Clinical trial NCT01121588
Conditions: Neoplasms Malignant
Keywords: neoplasm malignant lymphoma neuroblastoma Crizotinib anaplastic lymphoma kinase ALK
Sponsor: Pfizer
Start date: 2011-03-22; Completion date: 2023-09-07
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1 trial evaluating the safety and efficacy of crizotinib in patients with tumors except non-small cell lung cancer that are positive for ALK.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Crizotinib
Intervention descriptions: intervention 1: Crizotinib tablets, 250 mg BID, will be administered orally on a continuous dosing schedule

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
PHASE 1B OPEN-LABEL STUDY OF THE SAFETY AND CLINICAL ACTIVITY 
OF CRIZOTINIB (PF-02341066) IN TUMORS WITH GENETIC EVENTS 
INVOLVING THE ANAPLASTIC LYMPHOMA KINASE (ALK) GENE LOCUS
Compound:
PF-02341066
Compound Name:
Crizotinib
US IND Number :
73,544
European Clinical Trial Database 
(EudraCT) Number:
2010-022978-14
Protocol Number:
A8081013
Phase:
Phase 1b
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 5
13 August 2015
Dose modification and adverse event management guidances 
were revised based on updated safety information.  
Reduced Schedule of Activities was introduced for patients 
still ongoing after approval of Amendment 5. 
Text was added or replaced to ensure consistency with 
updated Pfizer global protocol template language, including
contraception guidelines, pregnancy testing, and serious 
adverse event reporting for oncology studies after permanent 
discontinuation of crizotinib treatment.  
Corrections of typographical errors and other administrative 
inconsistencies were made throughout the protocol.
Amendment 4
19 April 2013
Protocol amended to reduce the required tumor imaging 
frequency in patients on PF-02341066 treatment for more 
than 10 cycles (ie, 30 weeks) as this will be consistent with 
the frequency of assessments used in clinical practice and 
reduce patient exposure to radiation.  Frequency will be 
further reduced from Cycle 11 (assessment will be performed 
every 12 weeks), from Cycle 26 (assessment will be 
performed every 24 weeks) and from Cycle 52 (assessment 
will be performed every 52 weeks). 
Corrected footnotes 13 and 15 of schedule of events.
New wording regarding Sponsor Qualified Medical Personnel 
(Section 4.5) added.
Administration section text added in Section 5 regarding 
medication errors.
Updated wording regarding AE reporting period section.
Section 8 Adverse Event Reporting and Section 15
Communication of Results by Pfizer updated based on revised 
protocol template language.
Replacement of the word “subject” with “patient” where 
needed, for internal consistency.
Amendment 3
17 July 2012
New safety language regarding renal cysts and number of 
cases of hepatotoxicity added; clarification in target patient 
population and testing modalities for ALK detection added;
Cheson criteria (2007) added for NHL patients; frequency of 
clinic visits changed; new protocol template safety assessment
language incorporated; washout period for prior 
chemotherapy modified; low-dose steroids added as needed 
for tumor fever; updates in toxicity assessment, management,
and dose modifications made to align with other crizotinib
protocols, concomitant medications section updated; efficacy 
analysis updated to specifically include subset analysis of 
ALCL patients; definition of objective response added;
Appendix 4 added: NCI International Response Criteria for 


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Non-Hodgkin Lymphoma (2007).
Amendment 2
17 December 2010
Removal of 150 mg capsule strength; further clarification 
given on Dose Modifications for drug related toxicities; 
introduction of SAE reporting requirements for Drug Induced 
Liver Injury; inclusion/exclusion criteria updated.
Amendment 1
26 July 2010
Additional safety monitoring language for pneumonitis; 
inclusion/exclusion criteria updated.
Original protocol
25 March 2010
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.  


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PROTOCOL SUMMARY
Background and Rationale:
ALK is a receptor tyrosine kinase first identified as part of the t(2;5) chromosomal 
translocation associated with most anaplastic large cell lymphoma (ALCL) and a subset of 
B-cell non-Hodgkin’s lymphoma. ALK has been implicated in an increasing number of 
cancer settings. These include non-small cell lung cancer (NSCLC), neuroblastoma, 
inflammatory myofibroblastic tumour (IMT), diffuse large B cell lymphoma (DLBCL), and 
esophageal squamous cell carcinoma. The ALK genetic events include fusion/inversion, 
translocation, mutation, amplification, and aberrant expression. 
Crizotinib (PF-02341066) is a small-molecule inhibitor of anaplastic lymphoma kinase 
(ALK) and the c-Met/HGFR receptor kinase which has shown compelling clinical activity in 
patients with NSCLC with ALK fusions events in the expanded cohort of a Phase 1 trial. In 
50 evaluable patients, an objective response rate (ORR) of 64% and disease control rate 
(DCR) of 90% was reported by E.L. Kwak at the American Society of Hematology meeting 
in December of 2009. 
Based on the Phase 1 study (A8081001), there is a limited patient experience with crizotinib 
in patients with tumors other than NSCLC with changes in the molecular genetic profile of 
the tumor involving the ALK gene locus. One patient with IMT achieved a partial response 
(PR) (1PR of 2 IMT patients enrolled) and one neuroblastoma patient with an ALK mutation 
achieved stable disease (SD) lasting in excess of 6 months (1 SD of 1 neuroblastoma patient 
enrolled). One patient with ALCL associated with ALK translocation has been studied to 
date. In addition, in an ongoing pediatric study there has been preliminary evidence of 
activity in a patient with IMT based on communication with the study principal investigator.
A dose of 250 mg given orally BID was found to be the recommended Phase 2 dose from the 
escalating part of the Phase 1 study. The most common treatment-related adverse events 
seen to date were nausea, vomiting, diarrhea, and visual disturbance, which were primarily 
Grade 1-2 in severity. Nausea and vomiting were independent of dose or duration of 
treatment and were managed effectively using I.V. or oral anti-emetics. Treatment-related 
visual disturbances were observed and occurred at doses of 200 mg BID or above.  All of 
these visual events were Grade 1 in severity and were reversible upon discontinuation of 
crizotinib.
In a recent review of safety for crizotinib (PF-02341066) Pfizer has determined that there are 
4 potential cases of pneumonitis which may be related to crizotinib (PF-02341066). One 
such case was a radiation recall pneumonitis. Based on the other 3 cases that were not linked 
to radiation treatment and relative to all enrolled adult patients (N=273) who have been 
treated with crizotinib (PF-02341066), as of July 16 2010, the current frequency of 
non-radiation recall pneumonitis is 1.1%.  One of the 4 cases was fatal. The 3 other patients 
recovered from the event. One patient experienced radiation recall pneumonitis, was 
appropriately treated and was able to restart crizotinib (PF-02341066). The other 2 patients 
were permanently discontinued from crizotinib (PF-02341066). Interpretation of the 
3 non-radiation recall cases was complicated by the underlying non-small cell lung cancer for 


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which the patients were being treated. In addition these 3 cases were complicated by the 
co-administration of other drugs known to potentially cause pneumonitis and/or other 
pulmonary complications. One of the cases was considered not related to crizotinib 
(PF-02341066) by the investigator. Based on this new safety information suspected cases of 
pneumonitis will be evaluated and patients with pre-existing interstitial fibrosis or interstitial 
lung disease will be excluded from the entering the study.
The crizotinib adverse drug reaction (ADR) list was updated in the crizotinib Investigator’s
Brochure (IB) to include the development of complex renal cysts. The development of 
complex renal cysts has been reported in some patients with NSCLC treated with crizotinib. 
These cysts may be symptomatic or asymptomatic, and have developed from several weeks to 
several months after starting crizotinib. The precise nature and significance of these cysts is 
unclear; however, while no evidence of malignancy has been found based on aspiration of cyst 
fluid and biopsy in the reported cases, complex renal cysts may be associated with renal 
malignancy, and thus consultation with a urologist or suitable alternate medical expert is 
recommended. Neither renal impairment nor clinically relevant proteinuria has been observed in 
any of the cases.
Additionally, the IB has updated the Effects on the Liver Section 7.6.4. With more than 
1400 patients who have been treated with crizotinib in clinical trials, 2 new Hy's Law cases 
and 2 cases of fatal hepatic failure have recently (March 2012) been reported as serious 
adverse events related to crizotinib treatment (a fifth Hy’s Law case had previously been 
reported in an earlier version of the IB). Of all 5 of these cases, 2 patients presented with 
anorexia, 2 patients presented with weakness and fatigue, and 1 patient presented with 
abdominal pain. Four of these 5 cases, including the 2 fatal cases, were observed within the 
first 2 months after the start of crizotinib treatment, while significant transaminase elevation 
was observed after 6 months of crizotinib treatment in the fifth case.
Based on the promising clinical activity seen in NSCLC, it is expected that crizotinib may 
also be active in other tumors in which growth is driven by ALK genetic events. Patients 
whose tumors are found to have a translocation, mutation, or amplification involving ALK
will be enrolled into this study to explore the safety and potential clinical activity in diverse 
tumor types.
Objectives and Endpoints
Primary Objective:

Assess the safety of oral single-agent crizotinib administered to patients with 
advanced ALK-positive anaplastic large cell lymphoma or other advanced 
malignancy known to have an ALK genetic event (other than non-small cell lung 
cancer [NSCLC]) and screen for efficacy in these patients.


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Secondary Objectives:

To determine pharmacokinetics (PK) in this patient population using population PK 
(POPPK) methods and explore correlations between concentration, response and/or 
safety findings.

To correlate ALK genetic events (translocation, mutation/amplification) to outcome 
measures.
Endpoints:
Primary Endpoint:

Type, incidence, severity, seriousness and relationship to study medications of 
adverse events (AE) and any laboratory abnormalities.

Overall response rate (ORR) based on:

RECIST1 version 1.1 for non-hematologic malignancies;

NCI International Response Criteria for Non-Hodgkin’s Lymphoma for ALCL or 
other non-Hodgkin’s lymphomas.2
Secondary Endpoints:

PFS, overall survival (OS) at 6 months and 1 year, OS and duration of response (DR);

Plasma concentrations of crizotinib;

Proportion of patients with each of the ALK genetic events (translocation, mutation, 
amplification);

Phosphorylation status of ALK in the tumor samples from surgery or biopsy pre and 
post treatment when available.
Study Design:
This is an open-label, multi-center, single-arm exploratory trial of an oral agent, crizotinib, in 
patients with advanced ALK-positive ALCL or other advanced malignancy other than 
NSCLC with tumors harboring a translocation, inversion, mutation or amplification event 
involving the ALK gene locus.
At least 40 patients are expected to be enrolled into this trial. The sample size may be 
adjusted based on the number of patients identified and safety or evidence of antitumor 
activity within patient groups.


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Only ALK genetic event positive patients as determined by the investigative site may enter 
the study. ALK translocation/fusion, amplification, mutation and overexpression may be 
assessed by using any of the available technologies including fluorescence in-situ 
hybridization (FISH), immunohistochemistry (IHC), quantitative Polymerase Chain Reaction 
(qPCR), quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR), array 
Comparative Genomic Hybridization (aCGH) or direct sequencing. The methodology of 
ALK testing required will depend entirely on the malignancy in question and the existence of 
published data supporting a given methodology of ALK testing.  For example, ALCL is the 
only disease for which IHC alone is acceptable to document ALK positivity, as IHC has been 
shown to correlate with ALK fusion events in ALCL and is widely accepted as a means of 
documenting ALK positivity in ALCL.  For diffuse large B-cell lymphoma, IHC alone is not 
sufficient for enrollment, as an ALK gene fusion event must be documented by FISH or 
PCR.  For neuroblastoma, ALK gene amplification must be documented by either FISH or 
aCGH, or a known ALK activating point mutation must be documented by PCR or direct 
sequencing (IHC alone is not acceptable).  For inflammatory myofibroblastic tumor (IMT), 
IHC alone is not sufficient, unless the intercalated antibody-enhanced polymer (iAEP) 
method is used.12  FISH or PCR demonstrating an ALK fusion event is acceptable for IMT.  
Other diseases will be considered for enrollment if publications exist supporting ALK 
mutation/fusion/amplification as an oncogenic driver for the disease in question.
Patients may continue treatment with crizotinib on this trial as long as there is evidence of 
clinical benefit in the judgment of the investigator. 
Study Treatments:
Crizotinib, 250 mg BID, will be administered orally at approximately the same time each day 
on a continuous daily dosing schedule, ie, no break in dosing.  Crizotinib may be taken 
without regard to meals. 
Cycles are defined in 21-day periods to facilitate scheduling of visits and assessments.
Table 1 provides the required Schedule of Activities. A reduced schedule of activities will be 
followed for all ongoing patients after IRB/EC approval of Amendment 5 (see Table 6, 
Appendix 5). 
Data Analysis/Statistical Methods:
Sample Size Determination
The primary objective of this study is to assess the safety of oral, single agent crizotinib
administered to patients with advanced ALCL or other advanced malignancies (other than
NSCLC) known to have an ALK genetic event and to screen for efficacy in these patients.  
Estimation will be emphasized for the study endpoints. 
The sample size for this study is determined empirically based on expected small numbers of 
patients in the population of interest.  It is anticipated that a total of approximately 
40 patients will be enrolled in this study.


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Data Analysis
The study population for all analyses will include patients enrolled in the study who receive 
at least one dose of crizotinib. Data summaries/listings will be presented overall as well as 
separately for ALCL patients and patients with other malignancies (by tumor type, as 
applicable). 
Due to the exploratory nature of this study, no confirmatory inferential analyses are planned. 
Descriptive statistics (such as means, medians, standard deviations and ranges for continuous 
data and percentages for categorical data) will be used to summarize patient characteristics, 
treatment administration, efficacy, safety, biomarkers and pharmacokinetic parameters.


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Table 1.
Schedule of Activities
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  The investigator may schedule visits (unplanned visits) in addition to those listed on the Schedule of Activities, in order to 
conduct evaluations or assessments required to protect the wellbeing of the patient.
Note: Refer to Table 6 (Appendix 5) for reduced schedule of protocol activities after IRB/EC approval of Amendment 5.
Protocol Activities
Screening
Study Treatment[1]
End of Treatment
Cycle 1
Cycles 2
28 Days Prior to 
Dosing
Day 1 (2)[2]
Day 15 (2)
Day 1 (2; 7 for 
imaging)
End of 
Txt/Withdrawal[3]
Post Txt 
Follow-up
Baseline Documentation
Informed Consent[4]
X
Medical/Oncology History [5]
X
Baseline Signs/Symptoms
X
Mandatory Tumor Tissue for Molecular 
Profiling[6]
X
Physical Examination[7]
X
(X)
X
X
ECOG Performance Status
X
X
X
X
Ophthalmologic Examination[8]
X
See footnote 8 for details.
Laboratory Studies
Dipstick Urinalysis and Reflex 
Microscopy[18]
X (Korea only)
X (Korea only; for other countries,
see footnote 18)
X (Korea 
only)
Hematology[9]
X
(X)
X
X
X
Blood Chemistry[9]
X
(X)
X
X
X
Coagulation[9]
X
(X)
X
12-lead electrocardiogram ECG[10] 
X
X
Cycle 2
Female patients: Pregnancy Test (as 
appropriate)[11]
X
X


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Protocol Activities
Screening
Study Treatment[1]
End of Treatment
Cycle 1
Cycles 2
28 Days Prior to 
Dosing
Day 1 (2)[2]
Day 15 (2)
Day 1 (2; 7 for 
imaging)
End of 
Txt/Withdrawal[3]
Post Txt 
Follow-up
Disease Assessments
Radiographic studies for tumor 
assessment[12]
X
Beginning 
Cycle 3 then 
every other cycle
through Cycle 10, 
from Cycles 11 
every 12 weeks, 
from Cycle 26 
every 24 weeks 
and from 
Cycle 52 every 
52 weeks
X
Bone marrow biopsy and/or aspirate (for 
patients with NHL only)[19]
X
X
Other Clinical Assessments
Adverse Events [13]
X
X
X
X
X
X
Concomitant Medications/Treatments[14]
X
X
X
X
X
X
Survival Follow-up[15]
X
Study Treatment  
Crizotinib
Twice or Once Daily
Special Laboratory Studies
Optional Tumor Tissue for Molecular 
Profiling[16]
X
Pharmacokinetics[17]
X
Cycles 2, 3, 5
( ) – see footnote #2
Footnotes for Schedule of Activities
1.
Study Treatment: All assessments should be performed prior to dosing with study medications unless otherwise indicated.  Acceptable time windows for performing each 
assessment are described in the column headings.  All cycles are 21 days in duration. After completion of 7 cycles, ongoing patients will only need to visit the clinic every 
other cycle for study assessments instead of every cycle. Enough study medication for two cycles of treatment will be dispensed at each clinic visit.  During the non-visit 
cycle, patients must telephone the clinical site to provide an update of adverse events and concomitant medications and must still have required laboratory assessments 
performed.


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Footnotes for Schedule of Activities
2.
Cycle 1/Day 1: Blood chemistry, hematology, coagulation, and physical examination not required if acceptable screening assessment is performed within 7 days prior to the 
start of study treatment.
3.
End of Treatment/Withdrawal: Obtain these assessments if not completed during the previous 4 weeks on study (during the last 6 weeks for disease assessments).
4.
Informed Consent: Must be obtained prior to undergoing any trial specific procedure.
5.
Medical/Oncological history: To include information on prior regimens, surgery, and radiation.
6.
Mandatory Tumor Tissue for Molecular Profiling: These samples will be initially analyzed at the investigational site for the assessment by one of the following1) ALK
gene fusion by FISH, IHC and/or RT-PCR and sequencing, 2) ALK amplification events by FISH, qPCR, or aCGH, or 3) ALK activating point mutations determined by 
direct sequencing The genotyping test employed for a selected sample will depend on the tumor type and expected ALK genetic event.  Subsequently the tumor samples 
must be sent to the Pfizer designated central laboratory for confirmation, though this is not required for eligibility.  Paraffin block(s) of adequate size to allow if possible for 
at least 10 slides with cuts that are 5-microns thick.  If no block is available, then the sites should try to obtain, if possible, at least 10 slides with cuts that are 5-microns are 
acceptable.  Archived or fresh tumor samples are acceptable.  The mandatory tumor tissue may be obtained and analyzed outside of the 28 day screening window.
7.
Physical Examination: includes an examination of major body systems, height (at screening only); weight, blood pressure and pulse rate 
8.
Ophthalmologic Examination: includes visual acuity and slit lamp and should be performed by an ophthalmologist.  The ophthalmologic examination should be repeated 
during the study when clinically indicated, when visual disturbances have been observed or when there has been a reported change in CTCAE grade.
9.
Hematology, Blood Chemistry and Coagulation: Required tests are listed in Appendix 1 of protocol. For patients on crizotinib therapy: If ALT Grade 3 or ALT 
Grade 2 and total bilirubin  Grade 2, then liver function tests need to be repeated every 48-72 hours until ALT Grade 2. Crizotinib therapy should be withheld; see 
Table 3.  A 4 ml serum sample obtained just prior to the first dose of study medication will be stored frozen on-site through completion of the study for possible use as a 
baseline reference should additional laboratory tests be indicated, for example additional liver function testing to exclude drug induced liver injury (see Section 8 AE
reporting).
10. 12-lead ECG: See Section 7.2.6 for collection details.
11. Pregnancy Test: All female patients of child-bearing potential are required to have a negative pregnancy test at screening.  The test should be repeated whenever one 
menstrual cycle is missed during the active treatment period or a potential pregnancy is otherwise suspected. The test should also be repeated at the end of the study to 
confirm the patient has not become pregnant during the study.  Pregnancy tests may also be repeated as per the request of IRB/IECs or if required by local regulations.
12. Tumor Assessments: RECIST 1.1 will be used to determine the solid tumor response, and the NCI International Response Criteria for Non-Hodgkin’s Lymphoma (Cheson 
criteria, 2007) will be used for NHL. For patients with non-hematologic malignancies, CT or MRI scans will include chest, brain, abdomen and pelvis at screening but 
subsequently may include just involved sites of disease.  For patients with NHL, PET and CT or MRI or PET/CT may be used for NHL at baseline and for restaging.  Scans 
must include chest, abdomen, pelvis and neck for NHL patients at baseline, but subsequently may include only known and suspected sites of disease.  Baseline PET 
scanning is required for all NHL patients.  For all tumor types, brain must be included in subsequent tumor assessments if a patient has brain metastases, otherwise brain 
will only be evaluated when clinically indicated. Scans will be collected for a potential independent radiology review. CT or MRI scan should also be performed whenever 
disease progression is suspected (eg, symptomatic deterioration).  Bone scans are required if bone metastases are suspected.  A bone scan is also required at the time of 
confirmation of response for patients who have bone metastases.
13. Adverse Events: Patients must be followed for adverse events from the time they signed the informed consent until at least 28 days after the last dose of study treatment.  
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.  Serious adverse events should be monitored and reported from the time that the patient provides informed consent as described in the protocol.
14. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up to 28 days post 
the last dose of study treatment.  


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Footnotes for Schedule of Activities
15. Survival Follow-Up: After discontinuation of study treatment, post-study survival status will be collected every 2 months until death or until the last patient experiences 
progressive disease on the study.  Includes collection of information on subsequent anticancer therapies.  Telephone contact is acceptable.
16. Tumor Tissue for Molecular Profiling:  Sample will be sent to central laboratory (Section 7.5). An optional fresh tumor sample will be collected at the end of treatment if 
a patient discontinues due to disease progression.
17. Pharmacokinetics: See Section 7.3.2 for collection details.
18. Dipstick Urinalysis and Reflex Microscopy:  In Korea, repeat exams should be completed at Day 1 of every cycle and at the end of treatment; all other countries should 
perform as clinically indicated (for example, upon diagnosis of renal cysts).  Reflex Microscopy required if urine dipstick is positive for blood or protein.  See Section 5.6.5
for further details.  
19. Bone Marrow Aspirate and/or Biopsy: optional before study start and can be performed as clinically indicated during the study.  Required at end-of-treatment visit 
(ie, within 6 to 9 weeks after the last dose of investigational product, and must be 4 weeks from the last response assessment) for patients who otherwise meet the criteria 
for a CR unless the patient had an adequate bone marrow biopsy which was negative for lymphoma and performed within 28 days before first dose of investigational 
product or unless the patient had previously undergone a bone marrow procedure confirming the CR.  


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................16
APPENDICES .........................................................................................................................17
1. INTRODUCTION ...............................................................................................................18
1.1. Indication.................................................................................................................18
1.2. Background and Rationale ......................................................................................18
1.2.1. Role of ALK in Cancer................................................................................18
1.2.2. Crizotinib (PF-02341066) Non-Clinical Data ............................................19
1.2.3. Crizotinib Clinical Data..............................................................................19
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................21
2.1. Objectives................................................................................................................21
2.2. Endpoints.................................................................................................................22
3. STUDY DESIGN.................................................................................................................22
4. PATIENT SELECTION......................................................................................................23
4.1. Inclusion Criteria.....................................................................................................23
4.2. Exclusion Criteria....................................................................................................25
4.3. Randomization Criteria ...........................................................................................26
4.4. Life Style Guidelines...............................................................................................26
4.4.1. Contraception..............................................................................................26
4.4.2. Sunlight Exposure.......................................................................................28
4.4.3. Alcohol Consumption.................................................................................28
4.5. Sponsor’s Qualified Medical Personnel..................................................................28
5. STUDY TREATMENTS.....................................................................................................28
5.1. Allocation to Treatment ..........................................................................................28
5.2. Drug Supplies..........................................................................................................28
5.2.1. Formulation and Packaging........................................................................28
5.2.2. Preparation and Dispensing........................................................................29
5.2.3. Administration............................................................................................29
5.2.4. Compliance.................................................................................................29
5.3. Drug Storage ...........................................................................................................29
5.4. Drug Accountability................................................................................................30
5.5. Dose Modifications .................................................................................................30


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5.6. Management of Selected Crizotinib-Related Adverse Events ................................31
5.6.1. Nausea and Vomiting .................................................................................31
5.6.2. Diarrhea ......................................................................................................31
5.6.3. Bradycardia.................................................................................................31
5.6.4. Pneumonitis ................................................................................................32
5.6.5. Renal Cysts .................................................................................................32
5.7. Concomitant Medication(s).....................................................................................38
5.7.1. Crizotinib....................................................................................................38
5.7.2. Antiemetic and Antidiarrheal Therapy.......................................................38
5.7.3. Hematopoietic Growth Factors...................................................................39
5.7.4. Other Concomitant Medications.................................................................39
5.8. Concomitant Radiotherapy or Surgery....................................................................39
5.9. Rescue/Escape/Salvage (Select One) Therapy........................................................39
6. STUDY PROCEDURES .....................................................................................................40
6.1. Screening.................................................................................................................40
6.2. Study Period ............................................................................................................40
6.3. Follow-Up Visit.......................................................................................................40
6.4. Patient Withdrawal..................................................................................................40
7. ASSESSMENTS..................................................................................................................41
7.1. Efficacy Assessments..............................................................................................42
7.2. Safety Assessments .................................................................................................42
7.2.1. Adverse Events...........................................................................................43
7.2.2. Pregnancy Testing ......................................................................................43
7.2.3. Laboratory Safety Assessments..................................................................43
7.2.4. Physical Examination .................................................................................43
7.2.5. Performance Status.....................................................................................43
7.2.6. ECG Measurements....................................................................................43
7.2.7. Ophthalmology Examinations ....................................................................44
7.3. Pharmacokinetics ....................................................................................................44
7.3.1. Plasma Pharmacokinetic Assessment.........................................................44
7.3.2. Plasma Pharmacokinetic Assessment for Crizotinib..................................44
7.4. Tumor Tissue for Molecular Profiling ....................................................................45


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7.5. Tumor Tissue for Biomarker Analysis....................................................................45
8. ADVERSE EVENT REPORTING......................................................................................45
8.1. Adverse Events........................................................................................................45
8.2. Reporting Period .....................................................................................................45
8.3. Definition of an Adverse Event...............................................................................46
8.4. Medication Errors....................................................................................................47
8.5. Abnormal Test Findings..........................................................................................47
8.6. Serious Adverse Events...........................................................................................48
8.6.1. Protocol-Specified Serious Adverse Events ...............................................48
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................48
8.7. Hospitalization ........................................................................................................50
8.8. Severity Assessment................................................................................................51
8.9. Causality Assessment..............................................................................................51
8.10. Exposure During Pregnancy..................................................................................52
8.11. Occupational Exposure .........................................................................................53
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient 
Withdrawal)...............................................................................................................53
8.13. Eliciting Adverse Event Information ....................................................................53
8.14. Reporting Requirements........................................................................................53
8.14.1. Serious Adverse Event Reporting Requirements .....................................54
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................54
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................54
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................54
9.1. Sample Size Determination.....................................................................................54
9.2. Efficacy Analysis ....................................................................................................55
9.2.1. Analysis of Primary Endpoint ....................................................................55
9.2.2. Analysis of Secondary Endpoints...............................................................56
9.3. Analysis of Other Endpoints ...................................................................................56
9.3.1. Study Conduct and Patient Disposition......................................................56
9.3.2. Baseline Characteristics..............................................................................56
9.3.3. Treatment Administration/Compliance ......................................................56
9.3.4. Analysis of Clinical Labs............................................................................56


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9.3.5. Electrocardiogram Data..............................................................................57
9.3.6. Concomitant Medications...........................................................................57
9.3.7. Analysis of Pharmacokinetic Endpoints.....................................................57
9.3.8. Analysis of Molecular Profiling Endpoints................................................58
9.4. Interim Analysis ......................................................................................................58
9.5. Data Monitoring Committee ...................................................................................58
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................58
11. DATA HANDLING AND RECORD KEEPING .............................................................59
11.1. Case Report Forms/Electronic Data Record .........................................................59
11.2. Record Retention...................................................................................................59
12. ETHICS..............................................................................................................................60
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................60
12.2. Ethical Conduct of the Study ................................................................................60
12.3. Patient Information and Consent...........................................................................60
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................61
13. DEFINITION OF END OF TRIAL...................................................................................62
13.1. End of Trial in a Member State.............................................................................62
13.2. End of Trial in All Other Participating Countries.................................................62
14. SPONSOR DISCONTINUATION CRITERIA ................................................................62
15. PUBLICATION OF STUDY RESULTS..........................................................................62
15.1. Communication of Results by Pfizer ....................................................................62
15.2. Publications by Investigators ................................................................................63
16. REFERENCES ..................................................................................................................65
LIST OF TABLES
Table 1.
Schedule of Activities.............................................................................................9
Table 2.
Malignancies with Events Involving the ALK Gene Locus.................................18
Table 3.
Crizotinib Dose Modifications for Treatment-Related Toxicity (CTCAE 
v4.0)......................................................................................................................34
Table 4.
Probability of Observing Toxicity Given True Underlying Event Rates .............55
Table 5.
Response Evaluation Criteria in Solid Tumors ....................................................72
Table 6.
Reduced Schedule of Activities............................................................................81


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Table 7.
Reduced Laboratory Tests ....................................................................................83
APPENDICES
Appendix 1. Required Laboratory Tests..................................................................................66
Appendix 2. ECOG Performance Status..................................................................................67
Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria ..............................................68
Appendix 4. NCI International Response Criteria for Non-Hodgkin Lymphoma...................74
Appendix 5. Reduced Schedule of Activities ..........................................................................81


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1. INTRODUCTION
1.1. Indication
Crizotinib is indicated for the treatment of tumors with translocation, mutation, or 
amplification of the anaplastic lymphoma kinase (ALK) gene locus.
1.2. Background and Rationale
1.2.1. Role of ALK in Cancer
ALK is a receptor tyrosine kinase first identified as part of the t(2;5) chromosomal 
translocation associated with the majority of anaplastic large cell lymphoma (ALCL) and a 
subset of B-cell non-Hodgkin’s lymphoma. ALK has been implicated in an increasing 
number of cancer settings as shown in the Table 2 however the relevance to clinical cancer 
treatment is still unknown. 
Table 2.
Malignancies with Events Involving the ALK Gene Locus
Setting
ALK Genetic change
Frequency %
Anaplastic Large Cell lymphoma 
(ALCL)
ALK translocation/fusion, NPM, 
TFG, TPM3-, TPM4- ALK
60-803
Inflammatory myofibroblastic 
tumor (IMT)
ALK translocation/fusion,
TPM3, TPM4, CARS, 
CTLC-ALK
564
Neuroblastoma 
Amplification of ALK locus
Activating point mutations such 
as (germ line: G1128A, R1192P, 
R1275Q) (somatic: D1091N, 
M1166R, I1171N, F1174I, 
F1174L, F1245C, F1245V, 
I1250T)
205
Breast Cancer
ALK translocation/fusion
2.46
Colon Cancer
ALK translocation/fusion
2.46
Esophageal squamous cancer
TPM4-ALK 
Not reported
Diffuse large B cell lymphoma 
(DLBCL)
CLTC-ALK, NPM-ALK
Not reported
Other solid tumors: glioblastoma, 
melanoma, rhabdomyosarcoma
Wild type ALK overexpression
Not reported
There is evolving information about the role of ALK genetic events in a number of childhood 
and adult tumors. Mutations in ALK have been detected in a large number of neuroblastoma 
cell lines including both germline and somatic mutations.5, 7  ALK is detectable and is a 
positive prognostic factor in the setting of ALCL which is a T-cell disease and is most 
common with peak incidences in young adults (15-19 years of age) and children (5-14 years 
of age).5-11  In a series of 38 patients with ALK-positive DLBCL, the patients identified had 
primarily B-cell disease and were adults with aggressive disease unlikely to respond to 
current standards of care.8 IMT is a rare tumor of mesenchymal origin which is only 
minimally responsive to conventional chemotherapy and radiation. It is associated with 
various ALK translocations with immunohistochemical reactivity for ALK restricted to the 
cytoplasm in 56% of cases.4 ALK expression is of uncertain pathogenic significance in 
several additional cancers and may represent physiologic expression rather than a seminal 


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pathogenic event.9 There is very limited clinical data using an ALK inhibitor in these 
settings.
1.2.2. Crizotinib (PF-02341066) Non-Clinical Data
Crizotinib is a competitive small-molecule inhibitor of the ALK and c-Met/HGFR receptor
tyrosine kinase.  The rationale for use of this mechanism to treat cancer is supported by an 
emerging paradigm in oncology that robust clinical efficacy can be obtained with 
well-tolerated inhibitors directed toward oncogenic tyrosine kinases that are genetically 
altered through activating mutations, gene translocations, or gene amplification.  Recent 
examples include imatinib mesylate in gastrointestinal stromal tumors with mutant c-Kit or 
chronic myelogenous leukemia with BCR-Abl gene translocations, erlotinib in non-small cell 
lung cancer with mutant EGFR, tratuzumab in breast cancers with amplified HER-2/neu, and 
sunitinib targeting the VHL-dependent VEGF pathway in renal cell carcinoma.  Crizotinib
demonstrated activity against NPM-ALK, an oncogenic fusion protein variant of the ALK, 
which results from a chromosomal translocation which is implicated in the pathogenesis of 
human anaplastic large cell lymphoma.10 Consistent with its predicted mechanism of action, 
crizotinib inhibited target-dependent tumor cell proliferation or invasion, induced tumor cell 
apoptosis, and inhibited angiogenesis in nonclinical tumor models including neuroblastoma.  
Oral administration of crizotinib also demonstrated efficacy, including marked cytoreductive 
antitumor activity, in several tumor models that expressed activated c-Met/HGFR or 
NPM-ALK.  The collective rationale for investigation of crizotinib in clinical studies is built 
on genetic alteration of its molecular targets, its predicted ability to target multiple processes 
that are common to cancer progression, and non-clinical efficacy data.  
1.2.3. Crizotinib Clinical Data
An ongoing Phase 1 trial (A8081001) evaluating crizotinib as an oral single agent is being 
conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with 
advanced cancer (excluding leukemias).  This trial includes a dose escalation component 
followed by a dose expansion component in a selected cohort of molecularly-defined patients 
referred to as the enriched population.  During the dose escalation phase, crizotinib was 
administered under fasting conditions QD or BID on a continuous schedule.  The objectives 
of the dose escalation component of the trial were to establish the maximum tolerated dose 
(MTD), dose limiting toxicities (DLTs), and PK of crizotinib in patients with advanced 
cancer.  Enrollment for the dose escalation part of the trial is complete and 37 patients have 
been dosed.  Three DLTs were observed including Grade 3 ALT increase in 1 patient at
200 mg QD and Grade 3 fatigue in 2 patients at 300 mg BID.  The MTD was determined to 
be 250 mg BID administered in a continuous daily dosing regimen.  The most common 
treatment-related adverse events seen to date were nausea, vomiting, diarrhea, and visual 
disturbance, which were primarily Grade 1-2 in severity. Nausea and vomiting were 
independent of dose or duration of treatment and were managed effectively using I.V. or oral 
anti-emetics. Treatment-related visual disturbances which consisted mainly of seeing 
shadows or streaks during changes in light were observed and occurred at doses of 200 mg 
BID or above.  All of these visual events were Grade 1 in severity.  In some patients, these 
events resolved with continued treatment but are reversible upon discontinuation of 
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In a recent review of safety for crizotinib (PF-02341066) Pfizer has determined that there are 
4 potential cases of pneumonitis which may be related to crizotinib (PF-02341066). One 
such case was a radiation recall pneumonitis. Based on the other 3 cases that were not linked 
to radiation treatment and relative to all enrolled adult patients (N=273) who have been 
treated with crizotinib (PF-02341066), as of July 16 2010, the current frequency of 
non-radiation recall pneumonitis is 1.1%.  One of the 4 cases was fatal. The 3 other patients 
recovered from the event. One patient experienced radiation recall pneumonitis, was 
appropriately treated and was able to restart crizotinib (PF-02341066). The other 2 patients 
were permanently discontinued from crizotinib (PF-02341066). Interpretation of the 
3 non-radiation recall cases was complicated by the underlying non-small cell lung cancer for 
which the patients were being treated. In addition these 3 cases were complicated by the 
co-administration of other drugs known to potentially cause pneumonitis and/or other 
pulmonary complications. One of the cases was considered not related to crizotinib 
(PF-02341066) by the investigator. Based on this new safety information suspected cases of 
pneumonitis will be evaluated and patients with pre-existing interstitial fibrosis or interstitial 
lung disease will be excluded from the entering the study
The crizotinib adverse drug reaction (ADR) list was updated in the crizotinib Investigator’s
Brochure (IB) to include the development of complex renal cysts. The development of 
complex renal cysts has been reported in some patients with NSCLC treated with crizotinib. 
These cysts may be symptomatic or asymptomatic, and have developed from several weeks to 
several months after starting crizotinib. The precise nature and significance of these cysts is 
unclear; however, while no evidence of malignancy has been found based on aspiration of cyst 
fluid and biopsy in the reported cases, complex renal cysts may be associated with renal 
malignancy, and thus consultation with a urologist or suitable alternate medical expert is 
recommended. Neither renal impairment nor clinically relevant proteinuria has been observed in 
any of the cases.
Additionally, the IB has updated the Effects on the Liver Section 7.6.4. With more than 
1400 patients who have been treated with crizotinib in clinical trials, 2 new Hy's Law cases 
and 2 cases of fatal hepatic failure have recently (March 2012) been reported as serious 
adverse events related to crizotinib treatment (a fifth Hy’s Law case had previously been 
reported in an earlier version of the IB).  Of all 5 of these cases, 2 patients presented with 
anorexia, 2 patients presented with weakness and fatigue, and 1 patient presented with 
abdominal pain. Four of these 5 cases, including the 2 fatal cases, were observed within the 
first 2 months after the start of crizotinib treatment, while significant transaminase elevation 
was observed after 6 months of crizotinib treatment in the fifth case.  PK data are available 
for the first 80 patients enrolled in the ongoing Phase 1 trial. After oral administration of 
crizotinib single doses in the fasted state, peak plasma concentrations were reached at about 
4 hours and followed by a multi-exponential decline with an average terminal half-life of 43
to 51 hours across doses.  Following multiple oral dosing for 15 days or longer, crizotinib
AUCtau increased with median accumulation ratios ranging 1.7-3.4 after QD dosing and 
4.0-5.9 after BID dosing, respectively. The repeated administration at 250 mg BID for 
15 days or longer produced a median trough plasma concentration of 256 ng/mL (53 nM, free 
drug), exceeding the target efficacious levels (Ceff) predicted for inhibition of cMet and ALK
based on preclinical mouse tumor models. Non-linearity of pharmacokinetics was observed 


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at 50 and 100 mg QD doses as the AUCtau and Cmax increased more than proportionally with 
the dose.  However, patients receiving doses ranging from 100 mg QD to 300 mg BID 
generally demonstrated linear pharmacokinetics, as evidenced by proportional increases in 
mean AUCtau and Cmax after single or multiple doses.
Crizotinib showed time-dependent inhibition of CYP3A isozymes in human liver 
microsomes with a kinact of 0.11 min-1 and Ki of 3.0 M.  In order to assess the effect of 
crizotinib on CYP3A activity in the GI tract and the liver, the PK of midazolam (a CYP3A 
substrate probe) following a single oral 2 mg dose was evaluated before (Day -7) and after 
(Cycle 2 Day 1) repeated administration of crizotinib at 250 mg BID in 13 patients.  A 
3.6-fold (90% CI: 2.7-4.9) increase in the oral midazolam AUC was observed following 
28 days of crizotinib dosing at 250 mg BID, suggesting that crizotinib is a moderate inhibitor 
of CYP3A.
Results from a pilot food effect study suggested that co-administration with a standard 
high-fat meal did not to change the geometric mean of AUC24 and Cmax of crizotinib
following single 250-mg crizotinib doses in cancer patients. 
Crizotinib (PF-02341066) has shown compelling clinical activity in patients with NSCLC 
with EML4-ALK fusions events enrolled in the expanded cohort of a Phase 1 trial. In 
50 evaluable patients, an ORR of 64% and clinical benefit rate (CBR) of 90% was reported 
by E.L. Kwak at the American Society of Hematology meeting in December of 2009. To 
date, based on the Phase 1 study (A8081001), there is a limited patient experience in patients 
with tumors other than NSCLC with changes in their molecular genetic profile involving the 
ALK gene locus. One patient with IMT achieved a PR which has been ongoing for 1.5 years 
(1PR of 2 IMT patients enrolled) and one patient with adult neuroblastoma harboring an ALK
mutation achieved stable disease (SD) lasting in excess of 6 months (1 SD of
1 neuroblastoma patient enrolled). One patient with ALCL associated with ALK
translocation has been studied to date but failed to achieve a clinical response. In addition, in 
an ongoing pediatric study there has been preliminary evidence of activity in a patient with 
IMT based on communication with the study principal investigator.  Complete information 
on crizotinib (PF-02341066) may be found in the single reference safety document (SRSD), 
which for this study is the investigator’s brochure (IB).
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective:

Assess the safety of oral single agent crizotinib administered to patients with 
advanced ALK-positive ALCL or other advanced malignancy other than NSCLC 
known to have an ALK genetic event and screen for efficacy in these patients.


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Secondary Objectives:

To determine PK in this patient population using population PK (POPPK) methods 
and explore correlations between PK, response and/or safety findings.

To correlate ALK genetic events to outcome measures.
2.2. Endpoints
Primary Endpoint:

Type, incidence, severity, seriousness and relationship to study medications of 
adverse events (AE) and any laboratory abnormalities.

ORR based on RECIST version 1.11 for solid tumors and the NCI International 
Response Criteria for Non-Hodgkin Lymphoma for patients with ALCL or other 
NHL (2007)2
Secondary Endpoints:

PFS, OS at 6 months and 1 year, OS and DR.

Plasma concentrations of crizotinib.

Proportion of patients with each of the ALK genetic events (translocation, mutation, 
amplification).

Phosphorylation status of ALK in the tumor samples from surgery or biopsy pre and 
post treatment when available.
3. STUDY DESIGN
This is an open-label, multi-center, single-arm exploratory trial of an oral agent, crizotinib, in 
patients with advanced malignancy harboring a translocation, inversion, mutation or 
amplification event involving the ALK gene locus.
At least 40 patients are expected to be enrolled into this trial. The sample size may be 
adjusted based on the number of patients identified and safety or evidence of antitumor 
efficacy within patient groups. In addition, the eligibility criteria may be modified to exclude 
patients based on the lack of efficacy demonstrated in specific patient groups.
Only ALK genetic event positive patients, as determined by the investigative site, may enter 
the study. ALK translocation/fusion, amplification, mutation and overexpression can be 
assessed by using any of the available technologies including fluorescence in-situ 
hybridication (FISH), Immunohistochemistry (IHC), quantitative Polymerase Chain Reaction 
(qPCR), quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR), array 
Comparative Genomic Hybridication (aCGH) or direct sequencing. The methodology of 
ALK testing required will depend entirely on the malignancy in question and the existence of 


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published data supporting a given methodology of ALK testing.  For example, ALCL is the 
only disease for which IHC alone is acceptable to document ALK positivity, as IHC has been 
shown to correlate with ALK-fusion events in ALCL and is widely accepted as a means of 
documenting ALK positivity in ALCL.  For diffuse large B-cell lymphoma, IHC alone is not 
sufficient for enrollment; an ALK gene fusion event must be documented by FISH or PCR.  
For neuroblastoma, ALK gene amplification must be documented by either FISH or aCGH, 
or a known ALK activating point mutation must be documented by PCR or direct 
sequencing; IHC alone is not acceptable.  For inflammatory myofibroblastic tumor (IMT), 
IHC alone is not sufficient, unless the intercalated antibody-enhanced polymer (iAEP) 
method is used.12  FISH or PCR demonstrating a fusion event is acceptable for IMT.  Other 
diseases will be considered for enrollment if publications exist supporting ALK 
mutation/fusion/amplification as an oncogenic driver for the disease in question.
Patients may continue treatment with crizotinib on this trial as long as there is evidence of 
clinical benefit in the judgment of the investigator. 
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:
1. Histologically or cytologically proven diagnosis of  ALCL or other advanced malignancy 
other than NSCLC for whom no standard therapy is available
2. Positive for
a.
Translocation or inversion event involving the ALK gene locus (eg, NPM-ALK
fusion) as determined by immunohistochemistry (IHC) or any other suitable 
molecular tools such as FISH or RT-PCR or sequencing.  Cases of ALK positive 
anaplastic large cell lymphoma must be positive for ALK expression by IHC.  
OR
b. ALK amplification events defined as ALK/CEP2 ratio of 5 in 15% of evaluated 
cells by FISH or as greater than 7 copies by qPCR or aCGH. 
OR


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c.
ALK activating point mutations determined by direct sequencing of the ALK gene 
locus including but not limited to G1128A, R1192P, R1275Q, D1091N, M1166R, 
I1171N, F1174I, F1174L, F1245C, F1245V, I1250T.ALK.
3. Patients with brain metastases are eligible if neurologically stable for at least 2 weeks, 
and have no ongoing requirement for corticosteroids, for example, dexamethasone and 
are not taking any medications contraindicated in Exclusion Criteria #12-14.
4. Any major surgery must have been completed at least 4 weeks prior to study entry. Any 
prior chemotherapy, including corticosteroids intended to treat lymphoma, must have 
been completed at least 2 weeks prior to the study entry.  However, low-dose, 
low-potency steroids (ie, up to 100 mg hydrocortisone per day) may be used for the 
treatment of tumor fever in patients with lymphoma up to 48 hrs prior to the first dose of 
crizotinib.  Any prior radiation performed with curative (ie, not only palliative) intent or 
minor surgeries/procedures must have been completed at least 2 weeks prior to the 
initiation of study medication.  Palliative radiation (≤10 fractions) must have been 
completed 48 hrs prior to crizotinib therapy commencing. Any acute toxicity must have 
been recovered to Grade 1 (except alopecia).
5. Solid tumors must be measurable per RECIST version 1.1, and lymphomas must be 
measurable per NCI International Response Criteria for Non-Hodgkin’s Lymphoma (see 
Appendix 3 and Appendix 4).
6. Female or male, 15 years of age or older.  Admission of minors to the study will be as 
appropriate according to institutional approvals. For patients enrolled in Japan: consent 
from a legally acceptable representative is required for all patients who are under 
20 years old.
7. ECOG performance status 0-3.
8. Adequate organ function as defined by the following criteria:

Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 
2.5 x upper limit of normal (ULN), or AST/ALT 5 x ULN if the enzyme 
elevation is considered to be due to a cancer-related cause such as liver metastases 

Patients with an ALT >5X ULN considered to be due to a cancer-related cause 
such as liver metastases, may enroll after discussion with the sponsor. 

Total serum bilirubin 1.5 x ULN.

Absolute neutrophil count (ANC) 1000/L (750/L for hematologic 
malignancies).

Platelets 30,000/L.

Hemoglobin 8.0 g/dL (7.0 g/dL for hematologic malignancies).


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
Serum creatinine 2.0 x ULN.
9. Signed and dated informed consent document indicating that the patient (or legally 
acceptable representative) has been informed of all the pertinent aspects of the trial prior 
to enrollment.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures.
11. Male and female patients of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for 90 days after the last dose of 
assigned treatment.  A patient is of childbearing potential if, in the opinion of the 
investigator, he/she is biologically capable of having children and is sexually active.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the trial:
1. Mutations or amplification involving the c-Met gene but not the ALK gene locus.
2. Current treatment on another therapeutic clinical trial.
3. Prior therapy specifically directed against ALK, including prior treatment with crizotinib.
4. Prior allogeneic bone marrow transplant.
5. Clinically apparent or known carcinomatous meningitis, or leptomeningeal disease unless 
neurologically stable for at least 2 weeks and under treatment.
6. Spinal cord compression unless treated with the patient attaining good pain control and 
stable or recovered neurologic function. 
7. Any of the following within the 3 months prior to starting study treatment: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or 
cerebrovascular accident including transient ischemic attack.
8. Ongoing uncontrolled congestive heart failure.
9. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial fibrillation 
of any grade, or machine-read ECG with QTc interval >470 msec.
10. History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, 
and pulmonary fibrosis, but not history of prior radiation pneumonitis.
11. Pregnancy or breastfeeding.  


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12. Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to the
first dose of crizotinib, including but not limited to atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin, and voriconazole. Grapefruit or grapefruit juice should also be avoided. 
The topical use of these medications (if applicable), such as 2% of ketoconazole cream, 
may be allowed.
13. Concurrent use of drugs that are known potent CYP3A4 inducers within 12 days prior to 
the first dose of crizotinib, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort
14. Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but 
not limited to dihydroergotamine, ergotamine, pimozide, astemizole*, cisapride*, and 
terfenadine* (* withdrawn from U.S. market).
15. Prior malignancy (other than current malignancy): patients will not be eligible if they 
have evidence of active malignancy (other than non-melanoma skin cancer or in situ 
cervical cancer, or prostate cancer) within the last 3 years.
16. Other severe acute or chronic medical (including severe gastrointestinal conditions such 
as diarrhea or ulcer) or psychiatric conditions, or end-stage renal disease on hemodialysis 
or laboratory abnormalities that would impart, in the judgment of the investigator and/or 
sponsor, excess risk associated with study participation or study drug administration, and 
which would, therefore, make the patient inappropriate for study entry. 
17. Patients who are investigational site staff members or relatives of those site staff 
members or patients who are Pfizer employees directly involved in the conduct of the 
trial.
4.3. Randomization Criteria
This is an open-label single-arm study. Randomization is not applicable.
4.4. Life Style Guidelines 
4.4.1. Contraception
In this study, patients of childbearing potential will receive crizotinib, which has been 
associated with teratogenic risk.  After IRB/EC approval of Amendment #5, all male patients 
who are able to father children and female patients who are of childbearing potential must 
agree to use 2 methods of highly effective contraception throughout the study and continued 
for at least 90 days after the last dose.
The investigator or his/her designee, in consultation with the patient, will confirm the patient 
has selected 2 appropriate methods of contraception for the individual patient from the list of 
permitted list of contraception methods (see below), and will confirm the patient has been 
instructed in their consistent and correct use. After IRB/EC approval of Amendment #5, 
patients need to affirm that they meet at least two of the selected methods of contraception. 


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The investigator or his/her designee will discuss with the patient the need to use highly 
effective contraception consistently and correctly according to the Schedule of Activities 
(Table 1) and document such conversation in the patient’s chart.
In addition, the investigator or his/her 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 patient’s partner.  
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:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception are allowed provided the patient plans to remain on the 
same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
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 post vasectomy 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).
6. Female partner who meets the criteria for non-chilbearing potential, as described 
below.
Female patients of non-childbearing potential must meet at least one of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle stimulating hormone 
(FSH) level confirming the post-menopausal state. 
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.


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All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 90 days after the last 
dose.
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.
4.4.3. Alcohol Consumption
Patients should be advised to avoid alcohol consumption while receiving crizotinib.
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 Investigational Site Folder.
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 compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the patients 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the patient directly and if a patient calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
All patients will receive crizotinib.
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Crizotinib (PF-02341066) will be provided as capsules containing 200 mg or 250 mg of 
study medication and will be packaged in HDPE bottles.


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5.2.2. Preparation and Dispensing
The study medication should be dispensed at each visit according to the schedule of 
treatment administration (Section 5.2.3).  Dispensing will be done by a qualified staff 
member in bottles provided, in quantities appropriate for the study visit schedule. The 
patient/caregiver should be instructed to maintain the product in the bottle provided 
throughout the course of dosing and return the bottle to the site at the next study visit. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
5.2.3. Administration
Crizotinib (PF-2341066), 250 mg BID, will be administered orally at approximately the same 
time each day on a continuous daily dosing schedule, ie, no break in dosing. Crizotinib may 
be taken without regard to meals. Cycles are defined in 21-day periods to facilitate 
scheduling of visits and assessments.
Patients will swallow the study medication whole and will not manipulate or chew the 
medication prior to swallowing. Patients should be instructed that if they vomit anytime after 
taking a dose, then they must not “make it up” with an extra dose, but instead resume 
subsequent doses as prescribed.  Any missed dose may be taken up to 6 hours prior to the 
next scheduled dose, otherwise it should be skipped and dosing resumed with subsequent 
doses as prescribed.
5.2.4. Compliance
Patients receiving crizotinib will be required to return all bottles of study medication at the 
beginning of each cycle or every other cycle if beyond Cycle 7.  The number of capsules
remaining will be documented and recorded.
5.3. Drug Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under 
recommended storage conditions and in accordance with applicable regulatory requirements.
Investigational product 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, IB), will be 
superseded by storage conditions stated in the labeling.
Returned medication for crizotinib should be stored separately from medication that needs to 
be dispensed.  Any excursions from the product label storage conditions should be reported 
upon discovery. The site should actively pursue options for returning the product to labeled 
storage conditions, as soon as possible.  Deviations from the storage requirements, including 
any actions taken, must be documented and reported to the sponsor.  


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Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. Specific details regarding 
information the site should report for each excursion will be provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.
Site staff will instruct patients on the storage requirements for take home medications 
including how to report temperature excursions.
5.4. Drug Accountability
The Investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  All containers must be returned to the Investigator by 
the patient.  
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 study 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.
To ensure adequate records, crizotinib will be accounted for in the case report form (CRF) 
and drug accountability inventory forms as instructed by the sponsor.  Unless otherwise 
authorized, at the end of the clinical trial, all crizotinib supplies unallocated or unused by the 
patients must be returned to the sponsor or its designee.  
5.5. Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify their investigators at the first 
occurrence of any adverse event.  
Dose modifications may occur in 3 ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;


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
In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
Patients will be monitored closely for toxicity and the dose of crizotinib may be adjusted as 
indicated in Table 3.  Dosing interruption and/or intrapatient dose reduction by 1 and if 
needed, 2 dose level(s) will be allowed depending on the type and severity of toxicity 
encountered (Dose Level -1 is 200 mg BID; Dose Level -2 is 250 mg QD).  Management of 
patients requiring more than 2 dose reductions due to treatment-related toxicity should be 
discussed with the Sponsor.
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.  
5.6. Management of Selected Crizotinib-Related Adverse Events
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.
5.6.1. Nausea and Vomiting
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.
5.6.2. Diarrhea
CTCAE Grade 1: Symptomatic care such as loperamide (Imodium) or no intervention at 
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 Grades 3-4 (despite use of loperamide): Withhold treatment until recovery to 
Grade 1.
5.6.3. Bradycardia
For a heart rate <40 beats per minute, evaluate the patient fully including an assessment of 
concomitant medications.  Adjust the dosage of any medication known to be associated with 
bradycardia (eg, beta-blockers).  If the bradycardia is symptomatic at any time or does not 
improve within 7 days of adjusting the concomitant medications, hold crizotinib dosing until 
recovery to Grade 1.  Patient may continue treatment only with the agreement of both the 
sponsor and investigator. After IRB/EC approval of Amendment 5, concurrent use of 
crizotinib with other bradycardic agents (eg, beta-blockers, non-dihydropyridine calcium 
channel blockers such as verapamil and diltiazem, clonidine, digoxin) should be avoided to 
the extent possible due to the increased risk of symptomatic bradycardia.  Heart rate and 
blood pressure should be monitored regularly.  Dose modification is not required in case of 
asymptomatic bradycardia. For management of patients who develop symptomatic 
bradycardia, see Table 3. 


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5.6.4. 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 confirm or 
exclude the diagnosis of pneumonitis during this period in the absence of tumor progression 
in the lungs, other pulmonary disease, infection, or radiation effects: 

A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and mycobacterial pathogens;

Blood culture should be performed in febrile patients.  Consider appropriate 
serologies (mycoplasma, legionella, CMV, other viruses, etc.)

Thoracentesis if pleural fluid is present (culture, microbiology, cytology).

Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate. The BAL fluid 
should be sent for culture, microbiology, and cytology.

Lung biopsy (eg, open or thorascopic preferable, bronchoscopy with transbronchial 
biopsy) if appropriate.

A plasma sample for BNP (B-type Natriuretic Peptide) to evaluate for evidence of 
CHF.

For Asian patients, a blood sample for -D-glucan to evaluate for the presence of 
protozoal pneumonia (eg, Pneumocystis jirovecii).
If clinically appropriate, high-dose corticosteroid treatment should be initiated. 
Should the event be fatal, an autopsy is highly recommended to confirm/exclude the 
diagnosis.
For any case of drug-related pneumonitis, discontinue crizotinib and contact the Sponsor
(see Table 3). 
5.6.5. Renal Cysts
The development of complex renal cysts has been reported in some patients with NSCLC 
treated with crizotinib.  These cysts may be symptomatic or asymptomatic, and have
developed from 2 and 6 months after starting crizotinib.  The precise nature and significance 
of these cysts is unclear; however, while no evidence of malignancy has been found based on 
aspiration of cyst fluid and biopsy in the reported cases, complex renal cysts may be 
associated with renal malignancy, and thus consultation with a urologist or suitable alternate 
medical expert is recommended.  

Active surveillance with appropriate imaging (contrast-enhanced CT scanning or 
magnetic resonance imaging) should be performed at the time of the renal cysts 


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diagnosis and as scheduled per protocol.  After approval of Amendment 5, 
investigators should also review retrospectively all CT/MRIs for any prior occurrence 
of complex renal cysts.  

In addition, multitest dipstick urinalysis (should include test for protein and blood) 
should be performed at the time of the renal cysts diagnosis and Day 1 of each cycle 
thereafter; in Korea, dipstick urinalysis should be performed in all patients at 
screening and on Day 1 of each cycle thereafter and at end of treatment.  

Urine reflex microscopy is required whenever urine dipstick is positive for blood or 
protein.  


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Table 3.
Crizotinib Dose Modifications for Treatment-Related Toxicity (CTCAE v4.0)
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
ALT or AST elevation with 
total bilirubin <2 X ULN (in 
absence of cholestasis and 
hemolysis)
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.
See footnote for possible patient 
entry criteria§
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 Grade 3 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 bilirubin 
elevation ≥2X ULN (in 
absence of cholestasis or 
hemolysis)
Continue at the same 
dose level.  Obtain repeat 
ALT or AST and total 
bilirubin within 48 hrs, 
then repeat every 
48-72 hours until 
ALT/AST is Grade <1
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
Pneumonitis (not attributable 
to disease progression in the 
lung, infection, other 
pulmonary disease, 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


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Table 3.
Crizotinib Dose Modifications for Treatment-Related Toxicity (CTCAE v4.0)
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 once daily upon 
recovery to Grade 1 or 
to heart rate 60, with 
frequent monitoring.
Permanently 
discontinue for 
recurrence
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, 
then resume at 200 mg twice daily. 
In case of recurrence, withhold until 
recovery to Grade 1, then resume at 
250 mg once daily.
Permanently discontinue in case of 
further Grade 3 recurrence.
Discontinue treatment 
and do not retreat


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Table 3.
Crizotinib Dose Modifications for Treatment-Related Toxicity (CTCAE v4.0)
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Visual disturbance‡
Continue at the same 
dose level
Repeat ophthalmologic 
examination‡
Continue at the same dose 
level
Repeat ophthalmologic 
examination‡
Interrupt crizotinib until recovery.
Repeat ophthalmologic examination‡
Resume treatment by reducing the 
dose by 1 dose level
Discontinue crizotinib 
and do not retreat.
Repeat ophthalmologic 
examination‡
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.*
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*.
Hematologic (excluding 
lymphopenia**†)
Continue at the same 
dose level.
Continue at the same dose 
level.
See footnote for possible patient 
entry criteria.† 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**.
Withhold dose until 
toxicity is Grade 2, or 
has returned to baseline, 
then reduce the dose by 
1 level and resume 
treatment**. 
*   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.
** Patients who develop Grade 3 or 4 lymphopenia without other dose-limiting events (eg, opportunistic infection) may continue study treatment without 
dosing interruption.
† Patients entering with platelet counts 30,000 (<50,000 Grade 3) will be monitored for drug related decreases at which point dose modifications will be 
discussed with the Sponsor.
‡ 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 v4.0 grade change occurs from the previous 
visit.
§ Patients entering with ALT >5xULN (ie, Grade 3) in the presence of liver mets/tumor-related cause will be monitored for drug related increases at which 
point dose modifications will be discussed with the Sponsor.


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If a patient has a significant toxicity from crizotinib treatment which fails to recover within 42 (6 weeks) days or, in the opinion of the 
investigator, requires discontinuation of the treatment based on the severity of the adverse event, then further dosing with crizotinib 
should be discussed with the sponsor.


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5.7. Concomitant Medication(s)
All concomitant treatments, blood products, as well as non-drug interventions 
(eg, paracentesis) received by patients from screening to 28 days after the last dose of study 
treatment will be recorded on the CRF.
Systemic anticancer therapy with agents other than crizotinib (including corticosteroids for 
lymphoma) is not allowed.  Medications intended solely for supportive care (ie, antiemetics, 
analgesics, megestrol acetate for anorexia) are allowed.  
5.7.1. Crizotinib
The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in human 
liver microsomes and hepatocytes.  Co-administration with drugs that are CYP3A inhibitors 
and inducers may change the plasma concentrations of crizotinib in humans.  The concurrent 
use of potent CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice are not 
allowed in the study.  The topical use of these medications (if applicable), such as 2% 
ketoconazole cream, may be allowed.  The concurrent use of potent CYP3A inducers,
including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, 
and St. John’s wort, are not allowed in the study.
In vitro data indicate that the most pronounced inhibitory potential of crizotinib was observed 
toward CYP3A4 (testosterone)-mediated drug metabolism.  Crizotinib has minimal potential 
to inhibit other human CYP isoforms such as CYP1A2, 2C8, 2C9, 2C19, and 2D6.  
Crizotinib also showed time-dependent inhibition of CYP3A isozymes in human liver 
microsomes.  In cancer patients, a mean 3.6-fold (90% CI: 2.7-4.9) increase in the oral 
midazolam AUC was observed following 28 days of crizotinib dosing at 250 mg BID, 
suggesting that crizotinib is a moderate inhibitor of CYP3A.  Caution must be exercised in 
patients receiving crizotinib in combination with drugs that are predominantly metabolized 
by CYP3A, such as alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, and tacrolimus.  
In particular, co-administration of crizotinib with CYP3A4 substrates with narrow 
therapeutic indices including, but not limited to, ergotamine, dihydroergotamine, pimozide, 
astemizole*, cisapride*, and terfenadine* (* withdrawn from U.S. market) must be avoided 
from the time of the first dose of crizotinib until treatment discontinuation.
Additionally, the concurrent use of non-prescription drugs, complimentary medicines
(excluding vitamins) or herbal supplements is not recommended. Patients should avoid using 
acetaminophen at doses in excess of 2 grams per day.
5.7.2. Antiemetic and Antidiarrheal Therapy
Supportive care may include premedication with antiemetics to limit treatment-related nausea 
and vomiting.  Patients may receive prophylaxis of treatment-induced diarrhea.


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5.7.3. Hematopoietic Growth Factors
The use of hematopoietic growth factors is at the discretion of the treating physician and is in 
line with local regulatory guidelines.  Patients who enter the study on stable doses of 
erythropoietin or darbepoietin may continue this treatment, and patients may start either drug 
during the study at the discretion of the treating physician.  Patients with neutropenic fever or 
infection should be treated promptly and may receive therapeutic colony-stimulating factors 
if appropriate.
5.7.4. Other Concomitant Medications
Anti-inflammatory or narcotic analgesics may be offered as needed.  Packed red blood cell 
and platelet transfusions should be administered as clinically indicated.
Patients on this trial may be supported with appropriate hormone replacement therapy as 
clinically indicated in the absence of disease progression or unacceptable 
treatment-associated toxicity.
Bisphosphonate therapy for metastatic bone disease is permitted.  Bisphosphonate therapy 
should be given as per local medical practice.
Low dose acetaminophen (<2 g/day) is allowed.
Medications that are known to prolong the QT interval and bradycardic agents 
(eg, beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and 
diltiazem, clonidine, digoxin) should be used with caution during the study.
5.8. Concomitant Radiotherapy or Surgery
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  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) for any 
surgical procedures during the study.  The appropriate interval of time between surgery and 
crizotinib required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  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.  Postoperatively, the decision to reinitiate crizotinib treatment should be based on a 
clinical assessment of satisfactory wound healing and recovery from surgery.
5.9. Rescue/Escape/Salvage (Select One) Therapy 
Not applicable.


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6. STUDY PROCEDURES
6.1. Screening
See Table 1 for Schedule of Activities.
6.2. Study Period
For procedures during the study period, see Table 1 for Schedule of Activities.  A reduced 
schedule of assessments will be followed for all ongoing patients after IRB/EC approval of 
Amendment 5 (see Table 6, Appendix 5).
Sufficient study medication for a maximum of 6 cycles of treatment will be dispensed at each 
clinic visit. During the non-clinical visit cycles, laboratory tests should be performed every 
cycle and the Investigator is responsible for ensuring the patient contacts the clinical site in 
order to provide an update of adverse events and concomitant medications.  Where possible, 
laboratory tests should be performed at the clinical site’s local laboratory. Where that is not 
possible, patients will provide the laboratory test results carried out at a non-clinical site 
laboratory, eg, by telephone, and bring a copy of the laboratory test results at the next cycle 
visit; process depends on local medical practice.  The copy of the laboratory test results must 
be retained in the patient’s file at the clinical site for documentation purposes.
6.3. Follow-Up Visit
For follow-up visit procedures, see Table 1. After IRB/EC approval of Amendment #5, 
post-treatment follow-up visits for survival status will no longer be required (see Table 6, 
Appendix 5).
6.4. 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 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.  
Reasons for trial treatment discontinuation may include (further collection of data can still 
occur):

Disease progression by RECIST 1.11 or NCI International Response Criteria for 
Non-Hodgkin’s Lymphoma (2007).2

Unacceptable toxicity.

Need for treatment delay for more than 6 weeks due to lack of toleration should be 
discussed with the sponsor.

Protocol non-compliance.

Pregnancy.


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Reasons for trial discontinuations (no further collection of data) withdrawal from study 
follow up may include:

Withdrawal of consent.

Patient lost to follow-up (data may still be collected from other sources, eg, vital 
records, as allowed by local regulations.

Death.

Study terminated by Sponsor.
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 the patient to return all unused investigational 
product(s), request the patient to return for a final visit, if applicable, and follow-up with the 
patient regarding any unresolved adverse events.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study-specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
Note: after IRB/EC approval of Amendment #5, post-treatment follow-up visits for survival 
status will no longer be required.  
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 can not be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/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 fashion.
Assessment of efficacy, adverse events, laboratory safety assessment (hematology, 
coagulation, and chemistry), physical examination, ECG, tumor measurements, biomarker 
sampling and PK sampling will be done according to time points specified in Table 1.
After IRB/EC approval of Amendment #5, Schedule of Activities will be further reduced as 
indicated in Table 6 (Appendix 5).


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7.1. Efficacy Assessments
On-study tumor assessments are to be performed at the beginning of Cycle 3 and every other 
cycle up to and including Cycle 10.  After Cycle 10 tumor assessments will be performed 
every 12 weeks, and will be reduced to every 24 weeks from Cycle 26 and to every
52 weeks from Cycle 52.  CT or MRI scan should also be performed whenever disease 
progression is suspected (eg, symptomatic deterioration).  The determination of anti-tumor 
activity will be based on objective tumor assessments made according to the RECIST version 
1.1 or NCI International Response Criteria for Non-Hodgkin’s Lymphoma (2007)
(Appendix 3 and Appendix 4).  The CT scans used for tumor assessments should be 
performed with contrast agents unless contraindicated for medical reasons. The same 
imaging modality should be used throughout the study to measure disease.  Tumor evaluation 
by positron emission tomography (PET) scan or by ultrasound may not substitute for CT or 
MRI scans.  CT or MRI scans will include chest, abdomen and pelvis at screening (and neck 
for patients with NHL).  Subsequent staging scans may include only known sites of disease, 
unless scanning of additional sites is clinically indicated. CT/MRI head is required at 
screening. Brain must be included in subsequent tumor assessments if a patient has brain 
metastases, otherwise brain will only be evaluated when clinically indicated. Bone scans are 
required if bone metastases are suspected.  A bone scan is also required at the time of 
confirmation of response for patients who have bone metastases.  Scans will be collected for 
a potential independent radiology review.  PET scanning should be used to evaluate for 
complete response in those NHL patients whose CT/MRI scans suggest only a partial 
response.  Once a normal PET scan (ie, a PET scan suggesting complete response) has been 
obtained in a patient with NHL, repeat PET scanning is not required unless there is clinical 
evidence to suggest disease progression.  Bone marrow biopsy and/or aspirate should also be 
performed to document complete response for any NHL patients known to have bone 
marrow involvement at baseline or for any NHL patient whose marrow status was unknown 
at baseline.  
When new effusions or ascites are present and represent the only potential site of disease 
progression, cytologic analysis should be performed and the results, malignant or 
non-malignant, should be recorded on the CRF.
Measurable lesions that have been previously irradiated will not be considered target lesions 
unless increase in size has been observed following completion of radiation therapy.
After IRB/EC approval of Amendment #5, tumor assessments will be performed as per local 
clinical practice (see Table 6, Appendix 5), and will no longer be recorded on the CRF. The 
collection of scans for independent radiology review will be discontinued. However, tumor 
assessment information should be retained in the patient’s file for documentation purposes.
7.2. Safety Assessments
Safety assessments will include collection of AEs, serious adverse events, vital signs, 
physical examination, 12-lead ECGs, laboratory assessments including pregnancy tests, 
ophthalmological examinations and verification of concomitant treatments.


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7.2.1. Adverse Events 
Adverse events will be classified by type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events [CTCAE] Version 4.0), timing, 
seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded as adverse events during the 
trial if they worsen in severity or increase in frequency.
7.2.2. Pregnancy Testing
Prior to IRB/EC approval of Amendment 5, for female patients of childbearing potential, 
apregnancy test, with sensitivity of at least 25 mIU/mL, will be done at screening, before 
investigational product administration, whenever one menstrual cycle is missed during the 
treatment period (or when potential pregnancy is otherwise suspected), and at the end of 
treatment visit to confirm the patient has not become pregnant during the study.
After IRB/EC approval of Amendment 5, for female patients of childbearing potential, a 
serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be routinely performed at 
every cycle during the active treatment period, at the end of study treatment, and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
In the case of a positive confirmed pregnancy, the patient will be withdrawn from treatment 
but may remain in the study.  Additional pregnancy tests may also be undertaken if requested 
by IRB/ECs or if required by local regulations.
7.2.3. Laboratory Safety Assessments
For a listing of hematology, coagulation and blood chemistries, see Appendix 1.
7.2.4. Physical Examination
A complete physical examination will include the assessment of relevant body systems, the 
measurement of body weight, height (screening only) and vital signs.  Blood pressure and 
pulse rate will be obtained in the sitting position.  Blood pressure should be measured in the 
dominant arm, ie, writing arm, and recorded to the nearest mmHg.  The same arm should be 
used throughout the study.
7.2.5. Performance Status
ECOG Performance Status scale will be used (see Appendix 2).
7.2.6. ECG Measurements
A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  Triplicate ECG 
measurements will be obtained at all time points except a single ECG measurement at 
screening. For triplicate measures, three consecutive 12-lead ECGS will be collected 
approximately 2 minutes apart.  It is required that the machine used has a capacity to 
calculate the standard intervals automatically.  ECG measurements will include PR interval, 
QT interval, RR interval, and QRS complex.  Additional ECGs will be performed as 
clinically indicated. If the QTc is prolonged (500 msec), then the ECG should be read by a 


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cardiologist at the site for confirmation, and the values obtained by the cardiologist should 
also be entered into the CRF.  Crizotinib should be withheld until the drug relationship of the 
event is determined (rule out electrolyte imbalance or influence of concomitant medication).  
In case of a QTc interval measurement 500 msec (Grade 3) dosing should be interrupted, 
and permanently discontinued for a Grade 4 QTc prolongation.  For Grade 3 or 4 QTc 
prolongations, continuous electrocardiogram (ECG) monitoring will be done under physician 
supervision until the QTc recovers to Grade 1.  Triplicate ECG surveillance will again be 
performed when crizotinib is restarted on a reduced dose due to Grade 3 QTc prolongation as 
described in Table 3. The timing of the triplicate assessment of ECGs should be prior to 
(0 hour) and 2-6 hours after morning dosing of crizotinib on Day 1 of Cycles 1, 2, and 3.
7.2.7. Ophthalmology Examinations
At screening, each patient will have an ophthalmologic exam including visual acuity and slit 
lamp.  Additional eye examinations will be performed as clinically indicated.
Findings from the ophthalmology examinations should be reported as adverse events if a 
finding is considered to be an adverse event by the investigator or Sponsor.
7.3. Pharmacokinetics
7.3.1. Plasma Pharmacokinetic Assessment
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time 
relative to dosing. However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) from dosing will not be captured as a protocol deviation, as 
long as the exact time of the sample collection is noted on the source document and data 
collection tool (eg, CRF).  During the trial, actual collection times may change but the 
number of samples will remain the same.  
PK samples will be assayed using validated analytical method(s) in compliance with Pfizer 
standard operating procedures.  Details regarding the sample handling and shipping will be 
provided in the Lab Manual.
7.3.2. Plasma Pharmacokinetic Assessment for Crizotinib
Plasma samples for crizotinib will be obtained prior to and 2-6 hours following morning 
dosing on Day 1 of Cycles 1, 2, 3 and 5.  No pre-dose sample is required on Day 1 of 
Cycle 1. Additional blood samples may be requested from patients experiencing unexpected 
or serious adverse events.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
potential qualitative and/or quantitative metabolite analyses and/or evaluation of the 
bioanalytical methods for crizotinib and its metabolites (if possible). The results of such 
analyses may be included in the clinical report.
At each time point, blood samples (3 mL) for PK will be collected into appropriately labeled 
collection tubes containing K2EDTA at protocol-specified times. Once collected, samples 
should be processed immediately and kept out of direct sunlight due to the light sensitive 


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nature of crizotinib.  Blood samples will be placed immediately on ice-bath and centrifuged 
at approximately 1700 g for 10 minutes at 4º C. Plasma samples will be harvested and stored 
in appropriately labeled tubes at approximately -20°C within 1 hour of collection.  
7.4. Tumor Tissue for Molecular Profiling
Tumor sample must be provided to the designated central laboratory for retrospective 
confirmation of ALK genetic event by a Pfizer designated central laboratory. However this 
information will not be used to determine eligibility to enter the trial.
7.5. Tumor Tissue for Biomarker Analysis 
An optional tumor sample will be collected at the end of treatment if a patient discontinues 
due to disease progression.  The tumor tissue will be used to determine possible mechanisms 
for resistance to crizotinib treatment.  There is no restriction on the type of tumor sample, so 
cytology specimens as an alternative to solid tumor specimens may also be collected.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event (SAE) requiring immediate notification to Pfizer or 
its designated representative.  For all adverse events, sufficient information should be 
obtained by the investigator to determine the causality of the adverse event.  The investigator 
is required to assess causality.  Follow-up by the investigator may be required until the event 
or its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
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 
trial.  
8.2. Reporting Period
For serious adverse events, the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through and including 
28 calendar days after the last administration of the investigational product.  Serious adverse 
events occurring to a patient after the active reporting period has ended should be reported to 
the Sponsor if the investigator becomes aware of them; at a minimum, all serious adverse 


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events that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Sponsor.

Adverse events (serious and non-serious) should be recorded on the case report form 
(CRF) from the time the patient has taken at least one dose of investigational product 
through the patient’s last visit.

If a patient begins a new anticancer therapy, the adverse event reporting period for 
non-serious adverse events ends at the time the new treatment is started.  Death must 
be reported if it occurs during the serious adverse event reporting period after the last 
dose of investigational product, irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation patient
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breast feeding;

Medication error;


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
Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as adverse events 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 adverse events.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving 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.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

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 or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.


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8.6. 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;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a serious adverse event unless the outcome is 
fatal within the safety reporting period. Hospitalization due to signs and symptoms of 
disease progression should not be reported as a serious adverse event. If the 
malignancy has a fatal outcome during the study or within the safety reporting period, 
then the event leading to death must be recorded as an adverse event and as a serious 
adverse event with Common Terminology Criteria for Adverse Events (CTCAE)
Grade 5 (see the section on Severity Assessment).

Lack of efficacy should be reported as an adverse event when it is associated with a 
serious adverse event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other adverse event 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.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 


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drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least one time the 
upper limit of normal or if the value reaches 3 times the upper limit of 
normal (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  For oncology studies, the 
possibility of hepatic neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time should be considered potential Hy’s Law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s Law cases should be reported as SAEs.


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8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned 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.


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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.8. Severity Assessment
The investigator will use the following definitions of Severity in accordance with CTCAE
Version 4.0 to describe the maximum intensity of the adverse event.  If the event is serious, 
the CTC grade reported in the adverse event CRF must be consistent with the description of 
CTC 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 4.0 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 adverse event.  A severe 
event is not necessarily a serious adverse event.  For example, a headache may be severe 
(interferes significantly with patient's usual function) but would not be classified as serious 
unless it met one of the criteria for serious adverse events, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse 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 adverse event; 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 the section on 
Reporting Requirements).  If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records.  


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In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
directly 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 women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. 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 study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a SAE Report form and Exposure during
pregnancy (EDP) supplemental form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the EDP supplemental form.  
This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study 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.
8.11. 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 
investigational product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient Withdrawal)
Withdrawal due to adverse event should be distinguished from withdrawal due to other 
causes, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study patient.  In addition, each study patient will be 
questioned about adverse events.
8.14. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator 
awareness of the event.  
In particular, if the serious adverse event is fatal or life-threatening, notification to Pfizer 
must be made immediately, irrespective of the extent of available adverse event information.  
This timeframe also applies to additional new information (follow-up) on previously 
forwarded serious adverse event reports as well as to the initial and follow-up reporting of 
exposure during pregnancy, exposure via breastfeeding, and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study patient initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications, vaccines and/or illnesses 
must be provided.  In the case of a patient death, a summary of available autopsy findings 
must be submitted as soon as possible to Pfizer or its designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse events reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Sample Size Determination
A primary objective of this study is to assess the safety of oral, single agent crizotinib
administered to patients with advanced ALCL or other malignancy (other than NSCLC) 
known to have an ALK genetic event and screen for efficacy in these patients.  Estimation 
will be emphasized for the study endpoints. 


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The sample size for this study is determined empirically based on expected small numbers of 
patients in the population of interest.  It is anticipated that a total of approximately 40 
patients will be enrolled in this study.
The table below shows the probability of observing toxicity with different sample sizes given 
various true underlying toxicity rates.  For example, with 40 patients, the probability of 
observing toxicity occurring at least 5% of the time is 87%.
Table 4.
Probability of Observing Toxicity Given True Underlying Event Rates
True Underlying Toxicity Rate
5%
10%
15%
Probability of Observing at Least 1 Adverse Event
N=10
0.40
0.65
0.80
Probability of Observing at Least 1 Adverse Event
N=20
0.64
0.88
0.96
Probability of Observing at Least 1 Adverse Event
N=30
0.79
0.96
0.99
Probability of Observing at Least 1 Adverse Event
N=40
0.87
0.99
1.0
9.2. Efficacy Analysis
The study population for all analyses will include patients enrolled in the study who receive 
at least one dose of crizotinib. Data summaries/listings will be presented overall as well as 
separately for ALCL patients and patients with other malignancies (by tumor type, as 
applicable). Data for patients who are enrolled in the study but are later found to not have an 
ALK genetic event will be presented separately. 
Due to the exploratory nature of this study, no confirmatory inferential analyses are planned, 
and no imputation for missing data will be done.  Descriptive statistics (such as means, 
medians, standard deviations and ranges for continuous data and percentages for categorical 
data) will be used to summarize patient characteristics, treatment administration, efficacy, 
safety, molecular medicine and pharmacokinetic parameters.  Data will also be displayed 
graphically, where appropriate.  
9.2.1. Analysis of Primary Endpoint 
The study population for all analyses will include patients enrolled in the study who receive 
at least one dose of crizotinib. Data summaries/listings will be presented overall and, if 
applicable, separately by tumor type. Data for patients who are enrolled in the study but are 
later found to not have an ALK genetic event will be presented separately. 
Objective Response: the best response (CR, PR, SD or PD) per RECIST version 1.1, or the 
NCI International Response Criteria for Non-Hodgkin’s Lymphoma (2007) where applicable,
will be summarized.  The objective response rate (ORR) will also be summarized along with 
the corresponding exact 2-sided 95% confidence interval calculated using a method based on 
the F distribution.  


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Safety Analysis: Frequencies of patients experiencing at least one adverse event (AE) will 
be displayed by body system and preferred term according to MedDRA terminology.  
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study drug, action taken, and clinical 
outcome.  Severity of the AEs will be graded according to the NCI CTCAE Version 4.0.  
The number and percentage of patients who experienced any serious AE (SAE), treatment 
related AE, and treatment related SAE will also be summarized.  AE data will be presented 
across cycles and by cycle, as appropriate.  The denominator for each cycle is defined as 
those patients available at the start of the cycle who received at least 1 dose of crizotinib for 
that cycle.  Emphasis in the analyses will be placed on AEs classified as treatment emergent.  
Additional summaries of AEs and other safety data will be presented in tabular and/or 
graphical format and summarized descriptively, as appropriate.
9.2.2. Analysis of Secondary Endpoints
Secondary, time to event endpoints (eg, PFS, OS), will be summarized descriptively using 
Kaplan-Meier methods and displayed graphically, where appropriate.  
9.3. Analysis of Other Endpoints
9.3.1. Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  Patients not meeting the eligibility 
criteria will be identified.  Patients not completing the study will be listed along with the 
reason for their premature discontinuation.  Reasons for premature discontinuation will be 
summarized.
9.3.2. Baseline Characteristics
Demographic characteristics such as patient age, gender, weight, ethnicity, prior cancer 
therapy, medical history and ECOG performance status will be tabulated.
9.3.3. Treatment Administration/Compliance
Study drug administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered and dose intensity.
9.3.4. Analysis of Clinical Labs
Listing tables will be prepared for each laboratory measure, and will be structured to permit 
review of the data by patient as they progress on treatment.  The tables will list the day and 
cycle of treatment, dose, and associated NCI CTCAE toxicity grade.  Summary tables will be 
prepared to examine the distribution of these toxicities per cycle.
Graphic displays and shift tables may be provided to illustrate the results over time on study. 


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9.3.5. Electrocardiogram Data 
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged.  All summary statistics and data presentations will use the triplicate averaged data.  
Any data obtained from ECGs repeated for safety reasons after the nominal time points will 
not be averaged along with the preceding triplicates. QT measurements corrected by heart 
rate (QTc) using Bazett’s (QTcB) and Fridericia’s (QTcF) methods will be used for data 
summaries and interpretation.
9.3.6. Concomitant Medications
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary.  Patients who received 
concomitant medications will be listed. Follow-up systemic therapy for the primary 
diagnosis will be summarized by categories of follow-up therapy and will be listed for each 
patient as appropriate.
9.3.7. Analysis of Pharmacokinetic Endpoints
Concentration data of crizotinib will be listed by patient and by actual collection time and 
day.
Concentration-QTc modeling analysis will be conducted using the ECG data from this study 
and/or combined data with other clinical studies of crizotinib.  A separate study specific QT 
correction factor will be estimated for the QT-RR measurements in each clinical study of 
crizotinib.  Linear, log-linear, and/or saturable models will be examined for the 
concentration-QTc relationship. Exploratory analyses (via graphical displays and/or model 
fitting) include accounting for a delayed effect and the justification for the choice of 
pharmacodynamic model. Diagnostic evaluation will be included to explore the adequacy of 
the model.
Population pharmacokinetic analysis of samples collected in this study will be performed in 
accordance with the FDA guidance on Population Pharmacokinetics (February 1999).  All 
patients treated with crizotinib and for whom drug plasma concentration results (from at least 
1 visit) are available will be included in the population analysis.  The plasma concentration 
data set from this study will be pooled with data sets from additional crizotinib studies.  
Population pharmacokinetic analysis will involve mixed effects modeling performed using 
appropriate software (eg, NONMEM). The data from the analysis will describe the PK 
following multiple dose administration of crizotinib and describe covariates that are 
important determinants of crizotinib disposition.
In addition, population PK/PD analysis will be explored, as necessary, based on emerging 
safety/clinical response data.
The results of these modeling analyses may be reported separately from the clinical study 
report.


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9.3.8. Analysis of Molecular Profiling Endpoints
The types of ALK fusion/translocation, mutations, amplification and overexpression will be 
tabulated by tumor type.  Summaries of baseline molecular profiling results will be provided.  
Changes will be summarized for those patients with both pre and post treatment and end of 
treatment/withdrawal molecular profiling results.  
9.4. Interim Analysis 
No interim analysis is planned.
9.5. Data Monitoring Committee
An external Data Safety Monitoring Committee 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.  
Procedures include:

Surveillance for serious adverse events (SAEs) according to regulatory guidelines.

Routine monitoring of non-serious adverse events as they are recorded in the CRFs.

Periodic teleconferences with the principal investigators on individual studies to share 
experiences and ensure communication.
Findings of the periodic safety reviews, according to Sponsor procedures will be documented 
in the project files and action taken as appropriate.  Findings having immediate implication
for the management of patients on study will be communicated to all principal investigators 
in the timeframe associated with unexpected and drug-related SAEs.
In addition, an internal review committee including at least a medical oncologist and 
statistician will provide periodic review of safety data.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.
The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.


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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 case report form (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 is true. Any corrections to entries made in the CRFs, 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's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assent documents, copies of all CRFs, serious adverse event forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, telephone calls reports).  The records 
should be retained by the investigator according to International Conference on 
Harmonisation (ICH), according to local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 


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study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. The 
investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent 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 legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonization guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws.
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 is compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify the study patient. The study 
site will maintain a confidential list of patients who participated in the study linking their 
numerical code to the patient’s actual identity. In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of patient personal data consistent with 
applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.


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The informed consent/assent documents used during the informed consent process must be 
reviewed by the Sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study patient, or his/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 or legal 
guardian, 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/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.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative parent(s), or legal 
guardian and the patient’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC.  The 
investigator will retain the original of each patient's signed consent/assent 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 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application [CTA]) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of Trial in all other participating countries is defined as the time at which it is deemed 
that sufficient patients have been recruited and completed the study as stated in the regulatory 
application (ie, Clinical Trial Application [CTA]).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of crizotinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a timed period deemed appropriate by each 
institutional IRB/IEC.  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 for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.


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Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts 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 primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
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 has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.


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Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
EA Eisenhauer et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1).  Eur J Cancer 45: 228-27, 2009.
2.
Cheson B.D. et al., Revised response criteria for malignant lymphoma.  JCO; 30 (18) 
579-586, 2007.
3.
K. Pulford et al, The emerging normal and disease-related roles of anaplastic lymphoma 
kinase. Cell.Mol.Life Sci.: 2939-2953, 2004.
4.
Y. Mossé et al, Inhibition of ALK signaling for cancer therapy. Clin Cancer Res; 15(18): 
1509-5614, 2009.
5.
R George et al, Activating mutations in ALK provide a therapeutic target in 
neuroblastoma. Nature, 455, 975-978, 2008.
6.
E. Lin at al, Exon array profiling detects EML4-ALK Fusion in breast colorectal and 
non-small cell lung cancers. Mol Cancer Res 7 (9) 1466-1476, 2009.
7.
Y. Mossé et al, Identification of ALK as a major familial neuroblastoma predisposition 
gene. Nature 455, 930-936, 2008.
8.
C. Laurent et al, Anaplastic Lymphoma Kinase-positive Diffuse large B-Cell 
Lymphoma: a rare clinicopathologic entity with a poor prognosis. JCO; 27 (25), 
4211-4216, 2009.
9.
R. Palmer et al, Anaplastic Lymphoma kinase: signaling in development and disease. 
Biochem J, 420, 345-361, 2009.
10.
M Soda et al, A mouse model for EML4−ALK−positive lung cancer.  Proc  Natl Acad 
Sci USA 105:19893−97, 2008.
11.
Percy C.L. et al., Lymphomas and reticuloendothelial neoplasms 1990-1995, SEER 
Pediatric Monograph.
12.
Takeuchi K. et al., Pulmonary inflammatory myofibroblastic tumor expressing a novel 
fusion, PPFIBP1–ALK: reappraisal of anti-ALK immunohistochemistry as a tool for 
novel ALK fusion identification.  Clin Cancer Res 17 (10) 3341-48, 2011.


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Appendix 1. Required Laboratory Tests 
Conventional 
Units
Conversion 
Factor
SI Units
Hematology
Hemoglobin (Hgb)
g/dL
x 10
g/L
Platelet count (Plt)
103/mm3
x 109
1012/L
White blood count (WBC)
103/mm3
x 106
109/L
White blood cell differential
%
x 0.01
fraction
Chemistry
Total bilirubin
mg/dL
x 17.1
mol/L
Alanine transaminase (ALT)
U/L
N/A
U/L
Aspartate transaminase (AST)
U/L
N/A
U/L
ALKaline phosphatase
U/L
N/A
U/L
Total protein
g/dL
x 10
g/L
Albumin
g/dL
x 10
g/L
Sodium
MEq/L
x 1.0
mmol/L
Potassium
MEq/L
x 1.0
mmol/L
Chloride
MEq/L
x 1.0
mmol/L
Calcium
mg/dL
x 0.25
mmol/L
Phosphorus
mg/dL
x 0.323
mmol/L
Blood urea nitrogen (BUN)*
mg/dL
x 0.357
mmol/L
Urea *
n/a
n/a
mmol/L
Creatinine
mg/dL
x 88.4
mol/L
Uric acid
mg/dL
x 0.059
mmol/L
Magnesium
mg/dL
X 0.41
mmol/L
Glucose
mg/dL
x 0.055
mmol/L
LDH 
U/L
N/A
U/L
Coagulation
Protime INR
(unitless)
N/A
(unitless)
* either/or 
In cases of suspected Drug-
Induced Liver Injury (DILI) -
values eventually to be reported on 
SAE form and eCRF AE page as 
appropriate
Creatine kinase  (aka CPK)
U/L
N/A
U/L
Indirect bilirubin
mg/dL
x 17.1
mol/L
Direct bilirubin
mg/dL
x 17.1
mol/L
Gamma-glutamyl transferase (GGT)
U/L
N/A
U/L


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


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Appendix 3. RECIST Version 1.1 Tumor Assessment Criteria
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below 11:
Measurable Lesions
Lesions that can be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice 
thickness no greater than 5 mm).

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot 
be accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
Non-Measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a 10 but <15 mm short axis) as well as truly non-measurable lesions.  
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam and not measurable by reproducible imaging techniques.
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
Special Considerations Regarding Specific Lesions 
Bone Lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.

Blastic bone lesions are non-measurable. 


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


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


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


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Confirmation of Tumor Response 
Confirmation of response is required for non-randomized trials with primary endpoint 
of response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data.
Determination of Overall Response by RECIST version 1.1
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in
Table 5.
Table 5.
Response Evaluation Criteria in Solid Tumors
Target 
lesions
Non-target 
lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-P
D
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Best Overall Response
The best overall response is determined once all the data for the patient is known. Best 
response in trials in which confirmation of complete or partial response is not required 
(ie, randomized trails) is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment 


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has a best overall response of PR). When SD is believed to be the best response, it must also 
meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD. The 
same patient lost to follow-up after the first SD assessment would be considered inevaluable. 
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  Complete or partial responses may be claimed only if the criteria for each 
are met at a following time point as specified in the protocol (generally 4 weeks later).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the 
indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.


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Appendix 4. NCI International Response Criteria for Non-Hodgkin Lymphoma
A. Introduction
Response criteria for Non-Hodgkin Lymphoma (NHL) are based on the 1999 NCI 
International Workshop to standardize response criteria for NHL and recent updates to these 
criteria reported in 2007.  These updates incorporate additional technologies and 
assessments, which have become more widely available and have demonstrated predictive 
value.  The updates also eliminate a commonly misinterpreted response category.  Response 
criteria are based on assessments of tumor measurements and clinical findings.
B. Required Assessments
The following assessments are required at screening/baseline and at each subsequent time 
point required in the protocol:
1. Objective tumor measurements.
2. Clinical assessment including ECOG score, “B-symptoms,” (eg, fever, night sweats, 
weight loss) and liver and spleen size.
3. Bone marrow biopsies (or aspirates if biopsies were not obtainable), preferably 
bilateral, optimally of at least 20 mm in aggregate.  Note:  A bone marrow biopsy 
must be performed only to confirm a complete response (CR) if initially positive, or if 
clinically indicated by new abnormalities in the peripheral blood counts or blood 
smear.
4. Biochemical markers if definitely assignable to NHL (eg, lactate dehydrogenase).
C. Methods of Measurement
1. Computed tomography (CT) will be used to measure index lesions selected for 
response assessment; MRIs may be used if CT scans are not available or if the patient
cannot tolerate CT scans (eg, are intolerant of CT contrast media).  Positron emission 
tomography (PET) using [18F] fluorodeoxyglucose (FDG), when available, should 
also be considered together with CT results.  Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously.  Spiral CT 
should be performed by using an 8-mm or less contiguous reconstruction algorithm.  
CT scans of the chest, abdomen, and pelvis are required for each assessment.
Note:  A CT scan of the neck should be obtained if cervical disease is present.
2. Lesions on standard radiographs are not acceptable as measurable lesions.
3. All measurements should be taken and recorded in metric notation, using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 


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beginning of the investigational product treatment and never more than 4 weeks 
before the beginning of treatment.
4. The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at screening/baseline and during the 
study.
5. Lesions noted on physical examination, such as skin nodules and lymph nodes, will 
be considered measurable only if they are superficial and are 10 mm at initial 
assessment.  As often as possible, the same investigator using the same method of 
measurement should assess these lesions at all visits.
D. Baseline Documentation of “Index” and “NonIndex” Lesions
1. Up to a maximum of 6 of the largest dominant lesions should be identified and 
recorded as Index lesions and measured at baseline.  These nodes or masses should 
be selected according to the following features:

They should be clearly measurable in at least 2 perpendicular dimensions;

They should be from as disparate regions of the body as possible;

They should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved; and

They should be suitable for accurate repeated measurements (eg, relationship to 
identifiable landmarks).
2. The product of the longest transverse diameter and the longest perpendicular 
transverse diameter will be recorded for all Index lesions.  The sum of the product 
diameters (SPD) for all Index lesions will be calculated and reported as the baseline 
SPD.  The baseline individual product diameters and the baseline SPD will be used as 
the references by which the objective tumor response will be characterized.
3. All other lesions (or sites of disease) should be identified as NonIndex lesions and 
must also be recorded at baseline.  Both nodal and non-nodal (eg, masses present in 
the liver and/or spleen) are recorded.  Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout the study.
E. Response Criteria
1. Complete Response (CR) requires the following:
a.
Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease-related symptoms if present before 
therapy.


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b. All lymph nodes and nodal masses must have regressed on CT to normal size 
(1.5 cm in their greatest transverse diameter for nodes >1.5 cm before therapy).  
Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more 
than 1.0 cm in their short axis before treatment must have decreased to 1 cm in 
their in their short axis after treatment.  NOTE for PET scans: for patients with no 
pretreatment PET scan or when a PET scan was positive before treatment, a 
post-treatment residual mass of any size is permitted as long as it is PET negative.
c.
The spleen, if considered to be enlarged before therapy on the basis of a CT scan, 
must have regressed in size and must not be palpable on physical examination.  
Any macroscopic nodules in any organs detectable on imaging techniques should 
no longer be present.  Other organs considered to be enlarged before therapy as a 
result of involvement by lymphoma such as liver and kidneys, must have 
decreased in size.
d. If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy of the same site.  The 
sample on which this determination is made must be adequate (20 mm biopsy 
core).  If a sample is indeterminate by morphology, it should be negative by 
immunohistochemistry.  A sample that is negative by immunohistochemistry but 
that demonstrates a small population of clonal lymphocytes by flow cytometry 
will be considered a CR until data become available demonstrating a clear 
difference in patient outcome.
2. Partial Response (PR) requires the following:
a.
50% decrease in SPD of the six largest dominant nodes or nodal masses.
b. No increase in the size of other nodes, liver, or spleen.
c.
Splenic and hepatic nodules must regress by 50% in the SPD, or for single 
nodules, in the greatest transverse diameter.
d. With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present.
e.
Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive, the cell type 
should be specified in the report (eg, large-cell lymphoma, or low-grade 
lymphoma such as small, lymphocytic small cleaved, or mixed small and 
large cells).  Patients who achieve a CR by the above criteria, but who have 
persistent morphologic bone marrow involvement will be considered partial 
responders.  When the bone marrow was involved before treatment and a 
clinical CR was achieved, but with no bone marrow assessment after 
treatment, patients should be considered partial responders.


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f.
No new sites of disease.
g. NOTES for PET: For patients with follicular, diffuse large B-cell, or 
mantle-cell lymphomas (ie, typically FDG-avid lymphomas) and with no 
pretreatment PET scan or with a positive pretreatment PET scan, the 
post-treatment PET should be positive in at least one previously involved site.  
For patients with other NHLs (ie, variably FDG-avid lymphomas/FDG-avidity 
unknown) and without a pretreatment PET scan, or if a pretreatment PET scan 
was negative, CT criteria should be used.  In patients with follicular or 
mantle-cell lymphomas, a PET scan is only indicated with one or at most two 
residual masses that have regressed by more than 50% on CT; those with 
more than two residual lesions are unlikely to be PET negative and should be 
considered partial responders.
3. Stable disease (SD) is defined as less than a PR (see above) but is NOT progressive 
disease (see below, progressive disease).
a. NOTES for PET: For patients with follicular, diffuse large B-cell, or 
mantle-cell lymphomas (ie, typically FDG-avid lymphomas), the PET should 
be positive at prior sites of disease with no new areas of involvement on the 
post-treatment CT or PET.  For patients with other NHLs (ie, variably 
FDG-avid lymphomas/FDG-avidity unknown) and without a pretreatment 
PET scan or with a negative pretreatment PET, there must be no change in 
the size of the previous lesions on the post-treatment CT scan.
4. Relapsed disease (after CR)/ Progressive disease (after PR or SD) requires the 
following:
a.
NOTE: Lymph nodes should be considered abnormal if the long axis is more 
than 1.5 cm regardless of the short axis.  If a lymph node has a long axis of 
1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more 
than 1.0 cm.  Lymph nodes 1.0 1.0 cm will not be considered as 
abnormal for relapse or progressive disease.
b. Appearance of any new lesion more than 1.5 cm in any axis during or at the 
end of treatment, even if other lesions are decreasing in size.  NOTE for PET: 
Increased FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with other 
modalities.
c.
At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (eg, splenic or 
hepatic nodules).  To be considered progressive disease, a lymph node with a 
diameter of the short axis of less than 1.0 cm must increase by 50% and to a 
size of 1.5 1.5 cm or more than 1.5 cm in the long axis.


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d. At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis.
e.
NOTE for PET: Lesions should be PET positive if observed in a typical 
FDG-avid lymphoma (ie, follicular, diffuse large B-cell, or mantle-cell 
lymphomas) or the lesion was PET positive before treatment unless the lesion 
is too small to be detected with current PET systems (<1.5 cm in its long axis 
by CT).
f.
NOTE: Measurable extranodal disease should be assessed in a manner similar 
to that for nodal disease.  For these recommendations, the spleen is considered 
nodal disease.  Disease that is only assessable (eg, pleural effusions, bone 
lesions) will be recorded as present or absent only, unless, while an 
abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative.
Evaluation of Non-Index Lesions: Although a clear progression of "Non Index" 
lesions only is exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be confirmed later by 
the review panel.


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Response Criteria for Non-Hodgkin Lymphoma
Response Category
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance 
of all evidence 
of disease
Regression to 
normal size on 
CTa
Not palpable, 
nodules 
disappeared
infiltrate 
cleared on 
repeat biopsyb
PR
Regression of 
measurable 
disease and no 
new sites
50% decrease 
in SPD of 6 
largest dominant 
masses; no 
increase in size 
of other nodesc
50% decrease 
in SPD of 
nodules;d no 
increase in size 
of liver or 
spleen
Irrelevant if 
positive 
pretreatment; 
cell type 
should be 
specified
SD
Failure to attain 
CR, PR or 
progressive 
disease
On CT: no new 
sites; no change 
in size of 
previous 
lesionse
Relapsed or
Progressive 
Disease
New lesion or 
increase by 
50% of 
previously 
involved sites 
from nadir
New lesion(s) 
>1.5 cm (any 
axis); 50% 
increase in SPD 
of >1 node; or 
50% increase 
in longest 
diameter of 
previously 
identified node 
>1 cm in short 
axisf
>50% increase 
from nadir in 
the SPD of any 
previous
lesions
New or 
recurrent 
involvement
Reference: Cheson DB, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al.  Revised Response 
Criteria for Malignant Lymphomas. J Clin Oncol. 2007; 25: 579-586.
a.
For FDG-avid lymphomas (ie, follicular, diffuse large B-cell, or mantle-cell) with PET scan positive before 
treatment, post-treatment mass of any size permitted if PET negative.
b.
If indeterminate by morphology, immunohistochemistry should be negative.
c.
For FDG-avid lymphomas (ie, follicular, diffuse large B-cell, or mantle-cell) with PET scan positive before 
treatment, 1PET positive at previously involved site.
d.
For single nodule, 50% decrease in greatest transverse diameter.
e.
For FDG-avid lymphomas (ie, follicular, diffuse large B-cell, or mantle-cell), PET positive at prior sites of 
disease and no new sites on CT or PET.  For variably FDG-avid lymphomas/FDG-avidity unknown (ie, 
other NHLs) and negative pretreatment PET, no change in the size of the previous lesions on CT.
f.
Lesions PET positive if typical FDG-avid lymphoma (ie, follicular, diffuse large B-cell, or mantle-cell 
lymphomas) or PET positive before treatment.
Abbreviations: CR = complete response; CT= computed tomography; FDG = [18F]fluorodeoxyglucose;
NHL = Non-Hodgkin lymphoma; PET = positron emission tomography; PR = partial response;
SD = stable disease; SPD = sum of the product diameters.


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F. Response Evaluation
1. Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of progressive disease at that time should be 
classified as having "symptomatic deterioration."  Every effort should be made to 
document the objective progression even after discontinuation of treatment.
2. Evaluation of Best Overall Response: The best overall response is the best response 
recorded from the start of the treatment until progressive disease/recurrence (taking as 
reference for progressive disease, the smallest measurements recorded since the 
treatment started).
3. To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed 4 weeks after the criteria 
for response are first met.
G. Duration of Response
1. Overall Response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever status is recorded first) until 
the first date that recurrence or progressive disease is objectively documented, taking 
as reference for progressive disease the smallest measurements recorded since the 
treatment started.
2. Stable Disease: SD is measured from the start of the treatment until the criteria for 
progressive disease are met, taking as reference the smallest measurements recorded 
since the treatment started.  The minimal time interval for duration of SD is 4 weeks.
3. Time to Progression: Time to progression is the interval from the start of the 
treatment until the first date that recurrence or progression, or death secondary to 
progression is documented, censored at the last evaluation.


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Appendix 5. Reduced Schedule of Activities
After IRB/EC approval of Amendment 5, Table 6 provides an overview of the reduced 
required Schedule of Activities. Refer to STUDY PROCEDURES and ASSESSMENTS
sections of the protocol for detailed information on each procedure and assessment required 
for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
reduced Schedule of Activities in order to conduct evaluations or assessments required to 
protect the well-being of the patient.
Sufficient study medication for a maximum of 6 cycles of treatment will be dispensed at each 
clinic visit.  During the non-clinical visit cycles, the investigator is responsible for ensuring 
the patient contacts the clinical site in order to provide an update of adverse events and 
concomitant medications. Reduced hematology and blood chemistry laboratory tests will 
still be required on Day 1 of the non-clinical visit cycles (see Table 6). Of note, post-study 
survival status will no longer be collected after IRB/EC approval of Amendment 5.
Table 6.
Reduced Schedule of Activities
Protocol Activities
Study Treatment [1]
End of Treatment
Visits on Day 1 of every 6 Cycles
(maximum interval allowed) (4
days; except as noted below)
End of 
Txt/Withdrawal[2]
Post Txt 
Follow-up
Physical Examination [3]
X
X
Blood Pressure and Pulse Rate
X
X
Ophthalmologic Examination[4]
X
Laboratory Studies
Dipstick Urinalysis and Reflex 
Microscopy[6]
X (Korea only)
All other countries: as clinically 
indicated
X (Korea only)
Hematology [5]
Day 1 of alternate cycles (4 days)
X
Blood chemistry and LFTs:
ALT/AST/alkaline phosphatase/total 
bilirubin/creatinine[5]
Day 1 of each cycle (4 days )
X
Pregnancy Test (as appropriate)[7]
Day 1 of each cycle (4 days )
X
Contraceptive check[8]
Day 1 of each cycle (4 days )
X
Disease Assessments
Radiographic studies for tumor 
assessment[9]
As per local clinical practice
Other Clinical Assessments
Adverse Events[10]
X
X
X
Concomitant 
Medications/Treatments[11]
X
X
Study Treatment  
Crizotinib
Twice daily
Special Laboratory Studies
Optional Tumor Tissue for 
Molecular Profiling[12]
X


Crizotinib (PF-02341066)
A8081013
Final Protocol Amendment 5, 13 August 2015
PFIZER CONFIDENTIAL
Page 82
Footnotes for Schedule of Activities
1.
All assessments should be performed prior to dosing with study medications unless otherwise indicated.  All cycles are 
3 weeks in duration. Sufficient study medication for a maximum of 6 cycles of treatment will be dispensed at each 
clinic visit.  During the non-clinical visit cycles, the Investigator is responsible for ensuring the patient contacts the 
clinical site in order to provide an update of adverse events and concomitant medications. 
2.
End of Treatment/Withdrawal: Obtain blood pressure, pulse rate, hematology and LFTs, and physical examination if 
not completed during the previous 4 weeks on study.
3.
Physical Examination: Includes an examination of major body systems and weight.
4.
Ophthalmologic Examination: Includes visual acuity, slit lamp, and fundoscopy, and should be performed by an 
ophthalmologist.  The ophthalmologic examination should be repeated during the study when visual disturbances have 
been observed and when there is an increase in the grade for visual disturbances.  
5.
Hematology, Liver function tests and Urinalysis: Required tests are listed in Table 7. 
Where possible, laboratory tests should be performed preferably at the clinical site’s local laboratory, and, when not 
possible, patients will provide the laboratory test results copy (from the non-clinical site laboratory), eg, by telephone,
and bring a copy of the laboratory test results at the visit; process depends on local medical practice.  The copy of the 
laboratory test results must be retained in the patient’s file at the clinical site for documentation purposes.  If ALT or 
AST Grade 3 or ALT or AST Grade 2 and total bilirubin Grade 2, obtain repeat ALT or AST and total bilirubin 
within 48 hours and then repeat every 48-72 hours until ALT/AST Grade 1.
6.
Reflex Microscopy required if urine dipstick is positive for blood or protein.
7.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of 
at least 25 mIU/mL, will be routinely performed at every cycle during the active treatment period, at the end of study
treatment, and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics 
committee (IRB/ECs) or if required by local regulations.
8.
Contraceptive Check: Male patients who are able to father children and female patients who are of childbearing 
potential will need to affirm that they meet the criteria for correct use of at least 2 of the selected methods of 
contraception.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective 
contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, 
the investigator or his or her designee will instruct the patient to call immediately if aone or both selected 
contraception methods is are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner. 
9.
Tumor Assessments: Will be repeated at the frequency as per local clinical practice, and will no longer be recorded on 
the CRF. However, tumor assessment information should be retained in the patient’s file for documentation purposes.
10. Adverse Events: For serious adverse events, the active reporting period to Pfizer or its designated representative 
begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation 
in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and 
including 28 calendar days after the last administration of the investigational product.  Adverse events (serious and 
non-serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least one dose 
of investigational product through the patient’s last visit.
11. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded up to 28 days post 
the last dose of study treatment.  
12. Tumor Tissue for Molecular Profiling:  Sample will be sent to central laboratory (see Section 7.5).  An optional fresh 
tumor sample will be collected at the end of treatment if a patient discontinues due to disease progression.


Crizotinib (PF-02341066)
A8081013
Final Protocol Amendment 5, 13 August 2015
PFIZER CONFIDENTIAL
Page 83
Table 7.
Reduced Laboratory Tests
Conventional Units
Conversion Factor
SI Units
Hematology
Hemoglobin (Hgb)
g/dL
x 10
g/L
Platelet count (Plt)
103/mm3
x 109
1012/L
White blood count (WBC)
103/mm3
x 106
109/L
White blood cell differential
%
x 0.01
fraction
Liver Function Tests
Total bilirubin
mg/dL
x 17.1
mol/L
Alanine transaminase (ALT)
U/L
N/A
U/L
Aspartate transaminase (AST)
U/L
N/A
U/L
Alkaline phosphatase
U/L
N/A
U/L
Creatinine
mg/dL
x 88.4
mol/L
In cases of suspected Drug Induced 
Liver Injury (DILI) as described in 
Section 8.6.2, values to be reported on 
SAE form
Creatine kinase (CPK)
U/L
N/A
U/L
Indirect bilirubin
mg/dL
x 17.1
mol/L
Direct bilirubin
mg/dL
x 17.1
mol/L
Gamma-glutamyl transferase (GGT)
U/L
N/A
U/L
Urinalysis
Dipstick and Reflex Microscopy
(unitless)
N/A
(unitless)

SAP_001.pdf: 
Protocol A8081013 
Statistical Analysis Plan 
Version 3.0 – 15June2019 
Page 1 of 18 
This Document is Company Confidential 
 
 
 
 
 
 
Protocol A8081013 
 
 
 
PHASE 1B OPEN-LABEL STUDY OF THE SAFETY 
AND CLINICAL ACTIVITY OF CRIZOTINIB (PF- 
02341066) IN TUMORS WITH GENETIC EVENTS 
INVOLVING THE ANAPLASTIC LYMPHOMA 
KINASE (ALK) GENE LOCUS 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
Version: 
3.0 
 
Author: 
PPD 
 
 
 
Date: 
15th June 2019 


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Statistical Analysis Plan 
Version 3.0 – 15June2019 
Page 2 of 18 
This Document is Company Confidential 
 
 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 3 
1. AMENDMENTS FROM PREVIOUS VERSION(S) ............................................................ 4 
2. INTRODUCTION .................................................................................................................. 4 
2.1. Study Design .............................................................................................................. 5 
2.2. Study Objectives ........................................................................................................ 5 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING .................................. 5 
4. HYPOTHESES AND DECISION RULES ........................................................................... 6 
4.1. Statistical Hypotheses ................................................................................................ 6 
4.2. Statistical Decision Rules .......................................................................................... 6 
5. ANALYSIS SETS .................................................................................................................. 6 
5.1. Full Analysis Set ........................................................................................................ 6 
5.2. Safety Analysis Set .................................................................................................... 6 
5.3. Response Evaluable Analysis Set .............................................................................. 7 
5.4. Other Analysis Sets .................................................................................................... 7 
5.4.1. PK Analysis Set ............................................................................................ 7 
5.4.2. Molecular Profiling Set ................................................................................. 7 
5.5. Treatment Misallocations .......................................................................................... 7 
5.6. Protocol Deviations ................................................................................................... 7 
6. ENDPOINTS AND COVARIATES ...................................................................................... 8 
6.1. Efficacy Endpoint(s) .................................................................................................. 8 
6.2. Safety Endpoints ...................................................................................................... 11 
6.3. Other Endpoints ....................................................................................................... 11 
6.3.1. PK Endpoints .............................................................................................. 11 
6.3.2. Molecular Profiling Endpoints .................................................................... 11 
7. HANDLING OF MISSING VALUES ................................................................................ 11 
7.1. Missing PK Data ...................................................................................................... 12 
7.1.1. Concentrations Below Limit of Quantification ........................................... 12 
7.1.2. Deviations, Missing Concentrations and Anomalous Values ..................... 12 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ........................... 12 
8.1. Statistical Methods .................................................................................................. 12 
8.1.1. Analyses of Time-to-Event Endpoints ........................................................ 12 
8.1.2. Analyses of Binary Endpoint ...................................................................... 13 


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8.1.3. Analyses of Continuous Data ...................................................................... 13 
8.1.4. Analyses of Categorical Data ...................................................................... 13 
8.2. Statistical Analyses .................................................................................................. 13 
8.2.1. Primary Analysis ......................................................................................... 13 
8.2.2. Secondary Analyses .................................................................................... 13 
8.2.3. Safety Analyses ........................................................................................... 14 
8.2.4. Baseline Characteristics and Other Summaries ........................................... 17 
8.2.5. Analyses of Pharmacokinetic Endpoints ..................................................... 17 
8.2.6. Analyses of Molecular Profiling ................................................................. 17 
9. REFERENCES ..................................................................................................................... 18 
LIST OF TABLES 
Table 1. 
Probability of Observing Toxicity Given True Underlying Event Rates ................ 6 


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The changes from version 2.0 are: 
• Modified definitions of first tumor response date and PD date for PFS based on in 
consideration of tumor response data collection timing by RECIST or NCI 
International Response Criteria for Non-Hodgkin Lymphoma (Cheson criteria). 
• Clarified the definition of duration of response. 
• Clarified the on-treatment period time window. 
• Clarified the definition of treatment-emergent adverse event. 
• Modified the subgroups based on tumor types. 
• Added data presentation for pediatric patients. 
The changes from version 1.0 are: 
• Clarified use of RECIST vs. NCI International Response Criteria for Non-Hodgkin 
Lymphoma (Cheson criteria) in definition of tumor response. 
• Clarified timing of the final and other analyses. 
• Added the response evaluable analysis set and definition of “adequate baseline”. 
• Updated definitions of PFS and duration of response. 
• Updated definition of treatment emergent adverse events. 
• Modified Sections 8.2.3 and 8.2.6 to remove analyses that are no longer planned. 
• Safety will be analyzed by tumor group and overall. 
• Specified that all safety and efficacy data will be analyzed by tumor group 
(lymphomas, inflammatory myofibroblastic tumors [IMT], other tumors). 
• Included minor editorial clarifications and corrections to enhance clarity of the 
document. 
2. INTRODUCTION 
This document describes the planned statistical analyses for protocol A8081013 dated March 
25, 2010 and all subsequent protocol amendments (latest Amendment 5, dated August 13, 
2015). This analysis plan is meant to supplement the study protocol. Any deviations from 
this analysis plan will be described in the Clinical Study Report. 


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2.1. Study Design 
This is an open-label, multi-center, single arm exploratory trial of an oral agent, crizotinib, in 
patients with advanced malignancy other than NSCLC with tumors harboring a translocation, 
inversion, mutation or amplification event involving the ALK gene locus. 
Only ALK genetic event positive patients as determined by the investigative site may enter 
the study. ALK translocation/fusion, amplification, mutation and overexpression can be 
assessed by using any of the available technologies including fluorescence in-situ 
hybridization (FISH), immunohistochemistry (IHC), quantitative Polymerase Chain Reaction 
(qPCR), quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR), array 
Comparative Genomic Hybridization (aCGH) or direct sequencing. 
Crizotinib (PF-2341066), 250 mg BID, will be administered orally at approximately the same 
time each day on a continuous daily dosing schedule, ie, no break in dosing. Crizotinib may 
be taken without regard to meals. Cycles are defined in 21-day periods to facilitate 
scheduling of visits and assessments. 
At least 40 patients are expected to be enrolled into this trial. The sample size may be 
adjusted based on the number of patients identified and safety or evidence of antitumor 
activity within patient groups. 
Patients may continue treatment with crizotinib on this trial as long as there is evidence of 
clinical benefit in the judgment of the investigator. 
2.2. Study Objectives 
Primary Objective: 
• Assess the safety of oral single-agent crizotinib administered to patients with 
advanced ALK-positive anaplastic large cell lymphoma (ALCL) or other advanced 
malignancy other than NSCLC known to have an ALK genetic event and screen for 
efficacy in these patients. 
Secondary Objectives: 
• To determine PK in this patient population using population PK (POPPK) methods 
and explore correlations between PK, response and/or safety findings. 
• To correlate ALK genetic events to efficacy outcome measures including PFS 
and OS. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No formal interim analysis is planned for this study. 


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Internal procedures for periodic safety review will be adopted. Findings of the periodic 
safety reviews, according to Sponsor procedures will be documented in the project files and 
action taken as appropriate. Findings having immediate implication for the management of 
patients on study will be communicated to all principal investigators in the timeframe 
associated with unexpected and drug-related SAEs. 
Unblinding is not applicable. 
The final analysis will be performed after the last patient last visit; however, earlier analyses 
of the data may be performed for publication and regulatory reporting purposes. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
There are no formal statistical hypotheses for this study. 
4.2. Statistical Decision Rules 
As the primary objective of this study is to assess the safety of oral, single agent crizotinib 
administered to patients with ALK-positive ALCL or other advanced malignancy (other than 
NSCLC) known to have an ALK genetic event and screen for efficacy in these patients, no 
statistical decision rules were set. The sample size for this study is determined empirically 
based on expected small numbers of patients in the population of interest. It is anticipated 
that a total of approximately 40 patients will be enrolled in this study. 
The table below shows the probability of observing toxicity with different sample sizes given 
various true underlying toxicity rates. For example, with 40 patients, the probability of 
observing toxicity occurring at least 5% of the time is 87%. 
Table 1. 
Probability of Observing Toxicity Given True Underlying Event Rates 
 
True Underlying Toxicity Rate 
Sample Size 
5% 
10% 
15% 
N=10 
0.40 
0.65 
0.80 
N=20 
0.64 
0.88 
0.96 
N=30 
0.79 
0.96 
0.99 
N=40 
0.87 
0.99 
1.00 
5. ANALYSIS SETS 
5.1. Full Analysis Set 
The Full Analysis (FA) set includes all enrolled patients. This population may be employed 
in evaluating patient disposition. 
5.2. Safety Analysis Set 
The safety analysis (SA) set will include all patients enrolled who receive at least one dose of 
study medication. 


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This will be the primary set for summaries of demographics, safety, summaries of time-to- 
event efficacy data, and treatment evaluations. 
5.3. Response Evaluable Analysis Set 
The response evaluable (RE) analysis set will include all patients in the safety analysis set 
who have an adequate baseline tumor assessment by either RECIST 1.11 or Cheson2 criteria. 
This will be the primary set for evaluating all response related efficacy evaluations. 
The following must be met to qualify for “Adequate Baseline” assessment: 
• Baseline assessments of all lesions (target, and non-target) must be within 35 days, 
per protocol. 
• All lesions recorded at baseline must have an associated status recorded on the eCRF. 
• At least one target lesion present at baseline. 
• Baseline lesions must be assessed with an acceptable method of tumor assessment as 
specified in the protocol and could include: CT Scan, MRI, Bone Scan 
(for confirmation of bone metastases). 
5.4. Other Analysis Sets 
5.4.1. PK Analysis Set 
All patients in the SA set who have at least one PK blood sample will be included in the 
pharmacokinetic analysis set. 
5.4.2. Molecular Profiling Set 
All patients in the SA set with at least one data of molecular profiling will be included in the 
molecular profiling (MP) set. 
5.5. Treatment Misallocations 
As in this study there is only one treatment arm, treatment misallocations are not applicable. 
Patients enrolled that do not receive any dose of crizotinib will be counted in the full analysis 
set only and will be described in patient disposition. 
5.6. Protocol Deviations 
Patients who don’t receive any study medication will be excluded from all analyses, but will 
be described in patient disposition. 
Patients without measurable disease at baseline will not be evaluated for Overall Response 
Rate. 
Patients who are enrolled in the study but are later found to not have an ALK genetic event 
may be presented separately. 


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All deviations will be described when they appear and related to the statistical summaries or 
population, prior to database closure. They will be recorded in the protocol deviation log. 
6. ENDPOINTS AND COVARIATES 
For purposes of efficacy and safety endpoint definitions, the term “on-treatment” includes the 
period from the first dose of study treatment until and including 28 days after the last dose of 
study medication, or start of new anti-cancer drug therapy including transplant, whichever 
occurs first [minimum (28 days + last dose of study treatment, start day of new anti-cancer 
drug therapy – 1 day)]. 
For purposes of censoring definitions for time to event endpoints, “anti-tumor treatment” 
includes any anticancer therapy (other than study medication), radiation to target or 
non-target lesions and surgery for removal of target or non-target lesions. 
Analyses of endpoints dependent on disease assessments (ORR, PFS and DR) will be based 
on investigator assessment of tumor data according to RECIST 1.11 or the NCI International 
Response Criteria for Non-Hodgkin’s Lymphoma2 (Cheson criteria). 
Protocol Amendment 3 modified the collection of tumor response data to use Cheson criteria 
to determine tumor response for Non-Hodgkin Lymphoma (NHL) patients. Patients with 
solid tumors continued to have response reported using RECIST 1.1. Since this change was 
made after patients had been enrolled and treated in the study, NHL patients may have tumor 
response collected by either RECIST 1.1 only, Cheson criteria only, or both (ie, both 
RECIST and Cheson criteria results are reported at the same visits, RECIST results are 
reported at some visits and Cheson criteria results reported at other visits). The following 
conventions will be followed when reporting response for these patients: 
• If both RECIST and Cheson Criteria results are present then Cheson criteria results 
should be used to report BOR unless the Cheson has Indeterminate result, in which 
case the RECIST result will be reported. If only RECIST or only Cheson criteria 
results are present then BOR will be reported based on only RECIST or only Cheson 
criteria, respectively. 
• If results from either Cheson or RECIST criteria are reported at baseline, patients will 
still be considered to meet the criteria for adequate baseline tumor assessment. 
In this study two primary endpoints were defined: type, incidence, severity, seriousness and 
relationship to study medications of adverse events (AE) and any laboratory abnormalities 
for safety, and overall response rate (ORR) for efficacy. 
6.1. Efficacy Endpoint(s) 
Efficacy endpoints will be summarized in the RE or SA population, as described below for 
each endpoint, by tumor type: ALCL, inflammatory myofibroblastic tumors (IMT), or other 
tumor. All efficacy endpoints will be listed. 


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• Overall Response Rate (ORR) is the primary efficacy endpoint. It is defined as the 
percent of patients with confirmed complete response (CR) or confirmed partial response 
(PR) according to RECIST (1.1) as determined by the investigators, relative to patients in 
the RE set. ORR based on Cheson criteria is defined similarly however, confirmation of 
response is not required. If patient has tumor response assessed only by RECIST or 
Cheson, then ORR is based on the single result. If tumor response is assessed by both 
RECIST and Cheson, then ORR is reported based on tumor response by Cheson criteria 
unless the Cheson has indeterminate result, in which case the RECIST result will be 
reported. 
Patients will be considered non responders until proven otherwise. Thus, patients who: 
• Do not have CR or PR while on treatment, or 
• Do not have a post-baseline tumor evaluation, or 
• Receive anti-tumor treatment other than the study medication prior to reaching a CR 
or PR, or 
• Die, progress, or drop out for any reason prior to reaching a CR or PR, will be 
counted as non-responders in the assessment of ORR. 
To be assigned a status of PR or CR using RECIST 1.1 criteria, changes in tumor 
measurements in patients with responding tumors must be confirmed by repeat tumor 
assessment that should be performed at least 4 weeks after the criteria for response are 
first met. Confirmation of response is not required for status of PR or CR using Cheson 
criteria. If a patient has not achieved an objective response, but remains stable for at least 
6 weeks after first dose, then the best overall response for such a patient will be stable 
disease. 
• Progression Free Survival (PFS) is defined as the time from the date of first dose of 
study medication to the date of the first documentation of objective tumor progression or 
death on treatment due to any cause, whichever occurs first. If tumor progression data 
include more than 1 date, the first date will be used. PFS (in weeks) will be calculated as 
(date of first event − date of first dose +1)/7.0. PFS will be summarized for the SA set. 
Tumor assessments will be performed within a time window of ± 7 days around the 
scheduled visits (at Screening, Day 1 of Cycle 3 and every 2 cycles thereafter). 
Unscheduled scans may be performed to confirm response (≥4 weeks after initial 
assessment of response) and when disease progression is suspected. If PD is documented 
between scheduled visits, the actual date of progression will be used as an un-censored 
value in the analysis of PFS. If PD is reported by both RECIST 1.1 and Cheson criteria, 
then the earliest date of PD by either RECIST or Cheson criteria will be used in PFS 
calculation. Otherwise the date of PD by either RECIST 1.1 (if all tumor assessments are 
by RECIST 1.1) or Cheson criteria (if all tumor assessments are by Cheson criteria) will 
be used. 


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Patients with inadequate baseline assessments will have their event time censored on the 
date of first dose of study medication. Patients lacking an evaluation of tumor response 
after first dose or for whom the first on-treatment tumor evaluation occurs more than 
14 weeks after first dose, will also have their event time censored on the date of first dose 
unless death occurs ≤ Week 14 (in which case the death is an event). 
If patients have at least 1 on-treatment disease assessment, PFS data will be censored on 
the date of the last evaluable on-treatment tumor assessment by either RECIST 1.1 or 
Cheson criteria documenting absence of progressive disease for patients: 
• Who are alive, on treatment and progression free at the time of the analysis; 
• Who discontinue treatment without documented disease progression and who do not 
progress or die on treatment; 
• Who have documentation of disease progression or death >14 weeks after the last on- 
treatment tumor assessments; 
• Who are given anti-tumor treatment other than the study medication while on 
treatment and prior to documented disease progression or death on treatment. In this 
case, the last evaluable assessment prior to start of the anti-tumor treatment will be 
used. One exception to this rule is for patients who have documented PD or death 
within 14 days of anti-cancer therapy, the PD or death will be considered an event. 
•  Duration of Response (DR) is defined as the time from the first documentation of 
objective tumor response (CR or PR) to the first documentation of objective tumor 
progression or to death on treatment due to any cause, whichever occurs first. If patient 
has tumor response assessed only by RECIST or Cheson, the first objective tumor 
response date will be based on single result of either RECIST 1.1 or Cheson criteria 
(note: RECIST 1.1 results should be subsequently confirmed but Cheson criteria do not 
require response confirmation). If tumor response is reported by both RECIST 1.1 and 
Cheson criteria, the earliest date of tumor response by either RECIST or Cheson criteria 
will be used. DR (in weeks) will be calculated as (first date of PD or death − first date of 
CR or PR as defined above+1)/7.0. If the tumor progression data include more than 
1 date, the first date will be used. First date of PD will be defined the same as for PFS. 
Censoring for DR is identical to the censoring rules presented for PFS when patients have 
at least 1 on-treatment disease assessment. DR will only be calculated for the subgroup 
of patients with an objective tumor response. Summary statistics will be provided for 
patients with or without subsequent PD/death. Analysis for DR will also be done for 
patients with CR or PR separately. 
• Overall Survival (OS) is defined as the time from the date of first dose of study 
medication to the date of death due to any cause. OS (in months) is calculated as (date of 
death − date of first dose +1)/30.42. For patients still alive at the time of the analysis, for 
those who are lost to follow-up, and those who withdraw consent for additional 
follow-up, the OS will be censored on the last date that patients were known to be alive. 


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Patients lacking data beyond the first dose will have their OS censored at the date of first 
dose. OS will be summarized for the SA population. 
• Six Months and One-Year Survival Probability is defined as the probability of 
survival at 6 months and 1 year, respectively, after the date of the first dose based on the 
Kaplan-Meier estimate. 
6.2. Safety Endpoints 
Safety will be summarized for the SA set overall and separately, as applicable, by tumor type 
(ALCL, IMT, other tumors). Type, incidence, severity, seriousness and relationship to study 
medications of AEs and any laboratory abnormalities are the primary endpoint for safety. 
All AEs reported after initiation of treatment (Cycle 1, Day 1) and pre-existing conditions 
that worsen after the initiation of treatment will be considered as treatment emergent 
(Treatment Emergent Adverse Event: TEAE). 
AEs and laboratory measures will be graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. 
6.3. Other Endpoints 
6.3.1. PK Endpoints 
Plasma concentrations of Crizotinib. 
6.3.2. Molecular Profiling Endpoints 
Molecular profiling outcomes include one or more of the following: 
• ALK translocation /fusions; 
• ALK mutation; 
• ALK gene amplification; 
• ALK protein expression. 
If available, the tumor tissue from surgery or biopsy pre and post treatment will be used to 
determine possible mechanisms for resistance to PF-02341066 treatment. 
7. HANDLING OF MISSING VALUES 
In compliance with Pfizer standards, for start date, if the day of the month is missing for any 
date used in a calculation, the 1st of the month will be used to replace the missing date unless 
the calculation results in a negative time duration (eg, date of onset cannot be prior to day 
one date). In this case, the date resulting in 0 time duration will be used. Pfizer standards are 
also used if both month and day are missing (Jan 1 unless negative time duration). However, 
for to/end dates, last of the month and day are used for partial dates. 


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If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date. For primary and secondary efficacy 
analyses, no values will be imputed for missing data, except as specified in Section 6, where 
for time to event endpoints, non-event observations will be censored and for ORR, where 
patients with no post-baseline tumor evaluations will be counted as non-responders. 
7.1. Missing PK Data 
7.1.1. Concentrations Below Limit of Quantification 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings, BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification. 
7.1.2. Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, summary statistics will be calculated having 
set concentrations to missing if one of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is more than 10% from the nominal time or a 
concentration has been flagged anomalous by the pharmacokineticist. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods 
Due to the exploratory nature of this study, no confirmatory inferential analyses are planned. 
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration, efficacy endpoints, safety parameters, PK and biomarker variables. 
Pediatric patients (<18 years) will be listed separately for ALCL and IMT in baseline 
characteristics, treatment administration, efficacy endpoints, safety parameters, PK and 
biomarker variables. 
Data will also be displayed graphically, where appropriate. 
8.1.1. Analyses of Time-to-Event Endpoints 
Time-to-event endpoints (PFS, DR and OS) may be summarized, as appropriate, using the 
Kaplan-Meier method3 and displayed graphically when appropriate. Median event times 
(and other quartiles) and 2-sided 95% CIs for each quartile will be provided (Brookmeyer R 
and Crowley JJ4). 
Since the number of patients may limit the use of the Kaplan-Meier method, descriptive 
statistics may be presented (separately for patients who have an event and censored patients). 
Data will be summarized separately by tumor type (ALCL, IMT, other tumors). 


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8.1.2. Analyses of Binary Endpoint 
The rates of binary efficacy endpoints will be calculated and the 95% CI for the rate will be 
provided using the exact method based on the F-distribution. 
Data will be summarized separately by tumor type (ALCL, IMT, other tumors). 
8.1.3. Analyses of Continuous Data 
Descriptive statistics, including the mean, standard deviation, median, minimum, and 
maximum values, will be provided for continuous endpoints. 
Data will be summarized separately by tumor type (ALCL, IMT, other tumors). 
8.1.4. Analyses of Categorical Data 
The number and percentage of patients in each category will be provided for categorical 
variables. 
Data will be summarized separately by tumor type (ALCL, IMT, other tumors). 
8.2. Statistical Analyses 
8.2.1. Primary Analysis 
The best response will be summarized in the RE set which may exclude patients later found 
to not have an ALK genetic event. The number and percent of patients achieving objective 
response (CR or PR; confirmation required for RECIST 1.1) will be summarized with the 
corresponding exact 2-sided 95% CI calculated using a method based on the F distribution. 
Data will be presented by tumor type (ALCL, IMT, other tumors). 
8.2.2. Secondary Analyses 
Data will be presented by tumor type (ALCL, IMT, other tumors). 
• PFS: will be summarized in the SA set which may exclude patients who are found after 
enrolment to not have an ALK genetic event. The Kaplan-Meier method will be used and 
graphs displayed, where appropriate. The Hall Wellner 95% confidence band will be 
provided for individual Kaplan-Meier curve for each tumor type (ALCL, IMT, other 
tumors), as appropriate. The median event time (and other quartiles) and corresponding 
2-sided 95% CIs may be provided. 
• DR: will be summarized in RE set using Kaplan-Meier methods and displayed 
graphically where appropriate. DR will be calculated for the subgroup of patients with 
objective response (confirmation required for RECIST 1.1). The median event time (and 
other quartiles) and 2-sided 95% CI for the median will be provided if appropriate. 
Summary statistics for DR including mean, median, standard deviation, range will be 
provided for patients with and without subsequent progression or death. Summary will 
also be provided by CR and PR. 


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The number of patients experiencing CR and PR may be small and thereby the reliable 
use of the Kaplan-Meier method will be limited and in this case, descriptive statistics or 
listings will be provided. 
• OS: will be summarized in the SA set and estimates of the OS curves obtained from the 
Kaplan-Meier method may be presented. OS curve may also be displayed graphically. 
The Hall Wellner 95% confidence band will be provided for individual Kaplan-Meier 
curve for each tumor type (ALCL, IMT, other tumors), as appropriate. The median (and 
other quartiles) event time and corresponding 2-sided 95% CIs for the median may be 
provided. 
• 6-months and 1-year survival probability: will be estimated using the Kaplan-Meier 
method and a 2-sided 95% confidence interval for the log [-log (1-year survival 
probability)] will be calculated using a normal approximation and then back transformed 
to give a confidence interval for the 6 months and 1-year survival probabilities 
themselves. Survival probabilities for additional time points may also be estimated. 
8.2.3. Safety Analyses 
All safety analyses will be carried out on the SA set and presented by tumor type (ALCL, 
IMT, other tumors), or for overall study patients as appropriate. 
• Adverse events (AEs) - All AEs reported after initiation of treatment and pre-existing 
conditions that worsen after the initiation of treatment will be considered as treatment 
emergent (Treatment Emergent Adverse Event: TEAE). In the case that a patient 
receives new anticancer therapy including transplant, an AE occurring after the 
anticancer therapy start date will not be included in the patient summary but will be 
listed. All AEs will be coded by system organ class (SOC) and preferred term using the 
most recent version of MedDRA. The severity of all AEs will be coded by the 
Investigator using NCI CTCAE Version 4.0. 
An overall summary of AEs will be provided. The number and percentage of patients 
who experienced any AE, any serious adverse event (SAE), any treatment-related AE, 
any treatment-related SAE, grade 3 or 4 AE, grade 5 AE, who had dose reduction 
associated with an AE, and who discontinued because of an AE will be presented. 
Treatment-related AEs are those judged by the Investigator to be at least possibly related 
to study medication or for which relatedness is recorded as “unknown” by the 
Investigator. 
All AEs will be summarized by MedDRA SOC and preferred term (PT). A summary of 
AEs by preferred term and maximum CTCAE grade will be presented. A summary of 
AEs by preferred term and maximum CTCAE grade group 
(Grade 1-2 vs. Grade 3-4 vs. Grade 5) will also be presented. A summary of TEAEs by 
PT (decreasing frequency) will also be presented. The aforementioned summaries will 
also be presented by relationship to study drug. Summary tables may also be generated 
for clustered adverse events which combine several PTs associated with an event of 
interest (eg, events associated with visual disturbance). The clustered events are 
described in a list in the product’s Safety Review Plan maintained by the Sponsor. 


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Summaries of safety data by preferred term and clustered term in descending frequency 
will also be reported overall regardless of tumor type. Patients who experience AEs 
during the AE reporting period will be listed. 
All AEs and treatment related AEs will be presented across all cycles. 
Deaths will be summarized by time period (on-treatment vs. during follow-up) and cause 
of death. Deaths that occurred on or after the first dose of study medication and within 
28 days after the last dose of study medication are defined as on-treatment deaths. Death 
data will also be listed, and the listing will include all deaths that occurred during the 
reporting period for deaths. 
Patients who withdraw from study treatment because of an AE will be listed. Patient 
discontinuation will be determined from the AE CRF page (where action taken is 
“Permanently Discontinued”). Patients who temporarily discontinue study treatment or 
have a dose modification associated with an AE will also be listed. 
Treatment emergent SAEs and treatment-related SAEs will be summarized by MedDRA 
SOC and preferred term. Patients who experienced an SAE during the SAE reporting 
period will be listed. 
• Hematology and Blood chemistry – Hematology and blood chemistry results will be 
graded according to the NCI CTCAE Version 4.0. A summary of worst on treatment 
abnormality and a shift summary of baseline grade by maximum post-baseline CTCAE 
grade will be presented, as appropriate. Patients who developed toxicities of 
grade ≥3 will also be listed. 
• ECOG Performance Status – ECOG performance status will be summarized at 
baseline. 
• Vital Signs – The number and percent of patients in each of the following minimum and 
maximum blood pressure, body weight and pulse rate categories will be presented: 
 
Vital Sign 
Category 
Blood Pressure Maximum Change from baseline (decrease) in SBP of ≤ -40 mmHg 
Maximum Change from baseline (decrease) in SBP of ≤ -60 mmHg 
Maximum Change from baseline (increase) in SBP of ≥40 mmHg 
Maximum Change from baseline in DBP (decrease) of ≤ -20 mmHg 
Maximum Change from baseline in DBP (decrease) of ≤ -40 mmHg 
Maximum Change from baseline in DBP (increase) of ≥20 mmHg 
Body Weight 
Maximum change from baseline body weight ≥10% 
Maximum change from baseline body weight ≤ - 10% 
Pulse Rate 
Maximum Pulse Rate >120 bpm 
Minimum Pulse Rate <50 bpm 
Maximum Change from baseline (increase) ≥30 bpm 
Minimum Change from baseline (decrease) ≤ -30 bpm 


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• ECG - Triplicate ECG measurements will be obtained at all time points except a single 
ECG measurement at screening. The triplicate data will be averaged and all summary 
statistics and data presentations will use the averaged data. Any data obtained from 
ECGs repeated for safety reasons after the nominal time-points will not be averaged 
along with the preceding triplicates. 
QT measurements corrected by heart rate will be used for the data analysis and 
interpretation. The commonly used Bazett’s and Fridericia’s correction will be applied. 
Categorical analysis of ECG data will be conducted and summarized as follows. All 
planned and unplanned post-dose time points will be counted in these categorical 
summaries. All values meeting the criteria of potential clinical concern will be listed. 
Categorical analysis of the QTcF/QTcB data will be conducted and summarized as 
follows: 
1. The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (<30, 30- 60, and ≥60 ms); 
2. The number of and percentage patients with maximum post-dose QTcF/QTcB 
(<450, 450-<480, 480- <500, and >500 ms); 
3. PR changes from baseline ≥50% if absolute baseline value was <200 ms, and ≥25% if 
absolute baseline value was ≥200 ms; 
4. QRS changes from baseline ≥50% if absolute baseline value was <100 ms, and ≥25% 
if absolute baseline value was ≥100 ms. 
• Concomitant medications/Follow-up systemic therapy - All medications received 
during the treatment period will be considered as concomitant medications and will be 
coded by WHO medical dictionary. Concomitant medications will be summarized by 
categories and patients who received concomitant medications will be listed. Follow-up 
systemic therapy for primary diagnosis maybe summarized by categories of 
follow-therapy and will be listed for each patient. 
The following ophthalmologic analyses will be performed. If there are fewer than five 
patients with ophthalmological exam data, only listings will be provided. 
• Visual Acuity Exam Results: Visual acuity at baseline will be summarized for each eye. 
The worst change from baseline in visual acuity will be summarized by eye. 
• Biomicroscopy (Slit Lamp) and Fundoscopy Exam Results: For baseline results, 
percentage of patients falling into each category of the examination status (normal, mild, 
moderate or severe) will be summarized for each eye structure by eye. 
For post-baseline results, percentage of patients falling into each category of the 
examination status (normal, mild, moderate or severe) will be summarized for the worst 
on study finding for each eye structure by eye. 


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8.2.4. Baseline Characteristics and Other Summaries 
Descriptive statistics will be used to summarize patient disposition, baseline characteristics, 
and treatment administration/compliance, and presented by tumor type and overall (ALCL, 
IMT, other tumors). Summary of patient disposition and baseline characteristics will also be 
provided for overall study population. 
• Patient Disposition - patients not meeting eligibility criteria will be identified. Patients 
not completing the study will be listed along with the reason for their premature 
discontinuation. Reasons for premature discontinuation may be summarized in the FA 
set. 
• Baseline Characteristics - patient characteristics such as age, gender, height, weight, 
ethnicity, primary diagnosis, performance status (ECOG), smoking history, prior therapy, 
extent of disease, and medical history will be summarized in frequency tables and 
descriptive statistics will be provided for quantitative variables in the SA set. A summary 
of B-Symptoms at baseline will be provided for lymphoma patients. 
• Treatment Administration/Compliance – Administration of study medication in the 
SA set will be described in terms of the total number of cycles administered, the median 
(range) of cycles administered, dose intensity, dose modifications, and dose interruptions 
(more than one day). 
8.2.5. Analyses of Pharmacokinetic Endpoints 
Concentration data of crizotinib will be listed by patient and by actual collection time and 
day. The plasma concentration data may be combined with similar data from other studies 
for population PK analysis and the results will be reported separately if performed. 
Concentration-QTc modeling analysis may be conducted using the ECG data from this study 
and/or combined data with other clinical studies of crizotinib. A separate study specific QT 
correction factor will be estimated for the QT-RR measurements in each clinical study of 
crizotinib. Linear, log-linear, and/or saturable models will be examined for the 
concentration-QTc relationship. Exploratory analyses (via graphical displays and/or mode 
fitting) include accounting for a delayed effect and the justification for the choice of 
pharmacodynamic model. Diagnostic evaluation will be included to explore the adequacy of 
the model. The results on the concentration-QTc analysis will be reported separately if 
performed. 
The analysis population is the PK analysis set. 
8.2.6. Analyses of Molecular Profiling 
Patient listing of baseline molecular profiling results including ALK fusion/translocation, 
mutations, amplification and overexpression will be provided. 


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9. REFERENCES 
1. 
Eisenhauer EA et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45: 228-27, 2009. 
2. 
Cheson B.D. et al., Revised response criteria for malignant lymphoma. JCO; 30 (18) 
579-586, 2007. 
3. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc 1958; 53:457-481. 
4. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics 1982; 38:29-41.