathogens as above).

Lung biopsy (eg, open or thorascopic preferable, bronchoscopy with transbronchial 
biopsy) if appropriate.

A plasma sample for B-type Natriuretic peptide (BNP) to evaluate for evidence of
Congestive Heart Failure (CHF).

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 considered. 
Should the event be fatal an autopsy is highly recommended to confirm /exclude the 
diagnosis.
For any case of drug-related pneumonitis discontinue crizotinib and contact the Sponsor.  For 
appropriate dose modifications see Table 4.


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5.8. Dose Modifications
Investigators are encouraged to employ best supportive care according to local institutional 
clinical practices and according to the guidance for selected adverse events provided below.
Patients will be monitored for toxicity and the dose of crizotinib may be adjusted as indicated 
in Table 4.  Intrapatient dose reduction will be allowed depending on the type and severity of 
toxicity encountered as shown in Table 3.  Patients requiring dosing less than 250 mg QD 
due to treatment-related toxicity will be discontinued from the study. 
Table 3.
Available Study Medication Dose Levels
Highest Dose Level
250 mg BID
-1 Dose Level
200 mg BID
-2 Dose Level
250 mg QD


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Table 4.
Crizotinib Dose Modifications for Treatment-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
ALT or AST elevation with 
total bilirubin <2 × ULN (in 
absence of cholestasis or 
hemolysis).a
Continue at the same dose 
level.
Continue at the same dose 
level. Obtain repeat ALT or 
AST and total bilirubin 
when symptomatic or within 
7 days.  
Withhold dose until toxicity is 
Grade ≤1, or has returned to 
baseline, then resume treatment by 
reducing by one dose level.  If 
Grade 3 ALT or AST elevation 
recurs reduce further (at most by 
2 dose levels from the initial dose 
level).  If recurrence at dose level -2, 
then discuss with Sponsor whether 
or not to discontinue permanently.  
If ALT or AST elevation does not 
recur after at least 4 weeks, the dose 
may be escalated by single dose 
level increments up to the initial 
dose level.  
See Grade 3.
ALT or AST elevation 
concurrent with total 
bilirubin elevation ≥2× ULN 
(in absence of cholestasis or 
hemolysis).a
Continue at the same dose 
level.  Obtain repeat ALT or 
AST and total bilirubin 
within 48 hours, then repeat 
every 48-72 hours until 
ALT/AST Grade ≤1.
Discontinue treatment and 
do not retreat.
Discontinue treatment and do not 
retreat.
Discontinue treatment 
and do not retreat.


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Table 4.
Crizotinib Dose Modifications for Treatment-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Bradycardia (heart rate less 
than 60 beats per minute).
Continue at the same dose 
level.
Withhold until recovery to 
Grade ≤1 or to 
heart rate ≥60.
Evaluate concomitant 
medications known to cause 
bradycardia, as well as 
anti-hypertensive 
medications.
If contributing concomitant 
medication is identified and 
discontinued, or its dose is 
adjusted, resume at previous 
dose upon recovery to 
Grade ≤1 or to heart rate 
≥60.
If no contributing 
concomitant medication is 
identified, or if contributing 
concomitant medications are 
not discontinued or dose 
modified, resume at reduced 
dose upon recovery to 
Grade ≤1 or to 
heart rate ≥60.
Same as for Grade 2 bradycardia.
Permanently 
discontinue if no 
contributing 
concomitant 
medication is 
identified.
If contributing 
concomitant 
medication is 
identified and 
discontinued, or its 
dose is adjusted, 
resume at 250 mg QD 
upon recovery to 
Grade ≤1 or to heart 
rate ≥60, with frequent 
monitoring
Permanently 
discontinue for 
recurrence.
Pneumonitis (not attributable 
to NSCLC progression, 
other pulmonary disease, 
infection, or radiation 
effect).
Discontinue treatment and 
do not retreat.
Discontinue treatment and 
do not retreat.
Discontinue treatment and do not 
retreat.
Discontinue treatment 
and do not retreat.
Left ventricular systolic 
dysfunction.
Continue at the same dose 
level.
Continue at the same dose 
level.
Discontinue treatment and do not 
retreat.
Discontinue treatment 
and do not retreat.


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Table 4.
Crizotinib Dose Modifications for Treatment-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged QTc.
Continue at the same dose 
level.
Continue at the same dose 
level 
Assess electrolytes and 
concomitant medications
Correct any electrolyte or 
magnesium abnormalities.
Withhold until recovery to 
Grade ≤1, and then resume treatment 
by reducing the dose by one dose 
level.
Discontinue treatment 
and do not retreat.
Visual disturbance.b
Continue at the same dose 
level
Repeat ophthalmologic 
examination.b
Continue at the same dose 
level
Repeat ophthalmologic 
examination.b
Interrupt crizotinib until recovery.
Repeat ophthalmologic 
examination.b
Resume treatment by reducing the 
dose by one dose level.
Discontinue crizotinib 
and do not retreat. 
Repeat 
ophthalmologic 
examination.b
Non hematologic 
General (except those 
described above), 
eg, neuropathy, edema
(including peripheral edema 
and localized edema), 
fatigue, and skin rash 
(including erythematous, 
macular, papular, and 
pruritic rash).
Continue at the same dose 
level.
Continue at the same dose 
level.
Withhold dose until toxicity is 
Grade ≤1, or has returned to 
baseline, then resume treatment at 
the same dose or reduce the dose by 
1 level at the discretion of the 
investigator.c
Withhold dose until 
toxicity is Grade ≤1, 
or has returned to 
baseline, then reduce 
the dose by 1 level and 
resume treatment, or 
discontinue at the 
discretion of the 
investigator.c
Hematologic (excluding 
lymphopenia).d
Continue at the same dose 
level.
Continue at the same dose 
level.
Withhold dose until toxicity is 
Grade ≤2, or has returned to 
baseline, then resume treatment at 
the same dose level or reduce the 
dose by 1 dose level after discussion 
with the Sponsor.d
Withhold dose until 
toxicity is Grade ≤2, 
or has returned to 
baseline, then reduce 
the dose by 1 level and 
resume treatment.d
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; v = version; CTCAE = Common Terminology Criteria 
for Adverse Events; NCI = National Cancer Institute; ULN = upper limit of normal.
a.
Patients entering with ALT and/or AST ≥5 × ULN (ie, Grade ≥3) due to underlying malignancy will be monitored for potential drug related increases at 
which point dose modifications will be discussed with the Sponsor.
b.
Ophthalmologic examination includes visual acuity, fundoscopy, and slit lamp and should be performed by an ophthalmologist.  Ophthalmologic 
examinations should be repeated during the study whenever a vision disorder AE is observed or NCI CTCAE v4.03 grade change occurs from the previous 
visit.


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c.
Patients who develop Grade 4 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms may continue study treatment without interruption at 
the discretion of the investigator.  Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, to require dose modification.
d.
Patients who develop Grade 3 or 4 lymphopenia without other dose limiting events (eg, opportunistic infection) may continue study treatment without 
interruption. 


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5.9. Concomitant Treatment(s)
Anticancer therapy with agents other than crizotinib is not allowed.
Medications intended solely for supportive care (ie, antiemetics, analgesics) are allowed.  
Documentation of these medications will not be collected on the CRF but will need to be 
available from the patients’ medical record upon request by the sponsor. 
The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in human 
liver microsomes and hepatocytes.  Coadministration with drugs that are CYP3A inhibitors 
and inducers may change the plasma concentrations of crizotinib in humans.  The concurrent 
use of potent CYP3A inhibitors are not allowed in the study.  Caution must be exercised in 
patients receiving crizotinib in combination with other CYP3A substrates, particularly those 
with narrow therapeutic indices. Additionally, the concurrent use of non-prescription drugs 
(excluding vitamins) or herbal supplements is not recommended.  Low-dose acetaminophen 
(<2 g/day) is allowed.
The use of permitted concomitant medication must be in accordance with the China 
crizotinib LPD.
5.9.1. Concomitant Radiotherapy or Surgery
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  Crizotinib treatment should be interrupted during 
palliative radiotherapy – stopping 1 day before and resuming treatment 1 day after. 
The effect of crizotinib in wound healing is not known and has not been investigated; 
therefore, caution is advised on theoretical grounds (potential antiangiogenic effect).  In the 
event elective surgery is necessary during study participation, crizotinib dosing should be 
stopped 48 hours before surgery and resumed no sooner than 48 hours after surgery.
6. STUDY PROCEDURES 
Informed Consent: All patients being considered for this study must sign an informed 
consent document prior to any study-related procedures that are not considered to be standard 
of care and prior to receiving study drug.
Registration: The investigator will assign subject numbers sequentially to the patients as 
they are screened for the study. Assessments for screening and all other study time points are 
detailed in Table 1 and Table 2.
6.1. Screening
See Table 1 and Table 2 for Schedule of Activities.
6.2. Study Period
See Table 1 and Table 2 for Schedule of Activities.


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6.2.1. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the patient 
may be done via a phone call.
6.3. Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events (see also the Patient Withdrawal Section)
section) or behavioral reasons, or the inability of the patient to comply with the 
protocol-required schedule of study visits or procedures at a given study site. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record. In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product, request that the patient return for a final visit, if applicable, and follow up with the 
patient regarding any unresolved AEs.
Reasons for trial treatment discontinuation may include: 

Disease progression as determined by investigator unless the patient is considered to 
have ongoing clinical benefit by the investigator;

Unacceptable toxicity;

Global deterioration of health related symptoms;

Protocol noncompliance;

Pregnancy;

Withdrawal of consent;

Patient loss to follow up;

Death;

Study termination by Sponsor;

Participation in other studies involving investigational drug(s) or using any drug of 
cancer therapy during study participation.


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If the patient 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 patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessment
Safety will be assessed by physical examination (including blood pressure, temperature and 
pulse rate) and laboratory tests, and other procedures as necessary according to standard of 
care and in accordance with each site’s institutional guidelines to monitor for adverse events 
related to the underlying disease, treatment with crizotinib, or treatment with other supportive 
therapies.  Information generated from physical examinations will be captured in the 
patient’s own medical record and not recorded on CRFs for this protocol. Information 
generated from these assessments will be used to determine if an adverse event occurred as 
defined in Section 8.  All Grade 3-5 AEs, all AEs leading to permanent treatment 
discontinuation, and all SAEs will be recorded on CRFs and will be classified by type, 
incidence, severity (graded by the National Cancer Institute CTCAE Version 4.03), timing, 
seriousness, and relatedness.
7.1.1. Laboratory Safety Assessments
For a list of required hematology and blood chemistry tests, see Appendix 1.
Hematology and blood chemistry will be performed to verify patients’ eligibility at 
Screening, on Day 1 of the first cycle, then on Day 1 of each subsequent cycle of treatment
for all patients and may be additionally performed as clinically indicated. Patients who were 
randomized to the chemotherapy and did not cross over to receive crizotinib treatment in 
Studies A8081014 or A8081029 will have additional blood chemistry and hematology tests 
on Day 8, 15 and 22 in the first 2 cycles. 


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During the non-visit cycles, the investigator is responsible for ensuring that the patients have 
hematology and blood chemistry tests conducted and contacts the clinical site in order to 
provide an update of adverse events, concomitant medication, laboratory, and pregnancy tests 
which are conducted at an external facility or at the study site.  The laboratory test 
parameters that need to be assessed (eg, hematology, blood chemistry) are the same as those 
that are assessed when a patient visits a study site for a regular visit, as in Appendix 1.  A 
copy of laboratory test results is to be provided at the next visit to study site if laboratory 
tests are conducted at an external facility.
Blood chemistry and hematology do not need to be repeated if acceptable screening 
assessment is performed within 7 days prior to Cycle 1/Day 1.
If ALT/AST Grade 3 or ALT/AST Grade 2 and total bilirubin Grade 2, then liver 
function tests need to be repeated every 48-72 hours until ALT/AST Grade 1.
7.1.2. Physical Examination
A complete physical examination at screening will include the assessment of all body 
systems, the measurement of body weight, height, blood pressure, temperature and pulse rate.  
Symptom directed physical examination will be performed as per routine clinical practice 
during the study. Physical examinations will not be recorded on the CRF but will need to be 
available from the patient’s medical record upon request by the Sponsor.
7.1.3. Electrocardiogram (ECG) Measurements
A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  Additional 
ECGs should be performed as clinically indicated.  If the machine-read QTc is prolonged 
(500 msec), then the ECG should be read by a cardiologist and the QTc should be 
determined manually by a cardiologist at the site for confirmation (to look for spurious QT 
effect).  ECG measurements will not be recorded on the CRF, but all ECG information will 
need to be available from the patient’s medical record upon request by the Sponsor. 
7.1.4. Pregnancy Test
For female patients 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 at 
the screening. Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced and another negative pregnancy test result will then be 
required at the baseline visit before the patient may receive crizotinib.  Pregnancy tests will 
also be routinely repeated at Day 1 of every treatment 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.  During the non-visit cycles, the 
investigator is responsible for ensuring that the patients have pregnancy test conducted and 
contacts the clinical site in order to provide an update of the pregnancy test which are 
conducted at an external facility or at the study site. A copy of pregnancy result is to be 
provided at the next visit to study site if the test is conducted at an external facility. In the 
case of a positive confirmed pregnancy, the patient will be withdrawn from the study.  


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Additional pregnancy tests may also be undertaken if requested by institutional review 
board/Ethics Committee (IRB/EC) or if required by local regulations.
Pregnancy test results will not be recorded on the CRF, but all information will need to be 
available from the patient’s medical record upon request by the Sponsor. 
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by each site in accordance with instructions provided in its package insert.  
Patients who have missed a menstrual period or who show an indeterminate or positive result 
on the urine test may not further progress in the study until pregnancy is ruled out using 
further diagnostic testing (eg, a negative quantitative serum pregnancy test conducted at a 
certified laboratory).
7.2. Tumor Assessments
Tumor assessments are to be performed at screening and as per routine clinical practice and 
according to the patient’s clinical status thereafter.  Tumor assessment evaluations will be 
conducted as per local practice at each institution.  Tumor assessments will not be recorded 
on the CRF, but all tumor assessment information will need to be available from the patient’s 
medical record upon request by the sponsor. The interval for monitoring disease status and 
for progression of disease should not be longer than 6 months.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 4 types of events: (1) SAEs; 
(2) non-serious Grade 3 or 4 adverse events (AEs); (3) non-serious Grade 1 or 2 AEs if 
leading to permanent treatment discontinuation, and (4) exposure to the investigational 
product under study during pregnancy or breastfeeding, and occupational exposure. 


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Safety Event*
Recorded on the CRF*
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious Grade 3 or 
4 AE*
All
None
Non-serious Grade 1 or 2
AEs leading to permanent 
treatment discontinuation*
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)
*For the specific details around CRF recording and safety reporting, see Section 8.1.4.1 and Section 8.1.4.2.
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product will be reported as described in the following 
paragraphs, however, only Grade 3-5 AEs, AEs leading to permanent treatment 
discontinuation, as well as all SAEs will be recorded on the CRF.
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 as well as to the initial and follow-up reporting of exposure 
during pregnancy and exposure via breastfeeding.  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), requiring immediate notification to Pfizer or 
its designated representative.  For all Grade 3-5 AEs, AEs leading to permanent treatment 
discontinuation, as well as all SAEs, sufficient information should be obtained by the 
investigator to determine the causality of the AE.  The investigator is required to assess 
causality.  Follow-up by the investigator may be required until the event or its sequelae 
resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs with that 
assessment.  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 


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recorded on the CRF.  In general, this will include a description of the event in sufficient 
detail to allow for a complete medical assessment of the case and independent determination 
of possible causality.  Any information relevant to the event, such as concomitant 
medications and illnesses, must be provided.  In the case of a patient death, a summary of 
available autopsy findings must be submitted as soon as possible to Pfizer Safety.  Any 
pertinent additional information must be reported on the CT SAE Report Form; additional 
source documents (eg, medical records, CRF, laboratory data) are to be sent to Pfizer Safety 
ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious Grade 3-4 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 Grade 3-5 AEs, AEs leading to permanent treatment discontinuation, as well as all SAEs 
will be reported 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. For example, 
the same AE term should be used on both forms.  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 Grade 3-5 AEs, AEs leading to 
permanent treatment discontinuation, as well as all SAEs spontaneously reported by the 
study patient/legally acceptable representative.  In addition, each study patient/legally 
acceptable representative will be questioned about the occurrence of AEs in a non-leading 
manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.
When a patient withdraws from the study because of a 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.


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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of crizotinib.
Specifically, for those patients who roll-over from the parent studies A8081029 and 
A8081063, the active recording/reporting periods start at the end of the active reporting 
period for the parent studies (ie, 28 calendar days after the last dose). 
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
Specifically, for those patients who roll-over from the parent studies A8081029 and 
A8081063, any SAEs occurring within 28 calendar days from the last dose of Crizotinib in 
the parent study are still reported as an SAE in the parent study, and not in the rollover study 
A8081067.
After the end of the active reporting period for the parent studies A8081029 and A8081063 
(ie, 28 calendar days after the last dose), safety reporting for the rollover study (A8081067) 
follows the standard process, as per protocol.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to 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 patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious Grade 3-5 AEs, AEs leading to 
permanent treatment discontinuation, as well as SAEs are recorded on the CRF from the time 
the patient provides informed consent, through and including a minimum of 28 calendar days 
after the last administration of crizotinib.


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Specifically, for those patients who roll-over from the parent studies A8081029 and 
A8081063: 

All SAEs that occurs within 28 calendar days from the last dose of Crizotinib in the 
parent study are recorded in the AE page of the CRF of the parent study and as 
medical history in the CRF of the rollover study A8081067. 

All Non-serious AEs that occur within 28 calendar days from the last dose of 
Crizotinib in the parent study are recorded in the AE page of the CRF of the parent 
study and are recorded as medical history in the CRF of the rollover study A8081067.  
After the end of the active reporting period for the parent studies A8081029 and A8081063 
(ie, 28 calendar days after the last dose), study recording in the CRF for the rollover study 
(A8081067) follows the standard process as per protocol. 
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 patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all Grade 3-5 AEs, AEs 
leading to permanent treatment discontinuation, as well as all SAEs. 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 (see 
Requirements).  If the investigator's causality assessment is “unknown but not related” to 
investigational product, this should be clearly documented on study records.
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, 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 patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
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 a Grade 3 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.
NCI CTCAE v4.03 will be used to determine if a laboratory-associated AE will be reported.  
Laboratory test values will not be collected on the CRF but will need to be available from the 
patient’s medical record upon request by the Sponsor.  However, for laboratory-associated 
AEs, only SAEs, Grade ≥3 AEs, or AEs leading to permanent treatment discontinuation will 
be documented on the AE page of the CRF.
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.


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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 a 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 a SAE with CTCAE Grade 5 (see section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
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);


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
Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive 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 a 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
The investigator will use the following definitions of Severity in accordance with CTCAE 
Version 4.03 to describe the maximum intensity of the adverse event.  If the event is serious, 
the CTCAE grade reported in the adverse event CRF must be consistent with the description 
of CTCAE grade included in the narrative section of the serious adverse event report.
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily a SAE.  For example, a headache may be severe (interferes significantly with the 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.


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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 (see the Section on Requirements).
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 patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab sample).  In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST or ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST or ALT or TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. 
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.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the patient’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 patient
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
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 a SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, 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;


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
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 patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.3.2. 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 patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. 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


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8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving patient 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 patient.
Such medication errors occurring to a study patient are to be captured on the medication error
CRF, which is a specific version of the AE page.  In the event of medication dosing error, the 
sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
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 Pfizer.  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
Due to the nature of this rollover study, the number of patients to be enrolled is not 
predefined.  However, it is expected that approximately 75 patients will be enrolled. 
9.2. Efficacy Analysis
Efficacy will not be analyzed in this study.
9.3. Analysis of Other Endpoints
No statistical methods will be employed to test a specific hypothesis in this study. 
Descriptive statistics will be used to summarize safety data collected in this study as 
appropriate.


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Demographic characteristics such as patient age, gender, height, weight, ethnicity, prior 
anticancer therapy, medical history, extent of disease and ECOG performance status will be 
tabulated.
No inferential analyses are planned.
9.4. Safety Analysis
Safety data will be summarized for all patients receiving at least 1 dose of crizotinib.
All Grade 3-5 AEs, AEs leading to permanent treatment discontinuation and all SAEs with 
onset after initiation of treatment will be considered as treatment-emergent AEs.  AE 
incidence rates will be described both with and without regard to causality.  All AEs will be 
coded by system organ class, MedDRA preferred term, and severity grade using NCI 
CTCAE v4.03. 
The following safety data will be summarized: 

Grade 3-5 AEs and AEs leading to permanent treatment discontinuation – number 
and percent of patients with all-causality and treatment-related AEs.

SAEs – number and percent of patients with all-causality and treatment-related SAEs.

All recorded safety data on the CRF will be listed.
9.5. Data Monitoring Committee 
An External Data Monitoring Committee (E-DMC) will not be established for the study.  For 
the purpose of this protocol, sponsor procedures for periodic safety review will be applied to 
review individual and summary data collected in the safety and clinical databases.
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 


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investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator 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 patients 
(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.


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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.


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


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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 
crizotinib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within a time period set by Pfizer].  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
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.
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202570s000ltr.pdf.


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Appendix 1. Laboratory Safety Assessments
Hematology Panel
Blood Chemistry Panel
Hemoglobin 
AST
Absolute neutrophil count
ALT
Platelets
Total bilirubin 
Alkaline phosphatase
Serum creatinine


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Appendix 2. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
Adverse Event
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine Aminotransferase
ATP
Adenosine triphosphate
AST
Aspartate Aminotransferase
BAL
Bronchoalveolar Lavage
BID
Twice Daily
BNP
B-type Natriuretic peptide
CFDA
China Food and Drug Administration
CHF
Congestive Heart Failure
CK
Creatine Kinase
CRF
Case Report Form
CSA
Clinical Study Agreement
CT
Clinical Trial
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DAI
Dosage and administration instruction
DILI
Drug-induced Liver Injury
EC
Ethics Committee
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
E-DMC
External Data Monitoring Committee
EDP
Exposure During Pregnancy
EML
Echinoderm Microtubule Associated Protein-Like
EOT
End of Treatment
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
HDPE
High-Density Polyethylene
HGFR
Hepatocyte Growth Factor Receptor
ICH
International Council for Harmonisation
IND
Investigational New Drug 
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine Device
LFT
Liver Function Test


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Abbreviation
Term
LPD
Local Product Document
N/A
Not Applicable
NCI
National Cancer Institute
NPM
Nucleophosmin
NSCLC
Non-Small Cell Lung Cancer
PCD
Primary Completion Date
PI
Principal Investigator
PT
Prothrombin Time
QD
Once Daily
QTc
QT interval corrected by heart rate
RECIST
Response Evaluation Criteria in Solid Tumors
RON
Recepteur d’Origine Nantais
US
United States
SAE
Serious Adverse Event
SRSD
Single Reference Safety Document
TBili
Total Bilirubin
SAP
Statistical Analysis Plan
ULN
Upper Limit of Normal

SAP_001.pdf: 
Protocol A8081067 crizotinib (PF-02341066) Statistical Analysis Plan
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Page 1
Protocol A8081067
AN OPEN-LABEL, SINGLE-ARM STUDY OF THE LONG-TERM SAFETY OF 
XALKORI® IN PATIENTS FROM CHINA WITH ADVANCED NON-SMALL CELL 
LUNG CANCER (NSCLC) HARBORING A TRANSLOCATION OR INVERSION 
EVENT INVOLVING THE ANAPLASTIC LYMPHOMA KINASE (ALK) OR ROS1
LOCUS WHO HAVE PREVIOUSLY BEEN TREATED ON A STUDY OF 
XALKORI®
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
16-August-2019


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives .......................................................................................................4
2.2. Study Design .............................................................................................................4
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................5
3.1. Primary Endpoint(s) ..................................................................................................5
3.2. Secondary Endpoint(s) ..............................................................................................5
3.3. Other Endpoints.........................................................................................................5
3.4. Baseline Variables.....................................................................................................5
3.5. Safety Endpoints .......................................................................................................5
4. ANALYSIS SETS .................................................................................................................6
4.1. Full Analysis Set .......................................................................................................6
4.2. Per Protocol Analysis Set..........................................................................................6
4.3. Safety Analysis Set....................................................................................................6
4.4. Other Analysis Sets ...................................................................................................6
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................6
5.1. Hypotheses and Decision Rules ................................................................................6
5.1.1. Hypotheses and Sample Size Determination................................................6
5.1.2. Decision Rules..............................................................................................7
5.2. General Methods .......................................................................................................7
5.2.1. Analyses for Continuous Data......................................................................7
5.2.2. Analyses for Categorical Data......................................................................7
5.3. Methods to Manage Missing Data ............................................................................7
6. ANALYSES AND SUMMARIES ........................................................................................7
6.1. Primary Endpoint ......................................................................................................7
6.2. Secondary Endpoint(s) ..............................................................................................8
6.3. Other Endpoint(s)......................................................................................................8
6.4. Subset Analyses.........................................................................................................8
6.5. Baseline and Other Summaries and Analyses...........................................................8
6.5.1. Baseline Summaries......................................................................................8


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6.5.1.1. Demographic and Physical Characteristics.................................8
6.5.1.2. Medical Characteristics...............................................................8
6.5.2. Study Conduct and Subject Disposition .......................................................8
6.6. Safety Summaries and Analyses ...............................................................................8
6.6.1. Adverse Events.............................................................................................9
6.6.2. Laboratory Data..........................................................................................10
7. INTERIM ANALYSES.......................................................................................................10
7.1. Introduction .............................................................................................................10
7.2. Interim Analyses and Summaries............................................................................10
8. REFERENCES ....................................................................................................................11
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................4


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1. VERSION HISTORY
This  Statistical Analysis Plan (SAP) for study A8081067 is based on the protocol 
amendment 1 dated 02Aug2019.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Extended the study treatment duration  until 
disease progression, unacceptable toxicity, consent 
withdrawal, death, whichever comes first, to 
provide longer treatment access to the patients.
Updated AE and SAE collections.
Updated the primary/safety endpoints per the 
updated AE and SAE collections.
Protocol amendment 1
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A8081067. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
To evaluate the long-term safety of crizotinib in patients with advanced NSCLC harboring a 
translocation or inversion of the ALK gene or ROS1 gene locus.
2.2. Study Design
This is a multi-center, open-label, single arm study in China only. Eligible patients include 
those with advanced NSCLC harboring a translocation or inversion of the ALK gene or 
ROS1 gene locus who were enrolled and treated in Studies A8081005, A8081007, 
A8081014, A8081029, or A8081063 and are still receiving crizotinib treatment at the time of 
enrollment into this study. In addition, patients, randomized to the chemotherapy arm in 
Studies A8081014 or A8081029 and have not yet crossed over to receive crizotinib treatment 
at the time of enrollment into this study are eligible to enroll into this study after 
investigator-assessed disease progression. Approximately 75 patients will be enrolled into 
this study. Patients will continue single-agent crizotinib treatment on this study until disease 
progression, unacceptable toxicity, consent withdrawal, death, whichever comes first. Dose 
reductions and re-escalations are allowed based on tolerability.


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Adverse Events (AEs) and Serious Adverse Events (SAEs) will be collected for each patient 
from the time the patient provides informed consent through and including a minimum of 
28 calendar days after the last administration of crizotinib (“active collection period”). If a 
patient begins a new anticancer therapy, the recording period for non-serious AEs ends at the 
time the new treatment is started; however, SAEs must continue to be recorded on the CRF 
during the above-indicated active collection period. Specifically, for those patients who 
roll-over from the parent studies A8081029 and A8081063:

All SAEs that occurs within 28 calendar days from the last dose of Crizotinib in the 
parent study are recorded in the AE page of the CRF of the parent study and as 
medical history in the CRF of the rollover study A8081067. 

All Non-serious AEs that occur within 28 calendar days from the last dose of 
Crizotinib in the parent study are recorded in the AE page of the CRF of the parent 
study and are recorded as medical history in the CRF of the rollover study A8081067.  
After the end of the active reporting period for the parent studies A8081029 and A8081063 
(ie, 28 calendar days after the last dose), study recording in the CRF for the rollover study 
(A8081067) follows the standard process as per protocol. 
Medical history data and limited additional data will be collected as described in the Study 
Protocol Table 1 and Table 2, Schedule of Activities.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
All Grade 3-5 AEs, all AEs leading to permanent treatment discontinuation and all Serious 
Adverse Events (SAEs) as assessed by National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).
3.2. Secondary Endpoint(s)
No secondary endpoints are planned in this protocol.
3.3. Other Endpoints
No other endpoints are planned in this protocol.
3.4. Baseline Variables
Demographic characteristics, such as patient age, gender, height, weight, ethnicity, and 
medical history information, such as medical history and ECOG performance status, which
are collected within 28 days Prior to Cycle 1 Day 1, will serve as baseline variables. 
Baseline variables will be summarized and listed. 
3.5. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.


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On-treatment period is defined as the time from the first dose of study treatment through a 
minimum of 28 calendar days after the last administration of study drug or start of new 
anticancer therapy, whichever occurs first. However SAEs reported on the CRF after the last
administration of study drug even though after the start of new anticancer therapy will also
be included in the safety analyses and will be flagged.
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if:

the event occurs for the first time during the on-treatment period and was not seen 
prior to the start of treatment, or

the event was seen prior to the start of treatment but increased in severity during the 
on-treatment period.
Adverse events will be classified by type, incidence, severity, timing, seriousness, and 
relatedness to study treatment (severity graded by the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03).
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per Pfizer’s standard operating procedures. 
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The Full Analysis Set (FAS) is defined as all patients who have been enrolled in the study, 
regardless of whether treatment was received. 
4.2. Per Protocol Analysis Set 
Not applicable.
4.3. Safety Analysis Set
The Safety Analysis Set (SAS) is defined as those patients who received at least one dose of 
the study treatment. The safety analysis set is the primary population for safety analysis.
4.4. Other Analysis Sets
Not applicable.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Determination
There is no hypothesis testing planned for this study. 


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The number of patients to be enrolled is not predefined. However, it is expected that 
approximately 75 patients will be enrolled.
5.1.2. Decision Rules
The objective of this study is to evaluate the long-term safety, decision rules are not 
applicable.
5.2. General Methods 
5.2.1. Analyses for Continuous Data
Descriptive statistics, including the mean, standard deviation, median, minimum, and
maximum values, will be provided for continuous variables.
5.2.2. Analyses for Categorical Data
The number and percentage of patients in each category will be provided for categorical
variables.
5.3. Methods to Manage Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In compliance with Pfizer standards, CDISC Safety Rulebook1 will be followed when 
handling the missing/partial dates, treatment emergent AE algorithm, missing AE grades, etc. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
The primary endpoint analysis is to summary the frequencies of Grade 3-5 AEs, AEs leading 
to permanent treatment discontinuation and all SAEs in the safety analysis set (SAS) 
corresponding to system organ class (SOC) and preferred term (PT) according to MedDRA
terminology and maximum NCI CTCAE v4.03 grade. AE incidence rates will be described 
both with and without regard to causality. 
The following safety data will be summarized:

Grade 3-5 AEs and AEs leading to permanent treatment discontinuation– number and 
percent of patients with all-causality and treatment-related AEs.

SAEs – number and percent of patients with all-causality and treatment-related SAEs.

All recorded safety data on the CRF will be listed.


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6.2. Secondary Endpoint(s)
Not applicable.
6.3. Other Endpoint(s)
Not applicable.
6.4. Subset Analyses 
Not applicable.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following analyses will be based on the Full Analysis Set (FAS).
6.5.1.1. Demographic and Physical Characteristics
Gender (male, female), Age (<65, >= 65) and Ethnicity will be summarized by number and 
percentage.
Age (continuous), height (cm), weight (kg), will be summarized with descriptive statistics 
(mean, median, standard deviation, minimum, and maximum).
6.5.1.2. Medical Characteristics
Medical history and ECOG performance status recorded in CRFs at screening will be 
summarized by number and percentage.
6.5.2. Study Conduct and Subject Disposition
A summary of the number of patients enrolled by site will be provided. 
Permanent discontinuation of treatment and discontinuation of study will be summarized 
separately and by reason for discontinuation. Discontinuations of treatment will be 
summarized using the safety analysis set and discontinuations from other phases will be 
summarized using the full analysis set.
Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing the event will be considered
related to treatment. If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment.
Discontinuation due to SAEs will be summarized separately.
6.6. Safety Summaries and Analyses
AE data will be summarized for the SA set.


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6.6.1. Adverse Events
Adverse events (AEs) – All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The severity of all AEs will be graded by the Investigator using NCI 
CTCAE Version 4.03.
An overall summary of AEs will be provided: the number and percentage of patients who 
experienced any all-causality AE (including Grade 3-5 AEs and AEs leading to permanent 
treatment discontinuation), all-causality SAE, treatment-related AE, and treatment-related 
SAE will be summarized according to worst toxicity grades. 
Because the frequency of certain medical concepts or conditions may be underestimated by 
reliance on single MedDRA preferred terms, certain preferred terms will be analyzed in
aggregate using clustered terms.  Patients having more than 1 AE preferred term within a 
clustered term will contribute 1 event to the clustered term at the highest grade observed.  
Clustered terms to be used for summary of data from this study will be defined prior to data 
summary based on information included in the current Safety Risk Plan maintained by the 
Sponsor.

All Causality Adverse Events
A summary of AEs by System Organ Class (SOC), preferred term and maximum CTCAE 
grade will be presented.  A summary of AEs by preferred term/clustered term and maximum 
CTCAE grade will be presented, in decreasing order of frequency.  A summary of AEs by 
preferred term/clustered term and maximum CTCAE grade group (Grade 3-4 and Grade 5) 
will also be presented, in decreasing order of frequency.  AEs associated with permanent 
discontinuation of the study drug will be summarized (taking into consideration the action 
taken from the AE CRF page).

Treatment-Related Adverse Event
Treatment-related AEs are those judged by the Investigator to be at least possibly related to 
the study drug (with a cause related to study drug as indicated on the CRF) or for which 
relatedness is recorded as “unknown” by the Investigator.  Similar summaries as noted for all 
causality AEs will be provided for treatment-related AEs.

Serious Adverse Events and Death
Similar summaries as noted for all causality AEs will be provided for all causality and 
treatment-related SAEs.  Patients who experienced a SAE as reported in the clinical database 
will be listed for all enrolled patients. 
Deaths will be summarized, and by cause of death.  Deaths that occurred on or after Cycle 1 
Day 1 dose of crizotinib and within 28 days after the last dose of crizotinib are defined as 
on-study deaths. Death data will also be listed.


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6.6.2. Laboratory Data
NCI CTCAE v4.03 will be used to determine if a laboratory-associated AE will be reported. 
Grade >=3 AEs, AEs leading to permanent treatment discontinuation and SAEs associated 
with a laboratory test abnormality will be recorded on the AE page of the CRF and will be 
summarized as described above.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analyses are planned.
7.2. Interim Analyses and Summaries
Not applicable.


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8. REFERENCES
1.
CDISC Safety Rulebook. Available from: 
http://urlretrieval.pfizer.com/webtop/component/getcontent?objectId=0901201b8416a0
18&docbase=Gnosis.