PHASE 1 SAFETY, PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF PF-02341066, A MET/HGFR SELECTIVE TYROSINE KINASE INHIBITOR, ADMINISTERED ORALLY TO PATIENTS WITH ADVANCED CANCER
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer ALK-positive, Non-Small Cell Lung Cancer c-Met Dependent, Non-Small Cell Lung Cancer ROS Marker Positive, Systemic Anaplastic Large-Cell Lymphoma, Advanced Malignancies Except Leukemia
Sponsor: Pfizer

PF-02341066
A8081001
Final Protocol Amendment 25, 11 May 2021
PFIZER CONFIDENTIAL
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CLINICAL PROTOCOL
PHASE 1 SAFETY, PHARMACOKINETIC AND PHARMACODYNAMIC STUDY 
OF PF-02341066, A MET/HGFR SELECTIVE TYROSINE KINASE INHIBITOR, 
ADMINISTERED ORALLY TO PATIENTS WITH ADVANCED CANCER
Compound:
PF-02341066
Compound Name:
Crizotinib
United States (US) Investigational New 
Drug (IND) Number:
Protocol:
A8081001
Phase:
1
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.
CCI

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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 25
11 May 2021
Sections 5.2.1.1, 5.3 and Appendix 11 
updated to allow usage of the PF-02341066 
formulated capsules. (Japan specific 
amendment).
Amendment 24
26 March 2019
Sections 4.3 and 5.5.1 updated to clarify 
localized anticancer therapy (eg, topical 
treatment of skin malignancy, intravesical 
Bacillus Calmette-Guerin [BCG] treatment) 
may be acceptable upon prior Sponsor and 
Investigator agreement and prior written 
Sponsor approval.
Section 4.5.1 updated to clarify laboratory 
confirmation (eg, a serum follicle 
stimulating hormone levels) may be 
indicated to confirm postmenopausal status 
but is not required.
Inclusion Criterion #1 (Main study and 
Enriched Other Cohort) updated to include 
additional MET mutations potentially 
conferring sensitivity to PF-02341066.
Exclusion Criterion #15 (Main study and 
Enriched Other Cohort) clarified to exclude 
patients with known presence of any grade
interstitial fibrosis or interstitial lung 
disease, including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial 
pneumonia, obliterative bronchiolitis, and 
pulmonary fibrosis, but not a history of prior 
radiation pneumonitis.  
Exclusion Criterion #3 (Enriched Other 
Cohort) clarified to indicate MET-dependent 
tumors, prior therapy specifically directed 
against MET or HGF (Hepatocyte Growth 
factor); for ALK dependent tumors, prior 
therapy specifically directed against ALK; 
for ROS1 dependent tumors, prior therapy
specifically directed against ROS1.
Section 5.2.4 updated with guidance on 

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dosing compliance.
MET Amplified NSCLC Cohort high 
amplification group closed to further 
enrollment, and remaining enrollment slots 
transferred to the MET Exon 14 alterations 
NSCLC subgroup within the Enriched Other 
cohort.  
Tumor scans for all patients enrolled in the 
MET amplification cohort will no longer be 
collected for and submitted to an 
independent radiology review laboratory.
Added a Reduced Schedule of Activities 
(Appendix 13) for all ongoing patients to 
follow.
Section 7.5.6 updated to remove
requirement for collection of blood samples 
for plasma analysis of circulating nucleic 
acids. 
Section 7.2 updated to remove requirement 
for collection of blood samples for 
hypogonadism testing.
Administrative changes: updated enrollment 
numbers; corrected typographical errors, 
formatting, and protocol inconsistencies; 
clarified protocol language; italicized text 
related to cohorts/substudies that are closed 
and/or no longer enrolling patients; 
formalized Protocol Administrative 
Clarification Letters previously issued since 
Amendment #23.
Updated c-Met to MET throughout 
document.
Updated ROS to ROS1 throughout 
document.
Enrollment status as of Amendment #24
(patients treated):
Dose Escalation (closed to enrollment): 66 

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Rifampin interaction sub-study (closed to 
enrollment): 18
Itraconazole interaction sub-study (closed 
to enrollment): 18
RP2D Midazolam Interaction Cohort 
(closed to enrollment): 15
RP2D Enriched Population Cohort (484 
total planned slots for enrollment):
ALK-marker positive NSCLC (closed to 
enrollment): 154
MET amplification NSCLC (closed to 
enrollment): 41
ROS1 marker positive NSCLC (closed 
to enrollment): 50
Enriched Other Cohort (closed to 
enrollment): 171 total planned slots for 
enrollment; 153 patients treated.
ALK Marker Negative NSCLC Cohort 
#1 (closed to enrollment): 47
ALK Marker Negative NSCLC Cohort
#2 (closed to enrollment): 21
Amendment 23
21 February 2017
Added a separate group of approximately 
5 NSCLC patients whose tumors harbor 
MET Exon 14 alterations to be enrolled in 
clinical sites in Japan in Sections 9.1.3.4 and 
9.2.1.4.
For patients enrolled in clinical sites in 
Japan: Pharmacogenomic blood sampling is 
optional; will not participate in 
hypogonadism testing; will be followed for 
survival as a separate group; and female and 
male patients must be 20 years of age or 
older to be eligible for enrollment into the 
trial.
Extended survival follow-up for ROS1
marker positive NSCLC patients, and 
NSCLC patients with tumors harboring 

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MET gene amplification or MET Exon 14 
alterations to 2 years after the last patient in 
each of these cohorts has discontinued PF-
02341066 treatment, unless otherwise 
notified by the Sponsor in Appendices 9, 10, 
and 11, respectively.  
In Appendix 10 (ROS1 Marker Positive 
NSCLC cohort): Removed requirement for 
collection and shipment of tumor scans to an 
independent radiology laboratory for central 
review for patients enrolled in the ROS1
marker positive NSCLC cohort as central 
review has been completed.
In Appendix 11 (Enriched Other cohort): 
Added requirement for shipment of tumor 
scans to an independent radiology 
laboratory for central review for NSCLC 
patients whose tumors harbor MET Exon 14 
alterations.
Removed requirement to collect indirect 
bilirubin for new and ongoing patients as 
part of laboratory blood chemistry panel per 
updated Pfizer protocol template standards.
Updated the protocol language to ensure 
consistency with Pfizer protocol template 
standards.
Minor edits/clarifications to enhance clarity 
and to correct administrative 
inconsistencies.
Modified the number of patients to be 
enrolled based upon number of treated 
patients in Protocol Amendment #23:
Dose Escalation (closed to enrollment): 66 
Rifampin interaction sub-study (closed to 
enrollment): 18
Itraconazole interaction sub-study (closed 

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to enrollment): 18
RP2D Midazolam Interaction Cohort 
(closed to enrollment): 15
RP2D Enriched Population Cohort (470 
total planned slots for enrollment):
ALK-marker positive NSCLC (closed to 
enrollment): 154
MET amplification NSCLC (low 
category closed to enrollment;  medium 
and high categories open to enrollment): 
68 planned slots for enrollment
ROS1 marker positive NSCLC (closed 
to enrollment): 50
Enriched Other Cohort (open to 
enrollment): 130 planned slots for 
enrollment
ALK Marker Negative NSCLC Cohort 
#1 (closed to enrollment): 47
ALK Marker Negative NSCLC Cohort 
#2 (closed to enrollment): 21
Amendment 22
27 April 2016
Added rationale for analysis of NSCLC 
patients with tumors harboring MET Exon 
14 alterations in Protocol Summary and 
Section 1.2; added sample size justification
for analysis of NSCLC patients with tumors 
harboring MET Exon 14 alterations in 
Section 9.1.3.4.
Added analysis of NSCLC patients with
tumors harboring MET Exon 14 alterations 
in Section 9.2.1.4.
Changed “MET Exon 14 deletion” 
terminology to “MET Exon 14 alterations” 
throughout protocol to encompass various 
types of genetic alterations related to MET
Exon 14.  
Closed enrollment of patients into the MET
Low Amplification category and transferred

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remaining open enrollment slots to Enriched 
Other Cohort as described in Section 
9.1.3.2, Appendix 9, and Appendix 11.  
Other conditions including, but not limited 
to, slow enrollment in the medium and/or 
high level MET amplification categories
may trigger transfer of additional enrollment 
slots from these MET gene amplification 
categories to the Enriched Other cohort as 
described in Section 9.1.3.2.  
Added that with Sponsor written approval 
and IRB/EC notification, 10 to 15 additional 
patients may be enrolled (for a total overall 
enrollment of approximately 580 patients) to 
reach the target enrollment of approximately 
40 to 50 NSCLC patients with tumors
harboring MET Exon 14 alterations and 
approximately 20 to 25 male patients for 
hypogonadism evaluation in the event that 
overall enrollment is achieved prior to 
reaching these targets, as described in 
Sections 9.1.
Clarified survival endpoints in Sections 2.1
and 9.2.1.  
Extended survival follow-up for ROS1
marker positive NSCLC patients, and 
NSCLC patients with tumors haboring MET
gene amplification or MET Exon 14 
alterations to 1 year after the last patient’s 
End of Treatment visit in the cohort in 
Appendices 9, 10, and 11, respectively.  
In Appendix 11 (Enriched Other cohort): 
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Added text indicating that all tumor scans 
from all NSCLC patients with tumors 
harboring MET Exon 14 alterations will be 
collected and held at the investigative site.  
With Sponsor written approval and IRB/EC
notification, the Sponsor may request tumor 
scans from these patients to be submitted to 
an independent radiology laboratory for 
review at a later date. 
In Appendix 9 (MET amplified NSCLC 
cohort):  Added text indicating that all 
tumor scans from all NSCLC patients with 
tumors harboring MET gene amplification 
will be collected and held at the 
investigative site.  With Sponsor approval 
and IRB/EC notification, the Sponsor may 
request tumor scans from these patients to 
be submitted to an independent radiology 
laboratory for review at a later date.
Clarified that the use of medications known 
to prolong the QT interval and the use of 
bradycardic agents should be avoided to the 
extent possible during the study in Section 
5.5.4.
Removed respiratory rate assessment from 
Section 7.3, as this assessment was 
incorrectly required by the protocol.
Removed single-multiple dose 
pharmacokinetic (PK) cohort from 
crizotinib-itraconazole drug-drug interaction 
substudy (Appendix 7) 
 
 
due to 
anticipated significant delays in completing 
this substudy as a result of dose 
interruptions and missed PK assessments 
(rendering patients unevaluable for PK) in 
an advanced cancer population.
Clarified exclusion criterion #5 of 
crizotinib-itraconazole drug-drug interaction 
substudy (Appendix 7) to exclude patients 
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with history of or current evidence of 
congestive heart failure in accordance with 
the itraconazole United States Package 
Insert.
Added clarification to 
crizotinib-itraconazole drug-drug interaction 
substudy (Appendix 7) that a total of 
approximately 25 patients will be enrolled to 
achieve at least 8 evaluable patients for 
multiple dose PK, and that patients who are 
enrolled but not treated may be replaced to 
obtain 8 evaluable patients for multiple dose 
PK.
Removed expanded ophthalmology 
assessments (refractive error, pupil size, 
intraocular pressure, ocular coherence 
tomography, dilated fundus photography) 
for NSCLC patients as the requirement for
30 evaluable patients with these assessments 
had been achieved.
Clarified exploratory analysis of 
PF-06260182 (metabolite of PF-02341066) 
and definition of treatment periods in 
Itraconazole Substudy patients, as described 
in Section 9.2.2.5.
Updated Serious Adverse Event reporting 
contact information in Appendix 1.
Added text indicating that all sexually active 
male patients 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.
Corrected typographical errors, 
administrative inconsistencies, and 
formatting; included clarification language; 
italicized text related to cohorts/substudies
that are closed and/or no longer enrolling 

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patients.
Amendment 21
07 April 2015
Added details on hypogonadism testing to 
relevant Schedule of Activities (Appendix 9, 
11, and 12), and in the body of the protocol.  
Testing was added to explore potential 
effects of PF-02341066 on testosterone 
levels in males. 
Additional detail on population PK/PD 
analyses were included in Section 9.2.4. for 
added clarity.
 
 
 
 
 
Clarified repeat testing if ALT or AST 
≥Grade 3 and total bilirubin ≥ Grade 2.
Added language for PF-02341066 PK 
sampling at disease progression if patient is 
still taking PF-02341066.  This is only for 
patients enrolled in the MET-amplified 
NSCLC, ROS1 marker positive NSCLC and 
Enriched Other cohorts.
Updated survival data collection to every 
3 months after discontinuing study treatment 
until at least one year after the first dose of 
the last patient enrolled into the 
MET-amplified NSCLC Cohort to obtain 
more robust survival data. A similar change 
to the survival follow-up period was made 
to the ROS1 marker positive NSCLC Cohort 
and Enriched Other Cohort (Met Exon 14 
alterations NSCLC patients only).
Clarified that patients with tumors harboring 
Met Exon 14 alterations may be eligible to 
enroll into the Enriched Other cohort.
Criterion included to permit patients to 
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enroll in the Enriched Other cohort with 
molecular changes in other than ALK, Met 
and ROS1 if there are data supporting a 
biologic rationale for PF-02341066 
treatment. 
Clarified reasons for pharmacogenomic 
testing at baseline.
Updated pregnancy/contraception, medically 
qualified personnel, study drug storage, 
adverse event reporting, quality 
control/quality assurance and publication of 
study results language to be consistent with 
the Pfizer global template.
Corrected typographical errors and 
administrative inconsistencies.
Amendment 20
30 June 2014
Administrative changes made: outdated 
information “italicized”. 
Replaced ketoconazole with itraconazole for 
the drug-drug interaction sub-study with a 
CYP3A strong inhibitor based upon FDA 
guidance and modified sub-study design.
Clarified cohort requirements by adding 
Appendix 11 for the Enriched Other cohort.  
This cohort includes patients with cancer 
with molecular markers other than ALK 
marker positive NSCLC, ROS1 marker 
positive NSCLC and MET-amplified 
NSCLC that may confer sensitivity to 
PF-02341066.  Cross referenced sections of 
main protocol to this appendix, as 
applicable. 
Clarified Dose Limiting Toxicity language 
and modified protocol language to indicate 
that the QD MTD cohort will not be 
expanded.
For ALK-negative NSCLC Cohort #2, 
requirement for no MET or ROS1 testing to 
occur prior to enrollment was removed.  A 

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Note to File was issued 19 June 2012.  
Yearly ophthalmologic testing (2 weeks) 
added for NSCLC patients who have the
expanded ophthalmology testing.  Clarified 
that intraocular pressure testing should be 
done twice for each eye and if test results 
deviate by more than 2 mmHg of each other
a third reading must be obtained.
Added chemistry laboratory testing at 
Cycle 2 Day 15 to be consistent with the 
product label.
Updated the protocol language of several 
exclusion criteria to ensure consistency with 
the current version of the Investigator’s 
Brochure and Pfizer standards.
In addition, the exclusion criteria for QTc 
was modified to allow patients with a QTc 
>470 msec but <490 msec in the presence of 
a right bundle branch block or with an 
implanted cardiac pacemaker to enroll into 
the study upon agreement between the 
Investigator and Sponsor.
For sites using the Western Institutional 
Review Board, patients who lack capacity to 
consent for themselves will be excluded 
from this study.
Clarified that if tumor imaging was done 
within 6 weeks of last dose of PF-02341066, 
it will not be required to be repeated at the 
End of Treatment visit.
Removed requirement for collection and 
shipment of tumor scans to an independent 
radiology laboratory for central review for 
the ALK-negative NSCLC Cohort #1 and 
the ALK-positive NSCLC cohort. Note to 
File was issued 25 October 2012.  
Added requirement for collection and 
shipment of tumor scans to an independent 
radiology laboratory for central review for 

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the ROS1 marker positive NSCLC cohort.
Increased sample size for ROS1 marker 
positive NSCLC cohort from 30 to 
50 patients and provided the rationale for 
change.  Note to File was issued 
12 November 2012.  
Increased the number of patients enrolled 
for both the rifampin and itraconazole 
drug-drug interaction sub-studies from 15 to 
a maximum of 25 in order to obtain 
8 evaluable patients each.
Increased the overall sample size to 
approximately 550 patients based on
additional patient enrollment into the ROS1
marker positive NSCLC cohort, the 
Enriched Other cohort and the rifampin and 
itraconazole drug-drug interaction
sub-studies.
Protocol template language updated to be 
consistent with Pfizer standards.
Corrected typographical errors.
Amendment 19
27 April 2012 
Starting dose of PF-02341066 reduced from 
200 mg BID to 250 mg QD for ketoconazole 
sub-study.  In addition, clarified dose 
administration instructions.
For rifampin and ketoconazole sub-studies 
clarified that on days of PK sampling 
patients must take their morning doses at the 
clinic.
Administrative changes made: outdated 
information “italicized”.  Text previously 
italicized, was bolded and text previously 
bolded was underlined.
Clarified cohort requirements by adding 
Appendices for: cMET-amplified NSCLC, 
ROS1-positive NSCLC, and ALK-negative 
NSCLC #2 cohorts.  Cross referenced 

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sections of main protocol to appendices, as 
applicable.
Removed requirement for tumor 
assessments for rifampin and ketoconazole 
sub-studies.
Clarified that patients with Gilbert’s 
syndrome are permitted to enter the study 
with Sponsor approval.
Patients will be eligible to enter the study if 
they experienced any of the following 
within 6 months prior to starting study 
treatment: myocardial infarction, 
severe/unstable angina, coronary/peripheral 
artery bypass graft, congestive heart failure, 
cerebrovascular accident including transient 
ischemic attack or pulmonary embolus. 
For MET-amplified NSCLC cohort 
eligibility, removed reference to the test 
needing to be FISH.
Amendment 18
24 February 2012
Added 2 drug-drug interactions sub-studies:
rifampin, ketoconazole.
Included rationale for the number of 
ROS1-positive (positive for chromosomal 
translocations in the ROS1 gene) NSCLC 
patients to be enrolled.
Clarified the MET-amplified NSCLC 
cohort; enrolling 3 patient categories based 
on degree of MET amplification (low, 
medium, high).  Rationale for the numbers 
of patient updated in each category.
Updated concomitant medications for 
consistency across all PF-02341066 studies.
Clarified required imaging frequency should 
renal cysts be diagnosed.
Updated adverse event guidelines to be 

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consistent with Pfizer standards.
Amendment 17
27 September 
2011
Added a second cohort of ALK-marker 
negative NSCLC.
Added more detailed ophthalmology testing 
for NSCLC patients.
Defined MET-amplified NSCLC and 
provided the rationale for the number of 
patients required.
Amendment 16
08 August 2011
Added monitoring guidance for patients 
developing renal cysts and guidelines to 
manage potential cases of drug-induced liver 
injury.
Increased the number of patients enrolling in 
the dose escalation cohort and enriched 
population cohort.
Removed the Day -7 dosing requirement for 
all patients except those enrolled in the dose 
escalation cohort.
Modified the minimal acceptable platelet 
count eligibility criterion only for patients 
enrolled into the enriched population cohort. 
Clarified the dose reduction levels for 
patients enrolling into the enriched 
population cohort.
Updated and clarified the dose modification 
guidelines.
Allowed solution dosing as an alternative to 
tablet dosing.
Clarified ophthalmology examination 
guidelines.
Updated adverse event guidelines to be 

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consistent with Pfizer standards.
Amendment 15
5 August 2010
Safety monitoring for potential AEs of 
pneumonitis was added, exclusion criteria 
were updated to exclude patients with 
interstitial fibrosis or interstitial lung 
disease, and treatment guidelines of selected 
crizotinib-related AEs was added.
Amendment 14
1 June 2010
The survival monitoring period was 
modified, the food restriction criteria for 
prior to Cycle 2 Day 1 was removed, and 
evaluation of active metabolites in addition 
to the parent was added.
Amendment 13
8 April 2010
Atrial fibrillation criteria were modified to 
only exclude uncontrolled atrial fibrillation, 
Coumadin dosing restriction was removed, 
PK sampling time points for ALK-negative, 
Asian, and QD patients were modified.
Amendment 12
9 November 2009
An ALK-negative NSCLC cohort with a 
cycle length of 3 weeks was added. This 
cohort consisted of NSCLC patients who 
were negative for the ALK translocation as 
determined by the Abbott Molecular ALK 
break-apart FISH IUO assay used in 
Protocols A8081007 and A8081005. A 
minimum of 25 to a maximum of 
40 evaluable patients were planned to be 
enrolled into this cohort.
The dose-escalation cohort was reopened in 
order to determine a QD MTD.
The creatinine eligibility criteria were 
widened from 1.5 x ULN to 2 x ULN.
Day -7 dosing for all patients (except dose 
escalation and Asian patients) was waived.
50-mg and 100-mg tablets were to replace 
the 50-mg and 100-mg capsules once the 
capsule supply was depleted.
A screening ophthalmology examination 
was added, with any follow-up as clinically 

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indicated.
Crizotinib was allowed to be taken without 
regard to meals after Cycle 2 Day 1.
Increased the number of patients to be 
allowed to enter the study.
Patients with tumors having an ROS1 gene 
translocation were added as an option to the 
RP2D-enriched population cohort.
Amendment 11
30 June 2009
Patients with documented Gilbert’s 
syndrome were allowed to enter the study.
Amendment 10
14 May 2009
PET by both FDG-PET and FLT-PET was 
added as a new substudy, added an optional 
biopsy at time of disease progression, 
increased the number of patients allowed to 
enter, and modified PK collection criteria 
for Asian patients.
Amendment 9
5 March 2009
Patients with pulmonary embolism within 6 
months prior to starting study treatment 
were allowed to enter the study on a 
case-by-case basis.
Amendment 8
18 August 2008
Patients with stable brain metastases were 
allowed to enter the study.
Amendment 7 
23 June 2008
Patients with ECOG performance status 
scores of 2 were allowed to enter the 
RP2D-enriched population cohort, modified 
PK sampling time points, added MET
translocation/fusions as an option for the 
RP2D-enriched population cohort, and 
modified Cycle 1 Day 1 PK sampling for 
patients exempted from Day -7 dosing.
Amendment 6
4 March 2008
Patients with cytogenetic abnormalities 
defined in the RP2D-enriched population 
cohort could enter a lower cohort in the 
dose-escalation cohort that was shown to be 
tolerated (without Day -7 dosing) but were 
not considered evaluable for dose limiting 
toxicity assessment, criteria were added for 

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top dose to be evaluated, exempted patients 
enrolled in the RP2D-enriched population 
cohort from Day -7 dosing on a case-by-case 
basis, allowed dosing with a small amount 
of food starting on Cycle 2 Day 2, and 
modified PK sampling time points.
Amendment 5
23 January 2008
Eligibility criteria for albumin were 
removed, and PK time points were added to 
better characterize the half-life of crizotinib.
Amendment 4
29 October 2007
EML4-ALK-positive NSCLC patients were 
allowed to enter, QTc eligibility criteria 
were modified from >450 msec for males 
and >470 msec for females to >470 msec for 
both males and females, and the exclusion 
criterion of “prior radiotherapy to >25% of 
bone marrow” was removed.
Amendment 3
27 April 2007
Two RP2D cohorts were added: one to 
evaluate the effect of an MDZ drug-drug 
interaction and 1 to evaluate clinical activity 
in an enriched population (enriched 
population included patients with tumors 
harboring MET gene amplification or 
mutation, or anaplastic large cell lymphoma 
cases with ALK translocation) to obtain 
early evidence of clinical activity. In 
addition, [18F] FLT-PET was evaluated in a 
small subset of patients in the 
RP2D-enriched cohorts (N=6) as a
noninvasive measure of tumor inhibition. 
Lastly, 12 patients in this RP2D-enriched
cohort were to participate in a fed/fasted 
study to characterize the effect of food on 
the PK of crizotinib.
Amendment 2
30 August 2006
Lymphoma/myeloma patients were allowed
to enter, and indirect bilirubin, bicarbonate, 
and lactate dehydrogenase were added as 
part of the clinical laboratory test battery.
Amendment 1
19 January 2006
Minor changes were made in PK time
points.

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Original protocol
05 December 2005
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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ITALICIZED TEXT IS OUTDATED INFORMATION AND SHOULD BE 
DISREGARDED
SUMMARY
Indication: 
Advanced malignancies (with the exception of leukemia) refractory to standard of care 
therapy, or for whom no standard of care therapy is available.
Rationale:
Cancer remains an area with tremendous unmet medical need.  Each year, an estimated 
23 million people worldwide are diagnosed with the disease and more than half die from it.  
Across the seven major markets (US, 5 EU and Japan), three million individuals are 
diagnosed with cancer annually, and 1.5 million died from it in 2002.  The three cancers 
representing the largest frequency include non-small cell lung cancer (NSCLC), breast 
cancer, and colorectal cancer.  Taken together, these cancers account for more than 1 million 
cases of cancer per year in the major geographic markets.
An emerging paradigm in oncology is that robust clinical efficacy can be obtained with 
well-tolerated kinase inhibitors directed towards oncogenic kinases bearing activating 
mutations or other signal transduction perturbations.  Recent examples include Gleevecin 
Gastrointestinal stromal tumors (GIST) with mutant c-Kit, Tarcevaand Iressain NSCLC 
with mutant epidermal growth factor receptor (EGFR), and SU11248 targeting the 
VHL-dependent vascular endoethelial growth factor (VEGF) pathway in renal cell carcinoma 
(RCC). 
MET/Hepatocyte growth factor receptor (HGFR) has been well characterized for its role in 
regulation of cell growth, migration, and invasion of both tumor cells and endothelial cells.  
An extensive body of literature indicates that MET/HGFR is one of the receptor tyrosine 
kinases (RTKs) most frequently mutated or otherwise abnormally activated in late-stage 
human cancer.  When activated, MET/HGFR plays a critical role in regulation of tumor 
oncogenic processes such as mitogenesis, survival, and invasive growth, and especially in the 
metastatic process.  Additionally, the emerging role of MET/HGFR in the regulation of 
tumor angiogenesis indicates potential for dual anti-tumor and anti-angiogenic mechanisms.  
Activating mutations in MET/HGFR have been identified in multiple patient populations, 
including NSCLC, small cell lung cancer (SCLC), renal cancers, head and neck cancers, and 
hepatocellular cancer.  In addition to activation driven by mutation, MET/HGFR gene 
amplification/ overexpression resulting in increased kinase activity has been frequently 
observed in gastric and colorectal cancer patients.  Furthermore, MET/HGFR is also 
activated in human tumors by other mechanisms (eg, autocrine loops, paracrine activation 
from tumor-associated stroma).  Collectively, the dysregulation of MET/HGFR in tumors by 
multiple mechanisms along with the potential role of MET/HGFR in tumor angiogenesis 
comprises a large potential patient population.  Most importantly, in preclinical proof of 
concept studies, both neutralizing monoclonal antibody and RTK inhibitor exhibit 
convincing antitumor activity in several xenograft models, which supports the concepts that 
MET is a valid target for treatment of cancer.  

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Mutations in Met Exon 14 were previously reported to be oncogenic drivers in preclinical 
models of lung cancer (Ma et al, 2003; Ma et al, 2006; Kong-Beltran et al, 2006).22,23,24
Given the role of MET/HGFR in regulation of cell growth, migration, and invasion of both 
tumor cells and endothelial cells, there is increasing interest in understanding the potential 
effectiveness of tyrosine kinase inhibitors as a treatment in NSCLC patients with tumors 
harboring MET Exon 14 alterations. Paik et al (2015)21 reported on 3 crizotinib-treated 
patients with NSCLC harboring alterations leading to MET exon 14 skipping. All 3 patients 
were shown to have a partial response.  
Mechanism of Action and Pharmacodynamic Relationship to Anti-Tumor Efficacy:
PF-02341066 is a selective MET/HGFR aminopyridine tyrosine kinase inhibitor and a potent 
ATP-competitive inhibitor of recombinant, human MET/HGFR kinase activity with a mean 
Ki of 4 nM. 
The potency of PF-02341066 against MET/HGFR and selectivity against kinases identified 
in preliminary biochemical screens was further addressed in cellular kinase phosphorylation 
ELISAs. In these studies, PF-02341066 inhibited HGF-stimulated or constitutive total 
tyrosine phosphorylation of wild type MET/HGFR with a mean IC50 value of 11 nM across a 
panel of human tumor cell lines and demonstrated similar values in mouse or canine 
epithelial cell.  PF-02341066 demonstrated minimal variation (<4-fold variance) across the 
panel of cell lines, which were selected for these studies by virtue of increased expression of 
the ABC family of transporters that are implicated in tumor multidrug resistance.  These data 
indicate a moderate but manageable potential for intrinsic resistance to PF-02341066 due to 
expression of efflux transporters. 
The selectivity of PF-02341066 was evaluated in a panel of cell-based assays for selected 
kinases that were closely related to MET/HGFR and/or were identified in biochemical 
assays.  In these studies, PF-02341066 selectivity for MET/HGFR (IC50 = 11 nM) was 
greater than 1000-fold relative to 
or Sky RTKs, greater than 200-fold 
relative to IRK and Lck, approximately 40- to 60-fold relative to Axl, Tie2, TrkA, and TrkB, 
and approximately 20- to 30-fold relative to RON kinase.  Further studies to investigate the 
likelihood of inhibition of selected targets (ie, Tie-2) in pharmacodynamic assays in vivo 
indicated that pharmacologically relevant inhibition of these kinases by PF-02341066 would 
be unlikely at efficacious dose levels.  In contrast, PF-02341066 demonstrated potent activity 
against nucleophosmin (NPM)-anaplastic lymphoma kinase (-ALK), an oncogenic fusion 
protein variant of the ALK RTK, which results from a chromosomal translocation and is 
implicated in the pathogenesis of human ALCL (Pulford et al, 2004).4  These data indicate 
that the pharmacological activity of PF-02341066 is likely mediated by inhibition of 
MET/HGFR and ALK RTKs and their oncogenic variants. 
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To also investigate for potential antiangiogenic activity, PF-02341066 was shown to inhibit 
HGF-mediated HUVEC endothelial cell survival (IC50 = 11 nM) and matrigel invasion 
(IC50 = 35 nM) as well as HMVEC endothelial cell tubulogenesis in fibrin gels 
(IC50 = ~80 nM).  These data suggest that antitumor efficacy of PF-02341066 may be 
mediated by both direct effects on tumor cell growth or survival as well as antiangiogenic 
mechanisms.
To evaluate the pharmacodynamic (PD) inhibition of MET/HGFR by PF-02341066, 
GTL-16 gastric carcinoma tumors were harvested at several time points following oral 
administration of PF-02341066 in both single-dose and repeat-dose (steady-state) studies.  
MET/HGFR phosphorylation status in tumors was quantitated by ELISA over a range of 
doses.  With focus on steady-state PD studies (11-day administration) to draw a correlation 
with tumor growth inhibition, PF-02341066 demonstrated the following:

At 50 mg/kg/day: 100% tumor growth inhibition correlated with complete inhibition 
of MET/HGFR phosphorylation in GTL-16 tumors sustained for 24 hours.  
(25 mg/kg: near complete inhibition of both phosphorylation and tumor growth).  At 
12.5 mg/kg/day: 60% tumor growth inhibition correlated with 80 to 90% inhibition of 
MET/HGFR phosphorylation at 1 to 8 hours which decreased to 50% to 
60% inhibition by 16 to 24 hours.

At 6.25 mg/kg/day: non-significant trend toward tumor growth inhibition correlated 
with 30% to 50% inhibition of MET/HGFR phosphorylation at 1 to 8 hours with full 
recovery by 16 hours.
In summary, MET has been shown to be a valid target, and PF-02341066 is a potent and 
selective inhibitor of MET.  PF-02341066 exhibits convincing antitumor activity in several 
xenograft models.  Importantly, it delivers antitumor efficacy in xenograft models with a 
large safety window, providing increased confidence that mechanism-based toxicity will not 
be limiting in the clinic.
Objectives: 
1. Determine the safety profile of PF-02341066 including identification of dose limiting 
toxicity (DLT) and maximum tolerated dose (MTD).
2. Determine the recommended Phase 2 doses (RP2D) and regimens of PF-02341066.
3. Determine pharmacokinetic profile of PF-02341066 following oral administration
including the effect of food.
4. Perform initial evaluation of PF-02341066 related CYP3A4 inhibition using 
midazolam (MDZ) as a probe.
5. Determine the effect of the co-administration of rifampin on the multiple-dose plasma 
pharmacokinetics of PF-02341066.

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6. Determine the effect of the co-administration of itraconazole on the plasma 
pharmacokinetics of PF-02341066.
8. Document any evidence of anti-tumor activity of PF-02341066.
10. Evaluate the effect of PF-02341066 on parameters related to hypogonadism in males.
Trial Design:
Open label, multi-center Phase 1 dose escalation, safety, pharmacokinetic 
 
study.
Endpoints:
1. To determine the MTD and potential phase 2 dose(s) of PF-02341066.
2. To characterize the plasma pharmacokinetic (PK) profile following oral 
administration of PF-02341066, including the effect of food and a midazolam study to 
evaluate the potential for time-dependent inhibition (TDI) of CYP3A4 at different 
PF-02341066 dose levels.
3. To determine the safety, tolerability and the DLT of PF-02341066.
4. Plasma PK parameters of PF-02341066 and its metabolite(s) following multiple oral 
doses of PF-02341066 alone and when co-administered with rifampin.
5. Plasma PK parameters of PF-02341066 and its metabolite(s) following single (if 
possible) and multiple oral doses of PF-02341066 alone and when co-administered 
with itraconazole.  As of Protocol Amendment #22, the Single and Multiple-Dose 
Design will no longer be performed.
7. To document evidence of anti-tumor activity, including tumor response rate (by 
RECIST for solid tumors and response criteria for lymphomas and multiple 
myelomas), duration of response, time to response, progression free survival, overall 
survival, probabilities of survival at 6 and 12 months and others as appropriate.
CCI
CCI
CCI
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9. Blood testosterone and other blood parameters associated with detecting 
hypogonadism in males [Appendix 12].
Trial Treatments:
Figure 1 provides the status of each of the RP2D cohorts of this study, based on Protocol 
Amendment #24.
Figure 1.
Summary of RP2D Cohorts Based on Protocol Amendment #24
Dose Escalation:
PF-02341066 will be administered orally on an empty stomach once a day (QD) or twice a 
day (BID) in continuous 28-day cycles (see Schedule of Activities).  However, with the 
approval of Amendment #14, PF-02341066 may be administered without regards to meals.  
There will be a lead-in period in which single-dose pharmacokinetics of PF-02341066 or 
MDZ (for patients participating in the MDZ sub-study) will be characterized prior to 
initiation of continuous dosing in the first cycle of treatment unless patients who are 
exempted from the Day -7 lead-in dose (see below).  With the exception of cohorts in which 
the evaluation of a MDZ interaction is scheduled for patients who are exempted from the 
Day -7 lead-in dose (see below), all other patients will receive a single dose of PF-02341066 
seven days prior to the start of Cycle 1 (Day –7) in order to characterize the complete PK 
profile of PF-02341066 after a single dose.  With the approval of Amendment #13, only 
patients enrolled in the QD dose escalation part of the study or Asian patients enrolled in 
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any cohort will have the Day -7 lead-in dose.  Patients enrolled in the MDZ interaction 
sub-study will receive a single 2 mg oral dose of MDZ on Day –7.  These patients will 
receive another single 2-mg oral dose of MDZ concurrently with PF-02341066 on Cycle 2 
Day 1.  During the study, real-time pharmacokinetic monitoring will be conducted as much 
as possible.
After approval of Amendment #16, Day -7 dosing will only be required for dose escalation 
cohorts.
The PF-02341066 dose regimen may be changed if the pharmacokinetics and safety data 
suggest that a discontinuous regimen or another dosing frequency may be preferable.  
Dosing of oral PF-02341066 will be based on flat milligram increments without adjustment 
for body size.  The dose will be 50 mg QD in the initial cohort.
Patients will be successively assigned to the next available treatment slot within a dose level. 
Each dose cohort will initially include a minimum of 3 evaluable patients for assessment of 
toxicity within the first cycle.  Dose escalation will occur in 100% increments until either of 
the following occurrences: (1) drug related toxicity of Grade 2 severity occurs in 2 or more 
patients within a dose level; or (2) mean unbound AUC0-24 exceeds 2.4 g·h/mL (the highest 
unbound AUC tested in the one-month toxicology studies).  Escalation increments will then 
become 40%.  In any cohort, if 1 patient experiences a DLT, 3 additional patients will be 
enrolled to that dose level.  If 2/3 or 2/6 patients experience a DLT, no further dose 
escalation will occur.
If the highest cohort being evaluated is closed to new enrollment, additional patients who 
have a cytogenetic abnormality as described in Section 4.1 (Inclusion #1) may enter the 
study at the previous dose level.  These patients will not participate in the midazolam 
sub-study and will not have the Day -7 lead-in dose of PF-02341066 or any corresponding 
PK assessments.  They will be evaluated for safety but will not contribute to the DLT 
assessments.  These patients will enter the study on Day 1 of Cycle 1.  Additionally, patients 
scheduled to enroll in the RP2D enriched population cohort (see RP2D Cohorts Section) 
may be exempted from the Day -7 lead-in dose depending on the their overall medical 
condition.  This exemption will be granted on a case-by-case basis as agreed upon by the 
investigator and Sponsor.  Upon Institutional Review Board/Ethics Committee (IRB/EC)
approval of Amendment #12, non-Asian patients will also be exempt from the Day -7 lead-in 
dose.  Amendment #13 extends the requirements as described in the first paragraph of this 
section.
Doses may not be modified until a DLT has been reached.  The study investigator may 
implement dose suspension in order to ensure patient safety; this will be considered 
dose-limiting toxicity for the purpose of dose-escalation if PF-02341066 has to be suspended 
for more than 3 days.  Patients who discontinue treatment before completing Cycle 1 (DLT 
evaluation) for reasons other than treatment-related toxicity will be replaced.
One or more lower dose level(s) may be tested in search of the MTD, defined as the dose 
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may be stopped if 1) the maximum administered dose (MAD) produces PF-02341066 
concentrations that are at least 5-fold greater than the projected target concentration, 
2) exposure plateaus as the dose is increased and 3) MTD cannot be reached within a 
reasonable dose range (up to 2000 mg).  The MTD for both QD and BID dosing may be 
determined.
MDZ interaction sub-study: The potential for CYP3A inhibition due to PF-02341066 will be 
evaluated using MDZ as a CYP3A4 substrate probe at 3 dose levels of PF-02341066: the 
next higher dose after the initial dose, the efficacious dose, and the RP2D (see Figure 4).  
The MDZ interaction study will be conducted starting in the second dose cohort, and will be 
conducted in a higher dose in which the trough unbound plasma concentration of 
PF-02341066 at the steady state will equal or exceed the projected target unbound 
concentrations (8.1-12.8 nM) if target unbound plasma concentrations of PF-02341066 are 
not achieved in the second cohort.  In the second cohort or the efficacious dose cohort, at 
least 3 evaluable patients per cohort will be assessed for the effect of repeat PF-02341066 
administration on the pharmacokinetics of midazolam.  If a significant change in MDZ 
clearance (>3-fold increase in MDZ AUC in all 3 patients, or > 5-fold increase in 2 or more 
patients) is observed at any PF-02341066 dose level, further dose escalation may be 
terminated.  The effect of PF-02341066 on CYP3A activity will be evaluated at the RP2D.  
Eight evaluable patients will be required for the MDZ interaction study in one of the RP2D 
cohorts (see RP2D Cohorts Section).  Patients enrolled in the MDZ interaction sub-study will 
receive a single 2 mg oral dose of MDZ on Day –7 and another single 2-mg oral dose of 
MDZ concurrently with PF-02341066 on Cycle 2 Day 1.
Rifampin interaction sub-study:
This sub-study is to determine the effect of the co-administration of rifampin on the
multiple-dose plasma pharmacokinetic profile of PF-02341066.  The starting dose of 
PF-02341066 will be 250 mg BID and the dose of rifampin will be 600 mg QD.  
Approximately 25 patients with advanced malignancies refractory to standard of care 
therapy, or for whom no standard of care therapy is available will be enrolled into this 
sub-study to obtain 8 evaluable patients.  The rationale for the PF-02341066 starting dose of 
250 mg BID is provided below.
In vitro studies demonstrated that CYP3A4/5 are the major enzymes involved in the 
metabolic clearance of PF-02341066. Co-administration of a single 250 mg PF-02341066 
dose with rifampin (600 mg QD), a strong CYP3A inducer, resulted in 81.8% and 68.5% 
decreases in PF-02341066 AUCinf and Cmax, respectively, compared to when PF-02341066 
was given alone.  As PF-02341066 is also a CYP3A inhibitor, the magnitude of the effects of 
CYP3A inducers on steady state PF-02341066 exposures may differ from those seen after 
single doses. A mathematical modeling approach based on preclinical and clinical data 
indicate that rifampin co-administration is likely to result in an approximately 36% decrease 
in the PF-02341066 AUC. Based on these findings no safety issues in using a 250 mg BID 
PF-02341066 dose in combination with rifampin are anticipated.
Please see Appendix 6 for further details.

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Note that the Rifampin interaction sub-study will be enrolled prior to the enrollment of 
patients on the itraconazole interaction sub-study.
Itraconazole interaction sub-study: 
This sub-study is to determine the effect of itraconazole on the multiple-dose plasma 
pharmacokinetics of PF-02341066 when itraconazole is co-administered.  If multiple-dosing 
of PF-02341066 in combination with itraconazole is tolerable (as defined in the TRIAL 
DESIGN Section), a cohort of patients may be also enrolled to determine the effect of 
itraconazole on single and multiple-dose plasma pharmacokinetic profiles of PF-02341066.  
As of Protocol Amendment #22, the Single and Multiple-Dose Design will no longer be 
performed.  The starting dose of PF-02341066 will be 250 mg QD and approximately
25 patients will be enrolled to obtain at least 8 evaluable patients for multiple-dose PK. 
The magnitude of the effects of CYP3A inhibitors on steady state PF-02341066 exposures 
may differ from those seen after a single dose of PF-02341066 as PF-02341066 is also a 
CYP3A inhibitor.  An autoinhibition-mediated change in apparent clearance of 
PF-02341066 was observed during chronic PF-02341066 treatment.  There are limited data
with single doses of PF-02341066 administered with ketoconazole (200 mg BID), a strong 
CYP3A inhibitor.  Co-administration of a single 150 mg oral dose of PF-02341066 in the 
presence of ketoconazole, resulted in increases in PF-02341066 systemic exposure, with 
PF-02341066 AUCinf and Cmax values that were approximately 3.2 fold and 1.4 fold higher, 
respectively, than those seen when PF-02341066 was administered alone. SIMCYP (a 
population based pharmacokinetics modeling simulator) modeling based on preclinical and 
clinical data, predict a 2-fold increase in PF-02341066 AUC when PF-02341066 at steady 
state is co-administered with ketoconazole.  The effect of itraconazole on PF-02341066
exposure cannot be properly predicted due to the lack of a validated physiologically based 
pharmacokinetic model.  Based upon recent FDA guidance15 on the use of ketoconazole, 
ketoconazole was replaced with another CYP3A strong inducer, itraconazole.  However, it is 
expected that the magnitude of the effect of itraconazole would be no greater than that of 
ketoconazole given that itraconazole had a smaller inhibitory effect on the exposure of 
midazolam, a CYP3A probe, than ketoconazole.  Therefore, the PF-02341066 exposure at 
250 mg QD when administered with itraconazole is expected to be similar or lower than the 
PF-02341066 exposure at the maximum tolerated dose of 250 mg BID when administered 
alone.  For these reasons, the same starting dose of PF-02341066 proposed for the 
ketoconazole drug-drug interaction, will be used for the itraconazole drug-drug interaction, 
ie, 250 mg QD.  However, should additional data arise impacting this assumption, the 
Sponsor will adjust the starting dose of PF-02341066 accordingly. 
Please see Appendix 7 for further details.
RP2D Cohorts: The RP2D will be determined as a dose below or equal to MTD, at which 
PF-02341066 is unlikely to cause an inhibition of CYP3A4 activity.  There will be two RP2D 
cohorts:  
1. The first RP2D cohort will evaluate drug-drug interactions. This includes the MDZ, 
rifampin and itraconazole interaction sub-studies noted above.  

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a. The MDZ interaction sub-study requires 8 evaluable patients. Enrollment is 
closed with a total of 15 patients treated.
b. The Rifampin interaction sub---study requires 8 evaluable patients. 
Enrollment is closed with a total of 18 patients treated.
c.
The Itraconazole interaction sub--study requires 8 evaluable patients. 
Enrollment is closed with a total of 18 patients treated.
2. The second RP2D cohort will be composed of an enriched population of 
approximately 484 patients:  
a. A group of ALK marker positive NSCLC patients.  Enrollment is closed with a 
total of 154 patients treated.
b. Three categories of NSCLC patients with MET amplification defined as:
a.
MET/CEP7 (centromeric region of chromosome 7) ratio of 5.0 
(Group 1); As per the Protocol Administrative Clarification Letter 
(PACL) dated 15 May 2017, the MET/CEP7 ratio cut-off for this 
group was revised to ≥4.0. As per the PACL dated 11 September 
2018, this group was closed to further enrollment. The remaining 14 
enrollment slots were transferred to the MET exon 14 alterations 
subgroup within the Enriched Other cohort.
b. MET/CEP7 ratio of >2.2 to <5.0 (Group 2); As per the PACL dated 
15 May 2017, the MET/CEP7 ratio cut-off for this group was revised 
to >2.2 to 4.0 and this group was closed to further enrollment. The 
remaining 13 enrollment slots were transferred to the MET Exon 14 
alterations subgroup within the Enriched Other cohort;
c.
MET/CEP7 ratio of 1.8 to 2.2 (Group 3); As per the PACL dated 12 
October 2015, this group was closed to further enrollment.  
c.
A total of 68 slots are planned for enrollment. As of IRB/EC approval of 
Protocol Amendment #24, enrollment is closed with 41 patients treated.
Further details for the MET amplified NSCLC cohort are provided in 
Appendix 9. 
d. A group of 50 NSCLC patients positive for chromosomal translocations at 
ROS1 gene, including but not limited to CD74-ROS1 and SLC34A2-ROS1
fusion events, will be enrolled.  Enrollment is closed with 50 patients treated.  
Further details for the ROS1 marker positive NSCLC cohort are provided in 
Appendix 10.
e.
Approximately 171 patients with disease with molecular markers (other than 
ALK marker positive NSCLC and ROS1 marker positive NSCLC) that may 
confer sensitivity to PF-02341066 may also be enrolled into an ‘Enriched 

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Other’ cohort.  This cohort also includes NSCLC patients with tumors 
harboring MET Exon 14 alterations.  Sponsor approval is required for 
enrollment.  Further details for the Enriched Other cohort are provided in 
Appendix 11. After IRB/EC approval of Amendment #18, patients with 
NSCLC that is positive for ALK chromosomal translocations or gene 
amplifications will not be allowed to enter the Enriched Other cohort. As of 
the PACL dated 07 December 2017, the remaining 13 open enrollment slots in 
the Enriched Other cohort were assigned specifically to NSCLC patients with 
tumors harboring MET Exon 14 alterations rather than the broader Enriched 
Other cohort.  Thus, the Enriched Other cohort will be open only for 
enrollment of NSCLC patients with MET Exon 14 alterations. As of the 
Investigator Communication Letter dated January 7, 2019, further enrollment 
of NSCLC patients with tumors harboring MET exon 14 alterations is closed.
f.
ALK Marker Negative NSCLC Cohort #1: This cohort will consist of NSCLC 
patients who are negative for the ALK translocation as determined by the ALK 
break apart fluorescence in situ hybridization (FISH) assay used in Protocols 
A8081007 and A8081005.  A minimum of 25 to a maximum of 50 evaluable 
patients will be enrolled into this cohort.  Patients will be dosed at the RP2D, 
ie, 250 mg BID of PF-02341066, with a cycle length of 3 weeks. Enrollment 
is closed with 47 patients treated.
g. ALK Marker Negative NSCLC Cohort #2: This cohort will consist of NSCLC 
patients who are negative for the ALK translocation as determined by the ALK 
break apart fluorescence in situ hybridization (FISH) assay as determined by 
the central laboratory selected by the Sponsor.  Patients may have been 
pre-screened and determined to have ALK-marker negative NSCLC by a local 
test but no molecular testing for MET or ROS1 should have occurred prior to 
enrollment.  As of Note to File dated 19 June 2012, the requirement that no 
molecular testing for MET or ROS1 was to occur prior to enrollment was 
removed.  Thus, MET or ROS1 testing may have been performed prior to 
patient entry into this cohort.  However if the test result for either MET or 
ROS1 was positive, then the patient could not be enrolled into this cohort.  At 
least 20 patients will be enrolled into this cohort.  Patients will be dosed at the 
RP2D, ie, 250 mg BID of PF-02341066, with a cycle length of 3 weeks.  
Enrollment is closed with 21 patients treated.  Please see Appendix 8 for 
further details.
  In addition, if possible, up to 6 patients will undergo 
pre- and post-dose [18F]-fluorothymidine (FLT)-positron emission tomography (PET).  Also, 
if possible, the same patients who have biopsies performed, will undergo [18F]-FLT-PET. 
A separate sub-study with at least 6 evaluable patients with MET mutation or amplification 
will undergo pre- and post-dose [18F]-FLT-PET and [18F]-fluorodeoxyglucose (FDG)-PET.  
With the approval of Amendment #13 by the IRB/EC, no additional patients will undergo 
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PET imaging.  Finally, 12 evaluable patients in this cohort will participate in a fed/fast 
sub-study.  Clinical sites in Korea will not participate in this sub-study.  Depending upon the 
overall results from the RP2D cohorts, a different dose/schedule may be tested in additional 
cohorts.
Statistical Methods:
This is a Phase 1, open-label, multi-center, dose escalation study.  The number of patients to 
be enrolled will depend upon the observed safety profile and study objectives, which will 
determine the number of patients per dose level, the number of dose escalations and the 
number of cohorts.  Approximately 600 patients will be enrolled in the study including 
patients in the dose escalation and RP2D cohorts [see Figure 1].  All patients who receive at 
least 1 dose of PF-02341066 will be included in the study analyses.  All data will be 
tabulated and summarized using descriptive statistics. 
The plasma concentration-time data of PF-02341066 will be analyzed using 
non-compartmental methods to derive standard pharmacokinetic (PK) parameters including 
AUC0-last, Cmax and Tmax for individual patients.  Descriptive statistics of the PK parameters 
will be provided in tabular form.  The plasma concentration-time data of MDZ will be 
analyzed using non-compartmental methods to derive standard PK parameters including 
AUC0-last, Cmax and Tmax.  In the RP2D cohort, a mixed effects model will be used to analyze 
log-transformed MDZ AUC0-last for evaluation of the potential CYP3A4 inhibition due to 
PF-02341066.  In the rifampin and itraconazole drug-drug interaction sub-studies, a mixed 
effect model will be used to analyze log-transformed PF-02341066 AUC0-tau to assess the 
interaction. 
Inferential statistics will be provided for assessing food effect, inhibition of CYP3A and the 
comparison of anti-tumor effects in ALK marker negative NSCLC patients and ALK marker 
positive NSCLC patients (from Protocols A8081007 and/or A8081005, as appropriate).  In 
the food effect sub-study, a mixed effect model will be used to analyze log transformed 
AUC0-last between fasting and fed conditions for the evaluation of the food effect.

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Schedule of Activities
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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.
***  See Appendix 6 (Rifampin Sub-study) and Appendix 7 (Itraconazole Sub-study), Appendix 8 (ALK-Negative NSCLC 
Cohort #2), Appendix 9 (patients with MET-amplified NSCLC), Appendix 10 (ROS1 marker positive NSCLC patients), and 
Appendix 11 (Enriched Other cohort).
Note: Upon IRB/EC approval of Protocol Amendment #24, ongoing patients will follow a Reduced Schedule of Activities as indicated 
in Appendix 13.
Protocol Activity
Screening*
Lead-in 
PK 
Period31
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 
weeks** 
(Cycle ≥3)
Every 8 
Weeks****
End of 
Treatment
(28 Days 
Post Dose)*
Day –14 to 
Day 0
Day -7
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG)6
X
X
X
X
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination32
X [X]
[X]
[Cycle 3, one 
year and yearly 
thereafter]
[X]
Safety assessment (adverse events)11
X
X
X
X
X
X
X
Tumor assessment *,***12
X
X
X

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Protocol Activity
Screening*
Lead-in 
PK 
Period31
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 
weeks** 
(Cycle ≥3)
Every 8 
Weeks****
End of 
Treatment
(28 Days 
Post Dose)*
Day –14 to 
Day 0
Day -7
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Survival13
Until at least 1 year after the patient’s final dose (except for MET-amplified NSCLC Cohort, ROS1 marker positive NSCLC 
Cohort and NSCLC patients with tumors harboring MET Exon 14 alterations enrolled into the Enriched Other Cohort)
Concomitant medications14
X
X
X
X
X
X
Contraceptive Check (as applicable)34
X
X
X
X
X
Female patients: Pregnancy test15
X
X
X
X
X
Special Laboratory Studies
Plasma sampling for full PF-02341066 PK in 
patients not participating in the MDZ study16
X
X
X
X
Plasma sampling for full PF-02341066 PK in 
patients participating in the MDZ study17
X
X
X
Two plasma sampling points for 
PF-02341066 PK18
X
X (up to Cycle 
5; also at 
disease 
progression if 
patient is still 
taking
PF-02341066)  
Plasma sampling for full MDZ PK19
X
X
Blood sample for PF-02341066 metabolite 
profiling20
X
Blood sample for pharmacogenomics21
(Optional for clinical sites in Japan)
X
24-hour urine collection for PF-0234106622
X
Urine Sample for 6 
beta-hydroxycortisol/cortisol (6ß-OHC/C) 
ratio23
X
X
X
Plasma sample for circulating free nucleic 
acid profiling27 (As per the Protocol
Administrative Clarification Letter dated 12
October 2015, applicable only to NSCLC 
patients with tumors harboring MET Exon 14 
alterations and will be collected only at 
screening and End of Treatment)
X
X
X
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Protocol Activity
Screening*
Lead-in 
PK 
Period31
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 
weeks** 
(Cycle ≥3)
Every 8 
Weeks****
End of 
Treatment
(28 Days 
Post Dose)*
Day –14 to 
Day 0
Day -7
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
[18F]-FLT-PET and [18F]-FDT-PET30
X
X
PF-02341066 treatment28
X
Once a day or twice a day continuously
MDZ Treatment for patients participating in 
the MDZ study29
X
X
Male patients: Hypogonadism Testing for  
MET-amplified NSCLC and Enriched Other 
cohorts33
(Patients enrolled in Japan will not participate 
in hypogonadism testing)
X
X
X
Cycles 4, 6 and 
every 3 cycles 
thereafter
X
( ) If it has not been performed within 7 days.  
* Allowable window for tumor assessment imaging is 7 days; 2 days for all other assessments. 
* Allowable window for screening assessments is up to -7 days from Day -14 (ie, Day -21 to Day 0).
* End of Treatment (EOT) visit should be conducted 28 days postdose 2 days. If a patient withdraws from study treatment and new anticancer is subsequently 
administered, the EOT visit should occur prior to the initiation of new anticancer therapy.
[ ] Special ophthalmology tests for all NSCLC patients enrolled following IRB/EC approval of Amendment #17 until written notification by Sponsor.  As of the 
Note To File issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: 
refractive error, pupil size, intraocular pressure, ocular coherence tomography, dilated fundus photography.  See Section 7.3 for additional details.
**Cycle length is 4 weeks (28 days) except for ALK marker negative NSCLC patients in which cycle length is 3 weeks (21 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.  Once a patient has completed 15 cycles, tumor imaging may be 
performed every fourth cycle (every 12 weeks for the ALK marker negative NSCLC cohort based on 3-week calendar schedule).  For patients on 4-week cycles, 
once a patient has completed 24 cycles, tumor imaging may be performed every sixth cycle (every 24 weeks). However, for patients on 3-week cycles, once a 
patient has completed 35 cycles, tumor imaging may be performed every eighth cycle (every 24 weeks).  If tumor imaging was done within 6 weeks of the last 
dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
****Every 6 weeks for ALK marker negative NSCLC patients.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
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6.
12-Lead ECG: Three consecutive 12-lead ECGs will be performed at least 2 minutes apart during the screening period; Cycle 1 Day 1 at pre-dose (0 hour), 6 hours post-dose 
(4 hours as of June 16, 2008) (~Cmax), and 24 hours post-dose; Cycle 1 Day 15 and Cycle 2 Day 1 at pre-dose and 6 hours (4 hours as of June 16, 2008) (~Cmax) post-dose.  
Once IRB/EC approval of Amendment #17, patients in the RP2D cohorts and ALK Marker Negative NSCLC RP2D Cohort #2 will have triplicate ECGs collected at least 2 
minutes apart during the screening period; Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose (0 hour) and 2-6 hours post-dose which are corresponding to PK time points.  ECGs 
should be performed before PK blood draws at respective time points.  In addition to the time points noted, ECGs should be repeated as clinically indicated.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, alanine aminotransferase (ALT), asparatate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), total 
protein, albumin, sodium, potassium, chloride, CO2 (bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose. Upon IRB/EC approval of Amendment #23, 
indirect bilirubin will no longer be collected.  If ALT or AST Grade 3 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.  C2D15 chemistry required after approval of Amendment #20.
9.
Coagulation: PT and PTT.
10. Urinalysis: For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. Tumor Imaging: CT or MRI scan to be performed to assess disease status at screening, every 8 weeks, whenever disease progression is suspected (eg, symptomatic 
deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at the end/withdrawal from study treatment.  For 
patients in the ALK marker negative NSCLC cohort, tumor assessments will be performed every 6 weeks (based on a calendar schedule) starting after the first dose.  If renal 
cysts are observed, active surveillance with appropriate imaging should be performed at the time of renal cyst diagnosis and thereafter following the same schedule as for 
tumor imaging.
13. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment until at least one year after the patient’s final dose. For 
ROS1 marker positive NSCLC cohort, MET-amplified NSCLC cohort and MET Exon 14 alterations NSCLC patients (in the Enriched Other cohort, excluding patients 
enrolled in clinical sites in Japan): As of IRB/EC approval of Amendment #22, all patients enrolled into these cohorts should be followed for survival every 3 months after 
discontinuing study treatment until one year after the last patient in each of these cohorts has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.
As of IRB/EC approval of Amendment #23, all patients enrolled into these cohorts should be followed for survival every 3 months after discontinuing study treatment until 
two years after the last patient in each of these cohorts has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.  For NSCLC patients with tumors 
harboring MET exon 14 alterations enrolled in clinical sites in Japan: survival shall be followed every 3 months after discontinuing study treatment until two years after the 
last patient from Japan has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.
14. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from study treatment, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, 
whichever is later.
15. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  As of June 16, 2008, this test should be repeated 
whenever one menstrual cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of Institutional 
Review Board (IRB)/Ethic Committee (EC) or if required by local regulations.  As of IRB/EC approval of Protocol Amendment #21, for female patients of childbearing 
potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting study therapy; once at Screening and once 
at Cycle 1 Day 1 before PF-02341066 administration. Pregnancy tests will also be routinely repeated at every treatment cycle, at the end of treatment, and additionally 
whenever 1 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 
study medication.  Additional pregnancy tests may also be undertaken if requested by IRBs/ECs or if required by local regulations.  See Section 7.2 for further detail.

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16. See Section 7.5.1.1 for detailed procedures.
17. See Section 7.5.1.1 for detailed procedures.
18. Two PK sampling points (pre-dose and 4-8 hours [2-8 hours as of May 1, 2007] post-dose) will be obtained on Day 15 of Cycle 2, Day 1 of Cycle 3 and Day 1 of subsequent 
cycles (up to Cycle 5) for all patients.  Upon IRB/EC approval of Amendment #18, patients in the RP2D cohorts (ie, MET-amplified NSCLC and Enriched Other cohorts) and 
ALK Marker Negative NSCLC Cohort #2 will have PK samples collected on Day 1 of Cycle 1, 2, 3 and 5 at pre-dose (0 hour) and 2-6 hours post-dose.  In addition, for 
patients in the MET-amplified NSCLC, ROS1 marker positive NSCLC and Enriched Other cohorts, a PK sample should be taken around the time that disease progression is 
confirmed as long as the patient is on PF-02341066.
19. In the MDZ interaction sub-study, a pharmacokinetic profile of MDZ will be collected after a single oral MDZ dose on Day –7 (lead-in period) and Cycle 2 Day 1 at the 
following time points: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose.
20. A 5-mL blood sample will be collected at 4-8 hours post dose on Cycle 1 Day 15 in the RP2D midazolam interaction cohort for metabolite profiling of PF-02341066.
21. Blood sample for pharmacogenomics: A single whole blood biospecimen (4 mL) will be collected at baseline (within 2 weeks prior to the first dose) for possible analysis of 
DNA sequence variation in genes that may affect PK of the study drugs, may be associated with specific adverse events or toxicities, or may correlate with efficacy. (For 
patients enrolled in clinical sites in Japan: blood sample for pharmacogenomics is optional)  
22. Urine will be collected for 24 hours after PF-02341066 dosing on Cycle 1 Day 15 in the RP2D midazolam interaction cohort over the following intervals: 0 to 4 hours, 4 to 
12 hours and 12 to 24 hours post-dose.
23. Morning spot urine sample will be collected on Day 1 of Cycle 1, Day 15 of Cycle 1 and Day 1 of Cycle 2.  Once IRB/EC approval of Amendment #17, these samples will no 
longer be collected.
27. Plasma sample for circulating nucleic acid profiling (MET-amplified NSCLC and Enriched Other cohorts only): As of IRB/EC approval of Amendment #21, blood 
biospecimen (10 mL) for nucleic acid analysis (eg, circulating free DNA [cfDNA] or RNA [cfRNA]) will be collected.  As of the Protocol Administrative Clarification Letter
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dated 12 October 2015, plasma sample for circulating nucleic acid profiling is applicable only to NSCLC patients with tumors harboring MET Exon 14 alterations and only 
required at Screening and End of Treatment.
28. A single dose of PF-02341066 will be given on Day –7 (lead-in period) for all patients except the patients who are scheduled for the MDZ interaction sub-study.  After 
IRB/EC approval of Amendment #16, Day -7 dosing will only be required for dose escalation cohorts.
29. For patients who are scheduled for the MDZ interaction sub-study only.  A 2-mg single oral dose of MDZ will be given on Day –7 and Cycle 2 Day 1.  On Cycle 2 Day 1, 
MDZ will be given concurrently with PF-02341066.
30. If a biopsy is obtained, it should be performed no more than 3 days following completion of both [18F]-FLT-PET and [18F]-FDG-PET.  [18F]-FLT-PET and [18F]-FDG-PET 
should be performed at least 24 hours apart.  With the approval of Amendment #13 by the IRB/EC, no additional patients will undergo PET imaging. 
31. Not required for additional patients who enter the study at a previous dose level when enrollment is closed for the current dose level or for patients enrolled in the RP2D 
enriched population cohort who are exempted for Day -7 dosing.  Also, upon site IRB/EC approval of Amendment #12, Day -7 dosing is also not required for non-Asian 
patients in the enriched population or ALK marker negative NSCLC cohorts.  Upon IRB/EC approval of Amendment #13, only patients enrolled in the QD dose escalation 
part of the study or Asian patients enrolled in any cohort will have the Day -7 lead-in dose.
32. Once Amendment #12 is approved by the IRB/EC, an ophthalmology examination will be performed at screening for all new patients.  The ophthalmology examination should 
be repeated during the study when visual disturbances have been observed and when there is an increase in grade for visual disturbances (includes all ongoing patients).  The 
ophthalmology examination should include ocular characteristics, visual acuity, fundoscopy and slit lamp examination.  All NSCLC patients enrolled after Amendment #17 is 
approved by the IRB/EC will undergo additional special ophthalmological testing as described in Section 7.3 until written notification by the Sponsor.  As of the Note To File
issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive error, pupil size, 
intraocular pressure, ocular coherence tomography, dilated fundus photography.  All ophthalmology examinations should be performed by an ophthalmologist.  Time points of 
this special testing are designated by “[ ]” in the Schedule of Activities Table and are performed at Screening, Cycle 1 Day 15, Cycle 3 Day 1, one year, and yearly
thereafter.  For NSCLC patients on a 4-week cycle, the yearly ophthalmology examination will be done at Cycle 14 Day 1, and every 13 cycles thereafter.  For NSCLC 
patients on a 3-week cycle, the yearly ophthalmology examination will be done at Cycle 18 Day 1 and every 17 cycles thereafter. These tests should also be done within 2-8 
weeks after discontinuation of PF-02341066.  There is a 2 week window for the yearly ophthalmology examination.
33. Hypogonadism Laboratory Tests (male patients only): All male patients enrolled into the MET-amplified NSCLC and Enriched Other cohorts after IRB/EC approval of 
Protocol Amendment #21 will have hypogonadism laboratory tests.  Required tests include: total testosterone, free testosterone, sex hormone binding globulin (SHBG), 
luteinizing hormone, follicle stimulating hormone, dihydroepiandosterone sulfate, estradiol and prolactin.  Blood draws MUST be taken before PF-02341066 dosing and 
between 07:00 and 10:00 a.m. and, for each individual patient, the time of the draw should be as consistent across visits as feasible.  If either total testosterone or free 
testosterone  decrease to a value that is both 25% lower than baseline and below the lower limit of normal, then a repeat laboratory test of both of these parameters must be 
performed at the next clinic visit to confirm hypogonadism.  Note: Patients enrolled in clinical sites in Japan will not participate in hypogonadism testing.  See Section 7.2, 
Appendix 9, Appendix 11, and Appendix 12 for further details.
34. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 and, upon IRB/IC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods 
are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................41
LIST OF FIGURES .................................................................................................................41
APPENDICES .........................................................................................................................42
1. INTRODUCTION ...............................................................................................................43
1.1. Background .............................................................................................................43
1.2. Rationale..................................................................................................................48
1.2.1. Rationale for Selection of Starting Dose ....................................................49
1.2.2. Rationale for Evaluation of Midazolam (MDZ) Interaction.......................50
2. TRIAL OBJECTIVES .........................................................................................................50
2.1. Trial Endpoints........................................................................................................51
3. TRIAL DESIGN..................................................................................................................52
4. PATIENT SELECTION......................................................................................................52
4.1. Inclusion Criteria.....................................................................................................53
4.2. Exclusion Criteria....................................................................................................55
4.3. Withdrawal Criteria.................................................................................................57
4.4. Randomization Criteria ...........................................................................................58
4.5. Life Style Guidelines...............................................................................................58
4.5.1. Contraception..............................................................................................58
4.5.2. Sunlight Exposure.......................................................................................59
4.5.3. Dietary Restrictions ....................................................................................59
4.6. Sponsor’s Qualified Medical Personnel..................................................................60
5. TRIAL TREATMENTS ......................................................................................................60
5.1. Management of Selected PF-02341066-Related Adverse Events...........................68
5.1.1. Nausea and Emesis .....................................................................................68
5.1.2. Diarrhea ......................................................................................................68
5.1.3. Bradycardia.................................................................................................68
5.1.4. Pneumonitis ................................................................................................69
5.1.5. Renal Cyst...................................................................................................69
5.2. Drug Supplies..........................................................................................................74
5.2.1. Formulation and Packaging........................................................................74
5.2.1.1. PF-02341066 .............................................................................74
5.2.1.2. Midazolam (MDZ) ....................................................................74

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5.2.1.3. Rifampin....................................................................................74
5.2.1.4. Itraconazole ...............................................................................75
5.2.2. Preparation and Dispensing........................................................................75
5.2.2.1. PF-02341066 .............................................................................75
5.2.2.2. MDZ..........................................................................................76
5.2.3. Administration............................................................................................76
5.2.3.1. PF-02341066 .............................................................................76
5.2.3.2. MDZ..........................................................................................77
5.2.3.3. Rifampin....................................................................................77
5.2.3.4. Itraconazole ...............................................................................77
5.2.4. Patient Compliance.....................................................................................77
5.3. Drug Storage ...........................................................................................................78
5.4. Drug Accountability................................................................................................79
5.5. Concomitant Medication(s).....................................................................................80
5.5.1. PF-02341066...............................................................................................80
5.5.2. Antiemetic and Antidiarrheal Therapy.......................................................81
5.5.3. Hematopoietic Growth Factors...................................................................81
5.5.4. Other Concomitant Medications.................................................................81
5.5.5. Concomitant Radiotherapy or Surgery.......................................................82
6. TRIAL PROCEDURES.......................................................................................................82
6.1. Patient Withdrawal..................................................................................................82
7. ASSESSMENTS..................................................................................................................83
7.1. Adverse Events........................................................................................................84
7.2. Laboratory Safety Assessments ..............................................................................84
7.3. Other Safety Assessments .......................................................................................85
7.4. Disease Imaging Studies .........................................................................................87
7.5. Pharmacokinetics ....................................................................................................88
7.5.1. Plasma Pharmacokinetic Assessment.........................................................88
7.5.1.1. Plasma Pharmacokinetic Assessment for PF-02341066 ...........88
7.5.1.2. Plasma Pharmacokinetic Assessment for MDZ........................91
7.5.2. Urine for Analysis of PF-02341066 ...........................................................91
7.5.3. Plasma for PF-02341066 Metabolite Profiling...........................................91
7.5.4. Blood Sample for Pharmacogenomics........................................................91

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7.5.5. Urine Sample for 6 beta-Hydroxycortisol/Cortisol (6β-OHC/C) Ratio .....92
7.5.8. [18F]-FLT-PET and [18F]-FDG-PET Imaging (RP2D enriched 
population cohort only)....................................................................................93
8. ADVERSE EVENT REPORTING......................................................................................94
8.1. Adverse Events........................................................................................................94
8.2. Reporting Period .....................................................................................................94
8.3. Definition of an Adverse Event...............................................................................94
8.4. Medication Errors....................................................................................................95
8.5. Abnormal Test Findings..........................................................................................96
8.6. Serious Adverse Events...........................................................................................96
8.6.1. Protocol-Specified Serious Adverse Events...............................................97
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................97
8.7. Hospitalization ........................................................................................................98
8.8. Severity Assessment................................................................................................99
8.9. Causality Assessment............................................................................................100
8.10. Exposure During Pregnancy................................................................................100
8.11. Occupational Exposure .......................................................................................101
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient 
Withdrawal).............................................................................................................102
8.13. Eliciting Adverse Event Information ..................................................................102
8.14. Reporting Requirements......................................................................................102
8.14.1. Serious Adverse Event Reporting Requirements ...................................102
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................103
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............103
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................103
9.1. Sample Size Determination...................................................................................103
9.1.1. Dose Escalation Phase..............................................................................103
9.1.2. RP2D Midazolam Interaction Cohort.......................................................104
9.1.3. RP2D Enriched Population Cohort...........................................................104
9.1.3.1. ALK Marker Negative NSCLC Cohorts.................................105
9.1.3.2. MET-Amplified NSCLC Cohort ..............................................106
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9.1.3.3. ROS1 Marker Positive NSCLC Cohort ..................................107
9.1.3.4. Enriched Other Cohort ............................................................107
9.1.4. RP2D Rifampin Interaction Sub-study.....................................................109
9.1.5. RP2D Itraconazole Interaction Sub-study................................................109
9.1.6. Hypogonadism..........................................................................................110
9.2. Analysis.................................................................................................................110
9.2.1. Efficacy Analysis......................................................................................110
9.2.1.1. Analysis of ALK Marker Negative NSCLC Cohorts................111
9.2.1.2. Analysis of MET-Amplified NSCLC Categories ...................111
9.2.1.3. Analysis of ROS1 Marker Positive NSCLC Cohort ................111
9.2.1.4. Analysis of Enriched Other Cohort.........................................112
9.2.1.5. Hypogonadism Testing ...........................................................112
9.2.2. Analysis of Pharmacokinetics...................................................................112
9.2.2.1. Single- and Multiple-Dose PF-02341066 PK Analysis ..........112
9.2.2.2. Effect of PF-02341066 on MDZ PK.......................................113
9.2.2.3. Effect of Food on PF-02341066 PK........................................113
9.2.2.4. Effect of Rifampin on PF-02341066 PK.................................113
9.2.2.5. Effect of Itraconazole on Single- and Multiple-Dose
PF-02341066 PK.............................................................................113
9.2.4. Pharmacogenomics Analysis....................................................................114
9.2.6. Urinary 6 beta-Hydroxycortisol/Cortisol Ratio........................................115
9.2.7. PK/PD Modeling ......................................................................................115
9.2.8. Safety Analysis .........................................................................................115
9.2.9. [18F]-FLT-PET Analysis...........................................................................116
9.3. Interim Analysis ....................................................................................................116
9.4. Data Monitoring Committee .................................................................................116
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................117
11. DATA HANDLING AND RECORD KEEPING ...........................................................117
11.1. Case Report Forms/Electronic Data Record .......................................................117
11.2. Record Retention.................................................................................................118
12. ETHICS............................................................................................................................118
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12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................118
12.2. Ethical Conduct of the Trial................................................................................119
12.3. Patient Information and Consent.........................................................................119
12.4. Patient Recruitment.............................................................................................120
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................120
13. DEFINITION OF END OF TRIAL.................................................................................120
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................120
15. PUBLICATION OF TRIAL RESULTS..........................................................................120
16. REFERENCES ................................................................................................................122
LIST OF TABLES
Table 1.
Dose Limiting Toxicities...........................................................................62
Table 2.
Dose Modifications for PF-02341066 Associated Toxicity.....................70
Table 3.
Probability of Escalation to the Next Dose for Each True 
Underlying DLT Rate at a Dose Level ...................................................103
Table 4.
Probability of Failing to Observe Toxicity (at Least One DLT Given 
the True Underlying DLT Rate) at a Dose Level....................................104
Table 5.
Expected Precision for Effect of PF-02341066 on MDZ (90% CI, 
80% coverage probability, 25% CV)......................................................104
Table 6.
Power Calculation for ALK Marker Negative NSCLC Cohort #1 .........105
Table 7.
Expected Precision for Effect of Rifampin on PF-02341066 (90% 
CI, 80% Coverage Probability, 25% CV) ..............................................109
Table 8.
Expected Precision for Effect of Itraconazole on PF-02341066 
(90% CI, 80% Coverage Probability, 25% CV......................................110
Table 9.
Determination of Best Overall Response ...............................................128
Table 10.
Response Evaluation Criteria in Solid Tumors ......................................134
Table 11.
Best Overall Response When Confirmation of CR and PR Required....135
Table 12.
Drugs Whose Plasma Concentrations May Be Increased By 
Itraconazole1...........................................................................................150
LIST OF FIGURES
Figure 1.
Summary of RP2D Cohorts Based on Protocol Amendment #24............24
Figure 2.
Summary of 1-Month Repeat-Dose Toxicodynamics for 
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Figure 3.
Summary of RP2D Cohorts Based on Protocol Amendment #24............52
Figure 4.
Example of Dose Escalation Scenario......................................................67
Figure 5.
Schema for Design of PF-02341066 and Rifampin Interaction 
Sub-Study................................................................................................141
Figure 6.
PF 02341066 and Itraconazole Schema: Multiple Dose-Design...........155
Figure 7.
PF-02341066 and Itraconazole Interaction Schema: Single and 
Multiple-Dose Design.............................................................................156
APPENDICES
Appendix 1. Serious Adverse Event Reporting.....................................................................124
Appendix 2. ECOG Performance Status................................................................................125
Appendix 3. RECIST version 1.0 Tumor Assessment Criteria17...........................................126
Appendix 4. Common Terminology Criteria for Adverse Events v3.0.................................129
Appendix 5. RECIST version 1.1 Tumor Assessment Criteria18...........................................130
Appendix 6. Rifampin Drug-Drug Interaction Sub-Study.....................................................136
Appendix 7. Itraconazole Drug-Drug Interaction Sub-Study ...............................................145
Appendix 8. ALK Marker Negative NSCLC RP2D Cohort #2..............................................165
Appendix 9. MET-Amplified NSCLC Cohort.......................................................................172
Appendix 10. ROS1 Marker Positive NSCLC Cohort ..........................................................182
Appendix 11. Enriched Other Cohort ....................................................................................190
Appendix 12. Hypogonadism Testing ...................................................................................200
Appendix 13. Reduced Schedule of Activities ......................................................................201

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ITALICIZED TEXT IS OUTDATED INFORMATION AND SHOULD BE 
DISREGARDED
1. INTRODUCTION
1.1. Background
Human cancers comprise a diverse array of diseases that collectively are one of the leading 
causes of death in developed countries throughout the world (American Cancer Society, 
2005).1  The progression of cancers is caused by a complex series of multiple genetic and 
molecular events including gene mutations, chromosomal translocations, and karyotypic 
abnormalities (Hanahan & Weinberg, 2000).3  Although the underlying genetic causes of 
cancer are both diverse and complex, each cancer type has been observed to exhibit common 
traits and acquired capabilities that facilitate its progression.  These acquired capabilities 
include dysregulated cell growth, sustained ability to recruit blood vessels (ie, angiogenesis), 
and ability of tumor cells to spread locally as well as metastasize to secondary organ sites 
(Hanahan & Weinberg, 2000).3  Therefore, the ability to identify novel therapeutic agents 
that 1) inhibit molecular targets that are altered during cancer progression or 2) target 
multiple processes that are common to cancer progression in a variety of tumors is predicted 
to yield improved therapeutic benefit.
PF-02341066
Chemical Structure:
O
Cl
Cl
F
N
NH2
N
N
NH
Chemical Name: 
(R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridi
n-2-ylamine
Molecular Formula: C21H22Cl2FN5O
PF-02341066 is a small-molecule inhibitor of the MET (mesenchymal-epithelial transition
factor)/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.  

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Recent examples include Gleevec® in gastrointestinal stromal tumors with mutant c-Kit or 
chronic myelogenous leukemia with BCR-Abl gene translocations, Tarceva® in non-small 
cell lung cancer with mutant EGFR, Herceptin® in breast cancers with amplified HER-2/neu, 
and SU11248 targeting the VHL-dependent VEGF pathway in renal cell carcinoma.  An 
extensive body of literature indicates that MET/HGFR is one of the most frequently mutated 
or otherwise abnormally activated RTKs in various human cancers (Christensen et al, 2005).2  
Tumor types in which MET/HGFR was reported to be genetically altered by mutation or 
gene amplification include oncology indications with a strong unmet medical need such as 
renal, metastatic colorectal, glioma, non-small cell lung, gastric, and head and neck cancers 
(Christensen et al, 2005).2  In addition, PF-02341066 demonstrated potent activity against 
NPM-ALK, an oncogenic fusion protein variant of the Anaplastic Lymphoma Kinase, which 
results from a chromosomal translocation which is implicated in the pathogenesis of human 
anaplastic large cell lymphoma (Pulford et al, 2004).4  In addition to the rationale for 
PF-02341066 based on the genetic dysregulation of its tyrosine kinase targets, an additional 
rationale is based on its predicted ability to target multiple processes that are common to 
cancer progression in a variety of tumors.  Inappropriate activation of MET/HGFR (including 
wild-type MET) is implicated in dysregulation of multiple tumor oncogenic processes such 
as mitogenesis, survival, angiogenesis, invasive growth, and especially in the metastatic 
process (Christensen et al, 2005).2  Furthermore, the expression of MET and HGF, its sole, 
high-affinity ligand, were demonstrated to correlate with poor prognosis or metastatic 
progression in a number of major human cancers (Christensen et al, 2005).2  The other 
molecular target of PF-02341066, NPM-ALK, is implicated in the dysregulation of cell 
proliferation and apoptosis in ALCL lymphoma cells (Pulford et al, 2004).4  Consistent with 
its predicted mechanism of action, PF-02341066 inhibited target-dependent tumor cell 
proliferation or invasion, induced tumor cell apoptosis, and inhibited angiogenesis in 
nonclinical tumor models.  Oral administration of PF-02341066 also demonstrated efficacy, 
including marked cytoreductive antitumor activity, in several tumor models that expressed 
activated MET/HGFR or NPM-ALK.  The collective rationale for investigation of 
PF-02341066 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 
preclinical efficacy data. 
Safety:
The primary PF-02341066 toxicities in nonclinical studies were observed in the 
gastrointestinal tract (rat, dog, monkey), hematopoietic system (rat, dog, monkey), kidneys 
(rat), reproductive organs (rat), and actively growing long bones (rat).  Additional effects 
related to PF-02341066 administration involved the cardiovascular system based on safety 
pharmacology studies, and genetic toxicity findings.  Other findings of uncertain risk to 
humans include the decreased cellularity in lymphoid organs, elevated liver enzymes, 
potential for phototoxicity, and effects on the salivary glands.
Gastrointestinal Effects: Clinical signs of diarrhea were observed in rats (500 mg/kg/day), 
dogs (6 mg/kg/day), and monkeys (50 mg/kg/day).  Focal edema was observed in the 
gastric submucosa in rats given 500 mg/kg/day for 4 days, as well as focal ulceration, 
inflammation, and glandular hyperplasia in one female.  Gastrointestinal effects were not 
observed in the 1-month study in rats, where doses were tolerated for the full term of the 

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study.  Emesis and diarrhea were dose-limiting toxicities observed during the single-dose 
escalation range-finding study in dogs.  Following single doses of 10, 25, and 40 mg/kg, 
severe gastrointestinal effects were observed, including bloody emesis and diarrhea, along 
with mucous membranes in the feces.  Histopathological examination of the intestines 
revealed blood-filled dilated mucosal and submucosal vessels (congestion) and luminal 
contents of mucus admixed with low numbers of neutrophils.  In the 1-month study in dogs, 
PF-02341066 at 6 mg/kg/day induced emesis, the incidence and frequency of which 
decreased as the study progressed, and occasional diarrhea.  There was no effect on food 
consumption or body weight, and no histopathological correlate was identified at the end of
the study.  Diarrhea and soft feces were also observed in monkeys given 50 mg/kg/day of 
PF-02341066.  A decrease in phosphorus observed in this study may have been related to 
decreased intestinal absorption.  Marked cecal erosion and ulceration were observed in one 
monkey euthanized moribund on Day 21. 
Kidney Effects: Microscopic evidence of minimal to mild renal cortical tubule vacuolation 
was observed following 28 days of dosing in male rats treated with 50 mg/kg/day of 
PF-02341066.  Urinalysis revealed significant decreases in urine pH from 50 mg/kg/day in 
males and at 150 mg/kg/day in females.  The mechanism for renal tubular vacuolation is not 
known, however HGF is highly expressed in the kidney tubular epithelium (Birchmeier, 
2003)5 with reported cytoprotective effects on renal tubular epithelium (Liu, 1998).6  
Testes Effects: Microscopic evidence of minimal testicular pachytene spermatocyte 
degeneration was observed in rats given 50 mg/kg/day of PF-02341066 for 28 days.  The 
mechanism responsible for the degenerative effects in the testes is not understood, however 
MET is known to be expressed on human seminiferous epithelium and on immature and 
mature spermatozoa (Depuydt, 1996).7
Hematopoietic Effects: Bone marrow hypocellularity was observed in toxicity studies in rats 
and monkeys with PF-02341066.  Repeated administration of PF-02341066 for 28 days 
caused bone marrow hypocellularity at doses of 150 mg/kg/day (rats, males only) and 
50 mg/kg/day (monkeys).  Minimal bone marrow hypocellularity was also produced in rats 
of both sexes when PF-02341066 was administered for shorter time duration (2 days at 
2000 mg/kg and 4 days at 500 mg/kg/day).  Bone marrow hypocellularity was not observed 
in dogs, however a decrease in white blood cells was identified following 3 single doses up 
to 40 mg/kg and 7 days of PF-02341066 at 20 mg/kg/day.  In monkeys, cytospin examination 
showed evidence of increased numbers of macrophages and debris consistent with bone 
marrow cytotoxicity, and correlated with the bone marrow hypocellularity observed 
histopathologically.  Hematological analysis revealed decreased reticulocyte counts and
suggested suppression of erythroid production within the bone marrow.  In addition, WBC 
precursors lacked granulation characteristically present in these cells suggesting potential 
peroxidase deficiency in granulocytes.  This change in granulation was also noted in dogs 
given 20 mg/kg/day for 28 days.  Vacuolated lymphocytes were identified in male rats given 
150 mg/kg/day, the significance of which is unclear. 
Lymphoid Tissue Effects: Lymphoid depletion was observed in the thymus, spleen, lymph 
nodes, or GALT in rats and dogs given PF-02341066.  Findings in rats given 500 mg/kg/day 
for 4 days were attributed to stress (stress leukogram and clinical signs of intolerance were 

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observed).  Decreased cellularity was also observed in lymphoid organs in the 1-month study 
in rats at 50 mg/kg/day, however, these findings were considered of uncertain origin.  
Decreased thymus weight (6 mg/kg/day) correlated to thymic lymphoid depletion in male 
dogs given 20 mg/kg/day PF-02341066 for 28 days, and was also considered to be of 
uncertain relationship to treatment. 
Cardiovascular Effects: In vivo cardiovascular effects were observed in the safety 
pharmacology study in anesthetized dogs.  PF-02341066 administration was associated with 
decreases in heart rate and increases in LVEDP at 84 and 164 ng/mL free plasma 
concentration.  There were also statistically significant differences compared with 
vehicle-treated animals in myocardial contractility (LV+dP/dt) at 164 ng/mL free plasma 
concentration.  Although there was a statistically significant decrease in myocardial 
contractility, it should be noted that the actual myocardial contractility values in the treated 
animals were similar to the pre-dose values.  The main effects of PF-02341066 on ECG 
parameters were statistically significant increases in PR interval, QRS, and QT interval at 
84 and 164 ng/mL free plasma concentration.  The prolongation of PR-interval, QRS and 
QT-interval is probably due to the reduction in heart rate observed at these doses.  
Monophasic action potential duration during cardiac pacing is a heart rate-independent index 
of cardiac repolarization.  There were statistically significant increases in MAPD100 at sinus 
rhythm at 84 and 164 ng/mL free plasma concentration.  The increases in MAPD100 at sinus 
rhythm were consistent with the decreases observed in heart rate.  The plasma concentrations 
of PF-02341066 achieved in this study were up to 44 times the free efficacious plasma level 
predicted in humans (8.1 nM or 3.7 ng/mL).  In vitro, PF-02341066 blocked potassium 
currents or human ether-a-go-go-related gene (hERG) channel conduction with IC50 and IC20
values of 1.1 M (495 ng/mL) and 0.3 M (135 ng/mL), respectively.  In the rat aortic 
tension model, in vitro dog isolated Purkinje fibers, and in freshly isolated Guinea pig 
ventricular myocytes, PF-02341066 produced effects consistent with calcium channel 
antagonism.  The hERG assay, rat aortic model, Guinea pig myocyte assay, and Purkinje 
fiber data suggest that PF-02341066 is mixed-channel blocker and this may explain the lack 
of effect on MAPD100 during pacing in this study.  The decrease in diastolic blood pressure 
observed at a free plasma concentration of 164 ng/mL may reflect the calcium channel 
antagonist effects observed in the rat isolated aorta model.  The nonclinical data suggest that 
free plasma concentrations greater than or equal to 84 ng/mL may produce changes in the 
heart rate and at higher free plasma concentrations (164 ng/mL) changes in diastolic blood 
pressure.
Bone Effects: Repeated administration of PF-02341066 for 28 days caused minimal 
decreased bone formation at the primary spongiosa of growing long bones at a dose of 
150 mg/kg/day in male rats.  Though an off-target relationship cannot be ruled out, reports of 
in vitro data describe possible autocrine regulation of osteoclasts, paracrine regulation of 
osteoblasts (Grano, 1996),8 and modulation of bone resorptive activity of osteoclasts in 
response to HGF (Fuller, 1995),9 that may be suggestive of a pharmacological effect on bone.  
This toxicity is not expected in the adult patient population, whose growth plates are inactive.
Liver Effects: An elevation in liver enzymes (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST]) was observed in rats and monkeys given PF-02341066. Rats given 
2000 mg/kg/day for 2 days, 500 mg/kg/day for 4 days, or 50 mg/kg/day for 28 days showed 

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an elevation in liver enzymes without a microscopic correlate.  Monkeys given 50 mg/kg/day 
of PF-02341066 also had elevated ALT and AST without histological correlate.  The 
elevation of liver enzymes is of uncertain relevance.
Genotoxic Effects: PF-02341066 was associated with an increased frequency of structural 
chromosomal aberrations in the in vitro cytogenetics assay with and without metabolic 
activation under the 3-hour test condition.  In addition to the clastogenic response, the 
kinetochore staining results from the in vitro micronucleus evaluation and the observation of 
polyploidy in the cytogenetics assay were consistent with an aneugenic response to
PF-02341066.  Increased incidences in micronucleated polychromatic erythrocytes (and 
micronucleated normochromatic erythrocytes) were observed at all doses evaluated in vivo 
(rat) in males only.  The increases in micronuclei were associated with changes in other bone 
marrow parameters consistent with bone marrow toxicity. 
Phototoxic Effects: PF-02341066 potential for phototoxicity was evaluated due to significant 
absorbance in the UVA-UVB/visible range from 290 to 700 nm with a molar extinction 
coefficient of ≥1000 L/Mol/cm, and its photodegradative property.  PF-02341066 was 
evaluated in the 3T3 fibroblast NRU assay with probable phototoxicity results.  Distribution 
of PF-02341066 to tissues with likely sun exposure is not known.  Patients will be advised to 
avoid excessive sun exposure while on trial, eg by wearing long sleeve clothing and 
sunglasses and applying sunscreen when outdoors.
Other Effects: Single-cell necrosis was observed in the ovaries and salivary glands of rats 
given 500 mg/kg/day that were euthanized on Day 4 due to moribundity.  Mild depletion of 
secretory material was also observed in the salivary glands.  Effects in the ovaries and 
salivary glands were not observed in the subsequent 1-month study.  Increases in WBC 
counts were observed in the rat and monkey, consistent with an inflammatory response. 
Complete information on PF-02341066 may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure.

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Figure 2.
Summary of 1-Month Repeat-Dose Toxicodynamics for PF-02341066
1.2. Rationale
MET/HGFR has been well characterized for its role in regulation of cell growth, migration, 
and invasion of both tumor cells and endothelial cells.  An extensive body of literature 
indicates that MET/HGFR is one of the receptor tyrosine kinases (RTKs) most frequently 
mutated or otherwise abnormally activated in late-stage human cancer.  When activated, 
MET/HGFR plays a critical role in regulation of tumor oncogenic processes such as 
mitogenesis, survival, and invasive growth, and especially in the metastatic process.  
Additionally, the emerging role of MET/HGFR in the regulation of tumor angiogenesis 
indicates potential for dual anti-tumor and anti-angiogenic mechanisms.  Activating 
mutations in MET/HGFR have been identified in multiple patient populations, including 
NSCLC (Non Small Cell Lung Cancer), SCLC (Small Cell Lung Cancer), renal cancers, 
head and neck cancers, and hepatocellular cancer.  In addition to activation driven by 
mutation, MET/HGFR gene amplification/ overexpression resulting in increased kinase 
activity has been frequently observed in gastric and colorectal cancer patients.  Furthermore, 
MET/HGFR is also activated in human tumors by other mechanisms (eg, autocrine loops, 
paracrine activation from tumor-associated stroma).  Collectively, the dysregulation of 
MET/HGFR in tumors by multiple mechanisms along with the potential role of MET/HGFR 
in tumor angiogenesis comprises a large potential patient population.  Most importantly, in 
preclinical proof of concept studies, both neutralizing monoclonal antibody and RTK 
inhibitor exhibit convincing antitumor activity in several xenograft models, which supports 
the concepts that MET is a valid target for treatment of cancer.
Mutations in MET Exon 14 were previously reported to be oncogenic drivers in preclinical 
models of lung cancer (Ma et al, 2003; Ma et al, 2006; Kong-Beltran et al, 2006).22,23,24
Given the role of MET/HGFR in regulation of cell growth, migration, and invasion of both 
tumor cells and endothelial cells, there is increasing interest in understanding the potential 
effectiveness of tyrosine kinase inhibitors as a treatment in NSCLC patients with tumors 

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harboring MET Exon 14 alterations. Paik et al (2015) reported on 3 crizotinib-treated 
patients with NSCLC harboring alterations leading to MET Exon 14 skipping. All 3
crizotinib-treated patients were shown to have a partial response.21  
In conclusion, MET has been shown to be a valid target, and PF-02341066 is a potent and 
selective inhibitor of MET.  PF-02341066 exhibits convincing antitumor activity in several 
xenograft models.  Importantly, it delivers antitumor efficacy in xenograft models with a 
large safety window, providing increased confidence that mechanism-based toxicity will not 
be limiting in the clinic.
1.2.1. Rationale for Selection of Starting Dose
The starting dose for PF-02341066 in the first in human (FIH) trial in cancer patients has 
been determined to be 50 mg daily, based on information derived from the 1-month repeat 
dose toxicology studies in rats and dogs (see current IB).
The doses tested in the 1-month toxicology rat study were 10, 50, and 150 mg/kg/day orally 
and the doses in the 1-month dog study were 1, 6, and 20 mg/kg/day orally.  In the rat study, 
there were no deaths at any dose levels.  The NOAEL identified in the rat study was 
10 mg/kg/day.  Only mild to moderate toxicities were observed at the highest dose 
(150 mg/kg), indicating that the STD10 in rats was greater than 150 mg/kg (900 mg/m2).  
There was a significant gender difference suggesting that the male rat was more sensitive 
than the female, associated with increased plasma exposure of PF-02341066 in male rats.  In 
the dog study, no serious, irreversible toxicities were observed at any dose level.  Hence, the 
NOAEL was determined to be 20 mg/kg/day in the dog study.
According to DeGeorge et al. (1998),10 the currently accepted algorithm for calculating a 
starting dose in clinical trials for cytotoxic agents is to use one-tenth of the dose that causes 
severe toxicity (or death) in 10% of the rodents (STD10) on a mg/m2 basis, provided this 
starting dose does not cause serious, irreversible toxicity in a non-rodent species.  If 
irreversible toxicities are produced at the proposed starting dose in non-rodents or if the 
non-rodent is known to be the more appropriate animal model, then the starting dose would 
generally be one-sixth of the highest dose tested in the non-rodent that does not cause severe, 
irreversible toxicity.  Since one-tenth of the highest dose tested in rats (90 mg/m2, equivalent 
to 4.5 mg/kg in dogs) did not cause any serious, irreversible toxicity in dogs, the starting dose 
in humans can be estimated as 90 mg/m2, ie, 150 mg daily dose, assuming body surface area 
of 1.7 m2 for humans.
However, the 150 mg starting dose in humans would project a PF-02341066 plasma exposure 
(steady-state plasma AUC of 3.26 g·hr/mL) exceeding the NOAEL (AUC of 2.16 g·hr/mL 
at 10 mg/kg) in male rats, the most sensitive species.  Furthermore, since the plasma protein 
binding for PF-02341066 is lower in humans (90.7%) than in rats (94.3%), the unbound 
AUC (AUCu) in humans (0.303 g·hr/mL) at the 150 mg starting dose will be higher than 
that at the NOAEL in rats (0.123 g·hr/mL).  In humans, a dose of 61 mg is expected to yield 
an unbound drug plasma AUC approximately equal to that observed in rats at the NOAEL.  
Since the exposure-based human dose projection provides a lower estimate for the clinical 
starting dose (61 mg) than that based on 1/10 of the STD10 in rats (150 mg), this dose 

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rounded to 50 mg (the highest available strength for a single capsule) once daily will be used 
as the starting dose for the FIH study.
1.2.2. Rationale for Evaluation of Midazolam (MDZ) Interaction
PF-02341066 is predominantly metabolized via the CYP3A isozymes in human liver 
microsomes and hepatocytes.  PF-02341066 also showed time-dependent inhibition of 
CYP3A isozymes in human liver microsomes with a kinact of 0.11 min-1 and KI of 3.0 μM.  
Based on these values, the projected PF-02341066 therapeutic dose of 100 mg (Cmax, free
19 nM) is predicted to increase the systemic exposure (AUC) of co-administered drugs that 
are CYP3A substrates by approximately 80% due to CYP3A inhibition.  There is a potential 
for more potent inhibition in patients receiving higher doses, leading to substantial drug 
interactions with commonly coadministered drugs that are CYP3A substrates.  In addition, 
PF-02341066 may display nonlinear pharmacokinetics in patients that may require dose 
adjustments.  To mitigate these risks, a MDZ interaction sub-study has been built into this 
First in Human (FIH) study to assess the potential PF-02341066 related CYP3A inhibition. 
MDZ is a benzodiazepine used clinically for conscious sedation.  It undergoes extensive 
metabolism via CYP3A4/5 and is a widely accepted in-vivo probe for assessing CYP3A 
activity.  In the current trial, midazolam pharmacokinetics (PK) following a single oral 2-mg 
dose will be evaluated before and after repeated daily administration of PF-02341066 at 3 
dose levels (the next higher dose after the initial dose, the efficacious dose, and the RP2D),
in order to assess the effects of PF-02341066 on CYP3A activity in the GI tract and the liver.  
The results of MDZ interaction study will be used to assist selection of the RP2D and to 
determine if there is any need for concomitant medication restrictions or dose modifications 
in future studies. 
2. TRIAL OBJECTIVES
1. Determine the safety profile of PF-02341066 including identification of dose limiting 
toxicity (DLT) and maximum tolerated dose (MTD).
2. Determine the recommended Phase 2 doses (RP2D) and regimens of PF-02341066.
3. Determine pharmacokinetic profile of PF-02341066 following oral administration
including the effect of food.
4. Perform initial evaluation of PF-02341066 related CYP3A4 inhibition using 
midazolam (MDZ) as a probe.
5. Determine the effect of the co-administration of rifampin on the multiple-dose plasma 
pharmacokinetics of PF-02341066.
6. Determine the effect of the co-administration of itraconazole on the plasma 
pharmacokinetics of PF-02341066.
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8. Document any evidence of anti-tumor activity of PF-02341066.
10. Evaluate the effect of PF-02341066 on parameters related to hypogonadism in males.
2.1. Trial Endpoints
1. To determine the MTD and potential phase 2 dose(s) of PF-02341066.
2. To characterize the plasma pharmacokinetic (PK) profile following oral 
administration of PF-02341066, including the effect of food and a midazolam study to
evaluate the potential for time-dependent inhibition (TDI) of CYP3A4 at different 
PF-02341066 dose levels.
3. To determine the safety, tolerability and the DLT of PF-02341066.
4. Plasma PK parameters of PF-02341066 and its metabolite(s) following multiple oral 
doses of PF-02341066 alone and when co-administered with rifampin.
5. Plasma PK parameters of PF-02341066 and its metabolite(s) following single (if 
possible) and multiple oral doses of PF-02341066 alone and when co-administered 
with itraconazole.  As of Protocol Amendment #22, the Single and Multiple-Dose 
Design will no longer be performed.
7. To document evidence of anti-tumor activity, including tumor response rate (by 
RECIST for solid tumors and response criteria for lymphomas and multiple 
myelomas), duration of response, time to response, progression free survival, overall 
survival, probabilities of survival at 6 and 12 months and others as appropriate.
9. Blood testosterone and other blood parameters associated with detecting 
hypogonadism in males [Appendix 12].
CCI
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3. TRIAL DESIGN
Open label, multi-center Phase 1 dose escalation, safety, pharmacokinetic 
study.
Figure 3 provides the status of each of the RP2D cohorts of this study, based on Protocol 
Amendment #24.
Figure 3.
Summary of RP2D Cohorts Based on Protocol Amendment #24
4. PATIENT SELECTION
This clinical trial 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. 
Rifampin interaction sub-study: Refer to Appendix 6 for details on patient selection.
Itraconazole interaction sub-study: Refer to Appendix 7 for details on patient selection.
ALK-negative NSCLC Cohort #2: Refer to Appendix 8 for details on patient selection.
Patients with MET-amplified NSCLC: Refer to Appendix 9 for details on patient selection.
ROS1 marker positive NSCLC patients: Refer to Appendix 10 for details on patient 
selection.
Enriched Other cohort: Refer to Appendix 11 for details on patient selection.
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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate 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. Tumor eligibility:

All cohorts except RP2D enriched population cohort: Histologically 
confirmed advanced malignancies (except for leukemias) refractory to 
standard of care therapy, or for whom no standard of care therapy is available.

RP2D enriched population cohort: Histologically confirmed advanced 
malignancies that meet one of the following criteria:

Positive for MET amplification by FISH (excluding polysomy).  After 
IRB/EC approval of Amendment #16, enrollment of patients in this group 
must be approved by the Sponsor.

Positive for ALK chromosomal translocations or gene amplification 
including but not limited to NPM-ALK positive anaplastic large cell 
lymphoma, inflammatory myofibroblastic tumors, echinoderm 
microtubule-associated protein-like 4 (EML4)-ALK positive non-small 
cell lung cancer or ALK-positive melanoma.  After IRB/EC approval of 
Amendment #16, enrollment of patients in this group must be approved by 
the Sponsor.  After IRB/EC approval of Amendment #18 patients with 
NSCLC that is positive for ALK chromosomal translocations or gene 
amplifications will not be allowed to enter the enriched RP2D cohort.

Positive for known MET kinase domain activating mutations including but 
not limited to V1110L, H1112L, H1112Y, H1124D, M1149T, T1191I, 
V1206L, L1213V, V1238I, M1268T, P1009S, T1010I, R988C, V941L but 
excluding Y1248C, Y1248H, Y1248D, Y1253D; mutations in the 
intron/exon splice site regions flanking exon 14 resulting in exon 14 
deletion and Y1003X mutations in exon 14 affecting binding of the E3 
ubiqitin ligase, CBL (casitas B-lineage lymphoma).  After IRB/EC
approval of Amendment #16, enrollment of patients in this group must be 
approved by the Sponsor.

Chromosomal translocations/fusions that lead to altered transcriptional 
regulation of MET and/or HGF including metastatic alveolar soft part 
sarcoma, clear cell sarcoma, rhabdomyosarcoma, or translocation 
associated renal cell carcinoma.  Patients with these tumors may enter the 
study without prior confirmation of MET and/or HGF alterations.  After 
IRB/EC approval of Amendment #16, enrollment of patients in this group 
must be approved by the Sponsor.

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
Positive for chromosomal translocations at ROS1 gene including but not 
limited to CD74-ROS1 and SLC34A2-ROS1 fusion events in NSCLC and
FIG-ROS1 in glioblastoma.

Other molecular changes for which there are data to suggest a biologic 
rationale for PF-02341066 treatment, eg, TRK1 fusions.

ALK marker negative NSCLC Cohort #1: Histologically or cytologically 
proven diagnosis of NSCLC that is locally advanced or metastatic and of the 
adenocarcinoma subtype (including mixed adenosquamous histology).  
Patients must have received only one prior chemotherapy and this regimen 
must have been platinum-based.  Patients who have also been treated with an 
EGFR tyrosine kinase inhibitor may enter the trial.  However, on a 
case-by-case basis and in agreement between the Sponsor and Investigator, 
patients who have had at least one prior chemotherapy treatment may be 
allowed to enter the trial.  All patients must either be non-smokers, 
ex-smokers or light smokers (10 pack-years).

ALK marker negative NSCLC Cohort #2: Histologically or cytologically 
proven diagnosis of NSCLC that is locally advanced or metastatic and of the 
adenocarcinoma subtype (including mixed adenosquamous histology).  
Patients must have received at least one prior chemotherapy regimen.  
Patients must have been determined to be ALK-negative by the central 
laboratory but may have been pre-screened and shown to have ALK negative 
NSCLC by a local test.  All patients must either be non-smokers, ex-smokers 
or light smokers (10 pack-years).
2. Solid tumors must have measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.0).  However, for the enriched population RP2D cohort, 
patients whose tumors are not measurable, may enter the study upon approval by the 
Sponsor.  Target lesions that have been previously irradiated will not be considered 
measurable (lesion) unless increase in size is observed following completion of 
radiation therapy.  RECIST v 1.1 will be used to evaluate tumors for patients in the 
ALK marker negative NSCLC cohorts.
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older. For patients enrolled at clinical sites in 
Japan as part of the Enriched Other Cohort: Female or male, 20 years of age or older.
5. ECOG performance status 0 or 1.  However, patients in the RP2D enriched 
population cohort or ALK marker negative NSCLC cohorts with an ECOG 
performance status of 2 may enter the study upon agreement between the investigator 
and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to 
Grade 1 (except alopecia).

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7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase
(ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if 
liver function abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented 
Gilbert’s syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L.

Platelets 100,000/L (30,000/L for the enriched RP2D population cohort 
and the ALK marker negative NSCLC cohorts).

Hemoglobin 9.0 g/dL (≥8.0 g/dL after IRB/EC approval of 
Amendment #21).  

Serum creatinine 2.0 x ULN.
8. 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.  For investigational sites using the Western Institutional Review 
Board (WIRB), patients who lack the capacity to consent for themselves will not be 
able to enroll into this study. 
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of 
starting study treatment; within 2 weeks of starting study treatment for patients in the 
RP2D enriched population or ALK marker negative cohorts.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue except for 
patients with neuroblastoma, lymphoma or myeloma. 
3. For MET dependent tumors, prior therapy specifically directed against MET or HGF; 
for ALK dependent tumors, prior therapy specifically directed against ALK; for 
ROS1 dependent tumors, prior therapy specifically directed against ROS1.
4. Current treatment on another clinical trial.
5. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 4 weeks (2 weeks for the RP2D enriched population cohort and the ALK marker 
negative NSCLC cohorts) and not taking medications contraindicated to Exclusion 
Criteria #11-13.

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6. Any of the following within the 3 months prior to starting study treatment: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, congestive heart failure, cerebrovascular accident including transient ischemic 
attack or pulmonary embolus.  However, upon agreement between the investigator 
and Sponsor, the 3 month post-event-free period for a patient with a pulmonary 
embolus can be waived if due to advanced cancer.  Appropriate treatment with 
anticoagulants is permitted.  [Implement 3 month guidance upon IRB/EC approval of 
Amendment #20].
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc >470 msec.  Upon agreement between the 
Investigator and Sponsor, patients with QTc >470 msec but <490 msec in the 
presence of a right bundle branch block or with an implanted cardiac pacemaker may 
enroll into the study [Implement upon IRB/EC approval of Amendment #20]. 
8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
9. Pregnant female patients, breastfeeding female patients (including patients who 
intend to interrupt breastfeeding), male patients with pregnant female partners who 
are unwilling or unable to use a condom for the duration of the pregnancy, female and 
male patients of childbearing potential who are unwilling or unable to use 2 highly 
effective methods of contraception as outlined in this protocol for the duration of 
study treatment and for 90 days after the last dose of investigational product.
10. Other severe acute or chronic medical (including severe gastrointestinal conditions 
such as diarrhea or ulcer) or psychiatric condition including recent (within the past 
year) or active suicidal ideation or behavior, or end-stage renal disease on 
hemodialysis or laboratory abnormality that would impart, in the judgment of the 
investigator and/or Sponsor, excess risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and
would make the patient inappropriate for entry into this study. 
11. Use of drugs that are known strong CYP3A4 inhibitors within 7 days prior to the first 
dose of PF-02341066, including but not limited to atazanavir, clarithromycin, 
ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, indinavir, 
nelfinavir, saquinavir, nefazodone, and voriconazole.  Grapefruit or grapefruit juice
should also be avoided.  The topical use of these medications (if applicable), such as 
2% ketoconazole cream, may be allowed.  All concomitant medication must be 
approved by the Sponsor.
Itraconazole Interaction sub-study: Refer to Appendix 7 for further details.
12. Use of drugs that are known strong CYP3A4 inducers within 12 days prior to the first 
dose of PF-02341066, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.  All concomitant medication must 
be approved by the Sponsor.

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Rifampin interaction sub-study: Refer to Appendix 6 for further details.
13. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor.
14. Patients who will participate in the MDZ interaction sub-study must not: (1) have any 
contraindications to MDZ administration according to the current package insert for 
MDZ; (2) take any MDZ dose which is not specified in the protocol within 7 days of 
the first dose of MDZ; and (3) take any medications or herbal supplements known to 
be CYP3A inhibitors or inducers 7 days (for CYP3A inhibitors) or 12 days (for 
CYP3A inducers) prior to the first dose of MDZ.  All concomitant medication must be 
approved by the Sponsor.
15. Patients with known interstitial fibrosis or interstitial lung disease.  However after 
IRB/EC approval of Amendment #20: 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. As of IRB/EC approval of 
Protocol Amendment #24, this exclusion criterion is as follows: History of extensive 
disseminated/bilateral or known presence of any grade interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary 
fibrosis, but not history of prior radiation pneumonitis.  
16. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study [Implement upon IRB/EC approval of Amendment #20].
4.3. Withdrawal Criteria
Every effort within the bounds of safety and patient choice will be made to have each patient 
continue to receive study drug.  Patients are to discontinue study treatment when any of the 
following occurs:

Patient refusal of further therapy (withdrawal of consent);

Intolerable Adverse Event (AE) that does not improve with dose adjustments;

Objective tumor progression or clinical deterioration unless there is reasonable 
evidence of clinical benefit as agreed upon with the Sponsor to justify continuation of 
study treatment;

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
Investigator conclusion that it is in the patient’s best interest to discontinue therapy 
(eg, poor patient tolerance, poor compliance with either protocol monitoring or with 
taking the study drug, etc);

Initiation of treatment with another anticancer therapy.  Of note: localized anticancer 
therapy (eg, topical treatment of non-melanoma skin malignancy, intravesical 
Bacillus Calmette-Guerin [BCG] treatment) may be acceptable upon prior Sponsor 
and Investigator agreement and written Sponsor approval.

Pregnancy;

Complete response, at the investigator’s and patient’s discretion.  Complete response 
must be confirmed no less than 1 month after the initial response was observed prior 
to discontinuing study treatment.  
4.4. Randomization Criteria
This is an open-label, single-arm study.
4.5. Life Style Guidelines 
4.5.1. Contraception
In this study, patients of childbearing potential will receive PF-02341066, which has been 
associated with teratogenic risk. As of IRB/EC approval of Amendment #21, all male 
patients who are able to father children and female patients who are of childbearing potential, 
and are sexually active and at risk for pregnancy 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 contraception methods (see below), and will confirm the patient has been 
instructed in their consistent and correct use. Patients need to affirm that they meet the 
criteria for correct use of two of the selected methods of contraception. The investigator or 
his/her designee will discuss with the patient the need to use 2 highly effective contraceptive 
methods consistently and correctly according to the Schedule of Activities and document 
such conversation and, upon IRB/EC approval of Amendment #23, the patient’s affirmation 
in the patient’s chart. In addition, the investigator or his/her designee will instruct the patient
to call immediately if 1 or both of the selected contraceptive methods 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.

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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 at least one of the criteria for non-childbearing potential as 
described below (as of IRB/EC approval of Amendment #21):

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; laboratory confirmation [e.g., a serum follicle stimulating 
hormone level] may be indicated.
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.
Female patients of childbearing potential must take precautions to prevent pregnancy since 
the effects on the fetus are unknown.  
All sexually active male patients 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.
Note for patients enrolled in the rifampin interaction sub-study (see Appendix 6): female 
patients using oral or other systemic hormonal contraceptives should additionally use 
nonhormonal methods of birth control during rifampin therapy.  Refer to Appendix 6 for 
further details.
4.5.2. Sunlight Exposure
Patients treated with PF-02341066 should avoid sunbathing, prolonged unprotected sun 
exposure, or tanning for the duration of the study. 
4.5.3. Dietary Restrictions
There is special requirement for patients who will participate in the MDZ interaction 
sub-study:

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
Patients should not eat or drink products containing grapefruit from 7 days prior to 
enrollment until 24 hours after completion of MDZ administration on C2D1.
For patients enrolled in the rifampin interaction sub-study, refer to Appendix 6 for further 
details.
For patients enrolled in the itraconazole interaction sub-study, refer to Appendix 7 for 
further details.
4.6. 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 numbers, 
contact information for the investigational site, and contact details for a contact center 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 
patient’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the 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 the study team 
for advice on medical questions or problems that may arise during the study.  The contact
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. TRIAL TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient being tested in a clinical trial, including a product with a marketing authorization 
when used or assembled (formulated or packaged) in a way different from the approved 
form, or when used for an unapproved indication, or when used to gain further information 
about an approved use (ICH E6 1.33).  
For this study, the investigational product is PF-02341066.
PF-02341066 will be administered orally once or twice a day in continuous 28-day cycles 
except 21-day cycles for patients in the ALK marker negative NSCLC cohort (see Schedule 
of Activities and Appendix 8).
There will be a lead-in period in which single-dose pharmacokinetics of PF-02341066 or 
MDZ (for patients participating in the MDZ sub-study) will be characterized prior to 
initiation of continuous dosing in the first cycle of treatment.  With the exception of cohorts 
in which the evaluation of a MDZ interaction is scheduled or patients who are exempted 
from the Day -7 lead-in dose (see below), all other patients will receive a single dose of 

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PF-02341066 seven days prior to the start of Cycle 1 (Day –7) in order to characterize the 
complete PK profile of PF-02341066 after a single dose.  With the approval of 
Amendment #13, only patients enrolled in the QD dose escalation part of the study or Asian 
patients enrolled in any cohort will have the Day -7 lead-in dose.  Patients enrolled in the 
MDZ interaction sub-study will receive a single 2 mg oral dose of MDZ on Day –7.  These 
patients will receive another single 2-mg oral dose of MDZ concurrently with PF-02341066 
on Cycle 2 Day 1.  During the study, real-time pharmacokinetic monitoring will be conducted 
as much as possible.
The PF-02341066 dose regimen may be changed if the pharmacokinetics and safety data 
suggest that a discontinuous regimen or another dosing frequency may be preferable.  If a 
BID dosing regimen is incorporated, all study assessments will be based on morning dosing 
(Day -7 dosing will still be a single PF-02341066 dose).  Dosing of oral PF-02341066 will 
be based on flat milligram increments without adjustment for body size.  The dose will be 
50 mg QD in the initial cohort.
Patients will be successively assigned to the next available treatment slot within a dose level. 
Each dose cohort will initially include a minimum of 3 evaluable patients for assessment of 
toxicity within the first cycle.  Dose escalation will occur in 100% increments until either of 
the following occurrences: (1) drug related toxicity of Grade 2 severity occurs in 2 or more 
patients within a dose level; or (2) mean unbound AUC0-24 exceeds 2.4 g·h/mL (the highest 
unbound AUC tested in the one-month toxicology studies).  Escalation increments will then 
become 40%.  In any cohort, if 1 patient experiences a DLT, 3 additional patients will be 
enrolled to that dose level.  If 2/3 or 2/6 patients experience a DLT, no further dose 
escalation will occur (see Figure 4).  Patients will continue treatment at their assigned dose 
level for at least 2 cycles to observe for cumulative toxicity.  They may then be treated at the 
next higher dose level provided it has been shown to be safe in a previously treated cohort.
If the highest cohort being evaluated is closed to new enrollment, additional patients who 
have a cytogenetic abnormality as described in Section 4.1 (Inclusion #1) may enter the 
study at the previous dose level.  These patients will not participate in the midazolam 
sub-study and will not have the Day -7 lead-in dose of PF-02341066 or any corresponding 
PK assessments.  They will be evaluated for safety but will not contribute to the MTD 
assessments.  These patients will enter the study on Day 1 of Cycle 1.  Additionally, patients 
scheduled to enroll in the RP2D enriched population cohort (see RP2D Cohorts Section) 
may be exempted from the Day -7 lead-in dose depending on the their overall medical 
condition.  This exemption will be granted on a case-by-case basis as agreed upon by the 
investigator and Sponsor.  Upon IRB/EC approval of Amendment #12, non-Asian patients 
will also be exempt from the Day -7 lead-in dose.  Amendment #13 extends the requirements 
as described in the second paragraph of this section.  Upon IRB/EC approval of Amendment 
#16, Day -7 lead-in dose will only be required for the dose escalation cohort.
Definition of MTD
The MTD will be defined as the dose level at which at most one of six patients experience 
DLT after 28 days of treatment have occurred (end of Cycle 1) with the next higher dose 

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having at least 2/3 or 2/6 patients experiencing DLT.  The Sponsor with the agreement of the 
investigators may expand the cohort beyond six patients to better define the safety profile of 
this cohort in the search for the MTD.  The MTD may be determined for both QD and BID 
dosing.  As of Protocol Amendment #20, the MTD determined from the QD dose escalation 
cohort will not be expanded beyond 6 patients.
Definition of DLT
DLT will have occurred when the patient has one or more of the toxicities noted in the
Table 1.  To determine dose escalation between cohorts, a DLT must occur within the first 
28 days of treatment (end of Cycle 1).  Toxicities will be graded according to the NCI 
CTCAE Version 3.0 (see Table 1).
Table 1.
Dose Limiting Toxicities
Toxicity Category
Toxicity/Grade
Hematologic
Prolonged grade 4 neutropenia for >7 days
a Febrile neutropenia, defined here as grade 4 neutropenia with fever 
>38.5C, both sustained over a 24 hour period.
Neutropenic infection: Grade 3 neutropenia with Grade 3 infection
Grade 3 thrombocytopenia with bleeding or grade 4 lasting 7 days 
Lymphopenia is not considered a DLT unless accompanied by infection.
Other non-hematologic toxicity
Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, 
grade 3 hypertension with controlled blood pressure [<140/90], and 
Grade 3/4 hyperuricemia without signs and symptoms of gout).  Nausea, 
vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical 
therapy.
a
Febrile neutropenia qualifies as a DLT only if the fever and neutropenia are documented to be coincident 
in time and reconfirmed.
Doses may not be modified until a DLT has been reached.  The study investigator may 
implement dose suspension in order to ensure patient safety; this will be considered 
dose-limiting toxicity for the purpose of dose-escalation if PF-02341066 has to be suspended 
for more than 3 days.  The occurrence of a DLT necessitates immediate interruption of the 
scheduled study treatment in that patient.  Resumption of study treatment for patients 
experiencing DLTs is permitted, contingent on the return of the DLT to <Grade 1 severity 
and interruption or delay in treatment for no more than 4 weeks.  Resumption of treatment 
after resolution of a DLT will be at the next lower dose level tested (or 50% lower if the DLT 
occurs with the first dose level).  Patients who discontinue treatment before completing 
Cycle 1 (DLT evaluation period) for reasons other than treatment-related toxicity (ie, missed 
appointments, misplaced study drug supplies, development of coexisting medical condition 
rendering the patient unable to swallow medication, development of rapidly progressing 
disease) will be replaced.
To contribute information to the assessment of safety for any dose level, a patient must 
receive at least 75% of the planned PF-02341066 doses or experience a treatment-related 
AE that prompts early treatment interruption or discontinuation.

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One or more lower dose level(s) may be tested in search of the MTD, defined as the dose 
level immediately below that in which 2/3 or 2/6 patients experience DLTs.  Dose escalation 
may be stopped if 1) MAD produces PF-02341066 concentrations that are at least 5-fold 
greater than the projected target concentration, 2) exposure plateaus as the dose is increased 
and 3) MTD cannot be reached within a reasonable dose range (up to 2000 mg).
Midazolam interaction sub-study
The potential for CYP3A inhibition due to PF-02341066 will be evaluated using MDZ as a 
CYP3A4 substrate probe at 3 dose levels of PF-02341066: the next higher dose after the 
initial dose, the efficacious dose, and the RP2D (see Figure 4).  The MDZ interaction study 
will be conducted starting in the second dose cohort, and at a higher dose (ie, the predicted 
efficacious dose) in which the trough unbound plasma concentration of PF-02341066 at the 
steady state will equal or exceed the projected target unbound plasma concentrations 
(12.8 nM).  If the target unbound plasma concentration of PF-02341066 is achieved in the 
second cohort, then the MDZ sub-study may not be performed with the higher dose cohort.  
In the second cohort or the efficacious dose cohort, at least 3 evaluable patients per cohort 
will be assessed for the effect of repeat PF-02341066 administration on the 
pharmacokinetics of midazolam.  If a significant change in MDZ clearance (>3-fold increase 
in MDZ AUC in all 3 patients, or >5-fold increase in 2 or more patients) is observed at any 
PF-02341066 dose level, further dose escalation may be terminated.
The effect of PF-02341066 on CYP3A activity will be evaluated at the RP2D.  Eight 
evaluable patients will be required for the MDZ interaction study in one of the RP2D cohorts 
(see RP2D Cohorts Section).  The results of the MDZ interaction sub-study at the RP2D will 
be used to determine if there is any need for concomitant medication restrictions or dose 
modifications in future PF-02341066 studies. 
Patients enrolled in the MDZ interaction sub-study will receive a single 2 mg oral dose of 
MDZ on Day –7 and another single 2-mg oral dose of MDZ concurrently with PF-02341066 
on Cycle 2 Day 1 (morning dose if the BID regimen is employed).
Rifampin interaction sub-study: Refer to Appendix 6 for further details.
Itraconazole interaction sub-study: Refer to Appendix 7 for further details.
RP2D cohorts
The RP2D will be determined as a dose below or equal to MTD, at which PF-02341066 is 
unlikely to cause an inhibition of CYP3A4 activity.  There will be two RP2D cohorts:
1. The first RP2D cohort will evaluate drug-drug interactions. This includes the MDZ, 
rifampin and itraconazole interaction sub-studies noted above.  
a. The MDZ interaction sub-study requires 8 evaluable patients. Enrollment is 
closed with a total of 15 patients treated.

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b. The Rifampin interaction sub---study requires 8 evaluable patients.
Enrollment is closed with a total of 18 patients treated.
c.
The Itraconazole interaction sub--study requires 8 evaluable patients. 
Enrollment is closed with a total of 18 patients treated.
2. The second RP2D cohort will be composed of an enriched population of 
approximately 484 patients:
a. A group of ALK marker positive NSCLC patients.  Enrollment is closed with a 
total of 154 patients treated.
b. Three categories of NSCLC patients with MET amplification defined as: 
1) MET/CEP7 ratio of 5.0 (Group 1): As per the Protocol Administrative 
Clarification Letter (PACL) dated 15 May 2017, the MET/CEP7 ratio cut-
off for this group was revised to ≥4.0. As per the PACL dated 11 
September 2018, this group was closed to further enrollment. The 
remaining 14 enrollment slots were transferred to the MET Exon 14 
alterations subgroup within the Enriched Other cohort.
2) CEP7 ratio 2.2 to <5.0 (Group 2): As per the PACL dated 15 May 
2017, the MET/CEP7 ratio cut-off for this group was revised to >2.2 to 
4.0 and this group was closed to further enrollment. The remaining 13 
enrollment slots were transferred to the MET Exon 14 alterations 
subgroup within the Enriched Other cohort;
3) MET/CEP7 ratio 1.8 to 2.2 (Group 3): As per the PACL dated 12 
October 2015, this group was closed to further enrollment.  
A total of 68 slots are planned for enrollment. As of IRB/EC approval of 
Protocol Amendment #24, enrollment is closed. Further details for the 
MET-amplified NSCLC cohort is provided in Appendix 9.
c.
A group of 50 NSCLC patients positive for chromosomal translocations at 
ROS1 gene, including but not limited to CD74-ROS1 and SLC34A2-ROS1
fusion events, will be enrolled.  Enrollment is closed with 50 patients treated.  
Further detail for the ROS1 marker positive NSCLC cohort is provided in 
Appendix 10.
d. Approximately 171 patients with disease with molecular markers (other than 
ALK marker positive NSCLC and ROS1 marker positive NSCLC) that may 
confer sensitivity to PF-02341066 will be enrolled into the ‘Enriched Other’
cohort. This cohort also includes NSCLC patients with tumors harboring 
MET Exon 14 alterations. Sponsor approval is required for enrollment into 
this cohort. Further details for the ‘Enriched Other’ cohort are provided in 
Appendix 11. 

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After IRB/EC approval of Amendment #18 patients with NSCLC that is
positive for ALK chromosomal translocations or gene amplifications will not 
be allowed to enter the enriched cohort. As of the PACL dated 07 December 
2017, the remaining 13 open enrollment slots in the Enriched Other cohort 
were assigned specifically to NSCLC patients with tumors harboring MET 
Exon 14 alterations rather than the broader Enriched Other cohort.  Thus, the 
Enriched Other cohort will be open only for enrollment of NSCLC patients 
with MET Exon 14 alterations. As of the Investigator Communication Letter 
dated January 7, 2019, further enrollment of NSCLC patients with tumors 
harboring MET exon 14 alterations is closed.
ALK Marker Negative NSCLC Cohort #1: 
e.
This cohort will consist of NSCLC patients who are negative for the ALK 
translocation as determined by the ALK break apart FISH assay used in 
Protocols A8081007 and A8081005.  A minimum of 25 to a maximum of 
50 evaluable patients will be enrolled into this cohort.  Patients will be dosed 
at the RP2D, ie, 250 mg BID of PF-02341066, with a cycle length of 3 weeks.  
Every effort will be made to ensure that baseline characteristics for these 
patients are comparable to those of ALK marker positive patients enrolled in 
the A8081007 trial.  In addition to encouraging ALK marker negative patients
identified under the A8081007 study to consider enrollment in the Phase 1 
trial, baseline characteristics for patients in the A8081007 study will be 
evaluated in a pooled fashion across treatment groups and enrollment of 
patients in the Phase 1 trial may be adjusted to reflect characteristics on 
specific variables (eg, gender, age, etc).  However, upon agreement between 
the Sponsor and Investigator, patients who have similar baseline 
characteristics to the ALK positive NSCLC patients in this study may be 
allowed to enter this study.  In order to increase comparability of response 
evaluation between ALK marker negative and ALK marker positive patients, 
tumor scans from ALK marker negative patients enrolled in this trial will be 
evaluated by an independent radiology group. As of the Note to File issued 
25 October 2012, tumor scans from patients enrolled into ALK marker 
negative NSCLC Cohort #1 will no longer be collected for and submitted to 
an independent radiology laboratory for review. Enrollment is closed with 
47 patients treated.
f.
ALK Marker Negative NSCLC Cohort #2: This cohort will consist of NSCLC 
patients who are negative for the ALK translocation as determined by the ALK 
break apart FISH assay by the central laboratory selected by the Sponsor.  At 
least 20 patients will be enrolled into this cohort.  Patients will be dosed at the 
RP2D, ie, 250 mg BID of PF-02341066, with a cycle length of 3 weeks.  
Patients may have been pre-screened using a local ALK test.  However, only 
patients whose pre-screening ALK test was negative and confirmed negative 
by the central laboratory selected by the Sponsor may be enrolled in this trial.  
No molecular testing for MET or ROS1 may be performed prior to patient 
enrollment.  As of the Note to File dated 19 June 2012, the requirement that 

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no molecular testing for MET or ROS1 to occur prior to patient enrollment 
was removed.  Thus, MET or ROS1 testing may have been performed prior to 
patient entry into this cohort.  However if the test result is either MET or 
ROS1 positive, then the patient cannot be enrolled into this cohort.  Patients 
should, however, have sufficient tumor tissue, ie, 9 slides, if possible, each 
containing unstained tissue sections that are 5 microns thick, to be tested for 
ROS1 fusion, MET amplification 
 
  The Sponsor will provide tumor shipment 
instructions for ROS1 and MET testing under separate cover.  Enrollment is 
closed with 21 patients treated.  Further detail for the ALK marker negative 
NSCLC Cohort #2 is provided in Appendix 8.
In addition, if possible, up to 6 patients will undergo pre- and post-dose [18F]-FLT-PET.  
Also, if possible, the same patients who have biopsies performed, will undergo 
[18F]-FLT-PET.  A separate sub-study with at least 6 evaluable patients with MET mutation 
or amplification will undergo pre- and post-dose [18F]-FLT-PET and [18F]-FDG-PET.  With 
the approval of Amendment #13 by the IRB/EC, no additional patients will undergo PET 
imaging.  Finally, 12 evaluable patients in this cohort will participate in a fed/fast sub-study 
(see below). Clinical sites in Korea will not participate in this sub-study.  Depending upon 
the overall results from the RP2D cohorts, a different dose/schedule may be tested in 
additional cohorts.
For patients who participate in the fed/fast sub-study, the effect of a high-fat, high-calorie 
breakfast on PF-02341066 pharmacokinetics will be studied.  Each patient will serve as their 
own control in which PF-02341066 is administered under either “fed” or “fasted” 
conditions on Day -7 and Day 1 of Cycle 1 (morning dose if the BID regimen is employed).  
Pharmacokinetic sampling times are described in Section 7.5.1.1.  The testing order for fed 
versus fasted conditions will be as follows: the first 6 patients to participate in this sub-study 
will be tested under fed followed by fasted conditions, the next 6 patients will be tested under 
fasted followed by fed conditions.  If patients are receiving PF-02341066 on a BID dosing 
schedule, the evening dose of Day 1 of Cycle 1 will be cancelled.  Patients who have had a 
gastrectomy or have dietary restrictions or adverse events that preclude a 10-hour overnight 
fast or cannot consume the high-fat, high-calorie meal will not be required to participate in
this sub-study.  See Section 5.2.3.1 for additional details on the high-fat, high-calorie meal.
All tumor scans from ALK marker positive NSCLC patients enrolled in the enriched
population cohort (including ALK marker positive NSCLC patients in the dose escalation 
cohort) will be evaluated by an independent radiology group.  As of the Note to File issued 
25 October 2012, tumor scans from ALK marker positive NSCLC patients will no longer be 
collected for and submitted to an independent radiology laboratory for review.
All tumor scans from ROS1 marker positive NSCLC patients enrolled will be collected and 
submitted to an independent radiology laboratory for review until notification is received 
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from the Sponsor. As of IRB/EC approval of Protocol Amendment #23, tumor scans from 
ROS1 marker positive NSCLC patients will no longer be collected for and submitted to an 
independent radiology laboratory for review. As of IRB/EC approval of Protocol 
Amendment #23, all tumor scans from NSCLC patients with tumors harboring MET Exon 14 
alterations will be collected and submitted to an independent radiology laboratory for review 
until notification is received from the Sponsor.  All tumor scans from NSCLC patients with 
MET gene amplification will be collected and held at the investigative site until notification 
is received from the Sponsor. With Sponsor approval and IRB/EC notification, the Sponsor 
may request tumor scans from these patients to be submitted to an independent radiology 
laboratory for review at a later date.  As per PACL dated 9 March 2018, all tumor scans for 
patients enrolled in the MET-amplified NSCLC cohort will be collected and submitted to an 
independent radiology laboratory for review until notification is received from the Sponsor. 
As of IRB/EC approval of Amendment #24, tumor scans from patients with MET-amplified 
NSCLC will no longer be collected and submitted to an independent radiology review 
laboratory.
Figure 4.
Example of Dose Escalation Scenario
Cohort 1
50 mg QD
Cohort 2
100 mg QD
MDZ Sub-study*
Cohort 3
200 mg QD
MDZ Sub-study*
Cohort 4
280 mg QD
(MAD)
Cohort 5
250 mg QD
(MTD)
Cohort 6
250 mg QD
(RP2D)
MDZ Sub-study*
Cohort 4
150 mg QD
(RP2D)
MDZ Sub-study*
Cohort 4
400 mg QD
Cohort 6
1600 mg QD
(RP2D)
MDZ Sub-study*
Cohort 5
1600 mg QD
(MAD)
100%
100%
40%
100%
100%
100%
3. Dose escalation stopped due to significant CYP3A4
inhibition (> 3-fold increase in MDZ AUC in 3 patients
or > 5-fold in 2 or more )
2. Dose escalation
stopped due to MTD
1. Dose escalation stopped due to MTD
not reached at doses up to 2000 mg
2 or more Grade 2 toxicity
or
AUCu =/> 2.4 ug.hr/mL
MAD= Maximum Administered Dose
MTD = Maximum Tolerated Dose
RP2D = Recommended Phase 2 Dose
MDZ = Midazolam
* MDZ PK following a single oral 2-mg dose will be evaluated
before and after repeated daily administration of PF 02341066
to assess the effects of PF-02341066 on CYP3A activity.

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Dose Reductions
Intrapatient dose reduction after Cycle 1 (DLT evaluation period) will be permitted once a 
patient has experienced unexpected toxicity provided the criteria for patient withdrawal from 
study treatment have not been met.  All intrapatient dose reductions are relative to the next 
lowest dose of the current cycle (dose level).  Dose reduction of the regimen will be 
dependent on the attribution of toxicity as PF-02341066-related or possibly related to 
PF-02341066.  The investigator (in discussion with the Sponsor) has discretion as to whether 
to discontinue or modify the dosages of the study drug, depending on the severity and timing 
of the event(s).  A maximum of 2 dose reductions will be allowed per patient.
For patients enrolled in the RP2D cohorts, intrapatient dose reduction is permitted at any 
time.  Following IRB/EC approval of Amendment #16, dose level -1 is 200 mg BID and dose 
level -2 is 250 mg QD.  A maximum of 2 dose reductions will be allowed per patient.
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.
5.1. Management of Selected PF-02341066-Related Adverse Events
5.1.1. Nausea and Emesis
For nausea and emesis, treat with standard anti-emetics such as prochlorperazine or 
ondansetron.  Taking the medication with food may reduce nausea.  Prophylactic antiemetics
should be considered. 
5.1.2. Diarrhea
For CTCAE Grade 1 diarrhea, symptomatic care such as loperamide (Imodium) or no 
intervention at investigator judgment. 
For CTCAE Grade 2 diarrhea, 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. 
For CTCAE Grade 3 (despite use of loperamide), treatment should be withheld until 
recovery to Grade 1.
5.1.3. Bradycardia
Concurrent use of PF-02341066 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 cases of asymptomatic bradycardia.  For management of patients who develop 
symptomatic bradycardia, see Table 2b.

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It is important to counsel patients about the risk of bradycardia and inform them of what 
symptoms and signs to be aware of and actions to take.
5.1.4. Pneumonitis
Investigators must evaluate thoroughly patients who demonstrate potential signs /symptoms 
of pneumonitis.  If a patient has a potential diagnosis of pneumonitis or drug related lung 
injury, the following evaluations/procedures should be considered to assist or exclude the 
diagnosis of pneumonitis during this period in the absence of disease progression, other 
pulmonary disease, infection or radiation effects:
•
A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and 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;
•
A plasma sample for BNP (B-type Natriuretic peptide) to evaluate for evidence of 
CHF;
•
For Asian patients, a blood sample for β-D-glucan to evaluate for the presence of 
fungal pneumonia (eg, Pneumocystis jirovecii).
If clinically appropriate, high dose corticosteroid treatment should be initiated. 
Should the event be fatal an autopsy is highly recommended to confirm/exclude the 
diagnosis. 
For any case of drug-related pneumonitis, discontinue PF-02341066 and contact the Sponsor 
(see Table 2b).
5.1.5. Renal Cyst
The development of complex renal cysts has been reported in some patients with NSCLC 
treated with PF-02341066.  These cysts may be symptomatic or asymptomatic, and have 
usually developed within the first several months of starting PF-02341066.  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 
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performed at the time of the renal cyst diagnosis and thereafter following the same schedule 
as for tumor imaging. Contrast-enhanced CT scanning or magnetic resonance imaging 
should be performed assuring full visualization of the kidneys.  Investigators should also 
review retrospectively all CT/MRIs for any prior occurrence of complex renal cysts. 
Dipstick and urine microscopy should be performed on Day 1 of each cycle.
Table 2a and Table 2b describe the recommended dose modifications for study 
treatment-related toxicities prior to Amendment #12 and after Amendment #12, respectively 
(Note: Pneumonitis-related dose modification added with Amendment #15).
Table 2.
Dose Modifications for PF-02341066 Associated Toxicity
Table 2a
Dose Modifications for PF-02341066 Associated Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
Continue at the 
same dose level.
Continue at the same dose 
level.
For recurrent subjectively 
intolerable toxicity (at 
least a week interruption 
on 2 occasions) that is not 
controlled by optimal 
supportive medication, 
reduce the dose to next 
lower dose level tested.* 
Withhold dose until 
toxicity is Grade 1, 
or has returned to 
baseline, then resume 
treatment at the same 
dose level, or reduce 
the dose to next lower 
dose level tested* at 
the discretion of the 
investigator.**
Withhold dose until 
toxicity is Grade 
1, or has returned 
to baseline, then 
reduce the dose to 
next lower dose 
level tested* and 
resume treatment, 
or discontinue at 
the discretion of the 
investigator.**
Hematologic
Continue at the 
same dose level.
Continue at the same dose 
level.
Withhold dose until 
toxicity is Grade 2, 
or has returned to 
baseline, then resume 
treatment at the same 
dose level.***
Withhold dose until 
toxicity is Grade 
2, then reduce the 
dose to next lower 
dose level tested* 
and resume 
treatment.***
* If the next lower level is below the first dose level tested in the study (dose level of the first cohort of patients), reduce the 
dose by 50%.
** 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.
*** Patients with recurrent Grade 3 neutropenia or thrombocytopenia for >7 days will dose reduce in the next cycle.  
Patients who develop Grade 3 or Grade 4 lymphopenia may continue study treatment without interruption. 

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Table 2b.
Dose Modifications for PF-02341066 Associated Toxicity (after IRB/EC
Approval of Amendment #12) 
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
General 
(except as noted 
below: 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 level, 
or reduce the dose to 
next lower dose level 
tested at the 
discretion of the 
investigator.*
Withhold dose until 
toxicity is Grade 1, or 
has returned to baseline, 
then reduce the dose to 
next lower dose level 
tested and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator.*
ALT or AST 
elevation possibly 
related to 
PF-02341066 
with total 
bilirubin 
<2 x ULN (in the 
absence of
cholestasis or 
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.
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 2 dose levels 
from the initial dose 
level).  If recurrence 
at dose level-2, then 
discuss with Sponsor 
whether or not to 
discontinue 
permanently. If 
ALT or AST 
elevation does not 
recur after at least 
4 weeks, the dose 
may be escalated by 
single dose level 
increments up to the 
initial dose level.
See Grade 3.
ALT or AST 
elevation and 
total bilirubin 
elevation 2 x 
ULN (in absence 
of cholestasis or 
hemolysis) 
Continue at the 
same dose level.  
Obtain repeat 
ALT or AST and 
total bilirubin 
within 48 hours
then repeat every 
48-72 hours until 
ALT/AST 
≤Grade 1.
Discontinue treatment and 
do not retreat.
Discontinue 
treatment and do not 
retreat.
Discontinue treatment 
and do not retreat.
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.
Prolonged QTc
Continue at the 
same dose level
Assess electrolytes 
(particularly Ca+, K+ and 
Mg+) and concomitant 
medications.  Correct any 
electrolyte or magnesium 
Withhold until 
recovery to Grade 
≤1, then resume at 
200 mg twice daily.
Discontinue treatment 
and do not retreat.

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Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
abnormalities
Continue at the same dose 
level.  
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.
Pneumonitis (not 
attributable to
disease 
progression, 
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.
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.
Vision Disorder
Continue at the 
same dose level.  
Repeat 
ophthalmologic 
examination.
Continue at the same dose 
level.  Repeat 
ophthalmologic 
examination.
Interrupt 
PF-02341066 until 
recovery to 
Grade 1.  Repeat 
ophthalmologic 
examination+.  
Resume treatment by 
reducing by one dose 
level upon recovery 
to Grade 1.
Discontinue treatment 
until recovery.  Repeat 
ophthalmologic 
examination+.  
Hematologic 
(excluding 
lymphopenia**)
Continue at the 
same dose level.
Continue at the same dose 
level.
Withhold dose until 
toxicity is Grade 2, 
or has returned to 
baseline, then 
resume treatment at 
Withhold dose until 
toxicity is Grade 2, or 
has returned to baseline, 
then reduce the dose by
1 level and resume 

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Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
the same dose 
level**/*** or 
reduce by 1 dose 
level after discussion 
with Sponsor.
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 clinical correlate (eg, opportunistic infection) may continue study treatment 
without interruption.
*** Patients enrolling with platelet counts >30,000/µL (to <50,000/L) will be monitored for drug-related decreases at which point dose 
modifications will be discussed with the Sponsor.
+ Ophthalmologic examination includes ocular characteristics, visual acuity, fundoscopy and slit lamp examination and should be 
performed by an ophthalmologist. After IRB/EC approval of Protocol Amendment #17, only NSCLC patients will be evaluated for 
additional specialized ophthalmological testing which includes: refractive error, pupil size, fundus photography, optical coherence 
tomography and intraocular pressure.  These additional tests will be performed at screening, Cycle 1 Day 15, Cycle 3 Day 1, 1 year and 
yearly thereafter and then at 2 to 8 weeks after discontinuation of PF-02341066.  For all other patients, applicable ophthalmologic 
examinations should be repeated during the study whenever a vision disorder AE is observed or when there is an increase in CTCAE grade 
from the previous visit.  As of the Note To File issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment 
#17) are no longer required for NSCLC patients: refractive error, pupil size, intraocular pressure, ocular coherence tomography, dilated 
fundus photography.  See Section 7.3.
Every effort should be made to administer study treatment on the planned dose and schedule.
In the event of significant toxicity, dosing may be interrupted 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 2 ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
Dose Interruption
The study investigator may implement dose suspension and/or reduction in order to ensure 
patient safety; however interruption in treatment should last for no more than 6 weeks.  If a 
longer interruption is required, discussion with the Sponsor must occur and agreement must 
be reached between both the Sponsor and Investigator.
Dose Re-Escalation
Doses reduced for drug-related toxicity should generally not be re-escalated.  However, 
intrapatient re-escalation back one or two dose levels after at least 4 weeks of treatment at the 
reduced dose level may be permitted on a case-by-case basis depending on the clinical setting 
and assessment of risk/benefit ratio after discussion with the Sponsor.

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Overdose Instructions
In the event of an overdose, the Sponsor should be contacted to discuss the details of the 
overdose and formulate a clinical management plan. 
No information regarding overdose of PF-02341066 in humans is available.  No antidote 
exists for the treatment of PF-02341066 overdose.  In the event of an accidental overdose, the 
patient should be monitored for possible signs of toxicity as mentioned above.  As there is no 
specific antidote for overdose of PF-02341066, general supportive care should be provided. 
5.2. Drug Supplies
5.2.1. Formulation and Packaging
5.2.1.1. PF-02341066
Prior to IRB/EC approval of Amendment #12:
PF-02341066 is filled in two tone gray capsules containing 10, 50 or 100 mg of study 
medication for oral administration.  The drug product consists of PF-02341066 in a hard 
gelatin capsule.  The capsules are packaged in HDPE bottles and should be stored at room 
temperature (15 to 25C) and handled with care.
Following IRB/EC approval of Amendment #12:
PF-02341066 will also be provided as tablets containing 50 or 100 mg of study drug for oral 
administration.  The 50 mg tablets are round in shape whereas the 100 mg tablets are oval in 
shape.  The tablets are packaged in HDPE bottles and should be stored at 15 to 30C and 
handled with care.  PF-02341066 may also be supplied as an oral solution (25 mg/mL) upon 
Sponsor agreement and availability of supplies.  The oral solution is buffered, sweetened, and 
grape-flavored and is packaged in HDPE bottles.  Dosing instructions and storage conditions 
for the oral solution will be provided under separate cover.
Following IRB/EC approval of Amendment #25 (Japan specific amendment): 
PF-02341066 formulated capsules can also be administered. This capsule formulation has 
been shown to be bioequivalent to the tablets and a powder in capsule (PIC). Two capsule 
dosage strengths will be used: 200 mg and 250 mg of PF-02341066 for oral administration.
The capsules are packaged in HDPE bottles, should be stored at 1 to 30C and handled with 
care.
5.2.1.2. Midazolam (MDZ)
MDZ syrup (2 mg/mL) for oral administration will be used for patients who will participate 
in the MDZ interaction sub-study.  The drug name and lot number for MDZ should be 
recorded in Case Report Forms (CRFs).
5.2.1.3. Rifampin
See Appendix 6 for details.

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5.2.1.4. Itraconazole
See Appendix 7 for details.
5.2.2. Preparation and Dispensing
5.2.2.1. PF-02341066
The study medication should be dispensed 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 
PF-02341066.
Medication will be provided in bulk containers.  Investigational sites will also be provided 
with a supply of bottles and non-patient-specific labels.  Site personnel must ensure that 
patients clearly understand the directions for self-medication. Patients should be given 
sufficient supply to last until their next study visit, ie, supplies for one cycle, however; for 
patients who visit the clinic every 2 cycles (after completing 10 cycles), enough supply for 
2 cycles will be provided.
Once Amendment #12 is approved by the IRB/EC, all newly enrolled patients will receive 
tablet supplies.  For ongoing patients, tablets will be supplied gradually and eventually 
completely replace the capsule.
PF-02341066 is a cytotoxic agent that must be handled and administered with care.  Patients 
should be instructed to keep their medication in the bottles provided and not transfer it to any
other container.  Due to possible unknown hazards associated with topical and 
environmental exposure to experimental cytotoxic agents, capsules must not be opened 
and/or emptied into any vehicle for oral ingestion. Capsules or tablets must be swallowed 
intact.  However, PF-02341066 tablets may be dissolved according to specific dosing 
instructions which will be provided under separate cover after Sponsor approval is granted.  
Administration of PF-02341066 through any other means besides orally is not permitted.
Therefore, if a patient is unable to swallow the study drug intact, then 2 options exist:

When available, PF-02341066 may be supplied as an oral solution (25 mg/mL) as 
described in Section 5.2.1.1, or

PF-02341066 tablets may be dissolved according to specific dosing instructions as 
noted above.
In either circumstance, prior approval must be obtained from the Sponsor, and thereafter,
dosing instructions will be provided under separate cover.

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Note: For patients enrolled in rifampin and itraconazole interaction sub-studies, only the 
tablet formulation of PF-02341066 will be administered from the first dose of PF-02341066 
until the last dose of PF-02341066 when co-administered with rifampin or itraconazole.  
Refer to Appendix 6 and Appendix 7 for further details.
5.2.2.2. MDZ
Midazolam will be dispensed using the manufacturer specified dispensing instructions.  
Qualified personnel will prepare and dispense the MDZ dose in accordance with the current 
package insert. 
5.2.3. Administration
5.2.3.1. PF-02341066
Administration will be performed on an outpatient basis.  PF-02341066 should be taken with 
at least 8 oz. of water on an empty stomach, ie, patient should refrain from food and 
beverages (except water) for at least 2 hours prior to dosing and for at least 2 hours after 
dosing.  However, starting on Day 2 of Cycle 2, patients may take PF-02341066 without 
regard to meals.  With the approval of Amendment #14, patients may take PF-02341066 
without regards to meals upon the initiation of treatment unless otherwise indicated.  Patients 
should be instructed to take their medication at approximately the same time each day and to 
not take more than the prescribed dose at any time.  However, a variance of up to 12 hours 
for QD dosing and 6 hours for BID dosing either way is allowed for any given dose, rather 
than miss a day’s dose.  If a patient misses a day’s dose entirely, they must be instructed not 
to “make it up” the next day.  If a patient vomits anytime after taking a dose, they must be 
instructed not to “make it up,” but to resume subsequent doses the next day as prescribed.  If
a patient inadvertently takes 1 extra dose during a day, the patient should not take the next 
dose of PF-02341066.  Patients should also be instructed to swallow the trial medication 
whole and not chew the capsule or tablet prior to swallowing.  No capsule or tablet should be 
ingested if it is broken, cracked, or otherwise not intact.  Doses may be modified according to 
Table 2.  The study investigator may implement dose suspension and/or reduction in order to 
ensure patient safety.
For patients participating in the food effect study, PF-02341066 will be administered 
following an overnight fast of at least 10 hours.  For those patients scheduled to receive the 
“fed” treatment, a high-fat, high-caloric breakfast will be provided and must be consumed 
over 30 minutes.  PF-02341066 will be administered with approximately 8 oz of water 
30 minutes after the start of the meal.  No additional food will be allowed until at least 
2 hours post-dose.  For patients scheduled to receive the “fasted” treatment, PF-02341066 
will be administered with 8 oz of water.  No food will be allowed for an additional 2 hours 
post-dose.  For either treatment day, water will be allowed ad libitum.  A high-fat 
(approximately 50% of total caloric content of the meal) and high-calorie (approximately 
800-1000 calories) meal is recommended as a test meal.  This test meal should derive
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively.  An example test meal would be two eggs fried in butter, two strips of bacon 
(may be replaced with ham or cheese of similar caloric content), two slices of toast with 
butter, four ounces of hash brown potatoes and eight ounces of whole-fat milk.  However, it 

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is understood that some patients may not be able to consume the entire meal. Study staff 
should record the % of the standard breakfast that is consumed.
5.2.3.2. MDZ 
In the MDZ interaction sub-study, patients will receive a single 2 mg oral dose of MDZ on 
Day -7 and will receive another single 2-mg oral dose of MDZ concurrently with 
PF-02341066 on Cycle 2 Day 1. 
Patients should refrain from food and beverages (except water) 8 hours prior to MDZ dosing 
and 2 hours after dosing.  Qualified personnel will administer MDZ syrup (1 mL to provide 
2 mg of MDZ) using an oral disposable syringe followed by 8 oz. of ambient temperature 
water.  Additionally, to standardize conditions for PK sampling, patients should refrain from 
lying down (except as needed for vital sign and ECG assessments) in the 2-hour period 
following MDZ administration.
5.2.3.3. Rifampin
Please see Appendix 6 for details.
5.2.3.4. Itraconazole
Please see Appendix 7 for details.
5.2.4. Patient Compliance
Patients will be required to return all bottles of study drug at the beginning of each cycle.  
The number of capsules or tablets remaining will be documented and recorded.  Patients who
are considered non-compliant will be withdrawn from study (see Section 6.1).
As of the Note to File (NTF) dated 08 February 2018, the following guidance was issued to 
sites regarding dosing compliance:
Study Treatment (Crizotinib) Dosing
Report as
Protocol Deviation
Report as
Medication Error
Patient unintentionally misses a total of < 20% 
of his/her doses within a given cycle 
No
No
Patient unintentionally misses a total of ≥20% 
of his/her doses within a given cycle
Yes
Yes
Patient unintentionally takes 1 extra dose 
within a given cycle
Yes
No
Patient unintentionally takes >1 extra dose with 
a given cycle
Yes
Yes
Please note, unintentional missed or extra doses should be investigated further with the 
patient to determine other potential reasons for the missed or extra doses (ie, whether due to a 
possible adverse event), as well as how to minimize their reoccurrence

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5.3. Drug Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all study 
drugs, ie, PF-02341066, rifampin and itraconazole, are stored in a secured area with 
controlled access under recommended storage conditions and in accordance with applicable 
regulatory requirements.
PF-02341066 should be stored in its original container and in accordance with the drug label.  
See the Investigator’s Brochure for storage conditions of the product.
Storage conditions stated in the single reference safety document (Investigator’s Brochure) 
will be superseded by the storage conditions stated in the labeling.
Returned medication for PF-02341066 should be stored separately from medication that 
needs to be dispensed.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products). This should be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order.  
Any excursions from the product label storage conditions should be reported to the Sponsor 
upon discovery. The site should actively pursue options for returning the product to the 
storage conditions as described in the labelling, as soon as possible.  Deviations from the 
storage requirements, including any actions taken, must be documented and reported to the 
Sponsor. Once an excursion is identified, PF-02341066 must be quarantined and not used 
until the Sponsor provides documentation of permission to use it.  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 the temperature range described in the labeling are not 
considered excursions. More specific details will be provided to the sites separately.
Site staff will instruct patients on the proper storage requirements for take home medications.
If an excursion is identified for itraconazole, the Sponsor should be contacted.

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The investigational product manual should be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range.
The above requirements are to be implemented upon IRB/EC approval of Amendment #21 if 
not previously implemented.
Capsules: PF-02341066 investigational medication should be stored at 15-25C (room 
temperature).  Medication should be kept in a secured locked area at the study site in 
accordance with applicable regulatory requirements.  Patients should be instructed to keep 
their medication in its original container and stored at 15-25C (room temperature).  
Returned medication should be stored separately from medication that needs to be dispensed.
200 mg and 250 mg Formulated Capsules (Japan specific amendment): PF-02341066 
investigational medication should be stored at 1-30C. Medication should be kept in a 
secured locked area at the study site in accordance with applicable regulatory requirements.  
Patients should be instructed to keep their medication in its original container and stored at 
1-30C.  Returned medication should be stored separately from medication that needs to be 
dispensed.
Tablets: PF-02341066 investigational medication should be stored at 15-30C.  Medication 
should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements.  Patients should be instructed to keep their medication in its original 
container and stored at 15-30C.  Returned medication should be stored separately from 
medication that needs to be dispensed.
Oral Solution: In those cases when an oral solution is approved for use by the Sponsor, 
detailed instructions on storage will be provided under separate cover.
To ensure adequate records, all study drug will be accounted for in the CRF and drug 
accountability inventory forms as instructed by the Sponsor.  Unless otherwise authorized, at 
the end of the clinical trial all drug supplies unallocated or unused by the patients must be 
returned to the Sponsor or its designee.  Patients must return all containers to a designated 
study center participant.  All containers of PF-02341066 that were sent to the investigator 
throughout the study must be returned to the Sponsor or designee, whether they are used or 
unused, and whether they are empty or contain capsules.
5.4. Drug Accountability 
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  
To ensure adequate records, all study drugs will be accounted for in a drug accountability 
inventory form/record as instructed by the Sponsor.  Unless otherwise authorized by the 
Sponsor, all PF-02341066 supplies unallocated or unused by the patients must be destroyed 
by procedures approved by the Sponsor or returned to the Sponsor or its designee.  All 
containers must be returned to the Investigator by the patient.

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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 the 
Sponsor and all destruction must be adequately documented.
5.5. Concomitant Medication(s)
All concomitant treatments, blood products, as well as non drug interventions (eg, 
paracentesis) received by patients from screening (within 14 days of first dose) to 28 days 
after the last dose of study treatment will be recorded on the CRF.
5.5.1. PF-02341066
Concurrent anticancer therapy with agents other than PF-02341066 is not allowed. Upon 
IRB/EC approval of Amendment #24, localized anticancer therapy (eg, topical treatment of 
non-melanoma skin malignancy, intravesical Bacillus Calmette-Guerin [BCG] treatment)
may be acceptable upon prior Sponsor anad Investigator agreement and written Sponsor 
approval.  Medications intended solely for supportive care (ie, antiemetics, analgesics, 
megestrol acetate for anorexia) are allowed. 
PF-02341066 is a substrate of CYP3A4/5 and also a moderate inhibitor of CYP3A.  In vitro 
studies in human liver microsomes demonstrated that PF-02341066 is a time-dependent 
inhibitor of CYP3A.
Co-administration of PF-02341066 with strong CYP3A inhibitors may increase 
PF-02341066 plasma concentrations. The concomitant use of strong CYP3A inhibitors, 
including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and 
voriconazole, should be avoided. Grapefruit or grapefruit juice may also increase plasma 
concentrations of PF-02341066 and should be avoided. The topical use of these medications 
(if applicable), such as 2% ketoconazole cream, may be allowed.
Co-administration of PF-02341066 with strong CYP3A inducers may decrease PF-02341066 
plasma concentrations. The concurrent use of strong CYP3A inducers, including but not 
limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort, 
should be avoided.
PF-02341066 has been identified as an inhibitor of CYP3A both in vitro and in vivo. 
Caution should be exercised in administering PF-02341066 in combination with drugs that 
are predominantly metabolized by CYP3A, particularly those CYP3A substrates that have 
narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, fentanyl, 
quinidine, sirolimus, and tacrolimus. Co-administration of PF-02341066 should be avoided 
with CYP3A substrates that have narrow therapeutic indices and are associated with 
life-threatening arrhythmias, including but not limited to dihydroergotamine, ergotamine, and 
pimozide.
Patients participating in the MDZ interaction sub-study must not take any midazolam dose 
which is not specified in the protocol 7 days prior to the first dose of MDZ until 24 hours 

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after the last dose of MDZ.  These patients must not take medications including herbal 
supplements known to be CYP3A inhibitors or inducers for 7 days or 12 days, respectively, 
prior to the first dose of MDZ until 24 hours after the last treatment of MDZ.
Additionally, the concurrent use of non-prescription drugs (excluding vitamins) or herbal
supplements is not recommended. 
Rifampin interaction sub-study: Refer to Appendix 6 for further details.
Itraconazole Interaction sub-study: Refer to Appendix 7 for further details.
All concomitant medication must be approved by the Sponsor.
5.5.2. 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.
5.5.3. Hematopoietic Growth Factors
For patients enrolled into the Dose Escalation cohorts, prophylactic use of hematopoietic 
growth factors to support neutrophil or platelet counts may NOT be used before completion 
of Cycle 1 (DLT evaluation period).  After Cycle 1, the use of hematopoietic growth factors 
is at the discretion of the treating physician.  For patients enrolled into all other cohorts, 
prophylactic use of hematopoietic growth factors is permitted at any time.  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.
5.5.4. 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.
Testosterone replacement therapy will only be allowed in the presence of signs and 
symptoms clearly attributable to hypogonadism in consultation with an endocrinologist or 
other qualified medical personnel, who should also exclude any potential confounding effects 
of elevated prolactin and/or estradiol, or a recent change in corticosteroid dose before doing 
so.
Bisphosphonate therapy for metastatic bone disease is permitted.  Bisphosphonate therapy 
should be given as per local medical practice.
Acetaminophen/ paracetamol to a MAXIMUM total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.

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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 avoided to the extent possible during the study.
5.5.5. Concomitant Radiotherapy or Surgery
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  PF-02341066 treatment should be interrupted during 
palliative radiotherapy – stopping 1 day before and resuming treatment 1 day after.  
Irradiated lesions will be considered not evaluable for response but still can be used to assess 
disease progression.  The intensities, number, and dates of doses received for allowed 
palliative radiotherapy should be recorded on the appropriate CRFs. 
The effect of PF-02341066 on wound healing is not known and has not been investigated; 
therefore, caution is still advised on theoretical grounds (potential antiangiogenic effect) for 
any surgical procedures during the study.  The appropriate interval of time between surgery
and PF-02341066 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, 
PF-02341066 dosing should be stopped 48 hours before surgery and resumed no sooner than 
48 hours after surgery.  Postoperatively, the decision to reinitiate PF-02341066 treatment 
should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery.
6. TRIAL PROCEDURES
For trial procedures, please see Schedule of Activities and Section 7 (Assessments).  For 
rifampin interaction sub-study, itraconazole interaction sub-study, ALK-negative NSCLC 
Cohort #2, MET-amplified NSCLC Cohort, ROS1 marker positive NSCLC Cohort, and 
Enriched Other Cohort please refer to the Schedule of Activities in the corresponding 
appendices.  Upon IRB/EC approval of Protocol Amendment #24, for ongoing patients in the 
ALK marker positive NSCLC cohort, the ROS1 marker positive NSCLC cohort, the MET-
amplified NSCLC cohort, and the Enriched Other cohort (including NSCLC patients with
MET Exon 14 alterations) please refer to the Reduced Schedule of Activities in Appendix 13.
6.1. 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 investigational site. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  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 withdraws from study treatment and also withdraws consent for disclosure of 
future information, no further evaluations should be performed and no additional data should 

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be collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
If a patient withdraws from study treatment and new anticancer therapy is subsequently 
administered, the End of Treatment (EOT) visit should occur prior to the initiation of new 
anticancer therapy.
7. ASSESSMENTS
Assessment of adverse events, laboratory safety (hematology, coagulation, urinalysis,
chemistry and pregnancy tests), vital signs, physical examinations, ECGs, ophthalmology 
examinations, tumor assessment, PK sampling,
 
will be done according to time points specified in the Schedule of Activities table.
For details on the rifampin interaction sub-study refer to the Schedule of Activities table in 
Appendix 6. 
For details on the itraconazole interaction sub-study refer to the Schedule of Activities table 
in Appendix 7.
For details on ALK-negative NSCLC Cohort #2, refer to the Schedule of Activities table in 
Appendix 8.
For details on patients with MET-amplified NSCLC, refer to the Schedule of Activities table 
in Appendix 9.
For details on the ROS1 marker positive NSCLC patients, refer to the Schedule of Activities
table in Appendix 10.
For details on the Enriched Other cohort, refer to the Schedule of Activities table in 
Appendix 11.
Upon IRB/EC approval of Protocol Amendment #24, for ongoing patients in the ALK 
marker positive NSCLC cohort, the ROS1 marker positive NSCLC cohort, the MET-
amplified NSCLC cohort, and the Enriched Other cohort (including NSCLC patients with
MET Exon 14 alterations) refer to the Reduced Schedule of Activities table in Appendix 13.
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol-required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
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.
CCI

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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Adverse Events
Adverse Events: type, incidence, severity (graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events [CTCAE] Version 3.0), timing, seriousness, and 
relatedness; laboratory abnormalities.
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. Laboratory Safety Assessments
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.
Hematology: hemoglobin, platelet count, white blood cell count, and differential count. Upon 
IRB/EC approval of Amendment #24, hematology will be collected for ongoing patients on 
the reduced schedule of activities (Appendix 13), as per local clinical practice.
Chemistry: total and indirect bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, 
albumin, sodium, potassium, chloride, CO2 (bicarbonate), calcium, phosphorus, BUN, 
creatinine, uric acid, and glucose. Upon IRB/EC approval of Amendment #23, indirect 
bilirubin will no longer be collected. Upon IRB/EC approval of Amendment #24, LDH and 
uric acid will no longer be collected for ongoing patients on the Reduced Schedule of 
Activities (Appendix 13).
Coagulation: PT (Prothrombin Time) and PTT (Partial Thromboplastin Time). Upon IRB/EC 
approval of Amendment #24, coagulation will no longer be collected for ongoing patients on 
the Reduced Schedule of Activities (Appendix 13).
Urinalysis: For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and 
nitrites. Upon IRB/EC approval of Amendment #24, urinalysis will no longer be collected for 
ongoing patients on the Reduced Schedule of Activities (Appendix 13).
In cases of suspected drug-induced liver injury (DILI) as described in Section 8.6.2 the 
following laboratory tests should be obtained in addition to repeating measurements of AST, 
ALT and total bilirubin: albumin, creatine kinase, direct and indirect bilirubin, 
gamma-glutamyl transferase (GGT), prothrombin time (PT)/international normalized ratio 
(INR), total bile acids, alkaline phosphatase and acetaminophen drug and/or protein adduct 
levels.

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Pregnancy Test: Upon IRB/EC approval of Amendment #21 for female patients of
childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL, and assayed in a certified laboratory, will be performed on 2 occasions prior to 
starting study treatment; once at Screening and once at the Cycle 1 Day 1 visit before starting 
PF-02341066.  Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced and another negative pregnancy test result will then be 
required at Cycle 1 Day 1 before the patient may receive PF-02341066. 
Pregnancy tests will also be routinely repeated at every treatment cycle during the active 
treatment period, at the end of study therapy, and additionally whenever 1 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 study 
medication. (See Section 4.3).
Additional pregnancy tests may also be undertaken if requested by IRBs/ECs or if required 
by local regulations.
Hypogonadism Tests: All male patients enrolled into the MET-amplified NSCLC and 
Enriched Other cohorts, after IRB/EC approval of Protocol Amendment #21, will have the 
following laboratory tests done: total testosterone, free testosterone, sex hormone binding 
globulin (SHBG), luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone 
sulfate, estradiol and prolactin. Blood samples must be taken before PF-02341066 dosing 
and between 7:00 and 10:00 a.m. and, for each individual patient, the time of the draw 
should be as consistent across visits as feasible. Blood samples will be submitted to the 
central laboratory (See Laboratory Manual). Patients enrolled in clinical sites in Japan as 
part of the Enriched Other Cohort will not participate in hypogonadism testing.

Pre-dose blood samples will be taken at the following times: Cycle 1 Day 1, Cycle 1 
Day 15, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, every 3 cycles thereafter and
at the End of Treatment visit.

Repeat testing of total testosterone and free testosterone levels must be performed at 
the next clinic visit if a decrease of ≥25% from baseline to a value below the 
age-specific lower limit of normal is observed in either parameter.  
Upon IRB/EC approval of Protocol Amendment #24, sample collection for hypogonadism 
tests is no longer required.
Refer to Appendix 9 (MET-amplified NSCLC Cohort), Appendix 11 (Enriched Other 
Cohort), Appendix 12 (Hypogonadism Testing) for further details. 
7.3. Other Safety Assessments
Physical Examination.
ECOG Performance Status.

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Vital signs: body temperature, blood pressure, and heart rate (as of Protocol Amendment 22, 
“respiratory rate” was deleted as this assessment was incorrectly required by the protocol and 
has not been collected during this study).  
ECG: A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically. Triplicate ECG measurements will be obtained at all time points.  Three 
consecutive 12-lead ECGS will be collected approximately 2 minutes apart.  Additional 
ECGs should be performed as clinically indicated. Upon IRB/EC approval of Protocol 
Amendment #24, ECG is no longer required.
Ophthalmology examination: includes ocular characteristics, visual acuity, fundoscopy and 
slit lamp examination.  This ophthalmology examination should be performed for all patients 
at screening and repeated during the study when a visual change occurred or when there is an 
increase in grade for a visual change.  Once Amendment #17 is IRB/EC approved, all NSCLC 
patients enrolled after Amendment #17 approval will also undergo the following 
ophthalmology tests:

Best correct distance visual acuity;

Refractive error associated with best corrected distance visual acuity;

Pupil size under standardized lighting conditions;

Slit lamp biomicroscopy of the anterior segment including cell count and flare
grading;

Fundoscopy of the posterior segment;

Intraocular pressure must be done twice for each eye. If test results deviate by more 
than 2 mmHg of each other, a third reading must be obtained;

Ocular coherence tomography of the macula;

Dilated fundus photography of the retina.
These tests will be performed at screening, Cycle 1 Day 15, Cycle 3 Day 1, 1 year, yearly 
thereafter, and then 2-8 weeks after the last dose of PF-02341066.  A total of 30 NSCLC 
patients are required to complete all time points. All NSCLC patients enrolled after IRB/EC 
approval of Amendment #17 will continue to undergo these special tests until written 
notification from the Sponsor. As of the Note To File dated 18 March 2016, the following 
ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC 
patients: refractive error, pupil size, intraocular pressure, ocular coherence tomography, 
dilated fundus photography.  Findings from the ophthalmology examinations should be 
reported as an adverse event if a finding is considered to be an adverse event by the 
investigator or Sponsor.

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7.4. Disease Imaging Studies
Screening/baseline imaging assessments will include CT or MRI scans of the chest, 
abdomen, and pelvis.  Brain scans and bone scans will be performed at baseline if disease is 
suspected.  Scans should be repeated every other cycle (ie, every 8 weeks for patients on 
28 day cycle and every 6 weeks for patients on 21 day cycle) if disease is identified. 
Assessment of tumor response and progression will be performed using CT or MRI scans of 
disease documented at baseline or suspected to have arisen since baseline and bone scans as 
appropriate.  Disease response for solid tumors will be categorized using RECIST v. 1.0 
(Appendix 3).  For patients in the ALK marker negative NSCLC cohorts, disease response 
will be categorized using RECIST v. 1.1 (Appendix 5). 
For patients in the ALK marker negative NSCLC Cohort #1 only and ALK marker positive 
NSCLC enriched population cohort, their scans will be reviewed by an independent 
radiology laboratory.  As of the Note to File issued 25 October 2012, tumor scans from the 
ALK marker negative NSCLC Cohort #1 will no longer be collected for and submitted to an 
independent radiology laboratory for review.  As of Amendment #20, tumor scans from ALK 
marker positive NSCLC patients will no longer be collected for and submitted to an 
independent radiology laboratory for review.  
Tumor scans from ROS1 marker positive NSCLC patients enrolled will be collected and 
submitted to an independent radiology laboratory for review until notification is received 
from the Sponsor. As of IRB/EC approval of Protocol Amendment #23, tumor scans from 
ROS1 marker positive NSCLC patients will no longer be collected for and submitted to an 
independent radiology laboratory for review.  
As of IRB/EC approval of Protocol Amendment #23, all tumor scans from NSCLC patients 
with tumors harboring MET Exon 14 alterations will be collected and submitted to an 
independent radiology laboratory for review until notification is received from the Sponsor.  
All tumor scans from NSCLC patients with- MET gene amplification will be collected and 
held at the investigative site until notification is received from the Sponsor. With Sponsor 
approval and IRB/EC notification, the Sponsor may request tumor scans from these patients 
to be submitted to an independent radiology laboratory for review at a later date.  As per 
Protocol Administrative Clarification Letter dated 9 March 2018, all tumor scans for patients 
enrolled in the MET-amplified NSCLC cohort will be collected and submitted to an 
radiology laboratory for review until notification is received from the Sponsor.  As of 
IRB/EC approval of Amendment #24, tumor scans from patients with MET-amplified 
patients will no longer be collected and submitted to an independent radiology review 
laboratory..  However, response and progressive disease will still be based on the clinical 
site’s review of the scans.  Disease response for lymphomas and multiple myelomas will be 
categorized using specific response criteria for each disease.

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7.5. Pharmacokinetics
7.5.1. 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.
As part of understanding the pharmacokinetics of the PF-02341066, plasma samples may be 
used for metabolite identification and/or evaluation of the bioanalytical method once 
Amendment #12 has been IRB/EC approved.  These data will be used for internal 
exploratory purposes and will not be included in the clinical report. PK samples will be 
assayed for PF-02341066 (including its active moieties, if appropriate), MDZ or itraconazole
(if appropriate) using a validated analytical method in compliance with Pfizer standard 
operating procedures.  Details regarding the storage and shipping of plasma samples will be 
provided in the Study Manual.
7.5.1.1. Plasma Pharmacokinetic Assessment for PF-02341066
In all dose escalation cohorts, blood samples for PF-02341066 (including its active moieties, 
if appropriate) will be collected as follows:
1. For patients who do not participate in the MDZ interaction study, a full 
pharmacokinetic profile of PF-02341066 will be obtained after administration of a 
single dose on Day -7 (lead-in period) at the following time points: 0 (pre-dose), 1, 2, 
4, 6, 8, 9, 24, and 48 hours post dose.  In addition, blood samples will be obtained at 
any two time points of the following: 72, 96, 120 and 144 hours post-dose.  Blood 
samples for PF-02341066 pharmacokinetics will be also obtained on Day 1 of Cycle 
1 at predose and 6 (2 hours as of May 1, 2007; 4 hours as of February 1, 2008) hours 
post-dose only, and Day 15 of Cycle 1 and Day 1 of Cycle 2 at the following time 
points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose.
2. For patients who participate in the MDZ interaction sub-study or patients who are 
exempted from the Day -7 lead-in dose (see Section 5), blood samples for 
PF-02341066 pharmacokinetics will be collected on Cycle 1 Day 1, Cycle 1 Day 15,
Cycle 2 Day 1 at 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose. 
For patients in the RP2D midazolam interaction cohort, blood collections will be as 
described in #2 above.
For patients in the rifampin interaction sub-study refer to Appendix 6 for details on blood 
collections.
For patients in the itraconazole interaction sub-study refer to Appendix 7 for details on blood 
collections.

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For patients in the MET-amplified NSCLC cohort refer to Appendix 9 for details on blood 
collection. 
For patients in the Enriched Other cohort refer to Appendix 11 for details on blood 
collection.
Blood samples for PF-02341066 (including its active moieties, if appropriate) will be 
collected as follows (when Amendment #10 is activated, clinical sites in Korea [or when 
amendment #13 is activated for Asian patients from all other sites] should only follow 
instruction # 4 below):
1. For patients who participate in the food effect sub-study, a full pharmacokinetic 
profile of PF-02341066 will be obtained after dosing on Day -7 and Cycle 1 Day 1 at 
the following time points: 0 (pre-dose), 1, 2, 4, 6, 8, 9, and 24 hours post-dose.  
Additional PK samples will be obtained pre-dose and 2-8 hours post-dose on Day 15 
of Cycle 1 and Day 1 of Cycle 2.  Note: Clinical sites in Korea will not participate in 
this sub-study.
2. For patients who do not participate in the food effect sub-study, a full 
pharmacokinetic profile of PF-02341066 will be obtained after dosing on Day -7 at 
the following times: 0 (pre-dose), 1, 2, 4, 6, 8, 9, 24 and 48 hours post-dose.  In 
addition, blood samples will be obtained at any two time points of the following: 
72, 96, 120 and 144 hours post-dose.  Additional PK samples will be obtained 
pre-dose and 2-8 hours post-dose on Days 1 and 15 of Cycle 1 and Day 1 of Cycle 2.  
Once Amendment #13 is activated, the Day-7 blood collections will be eliminated.  
This change is only for non-Asian patients.  Asian patients will follow Instruction #4.  
After Amendment #16 is IRB/EC approved, this change will apply to all patients.
3. For patients who are exempted from the Day -7 lead-in dose, blood samples for 
PF-02341066 PK will be collected on Cycle 1 Day 1 at the following time points: 
0 (pre-dose), 1, 2, 4, 6, 8, 9, and 24 hours post-dose.  Additional PK samples will be 
obtained pre-dose and 2-8 hours post-dose on Day 15 of Cycle 1 and Day 1 of 
Cycle 2.  Once Amendment #13 is activated, only a 0 (pre-dose) and 2-8 hour post 
morning dose sample will be collected on Cycle 1 Day 1.  Once Amendment #13 is 
activated, the Day-7 blood collections will be eliminated.  This change is only for 
non-Asian patients.  Asian patients will follow Instruction #4.  After Amendment #16 
is IRB/EC approved, the Day -7 blood draws will be eliminated for all patients.
4. For patients who are enrolled in clinical sites in Korea, a full pharmacokinetic 
profile of PF-02341066 will be obtained after dosing on Day -7 at the following 
times: 0 (pre-dose), 1, 2, 4, 6, 8, 9, 24 and 48 hours post-dose.  In addition, blood 
samples will be obtained at any two time points of the following: 72, 96, 120 and 
144 hours post-dose.  Blood samples for PF-02341066 pharmacokinetics will be also 
obtained on Day 1 of Cycle 1 at predose and 2-8 hours post-dose, and Day 15 of 
Cycle 1 and Day 1 of Cycle 2 at the following time points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 
and 24 hours post dose. If the patient is exempted from the Day -7 lead-in dose, 
blood samples for PF-02341066 PK will be collected on Cycle 1 Day 1, Cycle 1 Day 

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15 and Cycle 2 Day 1 at the following times points: 0 (pre-dose), 1, 2, 4, 6, 8, 9, and 
24 hours post-dose. Once Amendment #16 is IRB/EC approved, all patients enrolled 
in clinical sites in Korea will follow the updated Instruction #3.
For all cohorts except for the ALK marker negative NSCLC cohorts, in order to assess 
pharmacokinetics in patients receiving long-term treatment with PF-02341066, two PK 
sampling points (pre-dose and 4-8 hours [2-8 hours as of May 1, 2007] post-dose) will be 
obtained on Day 15 of Cycle 2, Day 1 of Cycle 3 and Day 1 of subsequent cycles (up to 
Cycle 5) for all patients.
For the ALK marker negative NSCLC cohort, plasma PK samples will be collected prior to 
morning dosing on Day 1 of Cycles 1, 2, 3 and 5 and 2-6 hours following dosing on Day 1 of 
Cycles 1, 3 and 5.  Following IRB/EC approval of Amendment #18, patients in the RP2D 
MET-amplified NSCLC and Enriched Other cohorts and ALK marker negative NSCLC 
RP2D Cohort #2 will have PK samples collected on Day 1 of Cycles 1, 2, 3 and 5 at pre-dose 
(0 hour) and 2-6 hours post-dose.  In addition, for patients in the MET-amplified NSCLC, 
ROS1 marker positive NSCLC and Enriched Other cohorts, a PK sample should be taken 
around the time that disease progression is confirmed as long as the patient is still on 
PF-02341066 treatment.  
Further details for the ALK marker negative NSCLC cohort #2 are provided in Appendix 8.
Further details for the MET-amplified NSCLC Cohort are provided in Appendix 9.
Further details for the ROS1 marker positive NSCLC cohort are provided in Appendix 10.
Further details for the Enriched Other cohort are provided in Appendix 11. 
In addition to samples mentioned above, additional blood samples for PK evaluation may be 
requested from patients experiencing unexpected or serious adverse events; with evidence of 
disease progression; or with other events where PK sampling is considered useful (upon 
agreement between investigator and Sponsor).  More than one PK sample per patient may be 
collected throughout the study; however the total blood volume of additional PK samples 
collected per patient should not exceed 15 mL (ie, no more than 5, 3 mL samples). As of 
IRB/EC approval of Protocol Amendment #23, the total blood volume of additional PK 
samples collected per patient should not exceed 20 mL (ie, no more than 5, 4 mL samples).
Blood samples (4 mL) for PF-02341066 pharmacokinetic analysis will be collected into 
appropriately labeled collection tubes containing KEDTA at protocol-specified times.  Once 
collected, samples should be processed immediately and kept out of direct sunlight due to the 
light sensitive nature of PF-02341066.  Blood samples will be placed immediately on 
ice-bath and centrifuged at approximately 1700 g for 10 minutes at 4C.  Plasma samples 
will be stored in appropriately labeled tubes at approximately -20°C within 1 hour of 
collection.  Details regarding the sample preparation will be provided in the Laboratory 
Manual.
Upon IRB/EC approval of Protocol Amendment #24, blood samples for PK analysis will no 
longer be collected.

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7.5.1.2. Plasma Pharmacokinetic Assessment for MDZ
In the MDZ interaction sub-study, a pharmacokinetic profile of MDZ will be collected after a 
single oral MDZ dose on Day –7 (lead-in period) and Cycle 2 Day 1 at the following time 
points: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose. 
Blood samples (2 mL) for MDZ pharmacokinetic analysis will be collected into appropriately 
labeled collection tubes containing sodium heparin at protocol-specified times.  Blood 
samples must be placed immediately into an ice-water bath and centrifuged at approximately 
1700 g for 10 minutes at 4C prior to storage.  The plasma (approximately 1 mL) will be
stored in appropriately labeled screw-capped polypropylene tubes at -20C within 1 hour of 
sample collection.  Details regarding the sample preparation will be provided in the Study 
Manual. Note: Clinical sites in Korea and Australia will not participate in the MDZ
interaction sub-study. 
7.5.2. Urine for Analysis of PF-02341066
In the RP2D midazolam interaction cohort, urine samples will be collected for 24 hours after 
PF-02341066 dosing on Cycle 1 Day 15 to measure PF-02341066 concentrations, and 
thereby determine the renal elimination of PF-02341066 from the body.  Metabolites of 
PF-02341066 may also be measured in the urine samples.  Urine will be collected on Cycle 1 
Day 15 over the following intervals: 0 to 4 hours, 4 to 12 hours and 12 to 24 hours postdose.  
Patients will empty their bladder just prior to dosing on Cycle 1 Day 15. 
At the end of each urine collection period, the total volume will be measured and recorded.  
Voided urine should be collected in an amber container and protected from direct light.  The
urine will then be mixed thoroughly and a 20 mL aliquot will be withdrawn for the potential 
measurement of drug concentrations.  The sample will be protected from light and frozen at 
approximately -20°C. 
7.5.3. Plasma for PF-02341066 Metabolite Profiling
Additional 5-mL blood samples will be collected at 4-8 hours post dose on Cycle 1 Day 15 in 
the RP2D midazolam interaction cohort for metabolite profiling.
Detail collection procedure will be provided in the study manual.
7.5.4. Blood Sample for Pharmacogenomics
Blood samples for genotyping will be examined to assess the impact of allelic variants of 
drug-metabolizing enzymes and transporters.  Additionally, these samples may also be used 
for retrospective evaluation of additional genetic variants associated with variation in 
pharmacokinetics (PKs) or to explore the relationship with AEs.  Samples will be retained 
for a period of up to 3 years following the submission of the final clinical study report (CSR).
A 4-mL blood sample will be collected from each subject into a plastic dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) tube at times specified in the SCHEDULE OF 
ACTIVITIES section of the protocol.  

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The pharmacogenomic (PGx) samples must be processed and shipped as indicated in the 
instructions provided to the investigator site to maintain sample integrity. Any deviations 
from the PGx processing steps, including any actions taken, must be documented and 
reported to the Sponsor. On a case-by-case basis, the Sponsor may make a determination as 
to whether sample integrity has been compromised. Any sample deemed outside of 
established stability, or of questionable integrity, will be considered a protocol deviation.
For patients enrolled in clinical sites in Japan as part of the Enriched Other Cohort, blood 
sample collection for pharmacogenomics is optional.
7.5.5. Urine Sample for 6 beta-Hydroxycortisol/Cortisol (6β-OHC/C) Ratio 
A midstream morning spot urine sample (10 mL) will be collected into an appropriately 
labelled plastic screw topped collection container prior to dosing of any drug on Day 1 of 
Cycle 1, Day 15 of Cycle 1 and Day 1 of Cycle 2.  Urine samples should be frozen 
immediately and stored at -20°C. The urinary 6 beta-hydroxycortisol/cortisol (6β-OHC/C) 
ratio will be determined to evaluate the potential of CYP3A4 induction. These samples will 
no longer be collected once IRB/EC approval of Amendment #17.
Sample analysis will be performed using a validated bioanalytical method in accordance 
with Pfizer standard operating procedures.
CCI
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7.5.8. [18F]-FLT-PET and [18F]-FDG-PET Imaging (RP2D enriched population cohort 
only)
If possible, at least 6 evaluable patients with MET mutations/amplification will be enrolled 
into the imaging portion of the RP2D enriched population cohort.  These patients will 
undergo [18F]-FLT-PET and [18F]-FDG-PET imaging. Also, if possible, the same patients 
that have pre- and post-dose biopsies will undergo PET imaging. The screening
[18F]-FLT-PET and [18F]-FDG-PET will be used to determine evaluable index lesions for 
each patient. Tumor background ratios (TBR) and development of new sites of abnormality 
will be recorded.  A patient will be considered evaluable if they have 2 or more baseline 
target lesions each identified by both [18F]-FLT-PET and [18F]-FDG-PET imaging.  All 
evaluable lesions must have a baseline [18F]-FLT-PET SUV of at least 2, and a baseline 
[18F]-FDG-PET SUV ≥3.5 (liver) or ≥5 (non-liver). Results of the PET sub-study will be 
scored according to the methods developed by the American College of Radiology Imaging 
Network (ACRIN; http://www.acrin.org/petcorelab.html).  These assessments will be 
performed as per the Schedule of Activities. With the approval of Amendment #13 by the
IRB/EC, no additional patients will undergo PET imaging.
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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) (see Section 8.6) 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 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begin from the 
time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the clinical trial, ie, prior to undergoing any trial-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 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 

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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 breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under trial 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 case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the Sponsor
should be notified immediately.

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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 adverse 
event (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 trial dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the trial, 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.
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 serious adverse events unless the outcome is 

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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).
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 
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 pre-existing AST OR ALT 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 preexisting AST or ALT baseline values above the normal 
range; AST or ALT values 2 times the baseline values and 3 x ULN, or
8 x ULN (whichever is smaller).

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
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 x ULN 
or if the value reaches 3 x ULN (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, a detailed history and physical assessment.  The possibility of 
hepatic neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT and total bilirubin, laboratory tests should also include 
albumin, creatine kinase, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), 
prothrombin time (PT)/international normalized ratio (INR), total bile acids, alkaline 
phosphatase and acetaminophen and/or protein adduct levels.  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 serious adverse events.
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 of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit 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).

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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 lab abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a clinical trial (eg, for a procedure required by 
the trial 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.
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
If required on the adverse event case report forms, the investigator will use the following 
definitions of severity in accordance with National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) Version 3.0 to describe the maximum intensity of the 
adverse event.  If the event is serious, the CTCAE grade reported in the adverse event CRF 
must be consistent with the description of CTCAE grade included in the narrative section of 
the serious adverse event report. 
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in 
the Version 3.0 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

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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 
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 trial records.
In addition, if the investigator determines a serious adverse event is associated with trial 
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 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
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 any trial patient or trial patient’s partner becomes or is found to be pregnant during the trial 
patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (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 

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exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an adverse event 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 a serious adverse event (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 serious adverse events.
Additional information about pregnancy outcomes that are reported as serious adverse events 
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 serious adverse events.  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 
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, 

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the information is not reported on a Case Report Form (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 events 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 serious adverse event 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 trial patient.  In addition, each trial 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 
event.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
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 trial 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. 

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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 serious adverse event information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AEs reporting, including suspected serious unexpected adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Sample Size Determination
Up to approximately 600 patients will be enrolled in the study including patients in the dose 
escalation and RP2D cohorts see Figure 1.  With Sponsor written approval and IRB/EC 
notification, 10 to 15 additional patients may be enrolled (for a total overall enrollment of 
approximately 580 patients) to reach the target enrollment of approximately 40 to 50 NSCLC 
patients with tumor harboring MET Exon 14 alterations and approximately 20 to 25 male 
patients for hypogonadism evaluation in the event that overall enrollment is achieved prior 
to reaching these targets.
9.1.1. Dose Escalation Phase
The number of patients to be enrolled in the dose escalation phase of this study will depend 
upon the observed safety profile and study objectives, which will determine the number of 
patients per dose level, the number of dose escalations and the number of cohorts.
It is anticipated that a total of approximately 70 patients will be enrolled in the dose 
escalation phase of this study to determine both the QD MTD and the BID MTD. 
The operating characteristics for the dose escalation part of this study design are shown in
Table 3, which provides the probability of escalation to the next higher dose for each 
underlying true DLT rate.  For example, for a toxicity that occurs in 5% of patients, there is 
a greater than 95% probability of escalating.  Conversely, for a common toxicity that occurs 
with a rate of 70%, the probability of escalating is <5%.
Table 3.
Probability of Escalation to the Next Dose for Each True Underlying DLT 
Rate at a Dose Level
True Underlying DLT 
Rate
5%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of Escalating 
Dose
0.97
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.01
0.001

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Table 4 shows the probability of failing to observe toxicity in a sample size of 3 or 6 patients 
given various true underlying toxicity rates.  For example, with 6 patients, the probability of 
failing to observe toxicity occurring at least 40% of the time is less than 5%.
Table 4.
Probability of Failing to Observe Toxicity (at Least One DLT Given the True 
Underlying DLT Rate) at a Dose Level
True Underlying DLT Rate 5%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of Failing to 
Observe Toxicity, N=3
0.86
0.73
0.51
0.34
0.22
0.13
0.064
0.027
0.008
0.001
Probability of Failing to 
Observe Toxicity, N=6 
0.74
0.53
0.26
0.12
0.047
0.016
0.0041
<0.001
<0.001 <0.001
9.1.2. RP2D Midazolam Interaction Cohort
Eight evaluable patients will be required for the MDZ interaction study in the RP2D cohort.  
The effect of multiple doses of PF-02341066 on MDZ will be evaluated by estimating the 
AUC0-last ratio of MDZ in presence of PF-02341066 and MDZ alone.  Based on data from 
previous single dose MDZ studies conducted at Pfizer, it is estimated that the within-patient
coefficient of variation (CV) for the AUC0-∞data is 25%.  The standard deviation of the 
difference in log-transformed data is then estimated to be 0.348 [(sqrt 2) 
*(sqrt(ln(1+CV2)))].  If PF-02341066 increases MDZ AUC0-∞by 2 fold (a 100% increase), 
then 8 patients will ensure that the width of the 90% confidence interval for the ratio will be 
no longer than 1.12, with 80% probability (see Table 5).  A probable 90% confidence 
interval is calculated to be: (1.52, 2.64).  The sample size is calculated using a paired t-test 
(nQuery, Version 4.0). 
Table 5.
Expected Precision for Effect of PF-02341066 on MDZ (90% CI, 80% 
coverage probability, 25% CV)
Sample Size
Estimated Ratio
Probable CI, 
Lower Limit
Probable CI, Upper 
Limit
Probable CI Width
8
1.3
0.987
1.713
0.726
1.5
1.138
1.976
0.838
2.0
1.518
2.635
1.117
9.1.3. RP2D Enriched Population Cohort
It is anticipated that approximately 484 patients will be enrolled into the RP2D enriched 
population cohort.  Inclusion in this cohort is based on the inclusion criteria described in 
Section 4.1 and in Appendix 8 for ALK marker negative NSCLC patients, Appendix 9 for 
patients with MET-amplified NSCLC, Appendix 10 for ROS1 marker positive NSCLC 
patients and Appendix 11 for the Enriched Other cohort which includes patients with disease 
with molecular markers (other than ALK marker positive NSCLC, ROS1 marker positive
NSCLC and MET-amplified NSCLC) that may confer sensitivity to PF-02341066.  Two 
sub-studies will also be included in this cohort: (1) [18F]-FLT-PET and (2) food effect.  First, 
approximately 6 patients will participate in a [18F]FLT-PET sub-study which should be 
sufficient to identify at least a 15% decline in standardized uptake value (SUV) compared to 
baseline. 
 
 Second, 
CCI

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for the food effect sub-study, twelve patients will provide at least 80% power to detect at
least a 2-fold in the AUC or Cmax between fed and fasting drug administration (assumes an
intrapatient CV of 10% for AUC and Cmax).
9.1.3.1. ALK Marker Negative NSCLC Cohorts
9.1.3.1.1. ALK Marker Negative NSCLC Cohort #1
The main objective of this ALK marker negative NSCLC cohort is to evaluate the objective 
response in this group of patients and to compare with the objective response observed from 
ALK marker positive NSCLC patients enrolled in Study A8081007 and/or Study A8081005, 
as appropriate.  Depending on the recruitment for the ALK marker negative NSCLC cohort, 
patients with more than one previous treatment may be enrolled.  Response to PF-02341066 
among ALK marker negative patients is expected to be low (to date no objective responses 
were observed in the unselected population in this study).  Therefore, the subset of ALK 
marker negative patients in this cohort will be first limited to a total of 25 patients.
If 3 objective responses (CR or PR) are observed in the first 25 ALK marker negative 
patients, no additional ALK marker negative NSCLC patients will be enrolled into this trial. 
With 25 patients and exactly 3 objective responses, the 90% exact confidence interval (CI) 
(3%, 28%) around the observed response rate (12%) will not overlap with the 90% CI 
around the assumed estimate of 40% for ALK marker positive patients (assuming that 
159 ALK marker positive patients are enrolled in the PF-02341066 arm of Study A8081007).  
Of note, the patient population in the current trial has been heavily pre-treated with a 
median number of 3 previous systemic therapies and the observed objective response rate 
(ORR) for the ALK marker positive NSCLC group is ~60%.
If >3 objective responses are observed among the 25 ALK marker negative patients, 
additional patients may be enrolled in this trial as noted in Table 6.
Table 6.
Power Calculation for ALK Marker Negative NSCLC Cohort #1
Responses in
First 25 
ALK - Patients
Additional
ALK - Patients to 
be Enrolled
Total 
ALK - Patients 
in this Trial
Exact 90% CI * 
Around ORR
(column 1/ column 
3 x 100)
Exact 90% CI Around 
40% ORR Assumed for 
160 ALK + Patients
(Protocol A8081007)
4
5
30
(5%, 28%)
(34%, 47%)
5
10
35
(6%, 28%)
(34%, 47%)
6
15
40
(7%, 27%)
(34%, 47%)
*Assumes that no responses are observed after additional ALK marker negative patients are enrolled in this 
trial
If 7 responses are observed among the first 25 ALK marker negative patients, then no 
additional patients will be enrolled beyond 40 until read out of study A8081007 study results.
9.1.3.1.2. ALK Marker Negative NSCLC Cohort #2
In order to further characterize the anti-tumor activity of PF-02341066 in ALK marker 
negative NSCLC patients, at least 20 patients will be enrolled into this cohort.  These 
patients may have been pre-screened by a local ALK test but only those who were determined 
to have ALK-negative NSCLC may be eligible for enrollment.  The results of the negative 

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local test must be confirmed by the central laboratory before entry into the study.  No testing 
for ROS1 or MET may be performed prior to patient enrollment.  As of the Note to File dated 
19 June 2012, the requirement that no molecular testing for MET or ROS1 to occur prior to
enrollment was removed.  However, if MET or ROS1 testing was performed prior to patient 
enrollment and the test result for either MET or ROS1 was positive, then the patient could 
not be enrolled onto this cohort.
Further details for the ALK marker negative NSCLC Cohort #2 are provided in Appendix 8.
9.1.3.2. MET-Amplified NSCLC Cohort
In order to further evaluate the anti-tumor activity of PF-02341066 associated with MET
amplification, patients with MET-amplified NSCLC will be enrolled into one of the 
following categories:

High Level MET Gene Amplified Category (MET/CEP7 ratio 5.0; Group 1): As per 
the PACL dated 15 May 2017, the MET/CEP7 ratio cut-off for this group was revised 
to ≥4.0). As per the PACL dated 11 September 2018, this group was closed to further 
enrollment. The remaining 14 enrollment slots were transferred to the MET Exon 14 
alterations subgroup within the Enriched Other cohort.

Medium Level MET Gene Amplified Category (MET/CEP7 ratio >2.2 to <5; Group 
2): As per the PACL dated 15 May 2017, the MET/CEP7 ratio cut-off for this group 
was revised to >2.2 to 4.0 and this group was closed to further enrollment. The 
remaining 13 enrollment slots were transferred to the MET Exon 14 alterations 
subgroup within the Enriched Other cohort; 

Low Level MET Gene Amplified Category (MET/CEP7 ratio 1.8 to 2.2; Group 3):  
As per the PACL dated 12 October 2015, this group was closed to further enrollment.
For each category, an ORR of 10% was considered to be uninteresting for further study for 
this category with 30% considered interesting for further exploration.  Using a Simon optimal 
two-stage design with alpha=0.05 and 80% power, a test of the null hypothesis that p 
10% versus the alternative p 30% requires 10 evaluable patients in the first stage.  If 
1 objective response (CR or PR) is observed in the first 10 patients for any category, no 
additional patients in that category will be enrolled.  If 2 or more objective responses are 
observed in the first stage for any category, the first stage may be expanded by enrolling 
19 additional patients in that category.  However, upon completion and evaluation of the first 
stage, a decision will be made whether or not to expand to the second stage in any of the 
3 categories investigated.  Within a category, if >5 objectives responses are observed, the 
null hypothesis will be rejected. 
As of a PACL issued June 27, 2014, 4 objective responses were observed in the High Level 
MET Gene Amplification category and the cohort was expanded to an additional 19 patients, 
for a total of 29-31 patients.  As of a PACL issued October 28, 2014, 2 objective responses 
were observed in the Medium Level MET Gene Amplified category and the cohort was 
expanded to an additional 19 patients, for a total of 29-31 patients.  

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Further details for the MET-amplified NSCLC cohort are provided in Appendix 9.
To increase the likelihood of achieving the target enrollment of approximately 20 to 
25 evaluable male patients with hypogonadism testing in a timely manner, the Sponsor 
decided to close enrollment of patients into the MET low amplification NSCLC category 
(MET/CEP7 ratio 1.8 to 2.2) due to slow enrollment, effective as of the Protocol 
Administrative Clarification Letter dated 12 October 2015.  Thus, the remaining unused 
enrollment slots (estimated to be approximately 28: 9 from Simon first-stage and 19 from 
Simon second-stage) was transferred to the Enriched Other cohort.  With Sponsor approval 
and IRB/EC notification, other conditions including, but not limited to, slow enrollment in 
the medium and/or high level MET amplification categories, may trigger transfer of 
additional enrollment slots from these MET gene amplification categories to the Enriched 
Other cohort.  As per the PACL dated 15 May 2017, further enrollment of NSCLC patients 
into the MET intermediate amplification group was closed and the remaining 13 enrollment 
slots were transferred to the Enriched Other cohort to facilitate further enrollment of patients 
with MET Exon 14-positive NSCLC. As per the PACL dated 11 September 2018, further 
enrollment of NSCLC patients into the MET high amplification group was closed and the 
remaining 14 enrollment slots were transferred to the MET Exon 14 alterations subgroup
within the Enriched Other cohort.
9.1.3.3. ROS1 Marker Positive NSCLC Cohort
To further evaluate the anti-tumor activity of PF-02341066 in patients with NSCLC positive 
for a chromosomal translocation in the ROS1 gene, approximately 30 patients will be 
enrolled.  An ORR of 10% was considered to be uninteresting for further study for this cohort 
with 30% considered interesting for further exploration.  With 27 evaluable patients, there is 
at least 85% power to test the null hypothesis that the ORR is less than or equal to 0.10 vs. 
the alternative hypothesis that it is greater than 0.10 assuming an alternative target rate of 
0.30 with a one-sided alpha=0.05 using a single stage design.  The null hypothesis will be 
rejected if greater than or equal to 6 objective responses are observed among the 
27 evaluable patients.  A total of approximately 30 patients will be enrolled into this cohort 
to adjust for 10% loss of patients who are not evaluable for response.
As of a database snapshot date of 19 April 2012, 8 confirmed objective responses (CR, 
partial response [PR]) were observed in a total of 14 response evaluable patients enrolled in
the ROS1 marker-positive NSCLC cohort. Based on the number of confirmed objective 
responses observed (CR, PR), the null hypothesis was rejected. As recorded in the Note to 
File dated 12 November 2012, and in Protocol Amendment 20, the sample size of the ROS1
marker-positive NSCLC cohort was increased to a total of 50 patients in order to provide a 
more robust estimation of antitumor activity in this patient population.
Further details for the ROS1 marker positive NSCLC cohort are provided in Appendix 10.
9.1.3.4. Enriched Other Cohort
To evaluate the anti-tumor activity of PF-02341066 in patients with other tumor types that 
have a molecular marker that confers sensitivity to PF-02341066 (eg, other tumor types 
besides NSCLC), the sample size of the Enriched Other cohort will be dependent upon the 

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number of enrolled patients meeting the criteria for this cohort; however it is anticipated that 
approximately 171 patients will be enrolled.
Further details for the Enriched Other cohort are provided in Appendix 11.
In the Enriched Other cohort, approximately 50 NSCLC patients with tumors harboring MET
Exon 14 alterations will be enrolled.  In addition, a separate group of approximately 
5 NSCLC patients with tumors harboring MET Exon 14 alterations will be enrolled in 
clinical sites in Japan. With Sponsor written approval and IRB/EC notification, additional 
patients may be enrolled as described earlier in this section (Section 9.1) to reach this target 
enrollment in the event that overall enrollment is achieved prior to reaching this target.  
In NSCLC patients with tumors harboring MET Exon 14 alterations, an ORR of 10% will be
considered uninteresting for further study for this group, with 30% considered interesting for 
further exploration.  With 33 evaluable patients, there is at least 90% power to test the null 
hypothesis that the ORR is less than or equal to 0.10 versus the alternative hypothesis that it 
is greater than 0.10 assuming an alternative target rate of 0.30 with a one-sided α=0.05 based 
on a single stage design using exact test.  The null hypothesis will be rejected if 7 objective 
responses are observed among the first 33 evaluable patients.  As of data cutoff date 01 
August 2016, 11 confirmed objective responses (CR, PR) were observed in a total of 28 
response-evaluable patients with MET Exon 14-positive NSCLC.  Based on the number of 
confirmed objective responses observed, the null hypothesis was rejected. The proportion of 
responders will be estimated with better precision if the number of evaluable patients exceeds 
33 patients.
1. As of Amendment 23 (21 February 2017), the sample size in the Enriched Other 
cohort was further increased to a total of 130 patients, including approximately 
50 patients with MET Exon 14-positive NSCLC.  In addition, a separate group of 
approximately 5 patients with MET Exon 14-positive NSCLC was planned to be 
enrolled in clinical sites in Japan.  
2. As of the PACL issued 15 May 2017 further enrollment of NSCLC patients into the 
MET intermediate amplification group was closed and the remaining 13 enrollment 
slots were transferred to the Enriched Other cohort to facilitate further enrollment of 
patients with MET Exon 14-positive NSCLC.  As a result, the total enrollment for 
patients with MET Exon 14-positive NSCLC was increased to 68 patients (50 original 
patients + 13 transferred slots + 5 Japanese patients). 
3. As of the PACL issued 07 December 2017, sites were allowed to enroll additional 13 
patients with MET Exon 14-positive NSCLC into the Enriched Other cohort, which 
were originally slotted for the broader Enriched Other cohort and were now assigned 
specifically to patients with MET Exon 14-positive NSCLC.  As a result, the total 
enrollment of the Enriched Other cohort subset of patients with MET 
Exon 14-positive NSCLC increased to 81 patients (68 + 13 patients).  
4. As of the PACL issued 11 September 2018, further enrollment of NSCLC patients 
into the MET high amplification group was closed and the remaining 14 enrollment 

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slots were transferred to the MET Exon 14-positive NSCLC subgroup within the 
Enriched Other cohort. As a result, the total enrollment for patients with MET Exon 
14-positive NSCLC was increased to 103 patients (81+14+8 additional slots were 
permitted without exceeding the total overall study enrollment of approximately 600 
patients).
5. As of the Investigator Communication Letter dated January 7, 2019, further 
enrollment of NSCLC patients with tumors harboring MET Exon 14 alterations was 
closed.
9.1.4. RP2D Rifampin Interaction Sub-study
At least 8 evaluable patients, who complete full PK sampling for PF-02341066 on Cycle 1 
Day 15 and Cycle 2 Day 1, will be required for the rifampin interaction study in the RP2D 
cohort.  A total of approximately 25 patients will be enrolled into this cohort to obtain the 
8 evaluable patients (eg, adjust for loss of patients due to early discontinuations, etc). Eight 
evaluable patients will provide 90% confidence intervals for the difference between
treatments of 0. 276 on the natural log scale for steady state AUC (AUCss), with 
80% coverage probability.  An approximately 36% decrease in PF-02341066 AUCss is 
anticipated when co-administered with rifampin.11  (See Table 7).
Table 7.
Expected Precision for Effect of Rifampin on PF-02341066 (90% CI,
80% Coverage Probability, 25% CV)
Sample Size
Estimated Ratio
Probable CI, Lower Limit
Probable CI, Upper Limit
Probable CI Width
8
0.3
0.228
0.395
0.167
0.5
0.379
0.659
0.280
0.8
0.607
1.054
0.447
1.0
0.759
1.318
0.559
Table 7 presents the width of 90% confidence intervals for the AUC ratio for different 
estimated effects assuming a within-patient coefficient of variation (CV) of 25%. Sample size 
calculations are based on a 2-sided paired t-test with 80% tolerance probability (nQuery, 
Version 7.0).
For additional details on the rifampin sub-study, refer to Appendix 6.
9.1.5. RP2D Itraconazole Interaction Sub-study
At least 8 evaluable patients, who complete full PK sampling for PF-02341066 on Cycle 1 
Day 15 and Cycle 2 Day 1, will be required for the itraconazole interaction study in the 
RP2D cohort.  As of Protocol Amendment #22, the Single and Multiple-Dose PK Design will 
no longer be required.  Approximately 25 patients will be enrolled to obtain at least
8 evaluable patients for multiple-dose PK (eg, adjust for loss of patients due to early 
discontinuations, etc). Eight evaluable patients will provide 90% confidence intervals for the 
difference between treatments of 0.276 on the natural log scale for AUCss, with 
80% coverage probability.  An approximately 2-fold increase in PF-02341066 AUCss is 
anticipated when co-administered with itraconazole.12 (See Table 8).

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Table 8.
Expected Precision for Effect of Itraconazole on PF-02341066 (90% CI, 80% 
Coverage Probability, 25% CV
Sample Size
Estimated Ratio
Probable CI, Lower Limit
Probable CI, Upper Limit
Probable CI Width
8
1.0
0.759
1.318
0.559
2.0
1.517
2.635
1.118
3.0
2.277
3.955
1.678
Table 8 presents the width of 90% confidence intervals for the AUC ratio for different 
estimated effects assuming a within-patient coefficient of variation (CV) of 25%.  Sample size 
calculations are based on a 2-sided paired t-test with 80% tolerance probability (nQuery, 
Version 7.0).
For additional details on the itraconazole sub-study, refer to Appendix 7.  See the Statistical 
Analysis Plan for further details regarding complete evaluability criteria.
9.1.6. Hypogonadism 
The sample size for laboratory testing will be determined by the number of eligible male 
patients who enroll in the MET-amplified NSCLC and the Enriched Other cohorts.  
Accordingly, assuming 50% of patients enrolled will be male, projected sample sizes are as 
follows:

It is anticipated that up to 25 males (approximately 19 from the MET-amplified 
Cohort and approximately 6 from the Enriched Other Cohort) may be available for 
hypogonadism testing.  Testing will be performed at Cycle 1 Day 1, Cycle 1 Day 15, 
and Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, every 3 cycles and End of 
Treatment.  As few as 10 male patients may achieve the Cycle 6 Day 1 testing.
9.2. Analysis
Unless otherwise specified, the study population for all safety analyses will include all
patients enrolled in the study who receive at least one dose of PF-02341066.  The study 
population for efficacy analyses depends on the parameter; the analysis of some endpoints
(eg, ORR, disease control rate [DCR]) will be based on a response evaluable population
while the analysis of other endpoints (eg, progression free survival [PFS] and overall survival 
[OS]) will be based on the safety population.  
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/compliance, 
efficacy, safety, and pharmacokinetic parameters.  Data will also be displayed graphically, 
where appropriate.  
9.2.1. Efficacy Analysis 
For each cohort and tumor type, the best overall response (confirmed CR, confirmed PR, SD 
or PD according to RECIST criteria) for each patient evaluable for response will be listed.  
Other endpoints including overall response rate, duration of response, time to response, 

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progression free survival, probabilities of survival at 6 and 12 months and others as 
appropriate, may be summarized to further evaluate anti-tumor activity.  Details regarding 
endpoint definitions and methods of analysis are presented in the Statistical Analysis Plan.
For ORR summaries, patients enrolled into a specific cohort (eg, ALK marker negative 
NSCLC cohort) at the time of study entry but subsequently determined through molecular 
testing to be positive for a marker relevant to another cohort (eg, ROS1 marker positive or 
MET-amplified NSCLC) may be summarized together as a subgroup within their initial 
cohort and also pooled with patients in the other cohort as appropriate. 
9.2.1.1. Analysis of ALK Marker Negative NSCLC Cohorts
The best response (complete response [CR], partial response [PR], stable disease [SD] or 
progressive disease [PD]) per RECIST version 1.1 will be summarized.  ORR calculated as 
the number of evaluable patients with a best response of confirmed CR or PR divided by the 
total number of evaluable patients in the ALK marker negative cohort will be provided, along 
with the corresponding exact 2-sided 95% confidence interval calculated using a method 
based on the F distribution. 
Further details for the ALK marker negative NSCLC Cohort #2 are provided in Appendix 8.
9.2.1.2. Analysis of MET-Amplified NSCLC Categories
For each of the 3 MET-amplified NSCLC categories, the null hypothesis that the ORR is less 
than or equal to 0.10 vs. the alternative hypothesis that it is greater than 0.10 will be tested as 
described in Section 9.1.3.2.
The best overall response (complete response [CR], partial response [PR], stable disease 
[SD] or progressive disease [PD]) per RECIST version 1.0 will be summarized or listed, as 
appropriate. The ORR, calculated as the number of evaluable patients with a best overall 
response of CR or PR divided by the total number of evaluable patients, will be provided 
along with the corresponding exact 2-sided 95% confidence interval calculated using a 
method based on the F distribution. 
Further details for the MET-amplified NSCLC cohort are provided in Appendix 9.
9.2.1.3. Analysis of ROS1 Marker Positive NSCLC Cohort
The null hypothesis that the ORR is less than or equal to 0.10 vs. the alternative hypothesis 
that the ORR is greater than 0.10 will be tested as described in Section 9.1.3.3.
The best response per RECIST version 1.0 will be summarized.  ORR, calculated as the 
number of evaluable patients with a best overall response of CR or PR divided by the total 
number of evaluable patients, will be provided along with the corresponding exact 2-sided 
95% confidence interval calculated using a method based on the F distribution. 
Further details for the ROS1 marker positive NSCLC cohort are provided in Appendix 10.

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9.2.1.4. Analysis of Enriched Other Cohort
All data for the Enriched Other cohort will be listed, including the best overall response per 
RECIST version 1.0.  However, summaries of ORR will be presented by tumor 
type/molecular marker, as appropriate depending on the number of patients who have the 
same tumor type and molecular marker.
Specifically, all safety and antitumor activity data of NSCLC patients with tumors harboring 
MET Exon 14 alterations will be summarized separately from the Enriched Other Cohort. 
Data from patients with tumors harboring MET Exon 14 alterations who are enrolled outside 
of Japan will be summarized separately and may be combined, for specific reporting, as 
described in the Statistical Analysis Plan, with the data from patients enrolled in clinical 
sites in Japan.
ORR, calculated as the number of evaluable patients with a best overall response of CR or 
PR divided by the total number of evaluable patients, will be provided along with the 
corresponding exact 2-sided 95% confidence interval calculated using a method based on the 
F distribution. 
Further details for the Enriched Other cohort- are provided in Appendix 11.
9.2.1.5. Hypogonadism Testing
The statistical analysis of hypogonadism parameters (total and free testosterone levels, 
SHBG, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, 
estradiol and prolactin) will be exploratory. The laboratory parameter of primary interest is 
free testosterone, with secondary interest in total testosterone, SHBG, luteinizing hormone 
and follicle stimulating hormone.  Details regarding hypogonadism parameters, endpoint 
definitions and methods of analysis are decribed in the Statistical Analysis Plan..
9.2.2. Analysis of Pharmacokinetics
9.2.2.1. Single- and Multiple-Dose PF-02341066 PK Analysis
All patients who complete at least one day of PK blood sampling will be included in the PK 
analyses.  Standard plasma pharmacokinetic parameters including the maximum plasma 
concentration (Cmax), minimum plasma concentration (Cmin), time to maximum plasma 
concentration (Tmax), and area under the plasma concentration versus time curve from zero 
time to the time of the last measurable concentration (AUC0-last) and/or area under the plasma 
concentration versus time curve from zero time to the dosing interval time τ (AUCτ) for 
PF-02341066 (including its active moieties, if appropriate) will be estimated using 
non-compartmental analysis.  If data permit, area under the plasma concentration versus time 
curve to infinity (AUC0-), terminal elimination half-life (t1/2), oral plasma clearance (CL/F)
and apparent volume of distribution (Vd/F) will be also estimated.  Descriptive statistics of 
these PK parameters, including mean, standard deviation, coefficient of variation, and 
median, will be provided by dose and day of assessment in tabular form. 

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9.2.2.2. Effect of PF-02341066 on MDZ PK  
Plasma concentration-time data of MDZ after each dose will be analyzed using 
non-compartmental methods to estimate the following PK parameters in individual patient:  
Cmax, Tmax, AUC0-last, and, if data permit, AUC0-, T1/2, CL/F and Vd/F.  Descriptive statistics 
will be provided for these PK parameters in tabular form.
The primary pharmacokinetic parameter AUC0-last will be utilized to estimate the effect of 
multiple doses of PF-02341066 on a single dose of MDZ.  In the RP2D cohort, the parameter 
will be log transformed and analyzed using a mixed-effect model with treatment as the fixed 
effect and subject as the random effect.  Ninety-percent confidence intervals for the ratio of 
geometric means of MDZ AUC0-last in presence of PF-02341066 and MDZ alone will be 
computed to assess the interaction. 
9.2.2.3. Effect of Food on PF-02341066 PK
The effect food will be assessed based on AUC0-last, AUC0-, and Cmax by determining the 
ratios (fed/fast) of geometric means of these PK parameters and the 90% confidence 
intervals for the ratios.
9.2.2.4. Effect of Rifampin on PF-02341066 PK 
For the rifampin sub-study, plasma concentration-time data of PF-02341066 and its 
metabolite(s) before and after multiple doses of rifampin will be analyzed using non 
compartmental methods to estimate individual PK parameters including, but not limited to, 
Cmax, Tmax, Ctrough, AUCtau, CL/F (PF-02341066 only), and metabolite-to-parent ratio.  
Descriptive statistics will be provided for these PK parameters in tabular form.
The primary pharmacokinetic parameters AUCtau and Cmax will be utilized to estimate the 
effect of rifampin on multiple-dose PK of PF-02341066.  The parameters will be log 
transformed and analyzed using a mixed-effect model with treatment as the fixed effect and 
patient as the random effect.  The ratios (Test/Reference) of adjusted geometric means and 
90% confidence intervals for the ratios will be computed for PF-02341066 AUCtau and Cmax
to assess the interaction.  PF-02341066 alone will be the Reference and PF-02341066 in the 
presence of rifampin will be the Test.
For more details on the rifampin interaction study refer to Appendix 6.
9.2.2.5. Effect of Itraconazole on Single- and Multiple-Dose PF-02341066 PK 
As of Protocol Amendment #22, blood samples for single-dose PK parameters for 
PF-02341006 and its metabolite(s) will no longer be required.  For the itraconazole 
sub-study, plasma concentration-time data of PF-02341066 and its metabolite(s) following 
single (if possible) and multiple doses of PF-02341066 before and after itraconazole 
treatment will be analyzed using non compartmental methods to estimate individual PK 
parameters including, but not limited to, Cmax, Tmax, Ctrough, AUC0-t, AUCtau, CL/F 
(PF-02341066 only), and metabolite-to-parent ratio.  Descriptive statistics will be provided 
for these PK parameters in tabular form. 

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Plasma concentration data of itraconazole (if available) will be summarized and descriptive 
statistics will be provided in tabular form.
Pharmacokinetic parameters AUCtau and Cmax will be utilized to estimate the effect of 
itraconazole on multiple-dose PK of PF-02341066.  The parameters will be log transformed 
and analyzed using a mixed-effect model with treatment as the fixed effect and patient as the 
random effect.  The ratios (Test/Reference) of adjusted geometric means and 90% confidence
intervals for the ratios will be computed for PF-02341066 AUCtau and Cmax to assess the 
interaction. PF-02341066 alone will be the Reference and PF-02341066 in the presence of 
itraconazole will be the Test.  For exploratory purposes, the effect of itraconazole on the PK 
of PF-06260182 (metabolite of PF-02341066) will be analyzed according to the above 
description.
Multiple-Dose PK Design: Each patient is scheduled to receive treatment for two treatment 
periods (A followed by B) as described below: 
Treatment Period A (Test): PF-02341066 250 mg QD will be administered from 
Cycle 1 Day 1 to Cycle 1 Day 15 and itraconazole 200 mg QD from Cycle 1 Day 1 to 
Cycle 1 Day 16 (before Cycle 1 Day 16 PF-02341066 dosing).
Treatment Period B (Reference): PF-02341066 250 mg QD will be administered from 
Cycle 1 Day 16 to Cycle 2 Day 1.
If possible, pharmacokinetic parameters AUC0-t and Cmax will be utilized to estimate the 
effect of itraconazole on the single-dose PK of PF-02341066.  The parameters will be log 
transformed and analyzed using a mixed-effect model with treatment as the fixed effect and 
patient as the random effect.  The ratios (Test/Reference) of adjusted geometric means and
90% confidence intervals for the ratios will be computed for PF-02341066 AUC0-t and Cmax
to assess the interaction.  PF-02341066 alone will be the Reference and PF-02341066 in the 
presence of itraconazole will be the Test.
For more details on the itraconazole interaction sub-study refer to Appendix 7.
9.2.4. Pharmacogenomics Analysis
Data from pharmacogenomic assays will be summarized as applicable. 
CCI
CCI

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9.2.6. Urinary 6 beta-Hydroxycortisol/Cortisol Ratio 
Data from urine assays for 6 beta-Hydroxycortisol/Cortisol (6-OHC/C) Ratio will be 
summarized as applicable.
9.2.7. PK/PD Modeling
Population pharmacokinetic analysis of samples collected in this study will be performed in 
accordance with the FDA guidance on Population Pharmacokinetics (February 1999).18 The 
plasma concentration data set from this study may be pooled with data sets from other 
PF-02341066 clinical studies.  Population pharmacokinetic analysis will involve mixed 
effects modeling performed using appropriate software (eg, NONlinear Mixed-Effect 
Modeling (NONMEM)).  The data from the analysis will describe the PK following single 
and multiple dose administration of PF-02341066 and describe covariates that are important 
determinants of PF-02341066 disposition including, but not limited to, demographic data, 
concomitant medications, pharmacogenomics.
In addition, population PK/PD modeling will be attempted to investigate any causal 
relationship between PF-02341066 exposure (including its active moieties, if appropriate) 
and biomarker, safety, anti-tumor activity, and/or laboratory data.
These modeling analyses may be reported separately from the final Clinical Study Report.
9.2.8. Safety Analysis
For each dose escalation cohort (BID and QD), DLT’s will be summarized by category 
(hematologic and non-hematologic) and by MedDRA preferred term.
Adverse Events (AEs) will be coded by system organ class (SOC) and preferred term 
according to MedDRA terminology. AE severity will be graded according to NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0. 
A listing of all AEs including detailed information collected for each AE (description of 
event, onset date/time, duration, seriousness, severity, relationship to study drug, action 
taken, clinical outcome) will be presented. 
The number and percentage of patients who experienced any: AE, serious AE (SAE), 
treatment related AE, and treatment related SAE will be summarized.  The denominator used 
to calculate incidence percentages consists of patients receiving at least 1 dose of 
PF-02341066.  AE data will be presented by dosing schedule across cycles and for each 
cycle.  The denominator for each cycle is defined as those patients available at the start of the 
cycle who received at least 1 dose of PF-02341066 for that cycle.  Emphasis in the analyses 
will be placed on AEs classified as treatment emergent. 
Additional summaries of adverse events (AE) and of other safety data will be presented in 
tabular and/or graphical format and summarized descriptively, as appropriate.
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.  

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Summary tables, graphic displays and shift tables, as appropriate, will be prepared to 
illustrate the results over time on study.
9.2.9. [18F]-FLT-PET Analysis
For [18F]-FLT-PET, SUV will be calculated for each evaluable lesion at baseline and then 
average baseline SUV will be determined.  The mean change in the SUV from baseline for 
each lesion within a patient and overall for each patient will be determined and the overall 
mean change will be calculated.  Descriptive statistics in tabular form will be used to 
summarize the results.
9.3. Interim Analysis
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the Sponsor may conduct unblinded reviews/reporting of the data during 
the course of the study for the purpose of safety and efficacy assessment, facilitating 
dose-escalation decisions, facilitating pharmacokinetic (PK)/pharmacodynamic (PD) 
modeling, and/or to support clinical development.
9.4. Data Monitoring Committee 
An external Data Monitoring Committee (DMC) will not be established for the study.  The 
PF-02341066 Clinical Team will monitor safety throughout the project through the following 
efforts:

Surveillance for serious adverse experiences (SAEs) according to regulatory 
guidelines.

Routine monitoring of non-serious adverse experiences as they are recorded in the 
case report forms or appear in the source documents at the study sites.

Periodic teleconferences with the principal investigators on individual studies to share 
experiences and ensure communication.
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.
Safety surveillance studies will include routine monitoring of clinical laboratory parameters, 
physical examination, adverse event (AE) reporting, electrocardiogram (ECG) monitoring, 
and cardiac function studies.  Increased monitoring of certain serum biochemistry, blood 
count, imaging studies/cardiac studies and physical examination will be dependent on animal 
toxicology findings and consultation with The Food and Drug Administration (FDA).

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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during the study conduct to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the trial 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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator site and investigator 
will promptly resolve any discrepancies that are identified between the study data and the 
patient's medical records.  The investigator will promptly provide copies of the inspection 
findings to Pfizer or its agent.  Before response submission to the regulatory authorities, the 
investigator will provide Pfizer or its agents with an opportunity to review and comment on 
responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term 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 trial.
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 or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.

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In most cases, the source documents will be the hospital's or the physician's chart. In cases 
where the source documents are the hospital or the physician's chart, the information 
collected on the CRFs must match those charts. 
In some cases, the CRF, or part of the CRF, may also serve as the 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 documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH) 
guidelines, 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 trial 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or to and independent third party arranged by Pfizer.  Investigator records 
must be kept for a minimum of 15 years after completion or discontinuation of the study or 
for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.

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12.2. Ethical Conduct of the Trial
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guidelines for Good Clinical Practice, (ICH 1996), and the 
Declaration of Helsinki (World Medical Association 1996 and 2008).
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify the study patients. The 
study site will maintain a confidential list of patients who participated in the study linking 
each patient’s numerical code to his or her actual identity.
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of patients’ personal data consistent with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection. 
The investigator must ensure that each study patient, or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, then 
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, 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.

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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each patient's 
signed consent form.
Note: For investigational sites using WIRB, patients who lack the capacity to consent for 
themselves will not be able to enroll into this study.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
12.5. 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.
13. DEFINITION OF END OF TRIAL
End of Trial in all participating sites is defined as the time at which it is deemed that 
sufficient patients have been recruited and completed the trial as specified in the protocol and 
the clinical study report (CSR) has been finalized.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this clinical trial 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 PF-02341066 at 
any time.
If a trial 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 time period set by Pfizer.  As directed by 
Pfizer, all study materials must be collected and all CRFs completed to the greatest extent 
possible.
15. PUBLICATION OF TRIAL RESULTS
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 

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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for all 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.
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 prespecified 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
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.

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Grano M, Galimi F, Zambonin G, et al.  Hepatocyte Growth Factor is a coupling factor 
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Fuller K, Owens J, Chambers TJ.  The effect of Hepatocyte Growth Factor on the 
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DeGeorge J, Ahn C-H, Andres P, Brower M, Giorgio D, Goheer M, Lee-Ham D, 
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Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, and Nettleton D.  A Combined 
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Jamei M, Dickinson GL, Rostami-Hodjegan A.  A framework for assessing 
inter-individual variability in pharmacokinetics using virtual human populations and 
integrating general knowledge of physical chemistry, biology, anatomy, physiology and 
genetics: A tale of 'bottom-up' vs 'top-down' recognition of covariates. Drug Metab 
Pharmacokinet. 2009; 1, 53-75.

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13.
Huiping Xu, Melissa O'Gorman, Weiwei Tan, Cathie Leister, Maryam Monajati, 
Nicoletta Brega, Grace Ni, Suzanne Phillips, Patricia Pardo, and Akintunde Bello. 
Effect of a Strong CYP3A Inducer Rifampin on the Pharmacokinetics of Crizotinib, a 
Dual ALK/MET Inhibitor, in Healthy Subjects. Poster #: 5392. AAPS Annual Meeting, 
Washington DC, USA.
14.
Huiping Xu, Melissa O'Gorman, Weiwei Tan, Cathie Leister, Maryam Monajati, 
Nicoletta Brega, Grace Ni, Suzanne Phillips, Patricia Pardo, and Akintunde Bello. The 
Effect of a Potent CYP3A Inhibitor Ketoconazole on the Pharmacokinetics of 
Crizotinib, a Dual ALK/MET Inhibitor, in Healthy Subjects. Poster #: 5393. AAPS 
Annual Meeting, Washington DC, USA.
15.
http://www.fda.gov/Drugs/DrugSafety/ucm371017.htm.
16.
Drug Interaction Database, University of Washington, www.druginteractioninfo.org.
17.
Therasse P, Arbuck, SG, Eisenhauer EA, et al.  New guidelines to evaluate the response 
to treatment in solid tumors.  J Natl Cancer Inst 2000;92:205-216.
18.
EA Eisenhauer et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1).  Eur J Cancer 45: 228-27, 2009.
19.
U.S. Department of Health and Human Services, Food and Drug Administration.  
Guidance for Industry, Population Pharmacokinetics. February 1999. 
20.
Weickhardt AJ, et al.  Rapid-onset hypogonadism secondary to crizotinib use in men 
with metastatic non-small cell lung cancer.  Cancer: Article published online 4 April
2012, DOI:10.1002/cncr. 27450.
21.
Paik PK, et al. Response to MET Inhibitors in Patients with Stage IV Lung 
AdenocarcinomasHarboring MET Mutations Causing Exon 14 Skipping. Cancer Discov 
2015;5:842-9.
22.
Ma PC , Kijima T , Maulik G , et al. c- MET mutational analysis in small cell lung 
cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions . 
Cancer Res 2003; 63: 6272–81 .
23.
Ma PC , Jagadeeswaran R , Jagadeesh S , et al. Functional expression and mutations of 
c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non–
small cell lung cancer . Cancer Res 2005 ;65:1479–88 .
24.
Kong-Beltran M , Seshagiri S , Zha J , Zhu W , et al. Somatic mutations lead to an 
oncogenic deletion of met in lung cancer. Cancer Res 2006;66:283–9 .

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Appendix 1. Serious Adverse Event Reporting
All serious adverse events regardless of suspected relationship to study drug must be faxed 
within 24 hours to the Pfizer Drug Safety Unit.  If you have any questions please contact us
at the numbers listed below.
U.S.:
FAX: Toll-Free (local) 1 866 997-8322
Korea:
FAX: Toll-Free (local) 079814206-4512
Alternate 1: +82 2 317-2135
Alternate 2: +1 973-660-8938
Australia:
FAX: Toll-Free (local): 1 800-034-314
Alternate 1: +1 973-660-8913
Japan:
FAX: Toll-Free (local): 120 44-2370
Alt. 1:  +1 973-660-8963

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Appendix 2. ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, eg, light 
house work, office work
2
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours
3
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair
5
Dead
As published in Am J Clin Onc 5:649-655, 1982.

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Appendix 3. RECIST version 1.0 Tumor Assessment Criteria17
At baseline, tumor lesions will be categorized as measurable or non-measurable (defined 
below).
All baseline evaluations should be performed as close as possible to the first day of study 
treatment and never more than 4 weeks before starting therapy.
Measurable Lesions

Lesions that can be accurately measured in at least 1 dimension (longest diameter to 
be recorded) as 2.0 cm with conventional techniques or 1.0 cm with spiral 
CT scan.

A tumor lesion that is situated in a previously irradiated area is eligible for 
measurable disease provided: 1) there has been documented disease progression in 
this site; 2) the criteria for measurability as outlined above are met; 3) this is not the 
only site of measurable disease.

All measurements should be determined using a ruler, calipers or digital technology, 
and recorded on the CRF in metric notation.
Nonmeasurable Lesions
All other lesions, including small lesions (longest diameter <2.0 cm with conventional 
techniques or <1.0 cm with spiral CT) and truly nonmeasurable lesions.  Truly 
nonmeasurable lesions include bone lesions, leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitis cutis or pulmonis, abdominal 
masses that are not confirmed and followed by imaging techniques, and cystic lesions.
Documentation of Target and Nontarget Lesions
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and measured and 
recorded at baseline.  Target lesions (measurable) should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repetitive measurements 
(either by imaging techniques or clinically. A sum of the longest diameter (LD) for all target 
lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD will be 
used as reference by which to characterize the objective tumor response.
All other lesions (or sites of disease) should be identified as nontarget lesions and should also 
be recorded at baseline.  Measurements are not required, and these lesions should be 
followed as present or absent.

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Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Accepted methods of tumor assessment include:
Clinical examination: clinically detected lesions will only be considered measurable when 
they are superficial (eg, skin nodules and palpable lymph nodes).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is recommended.
Chest x-ray: lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.
CT and MRI: CT and MRI are the best currently available and most reproducible methods 
of measuring target lesions selected for response assessment.  Conventional CT and MRI 
should be performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT 
should be performed using a 5 mm contiguous reconstruction algorithm.
Ultrasound: should not be used to measure tumor lesions for objective response evaluation.  
It is however a possible alternative to clinical measurements of superficial palpable nodes, 
subcutaneous lesions and non-small cell lung nodules.  US might also be useful to confirm 
the complete disappearance of superficial lesions usually assessed by clinical examination.
Endoscopy and Laparoscopy: The utilization of these techniques for objective tumor 
evaluation has not yet been fully or widely validated.  Utilization of such techniques for 
objective tumor response should be restricted to validation purposes in specialized centers.  
 
Tumor markers: tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered a 
complete clinical response.
Cytology and histology: the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable disease 
(an effusion may be a side effect of the treatment) and progressive disease.
Response Criteria
The following RECIST criteria will be the primary method utilized in this study for the 
assessment and reporting of tumor response data.
CCI

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Complete Response (CR): Disappearance of all target and nontarget lesions, normalization 
of tumor marker levels, and no appearance of new lesions indicates complete response.  Each 
of these must be documented on 2 occasions separated by at least 4 weeks.
Partial Response (PR): At least a 30% decrease in the sum of the LDs of target lesions 
(taking as reference the baseline sum), without progression of nontarget lesions and no 
appearance of new lesions indicates partial response.  Each of these must be documented on 
2 occasions separated by at least 4 weeks.
Stable Disease (SD): Neither CR, PR or PD criteria are met.  Patients who have stable 
disease (SD) as their only response will be categorized as SD.
Progressive Disease (PD): 20% increase in the sum of the LD of target lesions taking as 
references the smallest sum LD recorded since the treatment started, unequivocal progression 
of existing nontarget lesions, or the appearance of 1 or more new lesions.  The occurrence of 
a pleural effusion or ascites is also considered PD if substantiated by cytologic investigation 
and not previously documented.  Pathologic fracture or collapse of bone is not necessarily 
evidence of disease progression; however, new bone lesions not previously documented are 
considered PD.
In cases where procedures used to assess tumor size suggest tumor necrosis or intratumor 
bleeding coincident with an increase in size, a PET scan or ultrasound should be considered 
because it is important to be sure that increasing lesions are due to increased tumor growth
and not necrosis or bleeding.
Determination of Best Overall Response:
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence.  For PD, taking as reference the smallest measurements 
recorded since treatment started.  For CR and PR the best response assignment will depend 
on the achievement of both measurement and confirmation (at the minimum of 28 days) 
criteria.  Stable disease rate will be defined as the percentage of patients with stable disease 
based on the total number of patients evaluable for response.
Determination of best overall response is summarized in Table 9 with more details provided 
in the Supplemental SAP.
Table 9.
Determination of Best Overall Response
Target 
Lesions
Nontarget 
Lesions
New 
Lesions
Overall 
Response
CRa
CR
No
CR
CR
Non-CR/Non-PD
No
PR
PRb
Non-PD
No
PR
SDc
Non-PD
No
SD
PDd
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
a
Complete response.
b
Partial response.
c
Stable disease.
d
Progressive disease.

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Appendix 4. Common Terminology Criteria for Adverse Events v3.0
Please use the link below to access the most recent CTCAE information:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

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Appendix 5. RECIST version 1.1 Tumor Assessment Criteria18
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below:
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.
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.

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Determination of Overall Response by the 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 10.
Table 10.
Response Evaluation Criteria in Solid Tumors
Target lesions
Non-target lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
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 
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).  In 
this circumstance, the best overall response can be interpreted as in Table 11.

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Table 11.
Best Overall Response When Confirmation of CR and PR Required
Overall response 
First time point 
Overall response 
Subsequent time point
BEST overall response
CR 
CR 
CR
CR 
PR 
SD, PD or PRa
CR 
SD
SD provided minimum criteria for SD 
duration met, otherwise, PD
CR 
PD
SD provided minimum criteria for SD 
duration met, otherwise, PD
CR
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE
PR 
CR 
PR
PR 
PR 
PR
PR 
SD 
SD
PR 
PD
SD provided minimum criteria for SD 
duration met, otherwise, PD
PR 
NE
SD provided minimum criteria for SD 
duration met, otherwise NE
NE 
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR.
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/
 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.
CCI

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Appendix 6. Rifampin Drug-Drug Interaction Sub-Study 
Patients will be enrolled into the rifampin interaction sub-study prior to the enrollment of 
patients in the itraconazole interaction sub-study.
Background:
The aim of this sub-study is to determine the effect of the co-administration of rifampin on the 
multiple-dose plasma pharmacokinetics profile of PF-02341066.  The starting dose of 
PF-02341066 will be 250 mg BID and approximately 25 patients will be enrolled to obtain 
8 evaluable patients.  See Section 9.1.4 for further details.
In vitro studies demonstrated that CYP3A4/5 are the major enzymes involved in the 
metabolic clearance of PF-02341066. Co-administration of a single 250 mg PF-02341066 
dose with rifampin (600 mg QD), a strong CYP3A inducer, resulted in 81.8% and 
68.5% decreases in PF-02341066 AUCinf and Cmax, respectively, compared to when 
PF-02341066 was given alone.13  As PF-02341066 is also a CYP3A inhibitor, the magnitude
of the effects of CYP3A inducers on steady state PF-02341066 exposures may differ from 
those seen after single doses. A mathematical modeling approach11 based on preclinical and 
clinical data indicate that rifampin co-administration is likely to result in an approximately 
36% decrease in the PF-02341066 AUC. Based on these findings no safety issues in using a 
250 mg BID PF-02341066 dose in combination with rifampin are anticipated.
Note: Clinical sites in Korea will not participate in the rifampin interaction sub-study.
Patient Population:  
This clinical trial 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. 
Inclusion Criteria:
Patient eligibility should be reviewed and documented by an appropriate 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 confirmed advanced malignancies (except for leukemias) refractory to 
standard of care therapy, or for whom no standard of care therapy is available.
2. Not applicable; included to ensure consistent numbering.
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older.

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5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to 
Grade 1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase
(ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver 
function abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L. 

Platelets 100,000/L.

Hemoglobin 9.0 g/dL.

Serum creatinine 2.0 x ULN.
8. 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.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of
starting study treatment; within 2 weeks of starting study treatment for anti-systemic 
therapy upon approval by the Sponsor.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue except for 
patients with neuroblastoma, lymphoma or myeloma. 
3. Current treatment on another clinical trial.

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4. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 4 weeks and not taking medications contraindicated to Exclusion Criteria 
#10-13.
5. Any of the following within the 6 months prior to starting study treatment: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, 
congestive heart failure, cerebrovascular accident including transient ischemic attack
or pulmonary embolus.  However, upon agreement between the investigator and 
Sponsor, the 6 month post-event-free period for a patient with a pulmonary embolus 
can be waived if due to advanced cancer.  Appropriate treatment with anticoagulants 
is permitted however care must be taken during the co-administration of rifampin and 
PF-02341066.
6. Ongoing cardiac dysrhythmias of NCI CTCAE grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc interval >470 msec.
7. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
8. Pregnancy or breastfeeding. Female patients must be surgically sterile or be 
postmenopausal, or must agree to the use of effective contraception during the period 
of therapy.  All female patients with reproductive potential must have a negative 
pregnancy test (serum or urine) prior to enrollment.  Male patients must be surgically 
sterile or must agree to use effective contraception during the period of therapy.  The 
definition of effective contraception will be based on the judgment of the principal 
investigator or a designated associate.  Female patients using oral or other systemic 
hormonal contraceptives should additionally use nonhormonal methods of birth 
control during rifampin therapy.
9. Other severe acute or chronic medical or psychiatric conditions or laboratory 
abnormality that would impart, in the judgment of the investigator and/or Sponsor, 
excess risk associated with study participation or study drug administration, which 
would make the patient inappropriate for entry into this study. 
10. Use of drugs or herbal supplements that are known CYP3A4 inhibitors within 7 days 
prior to the first dose of PF-02341066 until the completion of full PK sample 
collection on Cycle 2 Day 1. Grapefruit or grapefruit juice should also be avoided.  
The topical use of these medications (if applicable), such as 2% ketoconazole cream, 
may be allowed.  All concomitant medication must be approved by the Sponsor. 
Note: After the completion of PK blood sample collection on Cycle 2 Day 1, drugs 
that are known strong CYP3A4 inhibitors including (but not limited to) atazanavir, 
clarithromycin, ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, 
indinavir, nelfinavir, saquinavir, nefazodone, and voriconazole should be avoided.  
Grapefruit or grapefruit juice should also be avoided.  The topical use of these 
medications (if applicable), such as 2% ketoconazole cream, may be allowed. 

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11. Use of drugs or herbal supplements that are known CYP3A4 inducers (with exception 
of rifampin doses as required in the protocol) within 12 days prior to the first dose of 
PF-02341066 until the completion of full PK blood sample collection on Cycle 2 
Day 1. All concomitant medication must be approved by the Sponsor. 
Note: After the completion of full PK blood sample collection on Cycle 2 Day 1, 
drugs that are known strong CYP3A4 inducers including (but not limited to) 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort 
should be avoided. 
12. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor. 
13. Concurrent use of histamine H2 antagonists (eg, cimetidine, famotidine, nizatidine 
and ranitidine) or proton-pump inhibitors (eg, esomeprazole, lansoprazole, 
omeprazole, pantoprazole and rabeprazole) from the start of the first dose of 
PF-02341066 until the completion of full PK blood sample collection on Cycle 2 
Day 1.  All concomitant medication must be approved by the Sponsor.
14. Patients with known interstitial fibrosis or interstitial lung disease.
15. Patients with a history of hypersensitivity to any of the rifamycins.
16. Patients having any contraindications to rifampin administration according to the
current package insert (or regulatory equivalent) for rifampin.
Sample Size:
A total of 25 patients with advanced malignancies refractory to standard of care therapy, or 
for whom no standard of care therapy is available will be enrolled in this interaction 
sub-study to obtain 8 evaluable patients.  See Section 9.1.4 for further details.
Concomitant Medication:
Patients using oral or other systemic hormonal contraceptives should be advised to 
additionally use nonhormonal methods of birth control during rifampin therapy.
Rifampin has been observed to increase the requirements for coumarin-like anticoagulant 
drugs.  It is therefore recommended that the prothrombin time be performed as frequently as
necessary to establish and maintain the required anticoagulant dose.
The concurrent use of halothane or isoniazid is not permitted during the rifampin dosing 
period as the potential for hepatotoxicity is increased when these drugs are co-administered.
Probenecid and cotrimoxazole have been reported to increase rifampin blood levels and 
should be avoided during rifampin treatment.

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Patients must not: (1) take any medications, herbal supplements or food known to be CYP3A 
inhibitors 7 days prior to the first dose of PF-02341066 until the completion of the full PK 
blood sample collection on Cycle 2 Day 1; (2) take any medications, herbal supplements or 
food known to be CYP3A inducers 12 days prior to the first dose of PF-02341066 until the 
completion of the full PK blood sample collection on Cycle 2 Day 1; and (3) take histamine 
H2 antagonists (eg, cimetidine, famotidine, nizatidine and ranitidine) or proton-pump 
inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole) from 
the start of the first dose of PF-02341066 until the completion of the full PK blood sample 
collection on Cycle 2 Day 1.  All concomitant medications for patients enrolling in this 
sub-study must be approved by the Sponsor.
For further information please refer to the Rifampin Package Insert (or regulatory 
equivalent).
Administration:
PF-02341066 
PF-02341066 (tablets) will be administered at a dose of 250 mg BID.  PF-02341066 should 
be administered approximately 12 hours apart. PF-02341066 may be given with or without
food throughout the study except for at the time of co-administration of rifampin from 
Cycle 1 Day 16 until Cycle 2 Day 1. During this period, patients should fast for at least 
2 hours before and 1 hour after dosing.  On days of PK sampling, patients must take their 
daily dose of rifampin and morning dose of PF-02341066 at the clinic.
Refer to Section 5 Trial Treatments for details on PF-02341066 Formulation and Packaging 
(Section 5.2.1), Preparation and Dispensing (Section 5.2.2), Administration (Section 5.2.3) 
and Compliance (Section 5.2.4).
Rifampin
Commercially available rifampin will be administered at a dose of 600 mg QD starting on 
Cycle 1 Day 16.  Dosing will continue until Cycle 2 Day 1 (total of 14 days).  Rifampin 
should be administered at the same time of the morning dose of PF-02341066 either one 
hour before or 2 hours after a meal with a full glass of water (approximately 240 mL). 
Plasma Pharmacokinetic Assessment for PF-02341066:
Blood samples for PF-02341066 and metabolite PF-06260182 will be collected as follows:
A full PK profile will be obtained on Cycle 1 Day 15 and Cycle 2 Day 1 at the following time
points: 0 (pre-dose), 2, 4, 6, 8 and 10 hours following the morning dose of PF-02341066.  In 
addition sparse sampling will be done on Cycle 1 Day 25, Cycle 1 Day 27, Cycle 2 Day 15 
and Day 1 of Cycles 3 and 5 at the following time points: 0 (pre-dose) and 2-6 hours 
following the morning dose of PF-02341066.
Note: PK samples collected from Cycle 1 Day 15 to Cycle 2 Day 1 (rifampin 
co-administration period) will be analyzed for both PF-02341066 and its metabolite 
PF-06260182.

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In addition to samples mentioned above, additional blood samples for PK evaluation may be 
requested from patients experiencing unexpected or serious adverse events; with evidence of 
disease progression; or with other events where PK sampling is considered useful (upon 
agreement between investigator and Sponsor).  More than one PK sample per patient may be 
collected throughout the study; however the total blood volume of additional PK samples 
collected per patient should not exceed 15 mL (ie, no more than 5, 3 mL samples). 
Refer to Section 7.5.1.1 for details regarding sample collection for PF-02341066 PK. 
Note: No blood samples will be collected for the determination of rifampin concentrations.
Please see below for further details on dosing and PK sampling schedule (Figure 5).
Figure 5.
Schema for Design of PF-02341066 and Rifampin Interaction Sub-Study

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Schedule of Activities: Rifampin Drug-Drug Interaction Sub-study
Protocol Activity
Screening* 
Cycle 1= 28 days**
Cycle 2 = 28 
days**
Every 4 weeks** 
(after Cycle 
2-Cycle 5)
Every 8 
Weeks***
End of 
Treatment
(28 Days 
Post Dose)
Day -14 to 
Day 0
Day 1 
(pre-d
ose)
Day 
15 
Days 16, 
25 & 27
Day
1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG)6
X
X
X
X
Repeat as clinically indicated.
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination20
X [X]
[X]
[Cycle 3 only]
[X]
Safety assessment (adverse events)11
X
X
X
X
X
X
X
X
Imaging only if renal cysts are identified*12
X
Concomitant medications13
X
X
X
X
X
X
X
Pregnancy test14
X
X
X
Special Laboratory Studies
Plasma sampling for full PF-02341066 PK15
X
X
Sparse plasma sampling points for PF-02341066 
PK16
X (D25 & 
D27)
X
X ( Cycles 3 & 5)
Blood sample for pharmacogenomics17
X
PF-02341066 treatment18
X
X
X
X
X
X
X
Rifampin treatment19
X (D16)
X
( ) If it has not been performed within 7 days.  
* Allowable window for imaging is 7 day; 2 days for all other assessments with the exception of Days 16, 25 and 27.  There is a 1 day window for Days 25 and 27 (but these 
visits should be 2 days apart).  
* Allowable window for screening assessments is up to -7 days from Day -14 (ie, Day -21 to Day 0).
[ ] Special ophthalmology tests for all NSCLC patients enrolled until written notification by Sponsor.  See Section 7.3 for additional details.
**Cycle length is 4 weeks (28 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient does not have a 
clinic visit, a telephone contact is required before initiating the next cycle.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.

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2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening and on Day 1 of each cycle: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the Appendix 2 of the protocol.
6.
12- Lead ECG: Three consecutive 12-lead ECGs will be performed at least 2 minutes apart during the screening period; Cycle 1 Day 1 at pre-dose (0 hour); Cycle 1 
Day 15 at pre-dose (0 hour) and 4 hours post-dose (~Cmax); and Cycle 2 Day 1 at pre-dose, and 4 hours post-dose.  These time points correspond to PK time points.  
ECGs should be performed before PK blood draws at respective time points.  In addition to the time points noted, ECGs should be repeated as clinically indicated. 
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2, 
calcium, phosphorus, BUN, creatinine, uric acid, glucose.  If ALT Grade 3 and total bilirubin Grade 2, then liver function tests should be repeated every 48 hours 
until ALT Grade 2.
9.
Coagulation: PT and PTT.  Rifampin has been observed to increase the requirements for coumarin-like anticoagulant drugs.  It is therefore recommended that the 
prothrombin time be performed as frequently as necessary to establish and maintain the required anticoagulant dose if the patient is on a coumarin-like anti-coagulant.
10. Urinalysis: For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, 
or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be 
monitored and reported as described in the protocol. 
12. If renal cysts are observed, monitoring with appropriate imaging should be performed every 8 weeks following diagnosis.
13. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the 
patient has withdrawn from the study, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, 
whichever is later.
14. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated at Cycle 2 Day 15 
and whenever one menstrual cycle is missed during treatment or a potential pregnancy is otherwise suspected. 
15. A full pharmacokinetic profile of PF-02341066 and metabolite(s) will be obtained on Cycle 1 Day 15 and Cycle 2 Day 1 at the following time points: 0 (pre-dose), 2, 4, 
6, 8 and 10 hours. 

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16. Sparse PK sampling will be done on Cycle 1 Day 25 and Cycle 1 Day 27, Cycle 2 Day 15, and Day 1 of Cycles 3 and 5 at the following time points: 0 (pre-dose) and 
2-6 hours
17. A single blood sample will be collected at baseline (within 2 weeks prior to the first dose) to genotype the alleles of cytochrome P450 enzymes and drug transport 
proteins. 
18. PF-02341066 will be dosed at 250 mg BID.
19. Commercially available rifampin will be dosed at 600 mg QD starting Cycle 1 Day 16 and finishing on Cycle 2 Day 1 (14 days). 
20. An ophthalmology examination will be performed at screening for all patients.  The ophthalmology examination should be repeated during the study when visual 
disturbances have been observed and when there is an increase in grade for visual disturbances.  The ophthalmology examination should include ocular characteristics, 
visual acuity, fundoscopy and slit lamp examination.  All NSCLC patients enrolled will undergo additional special ophthalmological testing as described in Section 7.3
until written notification by the Sponsor.  All ophthalmology examinations should be performed by an ophthalmologist.  The time points of this special testing is 
designated by “[ ]” in the Schedule of Activities Table.

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Appendix 7. Itraconazole Drug-Drug Interaction Sub-Study
The aim of this sub-study is to determine the effect of itraconazole on the multiple-dose 
plasma pharmacokinetics of PF-02341066 when itraconazole is co-administered.  If 
multiple-dosing of PF-02341066 in combination with itraconazole is tolerable (as defined in 
the Study Design Section), a cohort of patients may be also enrolled to determine the effect of 
itraconazole on single and multiple-dose plasma pharmacokinetic profiles of PF-02341066.  
As of Protocol Amendment #22, the Single and Multiple-Dose Design will no longer be 
performed.  The starting dose of PF-02341066 will be 250 mg QD and approximately
25 patients will be enrolled to obtain at least 8 evaluable patients for multiple-dose PK.  See 
Section 9.1.5 for more details.  Patients who are enrolled in the study but not treated may be 
replaced to obtain at least 8 evaluable patients for multiple-dose PK.
The magnitude of the effects of CYP3A inhibitors on steady state PF-02341066 exposures 
may differ from those seen after a single dose of PF-02341066 as PF-02341066 is also a 
CYP3A inhibitor.  An autoinhibition-mediated change in apparent clearance of 
PF-02341066 was observed during chronic PF-02341066 treatment.  There are limited data
with single doses of PF-02341066 administered with ketoconazole (200 mg BID), a strong 
CYP3A inhibitor.  Co-administration of a single 150 mg oral dose of PF-02341066 in the 
presence of ketoconazole, resulted in increases in PF-02341066 systemic exposure, with 
PF-02341066 AUCinf and Cmax values that were approximately 3.2 fold and 1.4 fold higher, 
respectively, than those seen when PF-02341066 was administered alone.14 SIMCYP (a 
population based pharmacokinetics modeling simulator) modeling12 based on preclinical and 
clinical data, predict a 2-fold increase in PF-02341066 AUC when PF-02341066, at steady
state, is co-administered with ketoconazole. The effect of itraconazole on PF-02341066
exposure cannot be properly predicted due to the lack of a validated physiologically based 
pharmacokinetic model.  Based upon recent FDA guidance15 on the use of ketoconazole, 
ketoconazole was replaced with another CYP3A strong inhibitor, itraconazole.  However, it 
is expected that the magnitude of the effect of itraconazole would be no greater than that of 
ketoconazole given that itraconazole had a smaller inhibitory effect on the exposure of 
midazolam, a CYP3A probe, than ketoconazole.16  Therefore, the PF-02341066 exposure at 
250 mg QD when administered with itraconazole is expected to be similar to or lower than 
the PF-02341066 exposure at the maximum tolerated dose of 250 mg BID when administered 
alone.  For these reasons, the same starting dose of PF-02341066 proposed for the 
ketoconazole drug-drug interaction, will be used for the itraconazole drug-drug interaction, 
ie, 250 mg QD.  However, should additional data arise impacting this assumption, the 
Sponsor will adjust the starting dose of PF-02341066 accordingly. 
Note: Clinical sites in South Korea will not participate in the itraconazole drug-drug
interaction sub-study.

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Patient Population: 
This clinical trial 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. 
Inclusion Criteria:
Patient eligibility should be reviewed and documented by an appropriate 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 confirmed advanced malignancies (except for leukemias) refractory to 
standard of care therapy, or for whom no standard of care therapy is available.
2. Not applicable; included to ensure consistent numbering.
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older.
5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to 
Grade 1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase
(ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver 
function abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L. 

Platelets 100,000/L.

Hemoglobin 9.0 g/dL (8.0 g/dL after IRB/EC approval of Amendment #21).

Serum creatinine 2.0 x ULN.

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8. 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.  For investigational sites using WIRB, patients who lack the 
capacity to consent for themselves will not be enrolled into this study.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of 
starting study treatment; within 2 weeks of starting study treatment for anti-systemic 
therapy upon approval by the Sponsor.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue except for 
patients with neuroblastoma, lymphoma or myeloma. 
3. Current treatment on another clinical trial.
4. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 4 weeks and not taking medications contraindicated to Exclusion Criteria 
#10 - 12 & 16.
5. History of or current evidence of congestive heart failure, or any of the following 
within the 3 months prior to starting study treatment: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular 
accident including transient ischemic attack or pulmonary embolus.  However, upon 
agreement between the investigator and Sponsor, the 3 month post-event-free period
for a patient with a pulmonary embolus can be waived if due to advanced cancer.  
Appropriate treatment with anticoagulants is permitted.  
6. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc >470 msec. Upon agreement between the 
Investigator and Sponsor, patients with a QTc >470 msec but <490 msec in the 
presence of a right bundle branch block or with an implanted cardiac pacemaker may 
enter the study.
7. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).

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8. Pregnant female patients, breastfeeding patients, male patients with pregnant female 
partners who are unwilling or unable to use a condom for the duration of the 
pregnancy, female and male patients of childbearing potential who are unwilling or 
unable to use 2 highly effective methods of contraception as outlined in this protocol 
for the duration of study treatment and for 90 days after the last dose of 
investigational product.
9. Other severe acute or chronic medical (including severe gastrointestinal conditions 
such as diarrhea or ulcer) or psychiatric condition including recent (within the past 
year) or active suicidal ideation or behavior) or end-stage renal disease on 
hemodialysis or laboratory abnormality that would impart, in the judgment of the 
investigator and/or Sponsor, excess risk associated with study participation or study 
drug administration, which would make the patient inappropriate for entry into this 
study. 
10. Use of drugs or herbal supplements that are known CYP3A4 inhibitors (with 
exception of itraconazole doses as required in the protocol) within 7 days prior to the 
first dose of PF-02341066 until the completion of full PK sample collection on 
Cycle 2 Day 2. Grapefruit or grapefruit juice should also be avoided.  The topical 
use of these medications (if applicable), such as 2% ketoconazole cream, may be 
allowed.  All concomitant medication must be approved by the Sponsor. 
Note: After the completion of PK blood sample collection on Cycle 2 Day 2, drugs 
that are known strong CYP3A4 inhibitors including (but not limited to) atazanavir, 
clarithromycin, ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, 
indinavir, nelfinavir, saquinavir, nefazodone, and voriconazole should be avoided. 
Grapefruit or grapefruit juice should also be avoided.  The topical use of these 
medications (if applicable), such as 2% ketoconazole cream, may be allowed. 
11. Use of drugs or herbal supplements that are known CYP3A4 inducers within 12 days 
prior to the first dose of PF-02341066 until the completion of full PK blood sample 
collection on Cycle 2 Day 2. All concomitant medication must be approved by the 
Sponsor. 
Note: After the completion of full PK blood sample collection on Cycle 2 Day 2, 
drugs that are known strong CYP3A4 inducers including (but not limited to) 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort 
should be avoided. 
12. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor.

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13. Concurrent use of oral ergot alkaloids, dofetilide, felodipine, levacetylmethadol, 
lovastatin, methadone, midazolam (oral), nisoldipine, quinidine, simvastatin, or 
triazolam from the start of the first dose of itraconazole until the completion of full 
PK blood sample collection on Cycle 2 Day 2.  These drugs are also contraindicated 
with itraconazole use.
14. Concurrent use of histamine H2 antagonists (eg, cimetidine, famotidine, nizatidine 
and ranitidine) or proton-pump inhibitors (eg, esomeprazole, lansoprazole, 
omeprazole, pantoprazole and rabeprazole) from the start of the first dose of 
PF-02341066 until the completion of full PK blood sample collection on Cycle 2 
Day 2.  All concomitant medication must be approved by the Sponsor.
15. 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.
16. Patients with a history of hypersensitivity to itraconazole or its excipients or to other 
azole antifungals.
17. Patient having any contraindications to itraconazole administration according to the 
current package insert (or regulatory equivalent) for itraconazole.
18. Concurrent use of nevirapine until the completion of full PK blood sample collection 
on Cycle 2 Day 2.  Nevirapine will decrease plasma concentrations of itraconazole.
19. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
Sample Size:
Approximately 25 patients with advanced malignancies refractory to standard of care 
therapy, or for whom no standard of care therapy is available will be enrolled in this 
interaction study to obtain at least 8 evaluable patients for multiple-dose PK. See Section 
9.1.5 for further details.
Concomitant Medication:
Patients must not: (1) take any medications, herbal supplements or food known to be CYP3A 
inhibitors 7 days prior to the first dose of PF-02341066 until the completion of full PK blood 
sample collection on Cycle 2 Day 2; (2) take any medications, herbal supplements or food 
known to be CYP3A inducers 12 days prior to the first dose of PF-02341066 until the 
completion of full PK blood sample collection on Cycle 2 Day 2; and (3) take histamine 
H2 antagonists (eg, cimetidine, famotidine, nizatidine and ranitidine) or proton-pump 
inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole) from 

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the start of the first dose of PF-02341066 until the completion of full PK blood sample 
collection on Cycle 2 Day 2. 
Itraconazole may decrease the elimination of drugs metabolized CYP3A4, resulting in 
increased plasma concentrations of these drugs when they are administered with 
itraconazole (Table 12).  These elevated plasma concentrations may increase or prolong 
therapeutic and adverse effects of these drugs.  Whenever possible, plasma concentrations of 
these drugs should be monitored, and dosage adjustments made after concomitant 
itraconazole therapy is initiated.  When appropriate, clinical monitoring for signs or 
symptoms of increased or prolonged pharmacologic effects is advised.  Please refer to the 
Itraconazole Package Insert (or regulatory equivalent) for complete information on drug 
interactions, contraindications, warnings and precautions.
Table 12.
Drugs Whose Plasma Concentrations May Be Increased By Itraconazole1
Antiarrhythmics 
digoxin, dofetilide,2 quinidine,2 disopyramide 
Anticonvulsants 
carbamazepine 
Antimycobacterials 
rifabutin 
Antipsychotics 
pimozide2
Benzodiazepines 
alprazolam, diazepam, midazolam,2,3 triazolam2
Calcium Channel Blockers 
dihydropyridines (including amlodipine, felodipine2 and 
nisoldipine2), verapamil, diltiazem 
Gastrointestinal Motility Agents 
cisapride2
HMG CoA-Reductase Inhibitors 
atorvastatin, cerivastatin, lovastatin,2 simvastatin2
Immunosuppressants 
cyclosporine, tacrolimus, sirolimus 
Oral Hypoglycemics 
oral hypoglycemics 
Protease Inhibitors 
indinavir, ritonavir, saquinavir 
1 This list is not all-inclusive.  From Sporanox® (itraconazole capsules) Package Insert April 2012. 
2 Contraindicated with itraconazole based on clinical and/or pharmacokinetics studies.  Patients must not 
take these drugs from the first dose of itraconazole until the completion of full PK blood sample collection on 
Cycle 2 Day 2. 
3 Concomitant administration of itraconazole and oral midazolam is contraindicated.  If midazolam is 
administered parenterally, special precaution and patient monitoring are required since the sedative effect 
may be prolonged.
All concomitant medications for patients enrolling in this sub-study must be approved by the 
Sponsor.
Hepatic Effects:
Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver 
failure and death.  Some of these cases had neither pre-existing liver disease nor a serious 
underlying medical condition.  Some of these cases developed within the first week of 
treatment.  If clinical signs and symptoms of liver disease develop, itraconazole treatment 
should be discontinued and liver function testing be performed.
Neurotoxicity:
If neurotoxicity occurs that may be attributable to itraconazole, itraconazole should be 
discontinued.

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Study Design:
The study design will evaluate the effect of itraconazole on the multiple-dose PK of 
PF-02341066 (Figure 6). If multiple-dosing of PF-02341066 in combination with 
itraconazole is tolerable, PK testing may be expanded to evaluate the effect of itraconazole 
on the single and multiple-dose plasma pharmacokinetic profiles of PF-02341066 (Figure 7).  
As of Protocol Amendment #22, the Single and Multiple-Dose Design will no longer be 
performed.  Approximately 25 patients will be enrolled to obtain at least 8 patients evaluable 
for multiple-dose PK.  Patients who are enrolled in the study but not treated may be replaced 
to obtain at least 8 patients evaluable for multiple-dose PK.
Multiple-Dose Pharmacokinetic Design: Each patient is scheduled to receive treatment for 
two treatment periods (A followed by B) as described below: 
Treatment Period A (Test): PF-02341066 250 mg QD will be administered from 
Cycle 1 Day 1 to Cycle 1 Day 15 and itraconazole 200 mg QD from Cycle 1 Day 1 to 
Cycle 1 Day 16 (before Cycle 1 Day 16 PF-02341066 dosing).
Treatment Period B (Reference): PF-02341066 250 mg QD will be administered from 
Cycle 1 Day 16 to Cycle 2 Day 1.
Tolerability will be considered established if the first 3 patients enrolled have no 
treatment-related adverse events requiring dose interruption or reduction from the first dose 
until Cycle 2 Day 2. 
If the single and multiple-dose design is implemented, the ability of patients to complete the 
required PK evaluations of this design will be assessed.  If 2 of the first 6 patients enrolled 
under this design are able to complete the serial PK samplings for the full PK profile of 
PF-02341066 required on Day -5 (Lead-in period), Cycle 1 Day 1, Cycle 1 Day 15 and 
Cycle 2 Day 1, then the original multiple-dose PK design will be re-implemented.
Administration:
Multiple-Dose Pharmacokinetic Design
Itraconazole 
Commercially available itraconazole will be administered at a dose of 200 mg QD starting 
on Cycle 1 Day 1.  Dosing will continue through Cycle 1 Day 16 (total dosing of 16 days).  
On full PK profile days (Cycle 1 Day 15 and Cycle 1 Day 16) when itraconazole and 
PF-02341066 are to be co-administered, PF-02341066 should be dosed approximately 
3 hours after itraconazole dosing.  In addition, on Cycle 1 Days 15 and Cycle 1 Day 16 the 
dose of itraconazole will be administered in the clinic and must be taken with a standard
meal defined as one that provides 15%, 35%, and 50% of calories from protein, fat, and 
carbohydrate, respectively, with a total of 500-700 calories provided or as instructed by the 
investigative site.

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PF-02341066
PF-02341066 (tablets) will be administered at a dose of 250 mg QD starting on Cycle 1
Day 1 and dosing will continue through Cycle 2 Day 1.  Starting on Cycle 2 Day 2, 
PF-02341066 will be administered at a dose of 250 mg BID.  PF-02341066 BID doses 
should be administered approximately 12 hours apart.
On full PK profile days when itraconazole and PF-02341066 are co-administered, 
PF-02341066 should be dosed approximately 3 hours after itraconazole dosing (ie, Cycle 1 
Day 15 and Cycle 1 Day 16). PF-02341066 may be given with or without food throughout 
the study except on the following PF-02341066 PK collection days: Cycle 1 Day 15, Cycle 1 
Day 16 and Cycle 2 Day 1, when the dose of PF-02341066 should be taken without food.  
Patients should begin fasting after their itraconazole dose and for 1 hour after PF-02341066
administration on these PK collection days.
On days of PK sampling, patients must take their daily dose of itraconazole and 
PF-02341066 at the clinic.
See Figure 6 for a schematic regarding dosing and PK sample collection times.
See the Schedule of Activities PF-02341066 and Itraconazole Interaction Sub-Study Schema: 
Multiple Dose.
Single and Multiple-Dose Pharmacokinetic Design
Itraconazole
Commercially available itraconazole will be administered at a dose of 200 mg QD starting 
on Day -3.  Dosing will continue through Cycle 1 Day 16 (total dosing of 19 days).  On full 
PK profile days when itraconazole and PF-02341066 are to be co-administered, 
PF-02341066 should be dosed approximately 3 hours after itraconazole dosing (ie, Cycle 1 
Days 1, 3, 15 and 16).  In addition, on Cycle 1 Days 1, 3, 15 and 16, itraconazole will be 
administered in the clinic and must be taken with a standard meal defined as one that
provides 15%, 35%, and 50% of calories from protein, fat, and carbohydrate, respectively,
with a total of 500-700 calories provided or as instructed by the investigative site.
In addition, on Days -3, -2, (or -1) and Cycle 1 Day 2, itraconazole must be taken at the 
clinic with a standard meal provided or as instructed by the investigative site.
PF-02341066
PF-02341066 (tablets) will be administered.  A single 250 mg dose of PF-02341066 will be 
given on Day -5.  PF-02341066 dosing at 250 mg QD will start on Cycle 1 Day 1 through 
Cycle 2 Day 1.  However, no PF-02341066 dose will be administered on Cycle 1 Day 2.  
Starting on Cycle 2 Day 2, PF-02341066 will be administered at a dose of 250 mg BID.
PF-02341066 BID doses should be administered approximately 12 hours apart.

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On full PK profile days when itraconazole and PF-02341066 are co-administered, 
PF-02341066 should be dosed approximately 3 hours after itraconazole dosing.  
PF-02341066 may be given with or without food throughout the study except on the 
following PF-02341066 PK collection days: Day -5, Cycle 1 Days 1, 15, 16 and Cycle 2
Day 1, when the dose of PF-02341066 should be taken without food.  Patients should begin 
fasting after their itraconazole dose and for 1 hour after PF-02341066 administration on 
these PK collection days. 
See Figure 7 for a schematic regarding dosing and PK sample collection times.
See Schedule of Activities for PF-02341066 and Itraconazole Interaction Sub-Study Schema: 
Single and Multiple-Dose.
Plasma Pharmacokinetic Assessment for PF-02341066 and its metabolite, PF-06260182:
Multiple-Dose Pharmacokinetic Design
Blood samples for PK of PF-02341066 and PF-06260182, will be collected as follows
(Figure 6):
A full PK profile of PF-02341066 will be obtained after administration of multiple doses of 
itraconazole and PF-02341066 on Cycle 1 Day 15 and Cycle 2 Day 1 at the following time 
points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose.  In addition, pre-dose PK 
samples will be collected on Cycle 1 Day 11, Cycle 1 Day 13, Cycle 1 Day 25 and Cycle 1
Day 27.
Note: PF-02341066 PK sampling is relative to the timing of PF-02341066 dosing.
PK samples collected for PF-02341066 will be analyzed for both PF-02341066 and 
PF-06260182. In addition to samples obtained as described above, additional blood samples 
for PK evaluation may be requested from patients experiencing unexpected or serious 
adverse events; with evidence of disease progression; or with other events where PK 
sampling is considered useful (upon agreement between investigator and Sponsor).  More 
than one PK sample per patient may be collected throughout the study; however the total 
blood volume of additional PK samples collected per patient should not exceed 15 mL (ie, no 
more than 5, 3 mL samples).  As of IRB/EC approval of Protocol Amendment #23, the total 
blood volume of additional PK samples collected per patient should not exceed 20 mL (ie, no 
more than 5, 4 mL samples).
Plasma Pharmacokinetic Assessment for Itraconazole and its metabolite(s)
Blood samples collected for itraconazole PK will only be analyzed upon the request of 
Sponsor based on the need of these data to more fully understand the sub-study findings. 
Blood samples for itraconazole will be collected as follows:
Pre-dose PK samples (for itraconazole and its metabolites) will be taken prior to 
itraconazole dosing on Cycle 1 Day 15 and Cycle 1 Day 16 (Figure 6). 

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Note: Itraconazole PK sampling is relative to timing of Itraconazole dosing. 
Please see below for further details on the multiple dose and pharmacokinetic sampling 
schedule (Figure 6).
Single and Multiple-Dose Pharmacokinetic Design
Blood samples for PF-02341066 and PF-06260182, will be collected as follows (Figure 7):
A full PK profile of PF-02341066 will be obtained after administration of a single dose on 
Day -5 (lead-in period) and Day 1 of Cycle 1 at the following time points: 0 (pre-dose), 1, 2, 
4, 6, 8, 9, 24, 48 and either 72 or 96 hours post dose.  Blood samples for the PF-02341066
PK profile will be also obtained on Cycle 1 Day 15 and Cycle 2 Day 1 at the following time
points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose.  In addition, pre-dose PK 
samples will be collected on Cycle 1 Day 11, Cycle 1 Day 13, Cycle 1 Day 25 and Cycle 1
Day 27.
Note: PF-02341066 PK sampling is relative to timing of PF-02341066 dosing.
PK samples collected for PF-02341066 will be analyzed for both PF-02341066 and 
PF-06260182.
In addition to samples obtained as described above, additional blood samples for PK 
evaluation may be requested from patients experiencing unexpected or serious adverse 
events; with evidence of disease progression; or with other events where PK sampling is 
considered useful (upon agreement between investigator and Sponsor).  More than one PK 
sample per patient may be collected throughout the study; however the total blood volume of 
additional PK samples collected per patient should not exceed 15 mL (ie, no more than 
5, 3 mL samples).
Refer Section 7.5.1.1 for details regarding sample collection for PF-02341066 PK. 
Plasma Pharmacokinetic Assessment for Itraconazole and its metabolite(s):
Blood samples collected for itraconazole and its metabolite(s) PK will only be analyzed upon 
the request of Sponsor based on the need of these data to more fully understand the study 
findings. 
Blood samples for itraconazole will be collected as follows:
Pre-dose PK samples (for itraconazole and its metabolites) will be taken prior to 
itraconazole dosing on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 15 and Cycle 1 Day 16
(Figure 7).
Note: Itraconazole PK sampling is relative to timing of itraconazole dosing. 
Details regarding the sample preparation will be provided in the Laboratory Manual. 

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Please see below for further details on the single and multiple dose and pharmacokinetic 
sampling schedule (Figure 7).
ECGs:
Multiple-Dose Pharmacokinetic Design
Three consecutive 12-lead ECGs will be performed at least 2 minutes apart at the following 
timepoints: Screening; Cycle 1 Day 1 and Cycle 1 Day 15 at pre-PF-02341066 dose 
(0 hour), 1 hour post-PF-02341066 dose (~Tmax for itraconazole) and 4 hours 
post-PF-02341066 dose (~Tmax for PF-02341066); and Cycle 2 Day 1 at pre-PF-02341066
dose (0 hour) and 4 hours post-PF-02341066 dose.  These time points correspond to PK time 
points.  ECGs should be performed within 15 minutes before PK blood draws at respective 
time points. 
In addition to the time points noted, ECGs should be repeated as clinically indicated.
Single and Multiple-Dose Pharmacokinetic Design
Three consecutive 12-lead ECGs will be performed at least 2 minutes apart at the following 
timepoints: Screening; Day -5 lead-in dose at pre-PF-02341066 dose (0 hour); Cycle 1
Day 1 and Cycle 1 Day 15 at pre-PF-02341066 dose (0 hour), 1 hour post-PF-02341066
dose (~Tmax for itraconazole) and 4 hours post-PF-02341066 dose (~Tmax for PF-02341066);
and Cycle 2 Day 1 at pre-PF-02341066 dose (0 hour) and 4 hours post-PF-02341006 dose.  
These time points correspond to PK time points.  ECGs should be performed within 
15 minutes before PK blood draws at respective time points. 
In addition to the time points noted, ECGs should be repeated as clinically indicated.
Figure 6.
PF 02341066 and Itraconazole Schema: Multiple Dose-Design

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Figure 7.
PF-02341066 and Itraconazole Interaction Schema: Single and Multiple-Dose 
Design

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Schedule of Activities: PF-02341066 and Itraconazole Interaction Schema: Multiple-Dose Design
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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.
Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 28 days**
Every 4 weeks***
(Cycle ≥3)
Every 
8 Weeks****
End of Tx
(28 Days 
Post Dose)*
Day -14 to Day 0
Day 1
Day 11, 13
Day 15
Days 25, 27
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, 
BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram 
(ECG)6
X
X
X
X
Repeat as clinically indicated.
Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination20
X
Safety assessment (adverse 
events)11
X
X
X
X
X
X
X
X
X
Imaging only if renal cysts are 
identified12
X
Concomitant medications13
X
X
X
X
X
X
X
X
Contraceptive Check (as 
applicable)21
X
X
X
X
X
Female patients: Pregnancy 
test14
X
X
X
X
X

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Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 28 days**
Every 4 weeks***
(Cycle ≥3)
Every 
8 Weeks****
End of Tx
(28 Days 
Post Dose)*
Day -14 to Day 0
Day 1
Day 11, 13
Day 15
Days 25, 27
Day 1
Day 15
Day 1
Special Laboratory Studies
Plasma sampling for 
PF-02341066 and metabolite 
PK15
X Sparse
X Full PK 
(Cycle 1 Days 
15 & 16)
X Sparse
X Full PK 
(Cycle 2 Days 
1 & 2
Plasma sampling for 
Itraconazole and metabolite(s) 
PK16
X (Cycle 1 
Days 15 & 16)
Blood sample for 
pharmacogenomics17
X
PF-02341066 treatment18
X ------------------------------------------------------------------------------------------------------------X
Itraconazole treatment19
X --------------------------------X
(Starting Day 1) 
(Up to Day 16)
( ) If it has not been performed within 7 days. 
* Allowable window for imaging is 7 days; 2 day window for all other assessments with the exception of PK collection days.  There is a 1 day window for 
Days 11, 13, 25 and 27 (but these visits should be 2 days apart).  There is a 2 day window for PK collection on Cycle 1 Day 15 and Cycle 2 Day 1.  
* Allowable window for screening activities is up to -7 days from Day -14 (ie, Day -21 to Day 0).
* End of treatment visit should be conducted 28 days postdose 2 days. 
**Cycle length is 4 weeks (28 days); Tx = Treatment.
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.
****If renal cysts are observed, imaging should be performed every 8 weeks.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the Appendix 2 of the protocol.
6.
12- Lead ECG: Three consecutive 12-lead ECGs will be performed at least 2 minutes apart at the following timepoints: Screening; Cycle 1 Day 1 and Cycle 1 Day 15 at 
pre-PF-02341066 dose (0 hour), 1 hour post-PF-02341066 dose and 4 hours post-PF-02341066 dose and Cycle 2 Day 1 at pre-PF-02341066 dose (0 hour) and 4 hours 
post- PF-02341066 dose.  These time points correspond to PK time points.  ECGs should be performed within 15 minutes before PK blood draws at respective time points.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.

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8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose.  Upon IRB/EC approval of Amendment #23, indirect bilirubin will no longer be collected.  If 
ALT or AST Grade 3 and total bilirubin Grade 2, obtain repeat ALT or AST and total bilirubin within 48 hours then repeat every 48-72 hours until ALT/AST Grade 1.  
See Table 2b for further detail.
9.
Coagulation: PT and PTT.  If a patient is on a coumarin-like drug, the anticoagulant effects should be carefully monitored and titrated as needed during itraconazole 
administration, since itraconazole may enhance the anticoagulant effects of coumarin-like drugs. 
10. Urinalysis: For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. If renal cysts are observed, monitoring with appropriate imaging should be performed every 8 weeks following diagnosis.
13. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from the study, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, whichever is 
later.
14. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  As of IRB/EC approval of Protocol Amendment #21, for female patients of childbearing 
potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting study therapy; once at Screening and 
once at Cycle 1 Day 1 before PF-02341066 administration.  Pregnancy tests will also be routinely repeated at every treatment cycle, at the end of treatment, and additionally 
whenever 1 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 
study medication.  Additional pregnancy tests may also be undertaken if requested by IRBs/ECs or if required by local regulations.  See Section 7.2 for further detail.
15. A full PK profile of PF-02341066 will be obtained after administration of multiple doses of itraconazole and PF-02341066 on Cycle 1 Day 15 and Cycle 2 Day 1 at the 
following time points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose.  In addition, pre-dose PK samples will be collected on Cycle 1 Day 11, Cycle 1 Day 13, 
Cycle 1 Day 25 and Cycle 1 Day 27. 
16. Pre-dose PK samples will be taken prior to itraconazole dosing on Cycle 1 Day 15 and Cycle 1 Day 16.
17. Blood sample for pharmacogenomics: A single whole blood biospecimen (4 mL) will be collected at baseline (within 2 weeks prior to the first dose) for possible analysis of 
DNA sequence variation in genes that may affect PK of the study drugs, may be associated with specific adverse events or toxicities, or may correlate with efficacy.
18. PF-02341066 dosing at 250 mg QD will start on Cycle 1 Day 1 through Cycle 2 Day 1.  Starting on Cycle 2 Day 2, PF-02341066 will be administered at a dose of 250 mg 
BID. 
19. Itraconazole will be dosed at 200 mg QD starting Cycle 1 Day 1 and finishing on Cycle 1 Day 16 (16 days).
20. An ophthalmology examination will be performed at screening for all patients.  The ophthalmology examination should be repeated during the study when visual disturbances 
have been observed and when there is an increase in grade for visual disturbances.  The ophthalmology examination should include ocular characteristics, visual acuity, 
fundoscopy and slit lamp examination. 

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21. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 and, upon IRB/EC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.

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Schedule of Activities: PF-02341066 and Itraconazole Interaction Schema: Single and Multiple-Dose Design
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL PROCEDURES and If a 
patient withdraws from study treatment and new anticancer therapy is subsequently administered, the End of Treatment (EOT) visit 
should occur prior to the initiation of new anticancer therapy.
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.
Protocol Activity
Screening*
Lead-in 
PK Period
Cycle 1= 28 days**
Cycle 2 = 28 days**
Every 
4 weeks
***
(Cycle ≥3)
Every 
8 Weeks
*****
End of Tx
(28 Days 
Post 
Dose)
Day -19 to 
Day -6
Day -5, -4,
-3
Day 
1 (pre-dose)
Day 11, 
13
Day 
15
Days 25, 
27
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, 
temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram 
(ECG)6
X
X (Day-5)
X
X
X
Repeat as clinically indicated.
Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology 
Examination20
X
Safety assessment (adverse 
events)11
X
X
X
X
X
X
X
X
X
X
Imaging only if renal cysts 
are identified12
X

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Protocol Activity
Screening*
Lead-in 
PK Period
Cycle 1= 28 days**
Cycle 2 = 28 days**
Every 
4 weeks
***
(Cycle ≥3)
Every 
8 Weeks
*****
End of Tx
(28 Days 
Post 
Dose)
Day -19 to 
Day -6
Day -5, -4,
-3
Day 
1 (pre-dose)
Day 11, 
13
Day 
15
Days 25, 
27
Day 1
Day 15
Day 1
Concomitant medications13
X
X
X
X
X
X
X
X
X
Contraceptive Check (as 
applicable)21
X
X (Day-5)
X
X
X
Female patients: 
Pregnancy test14
X
X
X
X
X
Special Laboratory Studies
Plasma sampling for 
PF-02341066 and 
metabolite PK15
X Full PK 
(Days -5,-
4,-3 & 
either -2 
or -1)
X Full PK 
(Cycle 1 
Days 1,2,3 
and either 
Day 4 or 5)
X Sparse 
PK
X Full 
PK 
(Days 
15 & 
16)
X Sparse 
PK
X Full Pk 
(Cycle 
2 Days 1 
& 2
Plasma sampling for 
Itraconazole and 
metabolite(s) PK16
X (Days 1,2)
X 
(Days 
15,16)
Blood sample for 
pharmacogenomics17
X
PF-02341066 treatment18
X 
(Day -5 on
ly)
X (no dose on C1D2)--------------------------------------------------------------------------------------X
Itraconazole treatment19
X -----------------------------------------X 
(Starting Day -3)                        (up to Day 16)
( ) If it has not been performed within 7 days 
* Allowable window for imaging is 7 days, There is a + 7 day window for screening.  There is a 2 day window for all other assessments with the exception of 
PK collection days.  There is a 1 day window for Days 11, 13, 25 and 27 (but these visits should be 2 days apart).  Once PF-02341066 is dosed on Day -5, PK 
collection on Cycle 1 Day 1 must be performed per schedule.  There is a 2 day window for PK collection on Cycle 1 Day 15 and Cycle 2 Day 1.
**Cycle length is 4 weeks (28 days); Tx = Treatment.
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.
****If renal cysts are observed, imaging should be performed every 8 weeks.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.

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4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the Appendix 2 of the protocol.
6.
12- Lead ECG:  Three consecutive 12-lead ECGs will be performed at least 2 minutes apart at the following timepoints: Screening; Day -5 at pre-PF-02341066 dose 
(0 hour); Cycle 1 Day 1 and Cycle 1 Day 15 at pre-PF-02341066 dose (0 hour), 1 hour post-PF-02341066 dose and 4 hours post-PF-02341066 dose and Cycle 2 Day 1 at 
pre-PF-02341066 dose (0 hour) and 4 hours post- PF-02341066 dose.  These time points correspond to PK time points.  ECGs should be performed within 15 minutes before
PK blood draws at respective time points.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, glucose.  If ALT or AST Grade 3 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.  See Table 2b for further detail.
9.
Coagulation: PT and PTT.  If a patient is on a coumarin-like drug, the anticoagulant effects should be carefully monitored and titrated as needed during itraconazole 
administration, since itraconazole may enhance the anticoagulant effects of coumarin-like drugs. 
10. Urinalysis:  For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. If renal cysts are observed, monitoring with appropriate imaging should be performed every 8 weeks following diagnosis.
13. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from the study, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, whichever is 
later.
14. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/ECs or if required by local 
regulations.  As of IRB/EC approval of Protocol Amendment #21, for female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed on 2 occasions prior to starting study therapy; once at Screening and once at Cycle 1 Day 1 before PF-02341066 administration.  Pregnancy 
tests will also be routinely repeated at every treatment cycle, at the end of treatment, and additionally whenever 1 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 study medication.  Additional pregnancy tests may also be undertaken
if requested by IRBs/EC or if required by local regulations.  See Section 7.2 for further detail.
15. A full PK profile of PF-02341066 will be obtained after administration of a single dose on Day -5 (lead-in period) and Day 1 of Cycle 1 at the following time points: 
0 (pre-dose), 1, 2, 4, 6, 8, 9, 24, 48 and either 72 or 96 hours post dose. Blood samples for PF-02341066 PK will be also obtained on Cycle 1 Day 15 and Cycle 2 Day 1 at 
the following time points: 0 (pre-dose), 1, 2, 4, 6, 8, 9 and 24 hours post dose.  In addition, pre-dose PK samples will be collected on Cycle 1 Day 11, Cycle 1 Day 13, Cycle 1
Day 25 and Cycle 1 Day 27. 
16. Pre-dose PK samples will be taken prior to itraconazole dosing on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 15 and Cycle 1 Day 16. 
17. Blood sample for pharmacogenomics: A single whole blood biospecimen (4 mL) will be collected at baseline (within 2 weeks prior to the first dose) for possible analysis of 
DNA sequence variation in genes that may affect PK of the study drugs, may be associated with specific adverse events or toxicities, or may correlate with efficacy.

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18. A single 250 mg dose of PF-02341066 will be given on Day -5.  PF-02341066 dosing at 250 mg QD will start on Cycle 1 Day 1 through Cycle 2 Day 1.  However, no 
PF-02341066 dose will be given on Cycle 1 Day 2.  Starting on Cycle 2 Day 2, PF-02341066 will be administered at a dose of 250 mg BID. 
19. Itraconazole will be dosed at 200 mg QD starting Cycle 1 Day -3 and finishing on Cycle 1 Day 16 (19 days). 
20. An ophthalmology examination will be performed at screening for all patients.  The ophthalmology examination should be repeated during the study when visual disturbances 
have been observed and when there is an increase in grade for visual disturbances.  The ophthalmology examination should include ocular characteristics, visual acuity, 
fundoscopy and slit lamp examination.
21. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 one or both selected contraception methods are discontinued, or if pregnancy is known or suspected in the patient 
or the patient’s partner.  See Section 4.5.1 for further detail.

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Appendix 8. ALK Marker Negative NSCLC RP2D Cohort #2
This cohort will consist of NSCLC patients who are negative for the ALK translocation as 
determined by the ALK break apart fluorescence in situ hybridization (FISH) assay as 
determined by the central laboratory selected by the Sponsor.  Patients may have been 
pre-screened and determined to have ALK marker negative NSCLC by a local test but no 
molecular testing for MET or ROS1 should have occurred prior to enrollment. As of the 
Note to File dated 19 June 2012, the requirement that no molecular testing for MET or ROS1
to occur prior to enrollment was removed.  However, if MET or ROS1 testing was performed 
prior to patient enrollment and if the test result for either MET or ROS1 was positive, then 
the patient could not be enrolled onto this cohort.  The results of the negative local test must 
be confirmed by the central laboratory before entry into the study. 
Patient Population:
This clinical trial 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. 
Inclusion Criteria:
Patient eligibility should be reviewed and documented by an appropriate 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 NSCLC that is locally advanced 
or metastatic and of the adenocarcinoma subtype (including mixed adenosquamous 
histology).  Patients must have received at least one prior chemotherapy regimen.  
Patients must have been determined to be ALK-negative by the central laboratory but 
may have been pre-screened and shown to have ALK negative NSCLC by a local test.  
All patients must either be non-smokers, ex-smokers or light smokers 
(10 pack-years).
2. Solid tumors must have measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.1).  Patients whose tumors are not measurable may enter 
the study upon approval by the Sponsor.  Target lesions that have been previously 
irradiated will not be considered measurable (lesion) unless increase in size is 
observed following completion of radiation therapy. 
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older.

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5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to Grade 
1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase
(ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver 
function abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L. 

Platelets 30,000/L 

Hemoglobin 9.0 g/dL.

Serum creatinine 2.0 x ULN.
8. 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.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 2 weeks of 
starting study treatment. 
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
3. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.
4. Current treatment on another clinical trial.

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5. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 2 weeks and not taking medications contraindicated to Exclusion Criteria 
#11-13.
6. Any of the following within the 6 months prior to starting study treatment: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, 
congestive heart failure, cerebrovascular accident including transient ischemic 
attack, or pulmonary embolus.  However, upon agreement between the investigator 
and Sponsor, the 6 month post-event-free period for a patient with a pulmonary 
embolus can be waived if due to advanced cancer.  Appropriate treatment with 
anticoagulants is permitted.
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc interval >470 msec.
8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
9. Pregnancy or breastfeeding.  Female patients must be surgically sterile or be 
postmenopausal, or must agree to the use of effective contraception during the period 
of therapy.  All female patients with reproductive potential must have a negative 
pregnancy test (serum or urine) prior to enrollment.  Male patients must be surgically 
sterile or must agree to use effective contraception during the period of therapy.  The 
definition of effective contraception will be based on the judgment of the principal 
investigator or a designated associate.
10. Other severe acute or chronic medical or psychiatric condition, or laboratory 
abnormality that would impart, in the judgment of the investigator and/or Sponsor, 
excess risk associated with study participation or study drug administration, which 
would make the patient inappropriate for entry into this study. 
11. Use of drugs that are known strong CYP3A4 inhibitors within 7 days prior to the first 
dose of PF-02341066, including but not limited to atazanavir, clarithromycin, 
ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, indinavir, 
nelfinavir, saquinavir, nefazodone, and voriconazole.  Grapefruit or grapefruit juice 
should also be avoided.  The topical use of these medications (if applicable), such as 
2% ketoconazole cream, may be allowed.  All concomitant medication must be 
approved by the Sponsor.
12. Use of drugs that are known strong CYP3A4 inducers within 12 days prior to the first 
dose of PF-02341066, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.  All concomitant medication must 
be approved by the Sponsor. 

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13. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor. 
14. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.
15. Patients with known interstitial fibrosis or interstitial lung disease.
Sample Size:
To further characterize the anti-tumor activity of PF-02341066 in ALK marker negative 
NSCLC patients, at least 20 patients will be enrolled into this cohort. 
Concomitant Medications:
Refer to Section 5.5 Concomitant Medication(s) for further details.
Administration:
PF-02341066 tablets will be administered at a dose of 250 mg BID.  PF-02341066 doses 
should be administered approximately 12 hours apart.  PF-02341066 may be given with or 
without food throughout the study.
Refer to Section 5.2 Trial Treatments for details on Formulation and Packaging 
(Section 5.2.1), Preparation and Dispensing (Section 5.2.2), Administration (Section 5.2.3) 
and Compliance (Section 5.2.4).

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Schedule of Activities: ALK Marker Negative NSCLC Cohort***
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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.
Protocol Activity
Screening*
Cycle 1= 21 days**
Cycle 2 = 
21 days**
Every 3 weeks** 
(Cycle ≥3)
Every 6 
Weeks
End of 
Treatment
(28 Days 
Post Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG)6
X
X
X
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination21
X 
X
Cycle 3, Cycle 18 
& every 17 cycles 
thereafter
X
Safety assessment (adverse events)11
X
X
X
X
X
X
X
Tumor assessment *,  ***12
X
X
X
Survival13
Until at least 1 year after the final dose
Concomitant medications14
X
X
X
X
X
X
Contraceptive Check (as applicable)22
X
X
Female patients: Pregnancy test15
X
X
X
X
X
Special Laboratory Studies
Two plasma sampling points for PF-02341066 
PK16
X
X
Cycles 3 and 5
Blood sample for pharmacogenomics17
X
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Protocol Activity
Screening*
Cycle 1= 21 days**
Cycle 2 = 
21 days**
Every 3 weeks** 
(Cycle ≥3)
Every 6 
Weeks
End of 
Treatment
(28 Days 
Post Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
PF-02341066 treatment20
Twice a day continuously
( ) If it has not been performed within 7 days.  
* Allowable window for tumor assessment imaging is 7 days; 2 days for all other assessments.  
* Allowable window for screening assessments is up to -7 days from Day -14 (ie, Day -21 to Day 0).
* End of treatment visit should be conducted 28 days postdose 2 days.  
**Cycle length is 3 weeks (21 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.  Once a patient has completed 15 cycles, tumor imaging may be 
performed every 12 weeks based on 3-week calendar schedule. Once a patient has completed 35 cycles, tumor imaging may be performed every eighth cycle 
(every 24 weeks).  If tumor imaging was done within 6 weeks of the last dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the Appendix 2 of the protocol.
6.
12- Lead ECG: Patients will have triplicate ECGs collected at least 2 minutes apart during the screening period; Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose (0 hour) and 
2-6 hours post-dose, which are corresponding to PK time points.  ECGs should be performed before PK blood draws at respective time points.  In addition to the time points 
noted, ECGs should be repeated as clinically indicated.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose.  Upon IRB/EC approval of Amendment #23, indirect bilirubin will no longer be collected.  If 
ALT or AST Grade 3 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.  See Table 2b for further detail.  
9.
Coagulation: PT and PTT.
10. Urinalysis: For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 

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12. Tumor Imaging: CT or MRI scan to be performed to assess disease status at screening, every 6 weeks (based on calendar schedule) starting after the first dose, whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at 
the end/withdrawal from the study.  If renal cysts are observed, monitoring with appropriate imaging should be performed at the time of renal cyst diagnosis and thereafter 
following the same schedule as for tumor imaging.
13. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment until at least one year after the final dose.
14. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from the study, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, whichever is 
later.
15. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/EC or if required by local 
regulations.  As of IRB/EC approval of Protocol Amendment #21, for female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL, will be routinely performed at every cycle, at the end of treatment, and additionally whenever 1 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 study medication.  Additional pregnancy tests may also be undertaken 
if requested by IRBs/ECs or if required by local regulations.  See Section 7.2 for further detail.  Note: At the time of the required inclusion of additional pregnancy testing, no 
patients are being enrolled in this cohort and all ongoing patients are beyond Cycle 2. 
16. PK samples will be collected on Day 1 of Cycle 1, 2, 3 and 5 at pre-dose (0 hour) and 2-6 hours post-dose.  See Section 7.5.1.1.
17. A single blood sample will be collected at baseline (within 2 weeks prior to the first dose) to genotype the alleles of cytochrome P450 enzymes and drug transport proteins. 
20. PF-02341066 will be administered at a dose of 250 mg BID.
21. As of Protocol Amendment #17, all patients will undergo additional special ophthalmological testing as described in Section 7.3 until written notification by the Sponsor.  As 
of the Note To File issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive 
error, pupil size, intraocular pressure, ocular coherence tomography, dilated fundus photography.  All ophthalmology examinations should be performed by an 
ophthalmologist.  Ophthalmology examination(s) should be repeated if visual disturbances are observed or if there is an increase in grade for a visual side effect.  The time 
points of this special testing is designated by “[ ]” in the Schedule of Activities Table and includes Screening, Cycle 1 Day 15, Cycle 3 Day 1, 1 year, yearly thereafter, and 
then at 2 - 8 weeks after discontinuation of PF-02341066.  For NSCLC patients on a 3-week cycle, 1 year would be Cycle 18 Day 1 and every 17 cycles thereafter.  There is a 
±2 week window for the yearly ophthalmology examination.
22. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 and, upon IRB/EC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.
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Appendix 9. MET-Amplified NSCLC Cohort
To further evaluate the anti-tumor activity of PF-02341066 associated with MET
amplification, patients with MET-amplified NSCLC will be enrolled.
Patient Population:
This clinical trial 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. 
Inclusion Criteria:
Patient eligibility should be reviewed and documented by an appropriate 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 confirmed advanced NSCLC positive for MET amplification.  Patients 
must have a MET/CEP7 ratio of 1.8.
2. Solid tumors must have measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.0).  However, patients whose tumors are not measurable 
may enter the study upon approval by the Sponsor.  Target lesions that have been 
previously irradiated will not be considered measurable (lesion) unless increase in 
size is observed following completion of radiation therapy. 
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older.
5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to 
Grade 1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate transferase (AST) and serum alanine aminotransferase (ALT) 
2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver function 
abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

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
Absolute neutrophil count (ANC) 1500/L. 

Platelets 30,000/L. 

Hemoglobin 9.0 g/dL (≥8.0 g/dL after IRB/EC approval of Amendment #21).

Serum creatinine 2.0 x ULN.
8. 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.  For Sites using WIRB, patients who lack capacity to consent for 
themselves will be excluded from this study.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 2 weeks of 
starting study treatment.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 
3. Prior therapy specifically directed against MET or HGF.
4. Current treatment on another clinical trial.
5. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 2 weeks and not taking medications contraindicated to Exclusion Criteria 
#11-13.
6. Any of the following within the 3 months prior to starting study treatment: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, congestive heart failure, cerebrovascular accident including transient ischemic 
attack or pulmonary embolus.  However, upon agreement between the investigator 
and Sponsor, the 3 month post-event-free period for a patient with a pulmonary 
embolus can be waived if due to advanced cancer.  Appropriate treatment with 
anticoagulants is permitted.  [Implement 3 month guidance upon IRB/EC approval of 
Amendment #20].
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc >470 msec.  Upon agreement between the 
Investigator and Sponsor, patients with a QTc >470 msec but <490 msec in the 

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presence of a right bundle branch block or with an implanted cardiac pacemaker may 
enter the study [Implement upon IRB/EC approval of Amendment #20].
8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
9. Pregnant female patients, breastfeeding patients, male patients with pregnant female 
partners who are unwilling or unable to use a condom for the duration of the 
pregnancy, female and male patients of childbearing potential who are unwilling or 
unable to use 2 highly effective methods of contraception as outlined in this protocol 
for the duration of study treatment and for 90 days after the last dose of 
investigational product.
10. Other severe acute or chronic medical (including severe gastrointestinal conditions 
such as diarrhea or ulcer) or psychiatric conditions including recent (within the past 
year) or active suicidal ideation or behavior) or end-stage renal disease on 
hemodialysis or laboratory abnormality that would impart, in the judgment of the 
investigator and/or Sponsor, excess risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and
would make the patient inappropriate for entry into this study. 
11. Use of drugs that are known strong CYP3A4 inhibitors within 7 days prior to the first 
dose of PF-02341066, including but not limited to atazanavir, clarithromycin, 
ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, indinavir, 
nelfinavir, saquinavir, nefazodone, and voriconazole. Grapefruit or grapefruit juice 
should also be avoided.  The topical use of these medications (if applicable), such as 
2% ketoconazole cream, may be allowed.  All concomitant medication must be 
approved by the Sponsor.
12. Use of drugs that are known strong CYP3A4 inducers within 12 days prior to the first 
dose of PF-02341066, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.  All concomitant medication must 
be approved by the Sponsor. 
13. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor. 
14. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.

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15. Patients with known interstitial fibrosis or interstitial lung disease.  After IRB/EC 
approval of Amendment #20: 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, , 
obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation 
pneumonitis.
16. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study [Implement upon IRB/EC approval of Amendment #20].
Sample Size:
To further evaluate the anti-tumor activity of PF-02341066 associated with MET
amplification, 10 to 12 patients with MET-amplified NSCLC will be enrolled into each of the 
following 3 categories:

High Level MET Gene Amplified Category (MET/CEP7 ratio 5.0; Group 1): As per 
the PACL dated 15 May 2017, the MET/CEP7 ratio cut-off for this group was revised 
to ≥4.0).  As per the PACL dated 11 September 2018, this group was closed to further 
enrollment. The remaining 14 enrollment slots were transferred to the MET Exon 14 
alterations subgroup within the Enriched Other cohort.

Medium Level MET Gene Amplified Category (MET/CEP7 ratio >2.2 to <5; Group 
2): As per the PACL dated 15 May 2017, the MET/CEP7 ratio cut-off for this group 
was revised to >2.2 to 4.0 and this group was closed to further enrollment.  The 
remaining 13 enrollment slots were transferred to the MET Exon 14 alterations 
subgroup within the Enriched Other cohort;

Low Level MET Gene Amplified Category (MET/CEP7 ratio 1.8 to 2.2; Group 3):
As per the PACL dated 12 October 2015, this group was closed to further enrollment.
For further details refer to Section 9.1.3.2. 
Concomitant Medications:
Refer to Section 5.5 Concomitant Medication(s) for further details.
Administration:
PF-02341066 tablets will be administered at a dose of 250 mg BID.  PF-02341066 doses 
should be administered approximately 12 hours apart.  PF-02341066 may be given with or 
without food throughout the study.

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Refer to Section 5.2 Trial Treatments for details on Formulation and Packaging 
(Section 5.2.1), Preparation and Dispensing (Section 5.2.2), Administration (Section 5.2.3) 
and Compliance (Section 5.2.4).
Independent Radiology Review:
All tumor scans from NSCLC patients with tumors harboring MET gene amplification will be 
collected and held at the investigative site.  With Sponsor approval and IRB/EC notification, 
the Sponsor may request tumor scans from these patients to be submitted to an independent 
radiology laboratory for review at a later date.  As per PACL dated 9 March 2018, all tumor 
scans for patients enrolled in the MET-amplified NSCLC cohort will be collected and 
submitted to an independent radiology laboratory for review until notification is received 
from the Sponsor. As of IRB/EC approval of Amendment #24, tumor scans from patients 
with MET-amplified NSCLC will no longer be collected and submitted to an independent 
radiology review laboratory.

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Schedule of Activities: MET-Amplified NSCLC Cohort ***
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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: Upon IRB/EC approval of Protocol Amendment #24, ongoing patients will follow a Reduced Schedule of Activities as 
indicated in Appendix 13.
Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment
(28 Days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG)6
X
X
X
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination23
X 
X
Cycle 3, Cycle 14 
& every 13 cycles 
thereafter
X
Safety assessment (adverse events)11
X
X
X
X
X
X
X
Tumor assessment *, ***12
X
X
X
Survival13
Until two years after the last patient enrolled has discontinued PF-02341066 treatment, unless otherwise noted by the Sponsor
Concomitant medications14
X
X
X
X
X
X
Contraceptive check (as applicable)24
X
X
X
X
X
Female patients: Pregnancy test15
X
X
X
X
X

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Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment
(28 Days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Special Laboratory Studies
Two plasma sampling points for PF-02341066 
PK16
X
X
Cycles 3 & 5; also 
at disease 
progression if 
patient is still 
taking 
PF-02341066.
Blood sample for pharmacogenomics17
X
Plasma sample for circulating nucleic acid 
profiling20
(As of the Protocol Administrative Clarification 
Letter dated 12 October 2015, collection of 
plasma samples for circulating nucleic acid 
profiling in patients with MET-amplified 
NSCLC is no longer required.)
X
X
X
Male Patients: Hypogonadism Testing21
X
X
X
Cycles 4, 6 and
every 3 cycles 
thereafter
X
PF-02341066 treatment22
Twice a day continuously
( ) If it has not been performed within 7 days.  
* Allowable window for tumor assessment imaging is ±7 days; ±2 days for all other assessments.  
* Allowable window for screening visits is up to -7 days from Day -14 (ie, Day -21 to Day 0).
* End of Treatment (EOT) visit should be conducted 28 days postdose ±2 days.  If a patient withdraws from study treatment and new anticancer therapy is 
subsequently administered, the EOT visit should occur prior to the initiation of new anticancer therapy.
**Cycle length is 4 weeks (28 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.  Once a patient has completed 15 cycles, tumor imaging may be 
performed every fourth cycle.  Once a patient has completed 24 cycles, tumor imaging may be performed every sixth cycle (every 24 weeks).  If tumor imaging 
was done within 6 weeks of the last dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
CCI

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3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the Appendix 2 of the protocol.
6.
12- Lead ECG: Patients will have triplicate ECGs collected at least 2 minutes apart during the screening period; Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose (0 hour) and
2-6 hours post-dose, which are corresponding to PK time points.  ECGs should be performed before PK blood draws at respective time points.  In addition to the time points 
noted, ECGs should be repeated as clinically indicated.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose.  Upon IRB/EC approval of Amendment #23, indirect bilirubin will no longer be collected.  If 
ALT or AST Grade 3 and total bilirubin Grade 2, obtain repeat AST or AST and total bilirubin within 48 hours and then repeat every 48-72 hours until ALT/AST Grade 
1.  See Table 2b for further detail.  C2D15 chemistry required after approval of Amendment #20.
9.
Coagulation: PT and PTT.
10. Urinalysis:  For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. Tumor Imaging: CT or MRI scan to be performed to assess disease status at screening, every 8 weeks (based on calendar schedule) starting after the first dose, whenever
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at the 
end/withdrawal from study treatment.  All tumor scans from NSCLC patients with tumors harboring MET gene amplification will be collected and held at the investigative 
site.  With Sponsor written approval and IRB/EC notification, the Sponsor may request tumor scans to be submitted to an independent radiology laboratory for review at a 
later date. As per PACL dated 9 March 2018, all tumor scans for patients enrolled in the MET-amplified NSCLCcohort were to be collected and submitted to an independent 
radiology laboratory for review. As of IRB/EC approval of Amendment #24, tumor scans from all patients with MET-amplified NSCLC will no longer be collected for and 
submitted to an independent radiology review laboratory. If renal cysts are observed, monitoring with appropriate imaging should be performed at the time of renal cyst 
diagnosis and thereafter following the same schedule as for tumor imaging.
13. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment until at least one year after the patient’s final dose. As of 
IRB/EC approval of Amendment #22, all patients enrolled into this cohort should be followed for survival every 3 months after discontinuing study treatment until one year 
after the last patient in this cohort has discontinued PF-02341006 treatment, unless otherwise notified by the Sponsor. As of IRB/EC approval of Amendment #23, all patients 
enrolled into this cohort should be followed for survival every 3 months after discontinuing study treatment until two years after the last patient in this cohort has discontinued 
PF-02341066 treatment, unless otherwise notified by the Sponsor.
14. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from study treatment, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, 
whichever is later.

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15. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/EC or if required by local 
regulations.  As of IRB/EC approval of Amendment #21, for female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL 
will be performed on 2 occasions prior to starting study therapy; once at Screening and once at Cycle 1 Day 1 before PF-02341066 administration. Pregnancy tests will also 
be routinely repeated at every treatment cycle, at the end of treatment, and additionally whenever 1 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 study medication.  Additional pregnancy tests may also be undertaken if 
requested by IRBs/ECs or if required by local regulations.  See Section 7.2 for further detail.
16. PK samples will be collected on Day 1 of Cycle 1, 2, 3 and 5 at pre-dose (0 hour) and 2-6 hours post-dose.  See Section 7.5.1.1. As of IRB/EC approval of Amendment #21, a 
PK sample should be taken around the time that disease progression is confirmed as long as the patient is on PF-02341066.
17. Blood sample for pharmacogenomics: A single whole blood biospecimen (4 mL) will be collected at baseline (within 2 weeks prior to the first dose) for possible analysis of 
DNA sequence variation in genes that may affect PK of the study drugs, may be associated with specific adverse events or toxicities, or may correlate with efficacy.
20. Plasma sample for circulating nucleic acid profiling: As of IRC/EC approval of Amendment #21, blood biospecimen (10 mL) for nucleic acid analysis (eg, circulating free 
DNA [cfDNA] or RNA [cfRNA]) will be collected.  As of the Protocol Administrative Clarification Letter dated 12 October 2015, plasma sample for circulating nucleic acid 
profiling will no longer be required for patients enrolled in the MET amplified NSCLC cohort.
21. Hypogonadism Laboratory Tests (male patients only): All male patients enrolled into the MET-amplified NSCLC Cohort after IRB/EC approval of Amendment #21 will have 
hypogonadism laboratory tests.  Required blood tests include: total testosterone, free testosterone, SHBG, luteinizing hormone, follicle stimulating hormone, 
dihydroepiandrosterone sulfate, estradiol and prolactin.  Blood draws MUST be taken before PF-02341066 dosing and between 07:00 and 10:00 a.m. and, for each individual 
patient, the time of the draw should be as consistent across visits as feasible.  If either total testosterone or free testosterone  decrease to a value that is .both 25% lower than 
baseline and below the lower limit of normal, then a repeat laboratory test of both these parameters must be performed at the next clinic visit to confirm hypogonadism.  See
Section 7.2 for further details.
22. PF-02341066 will be administered at a dose of 250 mg BID.
23. As of Protocol Amendment #17, all patients will undergo additional special ophthalmological testing as described in Section 7.3 until written notification by the Sponsor.  As 
of the Note To File issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive 
error, pupil size, intraocular pressure, ocular coherence tomography, dilated fundus photography.  All ophthalmology examinations should be performed by an 
ophthalmologist.  Ophthalmology examination(s) should be repeated if visual disturbances are observed or if there is an increase in grade for a visual side effect.  The time 
points of this special testing is designated by “[ ]” in the Schedule of Activities Table and includes Screening, Cycle 1 Day 15, Cycle 3 Day 1, 1 year, yearly thereafter, and 
then at 2 - 8 weeks after discontinuation of PF-02341066.  For NSCLC patients on a 4-week cycle, 1 year would be Cycle 14 Day 1 and every 13 cycles thereafter.  There is a 
±2 week window for the yearly ophthalmology examination.
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24. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 and, upon IRB/EC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods 
are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.

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Appendix 10. ROS1 Marker Positive NSCLC Cohort
To further evaluate the anti-tumor activity of PF-02341066 in patients with NSCLC positive 
for a chromosomal translocation in the ROS1 gene (including but not limited to CD74 ROS1
and SLC34A2 ROS1 fusion events). 
Patient Population:
This clinical trial 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. 
Inclusion Criteria:
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:
1. Histologically confirmed advanced NSCLC positive for chromosomal translocations 
at ROS1 gene including but not limited to CD74-ROS1 and SLC34A2-ROS1 fusion 
events.
2. Solid tumors must have measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.0).  However, patients whose tumors are not measurable 
may enter the study upon approval by the Sponsor.  Target lesions that have been 
previously irradiated will not be considered measurable (lesion) unless increase in 
size is observed following completion of radiation therapy. 
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older.
5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to Grade 
1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum aminotransferase (ALT) 2.5 
x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver function 
abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L. 

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
Platelets 30,000/µL. 

Hemoglobin 9.0 g/dL.

Serum creatinine 2.0 x ULN.
8. 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.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 2 weeks of 
starting study treatment.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 
3. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.
4. Current treatment on another clinical trial.
5. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 2 weeks and not taking medications contraindicated to Exclusion Criteria 
#11-13.
6. Any of the following within the 6 months prior to starting study treatment: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, congestive heart failure, cerebrovascular accident including transient ischemic 
attack, or pulmonary embolus.  However, upon agreement between the investigator 
and Sponsor, the 6 month post-event-free period for a patient with a pulmonary 
embolus can be waived if due to advanced cancer.  Appropriate treatment with 
anticoagulants is permitted.
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc interval >470 msec.
8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).

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9. Pregnancy or breastfeeding.  Female patients must be surgically sterile or be 
postmenopausal, or must agree to the use of effective contraception during the period 
of therapy.  All female patients with reproductive potential must have a negative 
pregnancy test (serum or urine) prior to enrollment.  Male patients must be surgically 
sterile or must agree to use effective contraception during the period of therapy.  The 
definition of effective contraception will be based on the judgment of the principal 
investigator or a designated associate.
10. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that would impart, in the judgment of the investigator and/or Sponsor, 
excess risk associated with study participation or study drug administration, which 
would make the patient inappropriate for entry into this study. 
11. Use of drugs that are known strong CYP3A4 inhibitors within 7 days prior to the first 
dose of PF-02341066, including but not limited to atazanavir, clarithromycin,
ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, indinavir, 
nelfinavir, saquinavir, nefazodone, and voriconazole.  Grapefruit or grapefruit juice 
should also be avoided.  The topical use of these medications (if applicable), such as 
2% ketoconazole cream, may be allowed.  All concomitant medication must be 
approved by the Sponsor.
12. Use of drugs that are known strong CYP3A4 inducers within 12 days prior to the first 
dose of PF-02341066, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.  All concomitant medication must 
be approved by the Sponsor. 
13. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor. 
14. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.
15. Patients with known interstitial fibrosis or interstitial lung disease.
Sample Size:
To further evaluate the anti-tumor activity of PF-02341066 in patients with NSCLC positive 
for a chromosomal translocation in the ROS1 gene, approximately 50 patients will be 
enrolled. 
For further details refer to Section 9.1.3.3.
Concomitant Medications:
Refer to Section 5.5 Concomitant Medication(s) for further details.

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Administration:
PF-02341066 tablets will be administered at a dose of 250 mg BID.  PF-02341066 doses 
should be administered approximately 12 hours apart.  PF-02341066 may be given with or 
without food throughout the study.
Refer to Section 5.2 Trial Treatments for details on Formulation and Packaging 
(Section 5.2.1), Preparation and Dispensing (Section 5.2.2), Administration (Section 5.2.3) 
and Compliance (Section 5.2.4).
Independent Radiology Review:
All tumor scans from ROS1 marker positive NSCLC patients enrolled will be collected and 
submitted to an independent radiology laboratory for review until notification is received 
from the Sponsor. As of IRB/EC approval of Protocol Amendment #23, tumor scans from 
ROS1 marker positive NSCLC patients will no longer be collected for and submitted to an 
independent radiology laboratory for review.

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Schedule of Activities: ROS1 Marker Positive NSCLC Cohort ***
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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: Upon IRB/EC approval of Protocol Amendment #24, ongoing patients will follow a Reduced Schedule of Activities as 
indicated in Appendix 13.
Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment
(28 Days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG) 6
X
X
X
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination21
X 
X
Cycle 3, Cycle 14 
& every 13 cycles 
thereafter
[X]
Safety assessment (adverse events) 11
X
X
X
X
X
X
X
Tumor assessment *, ***12
X
X
X
Survival13
Until two years after the last patient enrolled in this cohort has discontinued PF-02341006 treatment, unless otherwise notified 
by the Sponsor
Concomitant medications14
X
X
X
X
X
X
Contraceptive Check (as applicable) 22
X
X
Female patients: Pregnancy test15
X
X
X
X
X

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Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment
(28 Days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Special Laboratory Studies
Two plasma sampling points for PF-02341066 
PK16
X
X
Cycles 3 & 5 and   
at disease 
progression (if 
patient is still 
taking 
PF-02341066)
Blood sample for pharmacogenomics17
X
PF-02341066 treatment20
Twice a day continuously
( ) If it has not been performed within 7 days. 
* Allowable window for tumor assessment imaging is ±7 days; ±2 days for all other assessments.  
* Allowable window for screening assessments is up to -7 days from Day -14 (ie, Day -21 to Day 0).
* End of Treatment (EOT) visit should be conducted 28 days postdose ±2 days.  If a patient withdraws from study treatment and new anticancer therapy is 
subsequently administered, the EOT visit should occur prior to the initiation of new anticancer therapy.
**Cycle length is 4 weeks (28 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.  Once a patient has completed 15 cycles, tumor imaging may be 
performed every fourth cycle.  Once a patient has completed 24 cycles, tumor imaging may be performed every sixth cycle (every 24 weeks).  If tumor imaging 
was done within 6 weeks of the last dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the 0 of the protocol.
6.
12-Lead ECG: Patients will have triplicate ECGs collected at least 2 minutes apart during the screening period; Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose (0 hour) and 
2-6 hours post-dose, which are corresponding to PK time points.  ECGs should be performed before PK blood draws at respective time points.  In addition to the time points 
noted, ECGs should be repeated as clinically indicated.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
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8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose.  Upon IRB/EC approval of Amendment #23, indirect bilirubin will no longer be collected.  If 
ALT or AST ≥Grade 3 and total bilirubin ≥Grade 2, obtain repeat ALT or AST and total bilirubin within 48 hours then repeat every 48-72 hours until ALT/AST ≤Grade 1.  
See Table 2b for further detail.  C2D15 chemistry required after approval of Amendment #20.
9.
Coagulation: PT and PTT.
10. Urinalysis:  For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. Tumor Imaging: CT or MRI scan to be performed to assess disease status at screening, every 8 weeks (based on calendar schedule) starting after the first dose, whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at the 
end/withdrawal from study treatment.  If renal cysts are observed, monitoring with appropriate imaging should be performed at the time of renal cyst diagnosis and thereafter 
following the same schedule as for tumor imaging.
13. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment until at least one year after the patient’s final dose. As of 
IRB/EC approval of Amendment #22, all patients enrolled into this cohort should be followed for survival every 3 months after discontinuing study treatment until one year 
after the last patient in this cohort has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.  As of IRB/EC approval of Amendment #23, all patients 
enrolled into this cohort should be followed for survival every 3 months after discontinuing study treatment until two years after the last patient in this cohort has discontinued
PF-02341066 treatment, unless otherwise notified by the Sponsor. 
14. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from study treatment, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, 
whichever is later.
15. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/ECs or if required by local 
regulations.  As of IRB/EC approval of Amendment #21, for female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL,
will be routinely performed at every cycle, at the end of treatment, and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by IRBs/ECs or if required by local regulations.  In the case of a positive confirmed pregnancy, the patient 
will be withdrawn from study medication.  See Section 7.2. for further details. Note: At the time of the required inclusion of additional pregnancy testing, no patients were 
being enrolled in this cohort and all ongoing patients are beyond Cycle 2. 
16. PK samples will be collected on Day 1 of Cycle 1, 2, 3 and 5 at pre-dose (0 hour) and 2-6 hours post-dose.  See Section 7.5.1.1. As of IRB/EC approval of Amendment #21, a 
PK sample should be taken around the time that disease progression is confirmed as long as the patient is on PF-02341066.
17. A single blood sample will be collected at baseline (within 2 weeks prior to the first dose) to genotype the alleles of cytochrome P450 enzymes and drug transport proteins. 
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20. PF-02341066 will be administered at a dose of 250 mg BID.
21. As of Protocol Amendment #17, all patients will undergo additional special ophthalmological testing as described in Section 7.3 until written notification by the Sponsor.  As 
of the Note To File issued 18 March 2016, the following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive 
error, pupil size, intraocular pressure, ocular coherence tomography, dilated fundus photography.  All ophthalmology examinations should be performed by an 
ophthalmologist.  Ophthalmology examination(s) should be repeated if visual disturbances are observed or if there is an increase in grade for a visual side effect.  The time 
points of this special testing is designated by “[ ]” in the Schedule of Activities Table and includes Screening, Cycle 1 Day 15, Cycle 3 Day 1, 1 year, yearly thereafter, and 
then at 2 - 8 weeks after discontinuation of PF-02341066.  For NSCLC patients on a 4-week cycle, 1 year would be Cycle 14 Day 1 and every 13 cycles thereafter.  There is a 
±2 week window for the yearly ophthalmology examination.
22. Contraceptive Check: As of IRB/EC approval of Amendment #21, male patients who are able to father children and female patients of childbearing potential will need to 
affirm that they meet the criteria for correct use of 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 and, upon IRB/EC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods 
are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.
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Appendix 11. Enriched Other Cohort
To further evaluate the anti-tumor activity of PF-02341066 in patients with molecular 
profiles that could potentially rendering disease sensitive to PF-022341066.
Patient Population:
This clinical trial 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. 
Inclusion Criteria:
Patient eligibility should be reviewed and documented by an appropriate 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. Tumor eligibility:

Histologically confirmed advanced malignancies that meet one of the following 
criteria:

Positive for MET amplification by FISH (excluding polysomy).  After IRB/EC
approval of Amendment #16, enrollment of patients in this group must be 
approved by the Sponsor.

Positive for ALK chromosomal translocations or gene amplification including but 
not limited to NPM-ALK positive anaplastic large cell lymphoma, inflammatory 
myofibroblastic tumors, echinoderm microtubule-associated protein-like 
4 (EML4)-ALK positive non-small cell lung cancer or ALK-positive melanoma.  
After IRB/EC approval of Amendment #16, enrollment of patients in this group 
must be approved by the Sponsor.  After IRB/EC approval of Amendment 
#18 patients with NSCLC that is positive for ALK chromosomal translocations or 
gene amplifications will not be allowed to enter the enriched cohort.

Positive for known MET kinase domain activating mutations including but not 
limited to V1110L, H1112L, H1112Y, H1124D, M1149T, T1191I, V1206L, 
L1213V, V1238I, M1268T, P1009S, T1010I, R988C, V941L but excluding 
Y1248C, Y1248H, Y1248D, Y1253D; mutations in the intron/exon splice site 
regions flanking exon 14 resulting in exon 14 deletion and Y1003X mutations in 
exon 14 affecting binding of the E3 ubiquitin ligase, CBL.  After IRB/EC
approval of Amendment #16, enrollment of patients in this group must be 
approved by the Sponsor.

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
Chromosomal translocations/fusions that lead to altered transcriptional regulation 
of MET and/or HGF including metastatic alveolar soft part sarcoma, clear cell 
sarcoma, rhabdomyosarcoma, or translocation associated renal cell carcinoma.  
Patients with these tumors may enter the study without prior confirmation of MET
and/or HGF alterations.  After IRB/EC approval of Amendment #16, enrollment 
of patients in this group must be approved by the Sponsor.

Positive for chromosomal translocations at ROS1 gene including but not limited 
to CD74-ROS1 and SLC34A2-ROS1 fusion events in NSCLC and FIG-ROS1 in 
glioblastoma.  ROS1 marker positive NSCLC patients may not be enrolled onto 
this cohort.

Other molecular changes for which there are data to suggest a biologic rationale 
for PF-02341066 treatment, eg, TRK1 fusions.
2. Solid tumors must have measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.0).  However, patients whose tumors are not measurable 
may enter the study upon approval by the Sponsor.  Target lesions that have been 
previously irradiated will not be considered measurable (lesion) unless increase in 
size is observed following completion of radiation therapy. 
3. Able, in the investigator’s opinion, to receive at least 2 cycles of treatment.
4. Female or male, 18 years of age or older. For patients enrolled in clinical sites in 
Japan: Female or male, 20 years of age or older.
5. ECOG performance status 0 or 1.  However, patients with an ECOG performance 
status of 2 may enter the study upon agreement between the investigator and Sponsor.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to 
Grade 1 (except alopecia).
7. Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase
(ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver 
function abnormalities are due to underlying malignancy.

Total serum bilirubin 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome; however enrollment must be approved by the Sponsor).

Absolute neutrophil count (ANC) 1500/L. 

Platelets 30,000/L. 

Hemoglobin 9.0 g/dL (≥8.0 g/dL after IRB/EC approval of Amendment #21).

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
Serum creatinine 2.0 x ULN.
8. 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.  For Sites using WIRB, patients who lack capacity to consent for 
themselves will be excluded from this study.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the trial:
1. Major surgery, radiation therapy, or systemic anti-cancer therapy within 2 weeks of 
starting study treatment.
2. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 
3. For MET dependent tumors, prior therapy specifically directed against MET or HGF; for 
ALK dependent tumors, prior therapy specifically directed against ALK; for ROS1 
dependent tumors, prior therapy specifically directed against ROS1. 
4. Current treatment on another clinical trial.
5. Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease unless appropriately treated and neurologically stable for at 
least 2 weeks and not taking medications contraindicated to Exclusion Criteria 
#11-13.
6. Any of the following within the 3 months prior to starting study treatment: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, congestive heart failure, cerebrovascular accident including transient ischemic 
attack, or pulmonary embolus.  However, upon agreement between the investigator 
and Sponsor, the 3 month post-event-free period for a patient with a pulmonary 
embolus can be waived if due to advanced cancer.  Appropriate treatment with 
anticoagulants is permitted. [Implement 3 month guidance upon IRB/EC approval of 
Amendment #20]
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade, or QTc >470 msec.  Upon agreement between the 
Investigator and Sponsor, patients with a QTc >470 msec but <490 msec in the 
presence of a right bundle branch block or with an implanted cardiac pacemaker may 
enter the study [Implement upon IRB/EC approval of Amendment #20].
8. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
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9. Pregnant female patients, breastfeeding female patients (including patients who 
intend to interrupt breastfeeding), male patients with pregnant female partners who 
are unwilling or unable to use a condom for the duration of the pregnancy, female and 
male patients of childbearing potential who are unwilling or unable to use 2 highly 
effective methods of contraception as outlined in this protocol for the duration of 
study treatment and for 90 days after the last dose of investigational product.
10. Other severe acute or chronic medical (including severe gastrointestinal conditions 
such as diarrhea or ulcer) or psychiatric conditions including recent (within the past 
year) or active suicidal ideation or behavior) or end stage renal disease on 
hemodialysis or laboratory abnormality that would impart, in the judgment of the 
investigator and/or Sponsor, excess risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and
would make the patient inappropriate for entry into this study. 
11. Use of drugs that are known strong CYP3A4 inhibitors within 7 days prior to the first 
dose of PF-02341066, including but not limited to atazanavir, clarithromycin, 
ketoconazole, itraconazole, telithromycin, troleandomycin, ritonavir, indinavir, 
nelfinavir, saquinavir, nefazodone, and voriconazole.  Grapefruit or grapefruit juice 
should also be avoided.  The topical use of these medications (if applicable), such as 
2% ketoconazole cream, may be allowed.  All concomitant medication must be 
approved by the Sponsor.
12. Use of drugs that are known strong CYP3A4 inducers within 12 days prior to the first 
dose of PF-02341066, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.  All concomitant medication must 
be approved by the Sponsor. 
13. Concurrent 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).  All concomitant 
medication must be approved by the Sponsor. 
14. Not applicable; included to ensure consistent numbering with exclusion criteria 
reported in Section 4.2.
15. Patients with known interstitial fibrosis or interstitial lung disease.  After IRB/EC 
approval of Amendment #20: 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. As of IRB/EC approval of Protocol 
Amendment #24, this exclusion criterion is as follows: History of extensive 
disseminated/bilateral or known presence of any grade interstitial fibrosis or 
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pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary 
fibrosis, but not history of prior radiation pneumonitis.
16. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study [Implement upon IRB/EC approval of Amendment #20].
Sample Size:
To further evaluate the anti-tumor activity of PF-02341066 in patients who have tumors with 
molecular alterations potentially conferring sensitivity to PF-02341066, approximately 
171 patients will be enrolled including approximately 103 patients with NSCLC harboring 
MET Exon 14 alterations including patients with NSCLC harboring MET Exon 14 
alterations who are enrolled in clinical sites in Japan.
For further details refer to Section 9.1.3.4.
Concomitant Medications:
Refer to Section 5.5 Concomitant Medication(s) for further details.
Administration:
PF-02341066 tablets will be administered at a dose of 250 mg BID.  PF-02341066 doses 
should be administered approximately 12 hours apart.  PF-02341066 may be given with or 
without food throughout the study.
Following IRB/EC approval of Amendment #25 (Japan specific amendment), PF-02341066 
formulated capsules can also be administered at a dose of 250 mg BID.  PF-02341066 doses 
should be administered approximately 12 hours apart.  PF-02341066 may be given with or 
without food throughout the study.
Refer to Section 5.2 Trial Treatments for details on Formulation and Packaging 
(Section 5.2.1), Preparation and Dispensing (Section 5.2.2), Administration (Section 5.2.3) 
and Compliance (Section 5.2.4).
Independent Radiology Review:
As of IRB/EC approval of Protocol Amendment #23, all tumor scans from all NSCLC 
patients with tumors harboring MET Exon 14 alterations will be collected and submitted to 
an independent radiology laboratory for review until notification is received from the 
Sponsor.  

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Schedule of Activities: Enriched Other Cohort *** 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to TRIAL 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: Upon IRB/EC approval of Protocol Amendment #24, ongoing patients will follow a Reduced Schedule of Activities as 
indicated in Appendix 13.
Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment 
(28 days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Informed consent1
X
Medical history2
X
Physical examination3
X
X
X
X
X
Weight, height, temperature, BP, pulse4
X
X
X
X
X
ECOG performance status5
X
X
X
X
X
12-Lead electrocardiogram (ECG)6
X
X
X
Registration/Hematology7
X
(X)
X
X
X
X
Chemistry8
X
(X)
X
X
X
X
X
Coagulation tests9
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Ophthalmology Examination22
X [X]
[X]
[X] [Cycle 3, one 
year and yearly 
thereafter]
[X]
Safety assessment (adverse events) 11
X
X
X
X
X
X
X
Tumor assessment *,  ***,12
X
X
X

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Protocol Activity
Screening*
Cycle 1= 28 days**
Cycle 2 = 
28 days**
Every 4 weeks** 
(Cycle ≥3)
Every 8 
Weeks
End of 
Treatment 
(28 days 
Post 
Dose)*
Day –14 to Day 0
Day 1 
(pre-dose)
Day 15
Day 1
Day 15
Day 1
Survival13
Until at least 1 year after the patient’s final dose (except for NSCLC patients with tumors harboring MET Exon 14 
alterations); For NSCLC patients with tumors harboring MET Exon 14 alterations: until two years after the last NSCLC 
patient with tumors harboring MET Exon 14 alterations has discontinued PF-02341066 treatment, unless otherwise notified 
by the Sponsor. MET Exon 14 alteration patients enrolled in clinical sites in Japan will be followed for survival as a 
separate group.
Concomitant medications14
X
X
X
X
X
X
Contraceptive check (as applicable) 23
X
X
X
X
X
Female patients: Pregnancy test15
X
X
X
X
X
Special Laboratory Studies
Two plasma sampling points for PF-02341066 
PK16
X
X
Cycles 3 & 5 and
at disease 
progression (if 
patient is still 
taking 
PF-02341066)
Blood sample for pharmacogenomics17
(Optional for patients enrolled in clinical sites in 
Japan)
X
Plasma sample for circulating nucleic acid 
profiling20
(As of the Protocol Administrative Clarification 
Letter dated 12 October 2015, only applicable to 
NSCLC patients with tumors harboring MET
Exon 14 alterations and required only at
Screening and End of Treatment)
X
X
X
Hypogonadism Testing 21
(Patients enrolled in clinical sites in Japan will 
not participate in hypogonadism testing)
X
X
X
Cycles 4, 6 and 
every 3 cycles 
thereafter
X
PF-02341066 treatment22
Twice a day continuously
( ) If it has not been performed within 7 days  
* Allowable window for tumor assessment imaging is ±7 days, ±2 days for all other assessments.  
* Allowable window for screening visit assessments is up to -7 days from Day -14 (ie, Day -21 to Day 0).
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* End of Treatment (EOT) visit should be conducted 28 days postdose 2 days.  If a patient withdraws from study treatment and new anticancer therapy is 
subsequently administered, the EOT visit should occur prior to the initiation of new anticancer therapy.
[X] Special ophthalmology tests for all NSCLC patients enrolled until written notification by Sponsor.  As of the Note To File issued 18 March 2016, the 
following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive error, pupil size, intraocular pressure, 
ocular coherence tomography, dilated fundus photography.  See Section 7.3 for additional details.
**Cycle length is 4 weeks (28 days).
***Once a patient has completed 10 cycles, clinic visits may be every other cycle.  Laboratory tests will still be performed on Day 1 of each cycle.  If a patient 
does not have a clinic visit, a telephone contact is required before initiating the next cycle.  Once a patient has completed 15 cycles, tumor imaging may be 
performed every fourth cycle.  Once a patient has completed 24 cycles, tumor imaging may be performed every sixth cycle (every 24 weeks).  If tumor imaging 
was done within 6 weeks of the last dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur prior to the 14-day screening period.
2.
Medical/Oncology History: To include information on prior regimens, including dosing and duration of administration plus description of best response observed and 
treatment failure.
3.
Physical Examination: During Screening, on Day 1 of each cycle and at the end of treatment: examination of major body systems.
4.
Height need not be collected after the first measurement.
5.
ECOG performance scale will be available in the 0 of the protocol.
6.
12-Lead ECG: Patients will have triplicate ECGs collected at least 2 minutes apart during the screening period; Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose (0 hour) and 
2-6 hours post-dose, which are corresponding to PK time points.  ECGs should be performed before PK blood draws at respective time points.  In addition to the time points 
noted, ECGs should be repeated as clinically indicated.
7.
Hematology: WBC with differential count, hemoglobin, and platelet count.
8.
Blood Chemistry: Total and indirect bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, chloride, CO2 
(bicarbonate), calcium, phosphorus, BUN, creatinine, uric acid, and glucose.  Upon IRB/EC approval of Amendment #23, indirect bilirubin will no longer be collected.  If 
ALT or AST Grade 3 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.  See Table 2b for further detail.  C2D15 chemistry required after approval of Amendment #20.
9.
Coagulation: PT and PTT.
10. Urinalysis:  For pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite at baseline, then Day 1 of each cycle thereafter.
11. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
12. Tumor Imaging: CT or MRI scan to be performed to assess disease status at screening, every 8 weeks (based on calendar schedule) starting after the first dose, whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at the 
end/withdrawal from study treatment. If renal cysts are observed, monitoring with appropriate imaging should be performed at the time of renal cyst diagnosis and thereafter 
following the same schedule as for tumor imaging. Upon IRB/IC- approval of Amendment #23, NSCLC patients with tumors harboring MET Exon 14 alterations will have 
scans collected and submitted to an independent radiology laboratory for review until notification is received from the Sponsor.  

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13. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment until at least one year after the patient’s final dose.  NSCLC 
patients with tumors harboring MET Exon 14 alterations only: As of IRB/EC approval of Amendment #22, patients should be followed for survival every 3 months after 
discontinuing study treatment until one year after the last NSCLC patient with cMet Exon 14 alterations in the cohort (excluding patients enrolled in clinical sites in Japan) 
has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor. As of IRB/EC approval of Amendment #23, patients should be followed for survival 
every 3 months after discontinuing study treatment until two years after the last NSCLC patient with cMet Exon 14 alterations in the cohort (excluding patients enrolled in 
clinical sites in Japan) has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor. For NSCLC patients with tumors harboring MET Exon 14 
alterations enrolled in clinical sites in Japan: survival shall be followed every 3 months after discontinuing study treatment until two years after the last patient has 
discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.
14. Concomitant Medications: Concomitant medications will be recorded from 14 days prior to the start of study treatment, at study entry, and during the study.  Once the patient 
has withdrawn from study treatment, concomitant medications and treatments should be recorded for 28 days or until all study drug-related toxicities have resolved, 
whichever is later.
15. Pregnancy Test (Serum or Urine): Women of reproductive potential must be tested within 14 days of the first treatment.  This test should be repeated whenever one menstrual 
cycle is missed during treatment or a potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/EC or if required by local 
regulations.  As of IRB/EC approval of Amendment #21, for female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, 
will be performed on 2 occasions prior to starting study therapy; once at Screening and once at Cycle 1 Day 1 before PF-02341066 administration.  Pregnancy tests will also 
be routinely repeated at every treatment cycle, at the end of treatment, and additionally whenever 1 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 study medication.  Additional pregnancy tests may also be undertaken if 
requested by IRBs/ECs or if required by local regulations.  See Section 7.2. for further detail.
16. PK samples will be collected on Day 1 of Cycle 1, 2, 3 and 5 at pre-dose (0 hour) and 2-6 hours post-dose.  See Section 7.5.1.1. As of IRB/EC approval of Amendment #21, a 
PK sample should be taken around the time that disease progression is confirmed as long as the patient is on PF-02341066. Refer to the Study A8081001 Laboratory Manual 
for Special Research-Related Testing for sample processing and shipping instructions.
17. Blood sample for pharmacogenomics: A single whole blood biospecimen (4 mL) will be collected at baseline (within 2 weeks prior to the first dose) for possible analysis of 
DNA sequence variation in genes that may affect PK of the study drugs, may be associated with specific adverse events or toxicities, or may correlate with efficacy.  (For 
patients enrolled in clinical sites in Japan: blood sample for pharmacogenomics is optional). Refer to the Study A8081001 Laboratory Manual for Special Research-Related 
Testing for sample processing and shipping instructions.  
20. Plasma sample for circulating nucleic acid profiling: As of IRC/EC approval of Amendment #21, blood biospecimen (10 mL) for nucleic acid analysis (eg, circulating free 
DNA [cfDNA] or RNA [cfRNA]) will be collected.  As of the Protocol Administrative Clarification Letter dated 12 October 2015, plasma sample for circulating nucleic acid 
profiling is only required for NSCLC patients with tumors harboring MET Exon 14 alterations and will be obtained at Screening and End of Treatment.  Refer to the Study 
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A8081001 Laboratory Manual for Special Research-Related Testing for sample processing and shipping instructions.  Upon IRB/EC approval of Protocol Amendment #24, 
collection of plasma samples for circulating nucleic acid profiling is no longer required.
21. Hypogonadism Laboratory Tests (male patients only): All male patients enrolled into the Enriched Other Cohort after IRB/EC approval of Amendment #21 will have 
hypogonadism laboratory tests.  Required blood tests include: total testosterone, free testosterone, SHBG, luteinizing hormone, follicle stimulating hormone, 
dihydroepiandosterone sulfate, estradiol and prolactin.  Blood draws MUST be taken before PF-02341066 dosing and between 07:00 and 10:00 a.m. and, for each individual
patient, the time of the draw should be as consistent across visits as feasible.  If either total testosterone or free testosterone  decrease to a value that is .both 25% lower than 
baseline and below the lower limit of normal, then a repeat laboratory test of both these parameters must be performed at the next clinic visit to confirm hypogonadism.  See
Section 7.2, for further details.  Refer to the Study A8081001 Covance Central Laboratory Services Manual for sample processing and shipping instructions.  Note: Patients 
enrolled in clinical sites in Japan will not participate in hypogonadism testing. Upon IRB/EC approval of Protocol Amendment #24, collection of hypogonadism samples is no 
longer required.
22. PF-02341066 will be administered at a dose of 250 mg BID. An ophthalmology examination will be performed at screening for all patients.  The ophthalmology examination 
should be repeated during the study when visual disturbances have been observed and when there is an increase in grade for visual disturbances.  The ophthalmology 
examination should include ocular characteristics, visual acuity, fundoscopy and slit lamp examination.  As of Protocol Amendment #17, all NSCLC patients enrolled will 
undergo additional special ophthalmological testing as described in Section 7.3 until written notification by the Sponsor.  As of the Note To File issued 18 March 2016, the 
following ophthalmologic tests (added in Protocol Amendment #17) are no longer required for NSCLC patients: refractive error, pupil size, intraocular pressure, ocular 
coherence tomography, dilated fundus photography.  All ophthalmology examinations should be performed by an ophthalmologist.  Time points of this special testing are 
designated by “[ ]” in the Schedule of Activities Table and are performed at Screening, Cycle 1 Day 15, Cycle 3 Day 1, one year, and yearly thereafter.  The yearly 
ophthalmology examination will be done at Cycle 14 Day 1, and every 13 cycles thereafter.  These tests should also be done within 2-8 weeks after discontinuation of 
PF-02341066.  There is a 2 week window for the yearly ophthalmology examination.  
23. Contraceptive Check: As of IRB/EC approval of Amendment #21, 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 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 and, upon IRB/EC approval of Amendment #23, the patient’s 
affirmation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods 
are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  See Section 4.5.1 for further detail.

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Appendix 12. Hypogonadism Testing
Hypogonadism testing was included based upon a publication reporting hypogonadism secondary to PF-02341066 use in men with 
metastatic non-small cell lung cancer.20  Therefore laboratory Testing has been added to the MET-amplified NSCLC cohort 
(Appendix 9) and the Enriched Other cohort (Appendix 11); the additional tests include:

Total testosterone.

Free testosterone.

SHBG.

Luteinizing hormone.

Follicle stimulating hormone.

Dihydroepiandrosterone sulfate.

Estradiol.

Prolactin.
Note that blood draws MUST be taken before PF-02341066 dosing and between 7:00 and 10:00 a.m. and, for each patient, every 
attempt should be made to draw blood at approximately the same time across visits. Blood draws are also to be done 
pre-PF-02341066 dose.
Patients with MET-amplified NSCLC: Refer to Schedule of Activities in Appendix 9 for additional details. 
Enriched Other cohort: Refer to Schedule of Activities in Appendix 11 for additional details.
Note: Patients enrolled in clinical sites in Japan will not participate in hypogonadism testing.
Refer to the Study A8081001 Covance Central Laboratory Services Manual for sample processing and shipping instructions.

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Appendix 13. Reduced Schedule of Activities
Upon IRB/EC approval of Protocol Amendment #24, ongoing patients in the ALK marker positive NSCLC cohort, the ROS1 marker 
positive NSCLC cohort, the MET-amplified NSCLC cohort, and the Enriched Other cohort (including NSCLC patients with MET 
Exon 14 alterations) will follow a Reduced Schedule of Activities. Refer to TRIAL PROCEDURES and ASSESSMENTSsections 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 wellbeing of the patient.
Protocol Activity
Study Treatment1
End of Treatment **
For Cycles 1-10, Visits on Day 1 (±4 
days ) of each Cycle
For Cycles >10, Visits on Day 1 (±4 
days )of Alternate Cycles (except as 
noted below)
End of Txt/Withdrawal
Post Txt Follow-up
Physical examination2
X
X
X
Weight, blood pressure and  pulse 
rate
X
X
X
Ophthalmology Examination3
X
Laboratory Studies
Hematology and Blood Chemistry, 
excluding Liver Function Tests 
(LFTs)4
As per local clinical practice.
LFTs: ALT/AST/alkaline 
phosphatase/total bilirubin5
X
Day 1 of each cycle (±4 days)
X
Contraceptive Check (as 
applicable)6
X
X
X
X
Female patients: Pregnancy test7
X
X
X
Disease Assessments
Tumor assessments for NSCLC 
patients with tumors harboring 
MET Exon 14 alterations only*, 8
X
X
X
Tumor assessment for all other 
cohorts (ALK marker positive 
cohort, ROS1 marker positive 
cohort, MET-amplified cohort, and 
Enriched Other cohort [excluding 
NSCLC patients with tumors 
harboring MET Exon 14 
alterations])9
As per local clinical practice.

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Protocol Activity
Study Treatment1
End of Treatment **
For Cycles 1-10, Visits on Day 1 (±4 
days ) of each Cycle
For Cycles >10, Visits on Day 1 (±4 
days )of Alternate Cycles (except as 
noted below)
End of Txt/Withdrawal
Post Txt Follow-up
Other Clinical Assessments
Safety assessment (adverse 
events)10
X
X
X
X
Concomitant 
Medications/Treatments11
X
X
X
X
Survival (for NSCLC patients with 
tumors harboring MET Exon 14 
alterations only)12
X
PF-02341066 treatment
Twice a day continuously
* Allowable window for tumor assessment imaging is 7 days. 
** End of Treatment (EOT) visit should be conducted 28 days postdose 2 days.  If a patient withdraws from study treatment and new anticancer is subsequently 
administered, the EOT visit should occur prior to the initiation of new anticancer therapy. 
1.
All assessments should be performed prior to dosing with study medication unless otherwise indicated. All cycles are 4 weeks in duration. Sufficient study medication for 2 
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.
Physical Examination: Includes an examination of major body systems.
3.
Ophthalmology examination: Includes ocular characteristics, visual acuity, fundoscopy and slit lamp examination and should be performed by an ophthalmologist.  The 
ophthalmology examinations should be performed at Sceening and repeated during the study when a visual change occurred or when there is an increase in grade for a visual 
change.  
4.
Hematology and Blood Chemistry, excluding Liver Function Tests (LFTs): Will be repeated at the frequency as per local clinical practice, and will no longer be recorded on 
the CRF. However, lab information should be retained in the pateint’s file for documentation purposes. NOTE: For Blood Chemstiry, LDH and uric acid are not required to be 
collected as part of the Reduced Schedule of Activities.
5.
LFTs: If ALT or AST Grade 3 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.
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 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 and the patient’s affirmation in the patient’s chart.  In addition, the investigator or his or her designee will 
instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or suspected in the patient or the patient’s 
partner.  See Section 4.5.1 for further detail.
7.
Pregnancy Test (Serum or Urine): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be routinely 
repeated at every treatment cycle, at the end of treatment, and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected. In the 

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case of a positive confirmed pregnancy, the patient will be withdrawn from study medication.  Additional pregnancy tests may also be undertaken if requested by IRBs/ECs or 
if required by local regulations.  See Section 7.2 for further detail.
8.
Once a patient has completed 15 cycles, tumor imaging may be performed every fourth cycle.  Once a patient has completed 24 cycles, tumor imaging may be performed 
every sixth cycle (every 24 weeks).  If tumor imaging was done within 6 weeks of the last dose of PF-02341066, it is not required to be repeated at the End of Treatment visit.
If renal cysts are observed, monitoring with appropriate imaging should be performed at the time of renal cyst diagnosis and thereafter following the same schedule as for 
tumor imaging. NSCLC patients with tumors harboring MET Exon 14 alterations will have scans collected and submitted to an independent radiology laboratory for review 
until notification is received from the Sponsor.
9.
Tumor Assessments: For ongoing patients in the ALK marker positive cohort, the ROS1 marker positive cohort, the MET amplified cohort, and the Enriched Other cohort 
(excluding NSCLC patients with tumors harboring MET Exon 14 alterations) 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: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events should be monitored 
and reported as described in the protocol. 
11. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded up to 28 days post the last dose of study treatment.
12. Survival: Upon IRB/EC approval of Protocol Amendment #24: Post-study survival status is no longer required for patients (excluding NSCLC patients with tumors harboring 
MET Exon 14 alterations). NSCLC patients with tumors harboring MET Exon 14 alterations should be followed for survival every 3 months after discontinuing study 
treatment until two years after the last patient has discontinued PF-02341066 treatment, unless otherwise notified by the Sponsor.