Clinical trial NCT02511184
Conditions: ALK-positive Advanced NSCLC
Keywords: crizotinib pembrolizumab ALK-positive NSCLC Lung Cancer ALK-translocated NSCLC Non Small Cell Lung Cancer
Sponsor: Pfizer
Start date: 2015-10-01; Completion date: 2017-12-01
Enrollment: 9 participants; Allocation: ; Intervention model: 

Brief summary:
The purpose of this study has 2 phases, a Dose Finding Phase will determine the maximum tolerated dose . The Dose Expansion Phase will explore the safety, tolerability, and anti-tumor activity of the combination.

Detailed description:
The patients will be screened for up to 28 days before they start treatment to determine if they meet eligibility criteria. The screening procedures will include physical examination, blood work and radiological scans.

In the dose finding phase, patients who meet eligibility criteria will receive crizotinib at the dose level assigned that will be taken on daily basis and pembrolizumab 200 mg intravenous infusion every 3 weeks.

Once a Crizotinib dose level is decided, the dose expansion cohort will start enrolling patients who meet eligibility criteria.

All patients will be followed up every three weeks. Blood samples will be drawn to test for safety and tumor activities and radiological scans will be performed on certain timepoints to determine the antitumor activities.

There will be a quality of life questionnaire administered at certain time points during the study.

The study will have a quality assurance plan that addresses data validation and registry procedures. There is a plan to visit the investigator site for routine monitoring and auditing.

The team will conduct source data verification to assess the accuracy, completeness, or representativeness of registry data by comparing the data to external data sources (e.g., medical records, paper or electronic case report forms, or interactive voice response systems).

The study will also include a statistical analysis plan describing the analytical principles and statistical techniques to be employed in order to address the primary and secondary objectives of this study, as specified in the study protocol or statistical plan.

Arms: arm 1: Find and expand the maximum tolerated dose of crizotinib in combination with pembrolizumab 200 mg iv infusion every 3 weeks.
Interventions: intervention 1: Crizotinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: To test 3 dose levels of crizotinib in combination with pembrolizumab 200 mg iv infusion every 3 weeks intervention 2: To test pembrolizumab at 200 mg every 3 weeks in combination with crizotinib at 3 dose levels.

Protocol documents:
Prot_000.pdf: 
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A PHASE 1B STUDY OF CRIZOTINIB IN COMBINATION WITH 
PEMBROLIZUMAB (MK-3475) IN PATIENTS WITH UNTREATED ADVANCED 
ALK-TRANSLOCATED NON-SMALL CELL LUNG CANCER
Compound:
PF-2341066/MK-3475
Compound Name:
Crizotinib/Pembrolizumab
United States (US) Investigational New 
Drug (IND) Number:
73,544
European Clinical Trials Database 
(EudraCT) Number :
Not Applicable
Protocol Number:
A8081054
Phase:
Phase 1b


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Document History
Document
Version Date
Summary of Changes
Original protocol
22 April 2015
Not Applicable (N/A)


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Abbreviations
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
1L
first line
Ab
antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
Adenosine triphosphate
AUC0-8
area under the plasma concentration-time 
curve from 0 to 8 hours post dose
AUCtau
area under the plasma concentration-time 
curve over the dosing interval
BAL
bronchoalveolar lavage
BCG
Bacillus Calmette–Guérin
BID
twice daily
BNP
B-type natriuretic peptide
BP
blood pressure
BUN
blood urea nitrogen
C
Cycle
CDR3
complementarity determining region 3 
CHF
congestive heart failure
CI
confidence interval
CL
clearance
CL/F
apparent plasma clearance
Cmax
maximum plasma concentration
CNS
central nervous system
CRF
case report form
CR
complete response
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse 
Events
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Abbreviation
Term
CTLA-4
cytotoxic T-lymphocyte antigen-4
CV
coefficient of variation
DAI
dosage and administration instructions
DCR
disease control rate
DL
dose level
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
duration of response
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
Eg
for example
EGFR
epidermal growth factor receptor
EGFR MT
epidermal growth factor receptor mutant
EML4
echinoderm microtubule associated protein-
like 4 gene
EORTC QLQ-LC-13
European Organisation for Research and 
Treatment of Cancer Quality of Life 
Questionnaire– Lung Cancer 13 
EORTC QLQ-C30
European Organisation for Research and 
Treatment of Cancer Quality of Life 
Questionnaire C30 
Etc
‘and other things’ or ‘and so forth’
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United 
States)
FDAAA
Food and Drug Administration Amendments 
Act (United States)
FFPE
formalin-fixed paraffin-embedded 
FISH
fluorescence in situ hybridization
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GI
gastrointestina
GITR
glucocorticoid-induced tumor necrosis factor 
receptor
GnRH
gonadotropin-releasing hormone 
GVHD
graft versus host disease
HBV
hepatitis B virus


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Abbreviation
Term
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDPE
high-density polyethylene
Hgb
hemoglobin
HGFR
hepatocyte growth factor receptor
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
Ie
that is (id est)
IHC
immunohistochemistry
IND
investigational new drug 
INR
international normalized ratio
irAEs
immune-related adverse events
IRB
institutional review board
IRC
internal review committee
irPFS
immune-related progression-free survival
irRC
immune-related response criteria
ITIM
immunoreceptor tyrosine-based inhibition 
motif
ITSM
immunoreceptor tyrosine-based switch motif
IUD
intrauterine device
IV
intravenous
KIR
killer cell immunoglobulin-like receptor
LAG3
lymphocyte activation gene-3
LFT
liver function test
LPD
local product document
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
mTPI
modified toxicity probability interval
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MFD
maximum feasible dose
mPFS
median progression-free survival
MRAUCtau    
metabolite to parent ratio AUCtau
MRCmax
metabolite to parent ratio Cmax
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N/A
not applicable
NCI 
National Cancer Institute 


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Abbreviation
Term
NHANES
National Health and Nutrition Examination 
Surveys
NONMEM
non-linear mixed effects modeling
NPM
nucleophosmin
NSCLC
non-small cell lung cancer
OBD
optimal biological dose
ORR
objective response rate
OS
overall survival
pT
target probability
PCD
primary completion date
PD
progressive disease
PD-1
programmed death receptor-1
PD-L1
programmed death receptor-1 ligand-1
PD-L2
programmed death receptor-1 ligand-2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
oral (per os)
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
QD
every day
QOL
quality of life
QT
time between the start of the Q wave and the 
end of the T wave
QTc
QT interval corrected for heart rate
R
Ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RON
Recepteur d’Origine Nantais
RP2D
recommended phase 2 dose
RR
response rate
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SEER
(NCI) Surveillance, Epidemiology and End 
Results
SOA
Schedule of Activities
SRSD
Single Reference Safety Document
SST
serum separator tube


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Abbreviation
Term
T
Time
T1/2
terminal elimination half-life
TCR
T-cell receptor
TILs
tumor infiltrating lymphocytes
TIM3
T-cell immunoglobin- and mucin-domain-3-
containing molecule 3
TKI
tyrosine kinase inhibitor
Tmax
time to maximum plasma concentration
TTP
time to progression
TTR
time to tumor response
ULN
upper limit of normal
UPM
unit probability mass
US
United States
USPI
United States Package Insert
UTN
Universal Trial Number
V/F
apparent volume of distribution
VSAQ-ALK
Visual Symptom Assessment Questionnaire 
ALK
WBC
white blood cell 


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PROTOCOL SUMMARY
Background and Rationale
Non-small cell lung cancer (NSCLC) is the most common cause of fatal malignancy in the 
United States among both men and women, representing 28% and 26% of all cancer-related 
deaths, respectively.  NSCLC represents the second most common cause of new cases of 
malignancies in men (14%) and women (13%) according to the National Cancer Institute’s 
Surveillance, Epidemiology and End Results (SEER) program.1  Similar results have been 
observed in Europe where NSCLC remains the most common cause of fatal malignancy.2  
There is also a growing burden of NSCLC in developing countries like India3 and China4
where the incidence in men is greater than women.  ALK-positive NSCLC represents
between 3 and 5% of all cases.  These patients tend to be young (average age 50 years at 
diagnosis), light or never smokers, and with no difference in sex or ethnicity.5
The results from single-arm clinical Studies A8081005 and A8081001 supported accelerated 
regulatory approval of crizotinib in the US in August 2011 for the treatment of patients with 
ALK-positive locally advanced or metastatic NSCLC.  The results of randomized Phase 3 
Study A8081007 demonstrated that crizotinib is superior to standard-of-care single-agent 
chemotherapy in patients with previously treated ALK-positive advanced NSCLC and 
confirmed the favorable benefit/risk profile of crizotinib in this population.  Based upon 
substantially prolonged PFS (median 7.7 months for crizotinib and 3.0 months for 
chemotherapy; hazard ratio [HR] 0.487, 95% confidence interval [CI]: 0.37, 0.64; 1-sided 
p-value <0.001) and increased ORR (crizotinib 65% and chemotherapy 20%, 2-sided p-value 
≤0.001), the results from this study supported conversion to full approval in the US.  
Validated questionnaires  (EORTC QLQ-C30 and QLQ-LC13) showed a statistically 
significantly greater improvement in patient-reported lung cancer symptoms and global 
quality of life receiving crizotinib as compared with chemotherapy.6,7  Recently, the results 
of randomized Phase 3 Study A8081014 demonstrated that crizotinib significantly prolonged 
PFS in the first-line treatment setting compared to standard platinum-based chemotherapy.  
The median PFS was 10.9 months for the 172 patients randomized to crizotinib and 
7.0 months for the 171 patients randomized to chemotherapy.  The HR comparing crizotinib 
with chemotherapy was 0.454 (95% CI: 0.346, 0.596) with a p-value of <0.0001.8  Similarly 
in Study A8081007, crizotinib showed a statistically greater improvement in patient-reported 
lung cancer symptoms and global quality of life receiving crizotinib as compared with 
chemotherapy.  Although crizotinib had impressive clinical activity in patients with 
previously untreated ALK-positive advanced NSCLC in each of these studies,8 progression 
of disease generally occurs and is often related to the development of crizotinib-resistant 
ALK mutation or signal transduction bypass pathways. Therefore, newer agents with novel 
mechanisms of action are still desperately needed.
Evidence has demonstrated that tumors require interaction with the host immune system for 
continued growth and spread.9  One way this occurs is by tumors interacting with the 
programmed death  receptor-1 (PD-1) on the tumor infiltrating lymphocytes (TILs), causing 
the effector T cells to become regulatory T cells.  The PD-1 receptor-ligand interaction is 
hijacked by tumors to suppress immune control.  The normal function of PD-1, expressed on 


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the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted 
or excessive immune responses, including autoimmune reactions.9-11  When PD-1 interacts 
with the ligand on the tumors, immune surveillance of the tumor ceases leading the body to 
consider the tumor a self-antigen and allowing tumor transit (spread) through the 
hematologic and lymphatic channels as well as increases in local vascular endothelial growth 
factor and correlates with a negative prognosis.9  There are also reduced levels of IL-2 
produced intratumorally when there is PD-1/PD-L1 interaction.  
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands, PD-L1 and PD-L2.  In the NSCLC cohort of the KEYNOTE-001 study, the 
ORR was 21% based on an independent radiology review using RECIST v 1.1 among all 
patients with NSCLC who received 3 or more prior lines of therapy.  The specific breakdown 
of the response rates were 16% for patients with advanced non-squamous NSCLC (4 of 
26 patients) and 33% for patients with advanced squamous NSCLC (2 of 6 patients).  The 
median PFS was 10.3 weeks for advanced non-squamous NSCLC patients and 15.2 weeks 
for advanced squamous NSCLC patients.12
Research on mouse models has been limited in the immune surveillance role and ALK-
positive NSCLC, but one small study provided supporting rationale for a combination of 
crizotinib with an anti-PD-1 inhibiting antibody using an ALK vaccine.  The tumors were 
noted to have lymphatic infiltration and these changed from regulatory to effector T cells, 
while the ALK-positive tumors were noted to have high levels of PD-L1. Using crizotinib in 
the place of ALK vaccine should not demonstrate a difference in response or changes to the 
lymphocytic infiltration noted.  By adding pembrolizumab, there may be a potential to utilize 
immune stimulation and PD-L1 levels with the known signal transduction inhibition of 
crizotinib.  
This study in previously untreated ALK-positive advanced NSCLC will consist of 2 phases, a
Dose Finding Phase and a Dose Expansion Phase.  The Dose Finding Phase will determine 
the maximum tolerated dose (MTD) of the combination of crizotinib and pembrolizumab
using a dose de-escalation design through a modified Toxicity Probability Interval (mTPI)13
design.  The Dose Expansion Phase will explore the safety, tolerability, and anti-tumor 
activity of the combination at the MTD in order to determine the recommended Phase 2 dose 
(RP2D).   
Study Objectives and Endpoints:
Primary Objective

To assess safety and tolerability of crizotinib in combination with pembrolizumab in 
the first-line treatment of patients with ALK-positive advanced non-squamous 
NSCLC in order to identify the maximum tolerated dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 


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Secondary Objectives

To evaluate the overall safety profile of crizotinib in combination with 
pembrolizumab.

To document the anti-tumor activity of crizotinib in combination with pembrolizumab 
in previously untreated ALK-positive advanced NSCLC patients.

To characterize the pharmacokinetics (PK) of crizotinib and pembrolizumab and to 
assess the effect of pembrolizumabon the PK of crizotinib.

To evaluate tumor PD-L1 expression, as assessed by PD-L1 immunohistochemistry, 
as a predictor of anti-tumor activity.
 
 
 
 

To evaluate the impact of combination therapy of crizotinib and pembrolizumab on 
patient-reported lung cancer symptoms (such as dyspnea, cough and pain) and global 
Quality of Life (QOL) per the validated cancer specific EORTC QLQ-C30, and its 
lung cancer module, QLQ-LC-13, and visual symptoms per the Visual Symptom 
Assessment Questionnaire (VSAQ-ALK).
Primary Endpoint

Dose-Limiting Toxicity (DLT).
Secondary Endpoints

Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
v.4.03), timing, seriousness and relationship to study treatments.

Objective response rate (ORR), as assessed using RECIST version 1.1, and also.

Duration of Response (DR).

Time to Tumor Response (TTR).
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
PFS, 6-month, 12-month, and 18-month PFS probabilities, OS, 12-month and 
18-month survival probabilities.

Laboratory abnormalities as characterized by type, frequency, severity, and timing.

The following PK parameters of crizotinib, its metabolite PF-06260182 and
pembrolizumab PK (as data permits):
Maximum plasma concentration (Cmax), time to maximum plasma concentration  
(Tmax), pre-dose concentration (Ctrough), area under the plasma concentration time 
curve from 0 to 8 hours (AUC0-8), area under the plasma concentration time curve 
over the dosing interval (AUCtau), and apparent plasma clearance (CL/F) for 
crizotinib;
Cmax, Tmax, Ctrough, AUCtau, metabolite to parent ratio for AUCtau (MRAUCtau), and 
metabolite–to-parent ratio for Cmax (MRCmax) for PF-06260182;
Ctrough for pembrolizumab;
Population-based PK parameters for pembrolizumab (if performed will be reported in 
a separate report).

Association between tumor PD-L1 expression assessed by PD-L1 
immunohistochemistry and endpoints of clinical outcome (response-related and time-
to-event endpoints).
 

Overall change from baseline in patient-reported lung cancer symptom, functioning, 
and global QOL scores.

Frequency of occurrence and degree of bothersomeness of visual disturbances as 
reported by the patients on the VSAQ-ALK questionnaire.
Study Design:
This is a Phase 1b, open-label, multi-center, multiple-dose, dose-finding, safety, and 
pharmacokinetic study of crizotinib in combination with pembrolizumab in sequential 
cohorts of adult patients with previously untreated ALK-positive advanced NSCLC.  The 
study includes 2 phases (Dose Finding Phase and Dose Expansion Phase – See Study Schema
in Figure 1).  
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Approximately 70 total patients are expected to be enrolled in this study.  The first phase of 
the study, the Dose Finding Phase, will use a mTPI method to determine the MTD of the 
combination.  The second study phase, the Dose Expansion Phase, will further evaluate the 
combination regimen at the MTD to determine whether the MTD will also be the RP2D.
Figure 1.
STUDY DESIGN
Screening
≤ 28 days
Crizotinib dose PO BID
Pembrolizumab dose IV Q3weeks
1st Part: Dose Finding Phase 
2nd  Part: Dose Expansion Phase
C1D1 C1D8
C2D1
C3D1
Cycle 
2
Cycle 
1
Cycle 
8
Cycle 
9
Cycle 
4
Cycle 
3
Cycle 
5
Cycle 
6
Cycle 
7
Cycle 
10
Cycle 
11
One cycle equals 21 days
C5D1
C7D1
C11D1
Tissue 
samples 
and 
biospeci
mens
Pembrolizumab
For DL 
-1
CT/MRI
Continue CT/MRI 
according to DL 
recommendations
DLT period
Then every
4 weeks
C1D15
Refer to Schedules of Activities and Protocol Guidelines for Visit Details
Study Treatment Administration:
Crizotinib will be administered orally BID or QD at approximately the same time in the 
morning and evening (BID) or morning only (QD) on a continuous daily dosing schedule, ie, 
without a break in dosing in the absence of drug-related toxicity.  Crizotinib capsules may be 
administered without regard to meals, and if administered on the BID schedule, the capsules 
should be taken approximately 12 hours apart.  During the PK sampling days, the crizotinib 
dose should be taken in the clinic under supervision of the study site personnel.
Pembrolizumab will be administered intravenously on Day 1 of Q3week cycles.  Treatment 
with pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons (such as holidays).  
The Dose Finding Phase will follow an “Up-and-Down” design (mTPI), using doses of 
crizotinib and pembrolizumab as shown in Table 6 (see Section 3.1.1).  In this dosing 
algorithm there are up to 4 potential dose levels (DLs), with crizotinib doses ranging from 
250 mg BID down to 250 mg QD, and pembrolizumab at a fixed dose of 200 mg Q3weeks.
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Dosing will start at Dose Level 0 (DL0) which is the target dose; there are no plans to 
escalate dose above DL0.  This study is designed to de-escalate doses as suggested by the 
safety profile.  The detailed dose-finding rules based on the mTPI are illustrated in Table 6 ( 
Section 3.1.1.1).
Rules for dose finding using the mTPI method include the following:

The target enrollment cohort size is 3 patients. The first 3 patients treated at each 
dose level will initiate dosing sequentially, at least 2 days apart from each other.

The next cohort will be enrolled when all patients at the current dose cohort have 
been evaluated for the first 2 cycles, ie, 6 weeks or experience a DLT, whichever 
comes first.  The next cohort will receive the dose level as assigned by Table 5.

If a patient does not receive at least 80% of the planned first 2 cycles dosing of 
crizotinib when combined with pembrolizumab, or both infusions of pembrolizumab 
within the DLT observation period for reasons other than study drug-related toxicity, 
another patient will be enrolled to current DL.

The Dose Finding Phase of the trial is completed when 10 DLT-evaluable patients 
have been treated at the highest dose associated with a DLT rate <0.33. This will be 
considered the MTD of the combination.  It is estimated that approximately 
30 DLT-evaluable patients will need to be enrolled to estimate the MTD. 

The RP2D will be confirmed in the Dose Expansion Phase, taking into account the 
MTD determination from the Dose Finding Phase, and other factors related to safety, 
efficacy, and PK/PD involving all available data from test cohorts.
Patients will continue with combination crizotinib and pembrolizumab treatment until 
RECIST-defined progression of disease and investigator decision that the patient is no longer 
receiving clinical benefit, or unacceptable toxicity, death, or consent withdrawal, whichever 
comes first.  
Tumor Assessments
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
then at Week 9, and every 6 weeks thereafter, using RECIST v 1.1 [See Schedule of 
Activities (SOA) – Table 1, and Table 3].  In addition, radiological tumor assessments will 
also be conducted to confirm a best response of CR or PR at ≥4 weeks after initial 
assessment of response, whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the time of End of Treatment/Withdrawal (if not performed in the 
previous 6 weeks.  In determining whether or not the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as non-target lesions and 
new lesions according to RECIST v1.1 (See Appendix 6).


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides details of the required protocol visits and 
procedures.  Refer to the Assessments section (Section 7) of the protocol for detailed
information on each assessment required for compliance with the protocol.   
To allow for patient and investigator schedules, holidays, and weather or other emergencies 
requiring clinical facilities to be closed, all patient visits can be performed ±2 days of 
scheduled visit.  The investigator may schedule visits (unplanned visits) in addition to those 
listed on the SOA, in order to conduct evaluations or assessments required to protect the 
well-being of the patient.


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SCHEDULE OF ACTIVITIES FOR DOSE LEVELS 0, -2, and -3 
Table 1.
Schedule of Activities: Crizotinib + Pembrolizumab: 21-Day Treatment Cycles
(Applicable to both the Dose Finding and Dose Expansion Phases of the Study)
CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screening
Day 1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow- up27
Visit Time 
Windowa (days)
(281)
(2)
(2)
(2)
(2)
Informed consent2
X
Tumor history
X
Medical history
X
Physical 
examination
X
X
X
X
X
Baseline signs and 
symptoms3
X
Height
X
Weight
X
X
X
X
X
Vital signs4
X
X
X
X
X
ECOG Performance 
status5
X
X
X
X
X
Laboratory
Hematology6
X
X
X
X
X
X
Blood 
Chemistry7
X
X
X
X
X
X
Coagulation8
X
X
X
X
X
T3, FT4, and 
TSH9
X
X
X9
X9
X
Urinalysis10
X
Pregnancy 
test11
X
X
X
X
X
Contraception 
checkb
X
X
X
X
X
X
12-Lead ECG12
X
X
X (Cycles 3 and 6 only)


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CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screening
Day 1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow- up27
Visit Time 
Windowa (days)
(281)
(2)
(2)
(2)
(2)
Registration and 
Treatment
Registration13
X
Administration of 
crizotinib14
BID Continuously (QD Continuously at DL-3b only)
Administration of 
pembrolizumab14
X
X
X
Tumor assessments
CT or MRI scan or 
equivalent15
X
To be assessed at Week 9 (+ 7 days) and every 6 weeks (+/- 7 days) thereafter
X
Other clinical 
assessments
AEs16





X
Concomitant 
treatments17





X
Other samplings
Archival tumor 
tissue18
X
De Novo Tumor 
Biospecimen19
X
 
 
 
 
 
 
 
 
 
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CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screening
Day 1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow- up27
Visit Time 
Windowa (days)
(281)
(2)
(2)
(2)
(2)
 
 
 
Blood for crizotinib 
PK24
X 24
X24
X24
Blood for 
pembrolizumab 
PK24
X24
X24
X24
X24
X24
X24
X24
 
 
 
Patient Reported 
Outcomes (EORTC 
QLQ-C30, QLQ-
LC-13, VSAQ)25
X
X
X
X
Survival Follow-
up27
X
Abbreviations: = ongoing/continuous event; 
; AEs = adverse events; C = cycle; CT = computed tomography; MRI =  magnetic 
resonance imaging; PK = pharmacokinetics
C
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a.
Day relative to start of study enrollment (Day 1).
b.
  Contraception 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 throughout the study and continued for at least 90 days after the last dose of 
crizotinib and 120 days after the last dose ofr  pembrolizumab.  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.  
c.
A cycle length is 3 weeks.
1.
Screening: To be obtained within 28 days prior to study enrollment.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study enrollment.  Baseline 
signs and symptoms will be recorded on the Adverse Events case report form (CRF) page.
4.
Vital Signs: Blood pressure and pulse rate to be recorded in seated position.
5.
ECOG Performance Status: See Appendix 2.
6.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 7 days prior to that date. See ASSESSMENTS section 
for Laboratory Tests list.
7.
Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  See ASSESSMENTS section for 
Laboratory Tests list.
8.
Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. See ASSESSMENTS section for Laboratory 
Tests list.
9.
Thyroid Function Tests: No need to repeat on C1D1 if screening assessment is performed within 7 days prior to study enrollment.  Performed in odd-
numbered cycles starting C1D1 or when clinically indicated.  See ASSESSMENTS section for Laboratory Tests list.  Thyroid function test are being 
performed due to the potential for immune-related hypo- or hyperthyroidism.
10. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if screening assessment performed within 7 days 
prior to that date.  See ASSESSMENTS section for Laboratory Tests list.
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, and 
assayed in a certified laboratory, will be performed on 2 occasions prior to starting study treatment - once at the start of screening and once at the baseline 
visit, immediately before investigational product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment 
period, at the end of study treatment and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional 
pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.


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12. 12-Lead ECG: All patients require a single ECG measurement at screening.  Triplicate ECGs measurements (approximately 2 minutes apart) will be 
measured at all other time points with all 3 measurements obtained within a 10-minute time window for each timepoint.  ECGs should be performed 
immediately before PK blood draws at respective time points.  ECGs should be obtained at 0 hour (pre-dose) on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 
Day 1 and Cycle 6 Day 1.  ECGs should also be obtained between 2 and 6 hours following morning crizotinib dosing on Cycle 1 Day 1, Cycle 2 Day 1, 
Cycle 3 Day 1 and Cycle 6 Day 1.  For all patients, if the QTc is prolonged (≥500 msec), then the ECG should be read by a cardiologist at the site for 
confirmation (to look for spurious QT effect).  Additional ECGs will be performed as clinically indicated.  See Section 7.1.4 for further details.
13. Registration: Patient number and dose level allocation operated by Pfizer Inc.
14. Study Treatment Administration: Crizotinib will be given orally BID  (or QD at DL-3) on a continuous daily dosing schedule.  Pembrolizumab will be 
given as a 30-minute infusion every 3 weeks.  Patients will continue with combination crizotinib and pembrolizumab treatment until RECIST-defined 
progression of disease and investigator determination that the patient is no longer receiveing clinical benefit or, unacceptable toxicity, death or consent 
withdrawal, whichever occurs first.  
15. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include chest, abdomen and pelvis CT or MRI 
scans.  Baseline central nervous system (CNS) imaging is required to rule out asymptomatic brain metastases, and brain imaging scans will be performed at 
baseline and assessed along with the CT/MRI scans of the chest, abdomen and pelvis.  CT or MRI scans are to be done starting at Week 9 (+1 week) after 
the start of pembrolizumab then repeated every 6 weeks (+/- 1 week).  Bone scans will be performed at baseline if bony metastases are suspected.  Patients 
with positive results on the bone scans will have these repeated every 12 weeks (± 1 week).  Tumor assessments must continue until disease progression has 
been determined by the radiologist in consultation with the treating physician to determine whether the patient would benefit from treatment beyond 
RECIST v1.1 disease progression.  Both target and non-target lesions are to be followed using the same modality used at baseline. Tumor assessment should 
be repeated to confirm response and disease progression and at the End of Treatment visit if more than 6 weeks have passed since the last evaluation. 
16. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  Patients must be followed for AEs for 28 days after the last study treatment 
administration or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer 
therapy in the meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 28 calendar days after the administraton of crizotinib or 90 calendar days after the last 
administration of pembrolizumab, whichever is later, and before initiation of a new anti-cancer treatment.  The prolonged follow-up is due to the 
pharmacokinetic properties of pembrolizumab.  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.
17. Concomitant Treatments: All concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
18. Archival Tumor Tissue: A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be provided that is of sufficient size to 
allow, if possible, for sectioning of fifteen (15) 5-micron tissue sections. If an FFPE tumor tissue block cannot be provided, sites should try to obtain fifteen 
(15) unstained slides each containing a 5-micron tissue section cut serially from the same FFPE block. If archived FFPE tissue is not available, every effort 
should be made to collect a de novo (ie, fresh) tumor sample  in accordance with local institutional practice for tumor biopsies. Archived or de novo tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted. Acquisition of 
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19. De Novo Tumor Biospecimen: An optional de novo (ie, fresh biopsy) tumor sample will be collected at End of Treatment if a patient discontinues due to 
disease progression. Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be 
submitted.
20.
 
21.
 
22.
 
 
 
 
23.
 
24. PK Sampling: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic 
 Sampling Schema Table 2.  For 
crizotinib PK assessments, blood samples (3 mL) to obtain plasma will be collected prior to crizotinib morning dose (pre-dose) on Day 1 of Cycles 1, 2, 4, 6, 
and 8, and between 28-35 days after last pembrolizumab dose (at the End of Treatment Visit). For pembrolizumab PK assessments, blood samples (3 mL) to 
obtain serum will be collected: 1) prior to pembrolizumab (predose) and at end of pembrolizumab infusion (Day 1), between 72-168 hours (Days 4-8), and 
336 hours (Day 15) of Cycle 1; 2) prior to pembrolizumab (predose) on Day 1 of Cycles 2, 4, 6, 8, and every 4 cycles thereafter and at the end of 
pembrolizumab infusion on Day 1 of Cycle 8; and 3) between 28-35 days (at the End of Treatment Visit) and at approximately 3 months (Follow-up) after 
last pembrolizumab dose (or until the patient starts new anti-cancer therapy).
 
 
Also see
Section 7.2. 
25. EORTC QLQ-C30, QLQ-LC13, and VSAQ-ALK: Patients will complete the EORTC QLQ-C30, QLQ-LC13, and VSAQ-ALK questionnaires at the 
clinic prior to any study or medical procedure. If  a person is illiterate and/or not able to read, they  need not complete these questionnaires. Translation of 
the VSAQ-ALK is available in many different languages.  However, if the VSAQ-ALK is not available in the patient’s preferred language the patient does 
not need to complete this assessment.  
26. End of Treatment: At least 28 days but no more that 35 days after the last dose of study treatment, patients will return to undergo review of AEs, and 
concomitant medications.  Patients continuing to experience treatment-related toxicity at this point following discontinuation of treatment will continue to be 
followed every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further improvement is expected.  
27. Follow-up:After discontinuation of study treatment, post-study survival status will be collected every 2 months until death or until 18 months after 
enrollment of the last patient, whichever occurs first.  Includes collection of information on subsequent anticancer therapies.  Telephone contact is 
acceptable.
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Table 2.
PK 
 Sampling Schema for Dose Levels 0, -2 and -3 (See Table 5)
Cycles 1, 2, 4, 6, 8
Cycle 12 and every 4 cycles
thereafter 
End of Treatment and Follow-up
Day 1
Days 4-15(Cycle 
1 only)
Day 1
PK 
Samples 
for 
crizotiniba
PK Samples for 
pembrolizumabb
PK Sample for 
pembrolizumabb
PK Sample for 
pembrolizumabb
 
PK Samples 
for crizotiniba
PK Sample for 
pembrolizumabb
c
Prior to 
crizotinib 
morning 
dosed
Prior to 
pembrolizumab 
dosee
 
 
Between 72 and 
168 hours (Day 
4-8) and 336 
hours (Day 15) 
after Cycle 1 
dosing. 
Prior to 
pembrolizumab 
dosee
 
 
Between 28-35
days after last 
pembrolizumab 
dose
Between 28-35
days after last 
pembrolizumab 
dose
 
End of 
pembrolizumab 
infusionf
(Only Cycles 1 
and 8)
Approximately 3 
months after last 
pembrolizumab 
dose
(or until the 
patient starts new 
anti-cancer 
therapy)
 
 
PK= pharmacokinetics; 
; note that PK samples for pembrolizumab 
 will be collected from all patients in 
the study. Crizotinib PK samples will be collected from all patients in the Dose Finding Phase and at least 8 patients in the Dose Expansion Phase. 
a.
One blood sample (3 mL) will be collected to obtain plasma at each time point for determining crizotinib and its metabolite PF-06260182 levels. Blood 
samples for crizotinib PK will be collected prior to crizotinib morning dose (pre-dose) on Day 1 of Cycles 1, 2, 4, 6, and 8, and between 28-35 days after last 
pembrolizumab dose (at the End of Treatment Visit). Also see Section 7.2.
b.
One blood sample (3 mL) will be collected to obtain serum at each time point for determing pembrolizumab levels. Blood samples for pembrolizumab PK 
will be collected: 1) prior to pembrolizumab (predose) and at end of pembrolizumab infusion (Day 1), between 72-168 hours (Days 4-8), and 336 hours 
(Day 15) of Cycle 1; 2) prior to pembrolizumab (predose) on Day 1 of Cycles 2, 4, 6, 8, and every 4 cycles thereafter and at the end of pembrolizumab 
infusion on Day 1 of Cycle 8; and 3) between 28-35 days (at the End of Treatment Visit) and at approximately 3 months (Follow-up) after last 
pembrolizumab dose (or until the patient starts new anti-cancer therapy). Also see Section 7.2.
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c.
 
d.
Pre-dose trough crizotinib PK sample hould be drawn within 1 hour before crizotinb dosing.
e.
Pre-dose trough pembrolizumab samples should be drawn within 24 hours before infusion of pembrolizumab.  
f.
Sample may be collected within 30 minutes after the end of pembrolizumab infusion. 
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SCHEDULE OF ACTIVITIES FOR PHASED-IN DOSE LEVEL -1 (See Table 5): Crizotinib monotherapy lead-in period for 
21 days prior to start of pembrolizumab
Table 3.
Schedule of Activities: Crizotinib + Pembrolizumab: 21-Day Treatment Cycles
(Applicable to both the Dose Finding and Dose Expansion Phases of the Study)
CYCLE -1
Lead-in for DL-1
(21 days)
CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screen
Day 1
Day 15
Day 
1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow-up27
Visit Time Windowa
(days)
(281)
Crizotinib 250 mg PO 
BID for 3 weeks
(2)
(2)
(2)
(2)
(2)
Informed consent2
X
Tumor history
X
Medical history
X
Physical examination
X
X
X
X
X
Baseline signs and 
symptoms3
X (prior to 
first dose 
of 
crizotinib 
only)
X
Height
X
Weight
X
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
ECOG Performance 
status5
X
X
X
X
X
X
Laboratory
Hematology6
X
X
X
X
X
X
X
X
Blood Chemistry7
X
X
X
X
X
X
X
X
Coagulation8
X
X
X
X
X
X
T3, FT4, and TSH9
X
X
X9
X9
X9
X
Urinalysis10
X
Pregnancy test11
X
X
X
X
X
X
Contraception checkb
X
X
X
X
X
X
X


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CYCLE -1
Lead-in for DL-1
(21 days)
CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screen
Day 1
Day 15
Day 
1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow-up27
Visit Time Windowa
(days)
(281)
Crizotinib 250 mg PO 
BID for 3 weeks
(2)
(2)
(2)
(2)
(2)
12-Lead ECG12
X
X
X
X (Cycles 3 and 6
only)
Registration and 
Treatment 
Registration13
X
X
Administration of 
crizotinib14
BID Continuously
Administration of 
pembrolizumab14
X
X
X
Tumor assessments
CT or MRI scan or 
equivalent15
X
To be assessed at Week 9 after the start of pembrolizumab (+ 7 days) then every 6 weeks 
(+/- 7 days) thereafter
X
Other clinical 
assessments
AEs16
X





X
Concomitant 
treatments17
X





X
Other samplings
Archival tumor tissue18
X
De Novo Tumor 
Biospecimen19
X
 
 
 
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CYCLE -1
Lead-in for DL-1
(21 days)
CYCLES 1-2
CYCLES 3-8
CYCLES >8
Visit Identifier
Screen
Day 1
Day 15
Day 
1
Day 
4-8
Day 
15
Day 1
Day 1
End of 
Treatment26
Follow-up27
Visit Time Windowa
(days)
(281)
Crizotinib 250 mg PO 
BID for 3 weeks
(2)
(2)
(2)
(2)
(2)
 
 
 
 
X
Blood for crizotinib PK24
X24
X24
X24
X24
Blood for 
pembrolizumab PK24
X24
X24
X24
X24
X24
X24
X24
Blood for 
pembrolizumab ADA 
(Immunogenicity) 
Testing24
X24)
X24
X24
X24
X24
Patient-Reported 
Outcomes (EORTC 
QLQ-C30, QLQ-LC-13, 
VSAQ)25
X
X
X
X
Survival Follow-up27
X
Abbreviations: = ongoing/continuous event; 
; AEs = adverse events; C = cycle; CT = computed tomography; MRI =  magnetic 
resonance imaging; PK = pharmacokinetics
a.
Day relative to start of study enrollment (Day 1).
b.
Contraception 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 throughout the study and continued for at least 90 days after the last dose of 
crizotinib and 120 days after the last dose ofr  pembrolizumab.  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.
c.
A cycle length is 3 weeks.
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1.
Screening: To be obtained within 28 days prior to study enrollment.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study enrollment  Baseline 
signs and symptoms will be recorded on the Adverse Events case report form (CRF) page.
4.
Vital Signs: Blood pressure and pulse rate to be recorded in seated position. 
5.
ECOG Performance Status: See Appendix 2.
6.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 7 days  prior to that date.  See ASSESSMENTS section 
for Laboratory Tests list.
7.
Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  See ASSESSMENTS section for 
Laboratory Tests list.
8.
Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. See ASSESSMENTS section for Laboratory 
Tests list.
9.
Thyroid Function Tests: No need to repeat on C1D1 if screening assessment is performed within 7 days prior to study enrollment.  Performed in odd-
numbered cycles starting from C1D1 or when clinically indicated.  See ASSESSMENTS section for Laboratory Tests list. Thyroid function test are being 
performed due to the potential for immune-related hypo- or hyperthyroidism.
10. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if screening assessment performed within 7 days 
prior to that date.  See ASSESSMENTS section for Laboratory Tests list.
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, and
assayed in a certified laboratory, will be performed on 2 occasions prior to starting study treatment once at the start of screening and once at the baseline 
visit, immediately before investigational product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment 
period, at the end of study treatment and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional 
pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
12. 12-Lead ECG: All patients require a single ECG measurement at screening.  Triplicate ECGs measurements (approximately 2 minutes apart) will be 
measured at all other time points with all 3 measurements obtained within a 10 minute time window for each timepoint.  ECGs should be performed 
immediately before PK blood draws at respective time points.  ECGs should be obtained at 0 hour (pre dose) on Lead-in Day 1, Cycles 1 Day 1, Cycle 2
Day 1, Cycle 3 Day 1 and Cycle 6 Day 1, and during the lead-in period in DL-1.  ECGs should also be obtained between 2 and 6 hours following morning 
crizotinib dosing on Lead-in Day 1, Cycles 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and Cycle 6 Day 1.  For all patients, if the QTc is prolonged (>500 msec), 
then the ECG should be read by a cardiologist at the site for confirmation (to look for spurious QT effect).  Additional ECGs will be performed as clinically 
indicated.  See Section 7.1.4 for further details.
13. Registration: Patient number and dose level allocation operated by Pfizer Inc. 
14. Study Treatment Administration: Crizotinib will be given orally BID  on a continuous daily dosing schedule.  Crizotinib will be given for 3weeks as 
monotherapy (Cycle -1) prior to starting pembrolizumab.  Pembrolizumab will be given as a 30-minute infusion every 3 weeks (as described in the STUDY 
TREATMENTS section).  Patients will continue with combination crizotinib and pembrolizumab treatment until RECIST-defined progression of disease and 
investigator determination that the patient is no longer receiveing clinical benefit or, unacceptable toxicity, death or consent withdrawal, whichever comes 
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15. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include chest, abdomen, and pelvis CT or MRI 
scans.  Baseline central nervous system (CNS) imaging is required to rule out asymptomatic brain metastases, and brain imaging scans will be performed at 
baseline and assessed along with the CT/MRI scan of the chest, abdomen, and pelvis.  CT or MRI scans are to be done starting at Week 9 (+1 week) after the 
start of pembrolizumab then repeated every 6 weeks (+/- 1 week).  Bone scans will be performed at baselinefor bony metastases are suspected.  Patients with 
positive results on the bone scans will will have these repeated every 12 weeks (±1 week).  Tumor assessments must continue until disease progression has 
been determined by the radiologist in consultation with the treating physician to determine whether the patient would benefit from treatment beyond 
RECIST v1.1 disease progression.  Both target and non-target lesions are to be followed using the same modality used at baseline and interval unless 
clinically indictated.  Tumor assessment should be repeated at to confirm response and disease progression and at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation. 
16. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  Patients must be followed for AEs for 28 days after the last study treatment 
administration or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer 
therapy in the mean time.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure 
and/or receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse 
events occurring to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a 
minimum, all serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigtional product are to be
reported to the sponsor.
17. Concomitant Treatments: All concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
18. Archival Tumor Tissue: A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be provided that is of sufficient size to 
allow, if possible, for sectioning of fifteen (15) 5-micron tissue sections. If an FFPE tumor tissue block cannot be provided, sites should try to obtain fifteen 
(15) unstained slides each containing a 5-micron tissue section cut serially from the same FFPE block. If archived FFPE tissue is not available, every effort 
should be made to collect a de novo (ie, fresh) tumor sample in accordance with local institutional practice for tumor biopsies. Archived or de novo tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted. Acquisition of 
the mandatory tumor tissue can be completed outside the 28-day screening window.
19. De Novo Tumor Biospecimen: An optional de novo (ie, fresh biopsy) tumor sample will be collected at End of Treatment if a patient discontinues due to 
disease progression. Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be 
submitted.
20.
 
21.
 
22.
 
 
 
 
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23.
 
 
24. PK Sampling: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic 
 Samples Collection Table 4. For 
crizotinib PK assessments, blood samples (3 mL) to obtain plasma will be collected prior to crizotinib morning dose (pre-dose) on Day 1 of Cycles 1, 2, 4, 
and 8, and between 28-35 days after the last pembrolizumab dose (at the End of Treatment Visit). In addition, blood samples for full crizotinib PK profiles 
will be collected prior to (pre-dose) and at 1, 2, 4, 6, and 8 hours after crizotinib morning dose on Day 15 of the Lead in Period and on Day 1 of Cycle 6. For 
pembrolizumab PK assessments, blood samples (3 mL) to obtain serum will be collected: 1) prior to pembrolizumab (predose) and at end of pembrolizumab 
infusion (Day 1), between 72-168 hours (Days 4-8), and 336 hours (Day 15) of Cycle 1; 2) prior to pembrolizumab (predose) on Day 1 of Cycles 2, 4, 6, 8, 
and every 4 cycles thereafter and at the end of pembrolizumab infusion on Day 1 of Cycle 8; and 3) between 28-35 days (at the End of Treatment Visit) and 
at approximately 3 months (Follow-up) after last pembrolizumab dose (or until the patient starts new anti-cancer therapy).
 
 
Also see Section 7.2.  
25. EORTC QLQ-C30, QLQ-LC13, and VSAQ-ALK: Patients will complete the EORTC QLQ-C30, QLQ-LC13, and VSAQ-ALK questionnaires at the 
clinic prior to any study or medical procedure. If a person is illiterate and/or not able to read, they need not complete these questionnaires. Translation of 
the VSAQ-ALK is available in many different languages.    However, if the VSAQ-ALK is not available in the patient’s preferred language the patient does 
not need to complete this assessment.
26. End of Treatment: At least 28 days after the last dose of study treatment but no more than 35 days, patients will return to undergo review of AEs, or 
concomitant medications.  Patients continuing to experience treatment-related toxicity at this point following discontinuation of treatment will continue to be 
followed every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further improvement is expected.  
27. Follow-up:.After discontinuation of study treatment, post-study survival status will be collected every 2 months until death or until 18 months after 
enrollment of the last patient, whichever occurs first.  Includes collection of information on subsequent anticancer therapies.  Telephone contact is 
acceptable.
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Table 4.
PK 
 Sampling Schema for Dose Level -1 (See Table 5)
Crizotinib 
Lead-In
(Cycle -1)
Cycles 1, 2, 4, 6, 8
Cycles 12 and every 4 Cycles 
thereafter 
End of Treatment and Follow-up
Day 15
Day 1
Days 4-15
Day 1
PK Samples for 
Crizotiniba]
PK Samples 
for 
crizotiniba
PK 
Samples 
for 
pembroli
zumabb
 
 
PK Sample for 
pembrolizumabb
PK Sample for 
pembrolizumabb
 
PK Samples 
for 
crizotiniba
PK Sample for 
pembrolizumabb
 
 
Prior to 
crizotinib 
morning dose
Prior to 
crizotinib 
morning 
dosed
Prior to 
pembroliz
umab 
dosee
 
 
between 72 and 
168 hours (Day 
4-8) and 336 
hours (Day 15) 
after Cycle 1 
dosing. 
Prior to 
pembrolizumab 
dosee
 
Between 28-
35 days after 
Last 
pembrolizu
mab dose
Between 28-35  
days after Last 
pembrolizumab 
dose
  
 
 
1 hr post 
crizotinib 
morning dose
1 hr post 
crizotinib 
morning 
dose
(Cycle 6 
only)
End of 
pembroliz
umab 
infusionf
(Cycles 1 
and 8)
Approximately 3 
months after last 
pembrolizumab 
dose
(or until the 
patient starts new 
anti-cancer 
therapy)
 
 
 
 
 
 
2 hrs post 
crizotinib 
morning dose
2 hrs post 
crizotinib 
morning 
dose
(Cycle 6 
only)
4 hrs post 
crizotinib 
morning dose
4 hrs post 
crizotinib 
morning 
dose
(Cycle 6 
only)
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Crizotinib 
Lead-In
(Cycle -1)
Cycles 1, 2, 4, 6, 8
Cycles 12 and every 4 Cycles 
thereafter 
End of Treatment and Follow-up
Day 15
Day 1
Days 4-15
Day 1
PK Samples for 
Crizotiniba]
PK Samples 
for 
crizotiniba
PK 
Samples 
for 
pembroli
zumabb
 
 
PK Sample for 
pembrolizumabb
PK Sample for 
pembrolizumabb
 
PK Samples 
for 
crizotiniba
PK Sample for 
pembrolizumabb
 
6 hrs post 
crizotinib 
morning dose
6 hrs post 
crizotinib 
morning 
dose
(Cycle 6 
only)
8 hrs post 
crizotinib 
morning dose
8 hrs post 
crizotinib 
morning 
dose
(Cycle 6 
only)
PK= pharmacokinetics; 
; note that PK samples for pembrolizumab 
 will be collected from all 
patients in the study.  Crizotinib PK samples will be collected from all patients in the Dose Finding Phase and at least 8 patients in the Dose Expansion Phase. 
a.
One blood sample (3 mL) will be collected to obtain plasma at each time point for determining crizotinib and its metabolite PF-06260182 levels.  Blood 
samples (3 mL) crizotinib PK to will be collected prior to crizotinib morning dose (pre-dose) on Day 1 of Cycles 1, 2, 4, and 8, and between 28-35 days after 
the last pembrolizumab dose (at the End of Treatment Visit). In addition,  blood samples for full crizotinib PK profiles will be collected prior to (pre-dose) and 
at 1, 2, 4, 6, and 8 hours after crizotinib morning dose on Day 15 of the Lead in Period and on Day 1 of Cycle 6. Also see Section 7.2.  
b. One blood sample (3 mL) will be collected to obtain serum at each time point for determining pembrolizumab levels.  Blood samples for pembrolizumab PK 
will be collected: 1) prior to pembrolizumab (predose) and at end of pembrolizumab infusion (Day 1), between 72-168 hours (Days 4-8), and 336 hours (Day 
15) of Cycle 1; 2) prior to pembrolizumab (predose) on Day 1 of Cycles 2, 4, 6, 8, and every 4 cycles thereafter and at the end of pembrolizumab infusion on 
Day 1 of Cycle 8; and 3) between 28-35 days (at the End of Treatment Visit) and at approximately 3 months (Follow-up) after last pembrolizumab dose (or until 
the patient starts new anti-cancer therapy). Also see Section 7.2.  
c.
 
  
d. Pre-dose trough sample for crizotinib should be drawn within 1 hour before crizotinb dosing.
e. Pre-dose trough samples should be drawn within 24 hours before infusion of pembrolizumab.  
f. Sample may be collected within 30 minutes after the end of pembrolizumab infusion. 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................36
LIST OF FIGURES .................................................................................................................36
APPENDICES .........................................................................................................................36
1. INTRODUCTION ...............................................................................................................37
1.1. NSCLC Background ...............................................................................................37
1.1.1. Mutations/Fusions in NSCLC.....................................................................37
1.1.2. Immune System and NSCLC......................................................................38
1.2. Background and Rationale ......................................................................................39
1.2.1. Clinical Safety and Efficacy of Crizotinib..................................................40
1.2.2. Pembrolizumab (MK-3475)........................................................................41
1.2.3. Rationale for Dose Selection/Regimen/Modification.................................43
1.2.4. Rationale for the Combination of Crizotinib and Pembrolizumab.............44
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................45
2.1. Objectives................................................................................................................45
2.2. Endpoints.................................................................................................................45
3. STUDY DESIGN.................................................................................................................47
3.1. Study Overview.......................................................................................................47
3.1.1. Study Treatment..........................................................................................47
3.1.1.1. Criteria for Dose De-Escalation ................................................49
3.1.2. Tumor Assessments....................................................................................51
3.1.3. Pharmacokinetic Assessment......................................................................51
3.1.5. Tumor Biopsy Requirements and Translational Studies ............................52
3.2. Dose-Limiting Toxicity Definition .........................................................................52
3.3. Maximum Tolerated Dose Definition .....................................................................53
3.4. Recommended Phase 2 Dose Definition.................................................................53
4. PATIENT SELECTION......................................................................................................53
4.1. Inclusion Criteria.....................................................................................................53
4.2. Exclusion Criteria....................................................................................................54
4.3. Lifestyle Guidelines ................................................................................................57
4.3.1. Contraception..............................................................................................57
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4.3.2. Sunlight Exposure.......................................................................................58
4.3.3. Food Limitations.........................................................................................58
4.4. Sponsor’s Qualified Medical Personnel..................................................................58
5. STUDY TREATMENTS.....................................................................................................59
5.1. Patient Compliance .................................................................................................59
5.2. Investigational Product Supplies.............................................................................59
5.2.1. Dosage Form(s) and Packaging..................................................................59
5.2.1.1. Crizotinib...................................................................................59
5.2.1.2. Pembrolizumab..........................................................................59
5.2.2. Preparation and Dispensing........................................................................60
5.3. Administration.........................................................................................................60
5.3.1. Crizotinib Administration...........................................................................60
5.3.2. Pembrolizumab Administration..................................................................61
5.3.3. Food Requirements.....................................................................................61
5.3.4. Recommended Dose Modifications............................................................61
5.3.4.1. Intra-Patient Crizotinib Dose Modifications.............................62
5.3.4.2. Intra-Patient Pembrolizumab Dose Modifications....................64
5.3.5. Dosing Interruptions...................................................................................74
5.3.6. Pembrolizumab Dosing Delays ..................................................................75
5.3.7. Crizotinib Dosing Reductions.....................................................................75
5.4. Allocation to Treatment ..........................................................................................75
5.5. Investigational Product Storage ..............................................................................75
5.6. Investigational Product Accountability...................................................................76
5.6.1. Destruction of Investigational Product Supplies ........................................76
5.6.2. Prohibited Medications When Using Crizotinib.........................................77
5.6.3. Prohibited Medications When Using Pembrolizumab ...............................77
5.6.4. Supportive Care ..........................................................................................78
5.6.5. Hematopoietic Growth Factors...................................................................78
5.6.6. Anti-Emetic, Anti-Diarrheal Therapy.........................................................78
5.6.7. Other Concomitant Medications.................................................................79
5.6.8. Surgery........................................................................................................79
5.6.8.1. Crizotinib Guidelines ................................................................79


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5.6.8.2. Pembrolizumab Guidelines .......................................................79
5.6.9. Pembrolizumab Infusion Reaction .............................................................79
6. STUDY PROCEDURES .....................................................................................................81
6.1. Screening.................................................................................................................81
6.1.1. Mandatory Tumor Biospecimen.................................................................81
6.2. Study Period ............................................................................................................81
6.3. End of Treatment/Withdrawal and Follow-up Visit ...............................................81
6.4. Patient Withdrawal..................................................................................................82
7. ASSESSMENTS..................................................................................................................83
7.1. Safety Assessment...................................................................................................83
7.1.1. Pregnancy Testing ......................................................................................83
7.1.2. Adverse Events...........................................................................................84
7.1.2.1. Events of Clinical Interest (ECI): Pembrolizumab....................84
7.1.3. Laboratory Safety Assessment ...................................................................85
7.1.4. Vital Signs and Physical Examination........................................................85
7.1.5. ECOG Performance Status .........................................................................86
7.1.6. (12-Lead) Electrocardiogram......................................................................86
7.2. Pharmacokinetics Assessments...............................................................................86
7.2.1. Blood Sample Collection for Pharmacokinetic 
 Analysis...........86
7.2.2. Collection of Crizotinib PK Samples .........................................................87
7.2.2.1. Processing, Storage and Shipment of Crizotinib PK 
Samples..............................................................................................87
7.2.3. Collection of Pembrolizumab Pharmacokinetic Samples...........................87
7.2.3.1. Processing, Storage and Shipment of Pembrolizumab PK 
Samples..............................................................................................87
7.3. Pharmacodynamic Assessments..............................................................................88
7.3.1. Archival Tumor Tissue and Optional De Novo End of Treatment 
Tumor Biopsies................................................................................................89
7.4. Tumor Response Assessments ................................................................................90
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7.6. Patient-Reported Outcomes.....................................................................................92
7.6.1. EORTC QLQ-C30 and QLQ-LC13............................................................92
7.6.2. VSAQ-ALK................................................................................................92
8. ADVERSE EVENT REPORTING......................................................................................93
8.1. Adverse Events........................................................................................................93
8.2. Reporting Period .....................................................................................................93
8.3. Definition of an Adverse Event...............................................................................94
8.4. Medication Errors....................................................................................................94
8.5. Abnormal Test Findings..........................................................................................95
8.6. Serious Adverse Events...........................................................................................95
8.6.1. Protocol-Specified Serious Adverse Events...............................................96
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................96
8.7. Hospitalization ........................................................................................................97
8.8. Severity Assessment................................................................................................98
8.9. Causality Assessment..............................................................................................99
8.10. Exposure During Pregnancy..................................................................................99
8.11. Occupational Exposure .......................................................................................100
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient 
Withdrawal (Section 6.4)) .......................................................................................101
8.13. Eliciting Adverse Event Information ..................................................................101
8.14. Reporting Requirements......................................................................................101
8.14.1. Serious Adverse Event Reporting Requirements ...................................101
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................102
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............102
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................102
9.1. Analysis sets..........................................................................................................102
9.2. Statistical Methods and Properties ........................................................................103
9.2.1. Statistical Methods for Dose De-escalation/Re-Escalation: mTPI...........103
9.2.2. Statistical Method for Estimating the MTD .............................................104
9.3. Sample Size Determination...................................................................................104
9.4. Efficacy Analysis ..................................................................................................105
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9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................106
9.5.1. Analysis of Pharmacokinetics...................................................................106
9.5.1.1. Pharmacokinetic Analysis of Crizotinib and 
Pembrolizumab................................................................................106
9.5.1.2. Effect of Pembrolizumab on Crizotinib Pharmacokinetics.....106
9.5.2. Analysis of Patient-Reported Outcomes...................................................107
9.6. Safety Analysis......................................................................................................107
9.6.1. Primary Endpoint Analysis.......................................................................108
9.6.2. Secondary Safety Endpoint Analysis........................................................108
9.6.2.1. Adverse Events........................................................................108
9.6.2.2. Laboratory Tests Abnormalities..............................................108
9.6.3. Electrocardiograms...................................................................................108
9.6.4. Vital signs.................................................................................................109
9.7. Data Safety Monitoring Committee ......................................................................109
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................109
11. DATA HANDLING AND RECORD KEEPING ...........................................................110
11.1. Case Report Forms/Electronic Data Record .......................................................110
11.2. Record Retention.................................................................................................111
12. ETHICS............................................................................................................................111
12.1. Institutional Review Board /Ethics Committee...................................................111
12.2. Ethical Conduct of the Study ..............................................................................111
12.3. Patient Information and Consent.........................................................................112
12.4. Patient Recruitment.............................................................................................113
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................113
13. DEFINITION OF END OF TRIAL.................................................................................113
13.1. End of Trial in a Member State...........................................................................113
13.2. End of Trial in All Other Participating Countries...............................................113
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................113
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15. PUBLICATION OF STUDY RESULTS........................................................................114
15.1. Communication of Results by Pfizer ..................................................................114
15.2. Publications by Investigators ..............................................................................114
16. REFERENCES ................................................................................................................116
17. APPENDICES .................................................................................................................122
LIST OF TABLES
Table 1.
Schedule of Activities: Crizotinib + Pembrolizumab: 21-Day Treatment 
Cycles ...................................................................................................................15
Table 2.
PK 
 Sampling Schema for Dose Levels 0, -2 and -3 (See Table 5) ......21
Table 3.
Schedule of Activities: Crizotinib + Pembrolizumab: 21-Day Treatment 
Cycles ...................................................................................................................23
Table 4.
PK 
 Sampling Schema for Dose Level -1 (See Table 5).......................29
Table 5.
Crizotinib and Pembrolizumab Dose Level Cohorts............................................48
Table 6.
Detailed Dose Re-Escalation/De-Escalation Scheme...........................................49
Table 7.
Crizotinib Dose Modifications .............................................................................62
Table 8.
Crizotinib and Pembrolizumab Dose Modifications for Treatment-Related 
Toxicity.................................................................................................................64
Table 9.
Pembrolizumab Infusion Reaction Treatment Guidelines....................................80
Table 10.
Summary of Biomarker Assessments...................................................................88
Table 11.
Response Evaluation Criteria in Solid Tumors ..................................................133
LIST OF FIGURES
Figure 1.
STUDY DESIGN .................................................................................................12
APPENDICES
Appendix 1. Required Laboratory Tests................................................................................122
Appendix 2. ECOG Performance Status................................................................................123
Appendix 3. EORTC QLQ-C30 Questionnaire.....................................................................124
Appendix 4. EORTC QLQ-LC13 Questionnaire...................................................................126
Appendix 5. Visual Symptom Assessment Questionnaire (VSAQ-ALK) ............................127
Appendix 6. RECIST version 1.1 Tumor Assessment Criteria .............................................129
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1. INTRODUCTION
This is a Phase Ib study of crizotinib (XALKORI®), an ATP-selective small-molecule oral 
inhibitor of the anaplastic lymphoma kinase (ALK), c-Met/hepatocyte growth factor receptor 
(HGFR), Recepteur d’Origine Nantais (RON), and ROS1 receptor tyrosine kinases and their 
oncogenic variants (eg, c-Met/HGFR mutations and ALK or ROS1 fusion proteins), in 
combination with pembrolizumab (KEYTRUDA®), a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype, which directly blocks the interaction 
between programmed death receptor-1 (PD-1) and its ligands, PD-L1 and PD-L2.  The study
is designed to determine the MTD and RP2D of this combination regimen in
first-line (1L) treatment of patients with ALK-positive advanced non-small cell lung cancer 
(NSCLC). 
1.1. NSCLC Background
Non-small cell lung cancer is the most common cause of fatal malignancy in the United 
States (US) among both men and women, representing 28% and 26% of all cancer-related 
deaths, respectively.  NSCLC represents the second most common cause of new cases of 
malignancies in men (14%) and women (13%) according to the National Cancer Institute’s 
Surveillance, Epidemiology and End Results (SEER) program.1  Similar results have been 
described in Europe where NSCLC remains the most common cause of fatal malignancy.2
There is also a growing burden of NSCLC in developing countries like India3 and China4
where the incidence in men is greater than women.  The incidence of NSCLC has been 
decreasing in the US and Europe due to tobacco cessation programs.1,2  The NSCLC rates 
have remained high in heavily polluted cities due to particulate matter, second-hand smoke 
exposure, and poor home ventilation systems where coal is used for cooking.4,14  Another 
important issue with NSCLC is the low 5-year survival rate of 16.6%.  This is usually due to 
the late stage of diagnosis but also due to the development of resistance to treatments.
1.1.1. Mutations/Fusions in NSCLC
Approximately 85% of all lung cancer cases are NSCLC.  Of these cases, about 60% are 
considered non-squamous histologically with the remaining being squamous.  Genetic 
aberrations have been noted to act as drivers for tumor growth in certain types of NSCLC.  
The presence of mutations and gene fusions, along with the development of targeted 
therapies, allowed for the improved treatment for patients with NSCLC.  The first mutations 
that were targeted, EGFR mutations especially del exon 19 and L858R translocation in exon 
21, showed improvement in objective response rate (ORR) and median progression-free 
survival (mPFS) using specific epidermal growth factor receptor (EGFR) tyrosine kinase 
inhibitors (TKIs) but no improvement in overall survival (OS).15,17-20
Anaplastic lymphoma kinase (ALK) gene rearrangements are another molecularly defined 
subgroup of lung cancer patients.  An inversion within chromosome 2p resulting in the 
formation of a fusion gene product comprising portions of the echinoderm microtubule 
associated protein-like 4 (EML4) gene and the ALK gene was discovered in 2007 in NSCLC 
cell lines and archived clinical specimens.21 A subsequent series of studies have described 
9 fusion variants of EML4-ALK plus additional but less common fusion partners with 
ALK.22-29 Currently, there are at least 27 different ALK fusion variants reported in the 


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literature, the majority of isoforms involve EML4-ALK.5  ALK-positive NSCLC patients, 
who represent between 3% and 5% of all non-squamous cases, tend to be young (average age 
50 years at diagnosis), and light to never smokers.5
1.1.2. Immune System and NSCLC
Recent evidence has shown that tumors require interaction with the host immune system for 
continued growth and spread.  Expression of antigens on the tumor cells are different from 
host cells due to genetic and epigenetic variations.  In order for immune removal of tumor 
cells, there must be antigen recognition, followed by antigen presentation to T cells.  The 
T cells will become activated and cell kill occurs. T cells are further modified by immune 
stimulatory and immune inhibitory signals; developed to prevent autoimmune diseases and 
inflammation.  The immune co-stimulatory molecules include CD28, CD137, glucocorticoid-
induced tumor necrosis factor receptor (GITR), and OX-40.  Co-inhibitory or checkpoint 
molecules include cytotoxic T-lymphocyte antigen-4 (CTLA-4), PD-1, T-cell 
immunoglobulin- and mucin-domain-3-containing molecule 3 (TIM3), lymphocyte-
activation gene-3 (LAG3), and killer cell immunoglobulin-like receptor (KIR).  These 
immune checkpoint molecules lead to immune tolerance of the tumor, leading to increased 
tumor growth and vascularization.30
Until recently, attempts to modulate the immune system in NSCLC have met with limited 
benefit.  Vaccine therapies have not shown benefits in NSCLC patients.  The anti-CTLA-4 
antibody ipilimumab was studied in combination with paclitaxel and carboplatin using 
2 different dosing regimens.  The phased regimen showed an improvement in median 
immune-related PFS (irPFS) of 5.7 vs. 4.6 months while the concurrent regimen showed an 
improvement in irPFS of 5.5 vs. 4.6 months.  The phased regimen showed statistical 
significance while the concurrent did not.31
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.32  Accumulating evidence shows a correlation 
between TILs in cancer tissue and favorable prognosis in various malignancies.33-37  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors.  The PD-1 receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD L2).9, 11  PD-1 and family members are type I transmembrane glycoproteins containing an 
Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which 
is responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signaling cascade.9,38,40,41  The mechanism 


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by which PD-1 down-modulates T-cell responses is similar to, but distinct from that of 
CTLA-4 as both molecules regulate an overlapping set of signaling proteins.42, 43  PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, T regs and Natural Killer cells.45, 45  Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells.46  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.42, 47-49  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs.  Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues.42  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
patients with melanoma.50  This suggests that the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention.
There have been a number of studies evaluating several different inhibitors of PD-1 or PD-L1 
in NSCLC.  Nivolumab (BMS-936558; a fully humanized anti-PD-1-antibody) showed an 
ORR of 18% in squamous and non-squamous NSCLC patients who were treated in the third-
line and beyond.51 Pembrolizumab (MK-3475; a fully humanized anti-PD-1 antibody) was 
studied in multiple tumor types.  In patients with unselected advanced NSCLC, 
pembrolizumab was associated with an ORR of 36% by immune-related response criteria 
(irRC).52  Studies using antibodies targeting the ligand on PD-1 (anti-PD-L1-antibodies), 
including MEDI4736 and MPDL3280A, are ongoing.  The most mature data presented uses
BMS-936559 (a fully humanized anti-PD-L1 antibody) that showed an objective response in 
5 of 49 patients with NSCLC.53  
1.2. Background and Rationale
Crizotinib (PF-02341066)Crizotinib (XALKORI®, PF-02341066) is indicated for the 
treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC) (actual indication varies according to region/country).5
Crizotinib is an oral inhibitor of ALK, HGFR, RON, and ROS1 receptor tyrosine kinases and 
their oncogenic variants (eg, c-Met/HGFR mutations and ALK or ROS1 fusion proteins). 
Consistent with this mechanism of action, crizotinib inhibited phosphorylation of 
c-Met/HGFR and selected ALK fusion or mutant variants in tumor cells both in vitro and in 
vivo, and RON and ROS1 in vitro.  Crizotinib exhibited potent and selective growth 
inhibitory activity against tumor cells exhibiting translocation/inversion or selected mutations 
involving the ALK gene locus (echinoderm microtubule-associated protein-like-4 [EML4]-
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1.2.1. Clinical Safety and Efficacy of Crizotinib
Clinical Safety
Overall, the AEs reported for crizotinib in clinical studies were considered generally 
tolerable and manageable.  For single-agent crizotinib, the most common AEs (≥20% of 
patients) reported from 1511 patients with advanced NSCLC regardless of causality were 
vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, 
fatigue and decreased appetite.  The majority of AEs were Grades 1 or 2 in severity, as 
treatment-related AEs of Grades 3, 4, or 5 in severity were observed among 547 (36.3%) 
advanced NSCLC patients who received at least 1 dose of single-agent crizotinib 250 mg 
BID.  The most common Grade 3 treatment-related AEs were neutropenia, elevated 
transaminases, hypophosphatemia, fatigue, leukopenia, lymphopenia, nausea, vomiting, 
electrocardiogram QT prolonged, and edema.  The most common Grade 4 treatment-related 
AEs were neutropenia, elevated transaminases, hepatotoxicity, interstitial lung disease, and 
abdominal pain.  The Grade 5 treatment-related AEs that occurred most commonly were 
interstitial lung disease (5 patients; 0.3%), death (4 patients; 0.3%), pneumonia (2 patients; 
0.1%), hepatotoxicity (2 patients; 0.1%), lung infection (2 patients; 0.1%), disseminated 
intravascular coagulation (1 patient; 0.1%), arrhythmia (1 patient; 0.1%), dyspnea (1 patient; 
0.1%), and pulmonary embolism (1 patient; 0.1%).7  
There are special warnings regarding crizotinib use that must be considered and are described 
in detail in the crizotinib Investigator’s Brochure (IB).  Drug-induced hepatotoxicity occurred 
in less than 1% of all patients treated with crizotinib and usually appeared within the first 
2 months of therapy.  Other warnings are pnerumonitis/interstitial lung disease and QTc 
prolongation which both occurred in fewer than 2% of patients and bradycardia which 
occurred in approximately 6% of patients.7  Specific management for these events is noted in 
Table 8.  
Clinical Efficacy
Clinical trials using crizotinib showed an impressive rate of objective tumor response that 
were were rapid and durable in Studies A8081001 and A8081005.  In Study A8081007 
(PROFILE 1007), treatment of advanced ALK-positive NSCLC patients in second-line (after 
initial platinum-based chemotherapy) with crizotinib demonstrated a statistically significant 
improvement in median PFS when compared to chemotherapy (pemetrexed or docetaxel 
monotherapy) of 3.0 months (median PFS: 7.7 months vs.of 3.0 months, respectively; HR 
0.487; 95% CI: 0.371, 0.638; P <0.001).  This study also showed an statistically significant 
improvement in ORR to 65% versus 20% for chemotherapy.  Validated questionnaires  
(EORTC QLQ-C30 and QLQ-LC13) showed a significantly greater improvement in patient-
reported lung cancer symptoms and global quality of life receiving crizotinib as compared 
with chemotherapy.6, 7 In Study A8081014 (PROFILE 1014), treatment of ALK-positive 
NSCLC with crizotinib in the first-line showed statistically significant improvement in 
median PFS and ORR when compared with pemetrexed plus platinum-based chemotherapy
(median PFS: 10.9 months vs. 7.0 months, respectively; HR 0.454; 95% CI: 0.346 -0.596; 
P <0.001; ORR: 74% vs. 45%, respectively; P <0.001).8  


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Complete information for crizotinib may be found in the crizotinib Single Reference Safety 
Document (SRSD) which for this study is the investigaor’s brochure (IB).7
1.2.2. Pembrolizumab (MK-3475)
Pembrolizumab [Keytruda® (US); previously known as lambrolizumab, MK-3475, and SCH
9000475] is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. 
Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the 
programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the 
treatment of cancer. Pembrolizumab has received its first global approval for the treatment of 
advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with 
disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-
positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory 
approval in the US, and is currently under regulatory review in the EU.74 Clinical Safety and 
Efficacy of Pembrolizumab in Solid Tumors
The safety and efficacy data regarding the use of pembrolizumab comes from the multi-arm 
study PN001, also referred to as KEYNOTE-001, which studied patients with solid tumors, 
including melanoma, and NSCLC.  This study is an open-label Phase 1 study, which includes 
a dose escalation component using 1, 3, and 10 mg/kg of pembrolizumab every 2 or 3 weeks 
in patients with solid tumors (Part A), subsequent expansion cohorts studying solid tumors at 
the MTD from Part A (Part B), at 2 different dose levels in patients with melanoma (Part D), 
expansion cohorts at the MTD from Part A in patients with melanoma (Part C), at 3 different 
dose levels in NSCLC (Part E), and at 2 different dose levels (1 mg/kg vs. 10 mg/kg only) in 
patients with NSCLC (Part F).  KEYNOTE-001 Part A evaluated 3 dose levels and all 3 dose 
levels were well tolerated, as no DLTs were observed.  Based on PK data showing a half-life 
of 21 days, the protocol was amended to include a dosing frequency of Q3weeks in the 
expansion cohorts (Parts B through F).  
Clinical Safety
The safety of pembrolizumab is being assessed in 26 different studies as noted in 
http://www.clinicaltrials.gov. Currently, safety data of single agent pembrolizumab are only 
available from KEYNOTE-001.122 57,58  Preliminary data59 are available from 479 patients 
enrolled in KEYNOTE-001: Part A (n=30) pembrolizumab 1 mg/kg, 3 mg/kg, and 10 mg/kg 
Q2weeks or Q3weeks, Part B (n=308) pembrolizumab 2 mg/kg or 10mg/kg Q2weeks or
Q3weeks, Part C (n=38) pembrolizumab 10 mg/kg Q3weeks, and Part D (n=103) 
pembrolizumab 2 or 10 mg/kg Q3weeks.  Of the 479 patients who have received 
pembrolizumab in KEYNOTE-001, 466 (97.3%) experienced all-causality AEs of which 
368 were considered to be treatment-related.  Serious adverse events (SAEs) were reported in 
30.1% of patients.  Potentially immune-related AEs (irAEs - also called immune-mediated 
adverse reactions) were observed, including pneumonitis (Grades 1-2) in patients with 
melanoma or NSCLC.  The most commonly reported an all-causality AEs experienced were 
fatigue, nausea, cough, pruritus, diarrhea and rash.  Most patients continued treatment, as
only 4.2% of patients discontinued pembrolizumab due to treated-related AEs.


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Of the 162 patients who received pembrolizumab 2 mg/kg Q3weeks in the treatment of 
melanoma in KEYNOTE-001, 160 experienced an treatment-related AEs of which 128 were 
considered to be treatment-related; 17 were Grades 3 or 4 in severity.  SAEs were reported in 
44 patients, but treatment-related SAEs were reported in 15 patients.  This included 1 episode 
of hyperthyroidism and 1 episode of adrenal insufficiency.  The most commonly reported all-
causality AEs experienced in this subset of patients were fatigue (30%), pruritus (21%), rash 
(21%), diarrhea (20%), nausea (10%), and cough (8%).  The most common treatment-related 
AEs included hypothyroidism (8%), vitiligo (9%), elevated AST (10%), elevated alanine 
aminotransferase (ALT) (8%), pneumonitis (4%), and immune-related renal failure (2%).57  
Additional safety signals that are seen with pembrolizumab related to its immune activity 
include hypophysitis, hypopituitarism, adrenal insufficiency, nephritis, uveitis, and diabetes 
mellitis.  In order to manage any potential endocrine-related AE, thyroid function tests, renal 
function tests, and serum blood glucose tests are being performed.
Clinical Efficacy
Preliminary efficacy from KEYNOTE-001 is available for 135 patients with advanced 
melanoma.57  The ORR across all dose cohorts, assessed by independent radiology review 
according to RECIST v1.1, was 38% (95% CI: 25, 44), with an ORR observed of 52% (95%
CI: 38, 66) in the cohort that received 10 mg/kg Q2weeks.  The ORR did not differ 
significantly between patients who had received prior ipilimumab (anti-CTLA-4 antibody)
treatment and those who were ipilimumab-naïve (ORR= 38% [95% CI: 23, 55] and 37% 
[95% CI: 26, 49], respectively).  Objective responses were durable in the majority of 
patients (median follow-up was 11 months); 81% (24/52) of the patients who had a response 
were still receiving treatment at the time of analysis.  The overall median PFS among 
the 135 patients was estimated to be longer than 7 months (median PFS was not yet 
reached).57
1.2.2.1.1. Clinical Safety and Eficacy of Pembrolizumab in NSCLC
Clinical Safety
In KEYNOTE-001, Part C (n=38), 20 patients experienced ≥1 treatment-related AE of any 
grade across all dose levels (1mg/kg, 3 mg/kg, and 10 mg/kg Q3weeks).  The most common
treatment-related AEs were rash (21%), pruritis (18%), fatigue (16%), diarrhea (13%), 
arthralgia (11%), back pain (5%), cough (5%), and decreased appetite (5%).  Grade 2 
treatment-related AEs included hypothyroidism (1 patient), hyperthyroidism (1 patient), and 
pneumonitis (1 patient).  There was 1 episode of a Grade 3 treatment-related AE (pulmonary 
edema).  There were no Grade 4 and 5 treatment-related AEs.12
Clinical Efficacy
The preliminary ORR using RECIST v1.1 in KEYNOTE-001 Part C (n=38) across all dose 
levels among all patients who received 3 or more lines of prior therapy for NSCLC was 24% 
by investigator assessment using immune-related response criteria.  The ORR was 21% as 
assessed by independent radiology review.  The specific breakdown of responses by 
independent radiology review assessed by RECIST v1.1 was 16% (4/26) for patients with 


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non-squamous NSCLC and 33% (2/6) for patients with squamous NSCLC.  The median PFS 
was 10.3 weeks for advanced non-squamous NSCLC patients and 15.2 weeks for advanced 
squamous NSCLC patients.12
The correlation of pembrolizumab activity with levels of tumoral PD-L1 was explored in a
substudy using 146 NSCLC tumor samples across all KEYNOTE-001 NSCLC cohorts.  
Among the tumors that had ≥ 50% PD-L1 staining, the ORR was 37%.  Among the tumors 
that had ≥1% PD-L1 staining, the ORR was 25%.58
Complete information for pembrolizumab may be found in the Single Reference Safety 
Document (SRSD), which for this study is the pembrolizumab IB.59
1.2.3. Rationale for Dose Selection/Regimen/Modification
The dosing of crizotinib was chosen to be 250 mg BID as this demonstrated robust antitumor 
activity in patients with ALK-positive advanced NSCLC.  Similarly, pembrolizumab has 
shown dramatic antitumor activity at 2 mg/kg Q3weeks.  There do not appear to be 
significant overlapping toxicities seen at these doses while there is a maximal antitumor 
activity. Because of these, this study will evaluate DL0 as the starting dose with crizotinib 
250 mg BID combined with pembrolizumab at the equivalent dose of 200 mg Q3weeks.  
In KEYNOTE-001, which treated a variety of tumor types, pembrolizumab showed evidence 
of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg, and 10 mg/kg Q2weeks). Dose level 10 mg/kg Q3weeks was evaluated 
in previously treated patients with NSCLC in Part C.
PK data analysis of pembrolizumab administered Q2weeks showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to pembrolizumab IB).59
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale 
for testing either a Q2weeks or Q3weeks dosing schedule. Previously treated patients with 
NSCLC in KEYNOTE-001 Part C have experienced durable objective responses with 
acceptable toxicity when treated with pembrolizumab at 10 mg/kg Q3weeks.
Preliminary data in patients with melanoma and NSCLC also demonstrated objective 
responses by pembrolizumab when administered at the 2 mg/kg Q3weeks dose and schedule. 
However, ongoing analysis of KEYNOTE-001 Parts B, C, and F may further define the 
activity of low vs. high doses included in this trial. In addition, given the lack of a dose 
response to date, modeling and simulation data indicate that a fixed dose of 200 mg provides 
adequate exposure for the largest patients based on body weight while not exceeding the 
exposure seen at 10 mg Q3weeks in the smallest patients based on body weight.  A 
population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, was within the 
range observed for other antibodies and would support both body weight normalized dosing 
or a fixed dose across all body weights.  Simulations were performed on the basis of the 


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population PK model, using a distribution of body weight reflective of the general population 
obtained from the National Health and Nutrition Examination Survey (NHANES) 2009-2010 
database. 
Differences in exposure for a 200 mg fixed dosing regimen relative to a 2 mg/kg Q3weeks
body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication.  Thus, a fixed dose of 
200 mg Q3weeks should result in adequate exposure to pembrolizumab across all body 
weights, similar to the exposures obtained with a 2 mg/kg Q3week regimen.
1.2.4. Rationale for the Combination of Crizotinib and Pembrolizumab
Patients with previously untreated ALK-positive advanced NSCLC treated with crizotinib 
have a median PFS of 10.9 months.23  Progression of disease is often related to the 
development of crizotinib-resistant ALK mutation or signal transduction bypass pathways.  
Another potential cause of disease progression is related to tumoral growth and protection 
related to lack of immune surveillance, often due to overexpression of PD-L1 within the 
tumor.  Although the incidence of changes in the tumor microenvironment are unknown, 
there remains the potential for improvement in ORR, DR, and PFS probability using a 
combination of targeted therapy (crizotinib) and immune therapy (pembrolizumab).  The 
increase in regulatory T cells also allows for the metastatic spread of tumor both 
lymphatically and hematogeneously as well as increases in local vascular endothelial growth 
factor.  These factors correlate with a negative prognosis for diseases like NSCLC.12  The 
primary efficacy evaluation of this study is to show that combination therapy of crizotinib 
and pembrolizumab improves the ORR based on historical single-agent crizotinib data from 
Study A8081014 (>75% for crizotinib).  Additional efficacy parameters evaluated will 
include PFS, duration of response (DR) and overall survival (OS).
Targeting of ALK has been noted because of the strong addiction for neoplastic cell growth 
and survival but also for the development of spontaneous immunogenicity.  This was first 
noted in patients with NPM-ALK-positive anaplastic large cell lymphoma (ALCL) where 
circulating antibodies to NPM-ALK proteins were noted.60, 61  CD8+ effector and memory 
T-cells were also found in these patients62, 63 as were CD4+ helper T-cells.64  The strongest 
immune response seen correlated with survival improvement in ALCL patients.65
Experiments using ALK DNA vaccination in mice showed a cytotoxic immune response to 
the injected cells.  Vaccination prevents lymphoma growth due to immune response and 
improved future immune protections as noted by increased interferon-gamma (IFN-γ) and 
CD8+ T-cells.66
Mice that were implanted with EML4-ALK- and TFG-ALK-expressing lung tumors 
developed lung masses with distant metastases.  An additional experiment used 3 rounds of 
ALK vaccination to determine antitumor response.  Cytotoxicity to the tumor occurred 
quickly.  There were increases in effector T cells intratumorally as well as an increase in 
regulatory T cells over time.  When the ALK vaccine was combined with an ALK TKI, 
tumors were noted to have increased PD-L1 expression by immunohistochemical (IHC) 
staining with delay in tumor relapse and extended survival.67  


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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To assess safety and tolerability of crizotinib in combination with pembrolizumab in 
the first-line treatment of patients with ALK-positive advanced non-squamous 
NSCLC in order to identify the Maximum Tolerated Dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 
Secondary Objectives

To evaluate the overall safety profile of crizotinib in combination with 
pembrolizumab;

To document the anti-tumor activity of crizotinib in combination with pembrolizumab 
in previously untreated ALK-positive advanced NSCLC patients;

To characterize the pharmacokinetics (PK) of crizotinib and pembrolizumab and to 
assess the effect of pembrolizumab on the PK of crizotinib;

To evaluate tumor PD-L1 expression, as assessed by PD-L1 immunohistochemistry, 
as a predictor of anti-tumor activity.
 
 
 
 

To evaluate the impact of combination therapy of crizotinib and pembrolizumab on 
patient-reported lung cancer symptoms (such as dyspnea, cough and pain) and global 
Quality of Life (QOL) per the validated cancer specific EORTC QLQ-C30, and its 
lung cancer module, QLQ-LC-13, and visual symptoms per the Visual Symptom 
Assessment Questionnaire (VSAQ-ALK).
2.2. Endpoints
Primary Endpoint

Dose-Limiting Toxicity (DLT).
Secondary Endpoints

Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
v.4.03), timing, seriousness and relationship to study treatments.
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
Objective response rate (ORR), as assessed using RECIST v1.1, and also:

Duration of Response (DR).

Time to Tumor Response (TTR).

PFS, 6-month, 12-month, and 18-month PFS probabilities, OS, 12-month and 
18-month survival probabilities.

Laboratory abnormalities as characterized by type, frequency, severity, and timing.

The following PK parameters of crizotinib, its metabolite PF-06260182 and
pembrolizumab PK will be determined as data permits: 

Maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax), pre-dose concentration (Ctrough), area under the plasma concentration time 
curve from 0 to 8 hours (AUC0-8), area under the plasma concentration time curve
over the dosing interval (AUCtau), and apparent plasma clearance (CL/F) for 
crizotinib; 

Cmax, Tmax, Ctrough, AUCtau, metabolite to parent ratio for AUCtau (MRAUCtau), and 
metabolite to parent ratio for Cmax (MRCmax) for PF-06260182;

Ctrough for pembrolizumab;

Population-based PK parameters for pembrolizumab (if performed, will be
reported in a separate report).

Association between tumor PD-L1 expression assessed by PD-L1 
immunohistochemistry and endpoints of clinical outcome (response-related and time-
to-event endpoints).
 

Overall change from baseline patient-reported lung cancer symptom, functioning, and 
global QOL scores using the EORTC QLQ-C30 and QLQ-LC-13 questionnaires;

Frequency of occurrence and degree of bothersomeness of visual disturbances as 
reported by the patients on the VSAQ-ALK questionnaire.
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multicenter, multiple-dose, dose-finding, safety, and 
pharmacokinetic study of crizotinib in combination with pembrolizumab in sequential 
cohorts of adult patients with previously untreated ALK-positive advanced NSCLC with 
2 phases (Dose Finding Phase and Dose Expansion Phase).  
Approximately 70 total patients are expected to be enrolled in this study.  The first phase of 
the study, the Dose Finding Phase, will utilize the mTPI method to determine the MTD of the 
combination regimen.  The second phase, the Dose Expansion Phase, will further evaluate 
the combination regimen at the MTD to determine whether or not the MTD will also be the 
RP2D.
3.1.1. Study Treatment
Crizotinib will be given orally (PO) either BID or QD, with or without food on a continuous
daily dosing schedule.  Pembrolizumab will be given as a 30-minute intravenous (IV) 
infusion Q3 weeks.  Patients will continue with combination crizotinib and pembrolizumab 
treatment until RECIST-defined progression of disease and investigator decision that the 
patient is no longer experiencing clinical benefit, or unacceptable toxicity, death, or consent 
withdrawal, whichever occurs first (see Section 7.4).  
The initial starting dose for the Dose Finding Phase of the study will be crizotinib 250 mg 
given BID on a continuous schedule with pembrolizumab 200 mg given intravenously 
Q3weeks starting on Cycle 1 Day 1 as described in Table 5.
In the Dose Finding Phase, lower doses of crizotinib may or may not be administered in 
subsequent cohorts of patients according to Table 5 and Table 6 depending on the incidence 
of DLTs at DL0.  However, if DL0 exceeds the MTD, then patients will be enrolled into the 
next lower dose level (DL-1) except as described in the Table 5 footnotes.  DL-1 will use the 
same crizotinib and pembrolizumab dosing regimens in combination after assessing whether 
or not patients tolerate a 3-week lead-in period using crizotinib 250 mg BID as a 
monotherapy for 3 weeks, henceforth referred to as Cycle -1 in the SOA (see Table 3). 
During this lead-in period, additional laboratory studies and ECGs will be performed, as well 
as additional PK analyses (see Table 4).  This will be followed by the addition of 
pembrolizumab 200 mg Q3weeks.  This will allow both drugs to remain at their respective 
maximum effective doses before lowering the doses of crizotinib to a lower dose level.  A 
lead-in period using pembrolizumab monotherapy will not be considered at this time due to 
the paucity of data in ALK-positive NSCLC patients in the 1L treatment setting.
If dose de-escalation is neccessary after evaluation is completed for DL-1, then the next dose 
level will be determined by the types of adverse events that occur.  If the adverse events are 
immune-related and considered to be only related to pembrolizumab, such as thyroiditis or 
endocrinopathies, the next cohort of patients will be assigned to DL-2 to test a lower dose of 
crizotinib in combination with pembrolizumab.  If the adverse events are considered to be 
only related to crizotinib, such as diarrhea, visual changes, or LFT abnormalities as described
in the crizotinib IB, then the next cohort of patients will be assigned to DL-2 or DL-3.  


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Table 5.
Crizotinib and Pembrolizumab Dose Level Cohorts
Dose Level
Crizotinib
Pembrolizumab
0*
250 mg BID
200 mg Q3weeks
-1
250 mg BID x 3 
weeks as 
monotherapy, then
if tolerated, in 
combination with 
pembrolizumab 
thereafter
200 mg Q3weeks after 
crizotinib monotherapy 
lead-in period
-2**
200 mg BID
200 mg Q3weeks
-3
250 mg QD
200 mg Q3weeks
*If the adverse events meeting DLT criteria in DL0 are considered related to one or both study drugs, then
further dose levels of crizotinib may be explored.
**If the adverse events meeting DLT criteria in DL0 are considered to be only related to crizotinib, such as 
diarrhea, visual changes, or LFT abnormalities as described in the crizotinib IB, patients, then the next dose 
level will be DL-2 or DL-3 which decreases the crizotinib dose to 200 mg BID and 250 mg QD, respectively.
Patients will be monitored closely for toxicity, and, in the event of significant toxicity, dosing 
may be delayed (see Section 5.3.4 and Section 5.3.5).  Further adjustment of crizotinib may 
be performed by dosing interruption with or without dose reduction after the DLT evaluation 
period (see Section 5.3.4.1).  Pembrolizumab dose modification will be performed based 
upon treatment-related irAEs including nephritis, enterocolitis, or endocrine abnormalities 
(see Section 5.3.4.2).  Refer to pembrolizumab Events of Clinical Interest (ECI) Guidance 
Document for supportive care guidance.  The ECI Guidance Document is a separate 
document that is located in the study reference manual. 
The Dose Finding Phase of the trial will be completed when 10 DLT-evaluable patients have 
been treated at the highest DL associated with a DLT rate of <0.33. 
If a cohort has a lower starting dose of crizotinib than 250 mg BID, then after completion of 
the DLT observation period, the dose of crizotinib may be re-escalated up to a maximum 
dose of 250 mg BID on an individual basis if no DLTs are observed.  This will be decided by 
the investigator in consultation with the Sponsor on a case-by-case basis.
The proposed doses, schedule(s), and PK timepoints may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
Patients will continue with combination crizotinib and pembrolizumab treatment until 
RECIST-defined progression of disease and investigator decision that the patient is no longer 
receiving clinical benefit, or unacceptable toxicity, death or consent withdrawal, whichever 
occurs first.  If radiologic imaging shows PD and the patient is perceived to be experiencing 
clinical benefit (see Section 7.4), repeat tumor assessment is to be performed ≥4 weeks later 
in order to confirm tumor status; study treatment may be continued at the investigator’s 
discretion while awaiting radiologic confirmation of disease progression. 


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3.1.1.1. Criteria for Dose De-Escalation
The Dose Finding Phase will follow the “Up-and-Down” design, using doses of crizotinib
and pembrolizumab as shown in Table 5. Briefly, the mTPI method relies upon a statistical 
probability algorithm, calculated using all patients treated at the same dose level to determine 
where future cohorts should involve dose de-escalation, no change in dose, or dose re-
escalation.  The detailed dose-finding rules based on the mTPI are illustrated in Table 6.
In this dosing algorithm there are up to 4 potential dose levels as described in Table 5.
The specific sequence to be followed depends upon the number of overall patients enrolled in 
the study and the number of DLTs observed at each specific dose combination. 
Dosing will begin at DL0.  If no DLTs are observed, then the cohort will be expanded up to a 
total of 10 DLT-evaluable patients prior to opening this DL to the Dose Expansion Phase.  If 
1or more DLTs occur at DL0, then dosing will be continued with DL0 or will be de-escalated 
to DL-1 according to Table 6 see Section 3.1.1.1. Dose re-escalation from levels DL-1 (or 
lower dose levels as shown in Table 6) back to DL0 will be allowed as long as DL0 has not 
been determined to have exceeded the MTD.  
Table 6.
Detailed Dose Re-Escalation/De-Escalation Scheme
Number of Patients Treated at Current Dose
1
2
3
4
5
6
7
8
9
10
Number of tDLTs
0
NA
NA
RE
RE
RE
RE
RE
RE
RE
RE
1
NA
NA
S
S
S
RE
RE
RE
RE
RE
2
NA
D
S
S
S
S
S
RE**
RE**
3
DU
DU
D
D
S
S
S
RE**
4*
DU
DU
DU
DU
DU
DU
DU
5
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU
*A modification has been applied to the original mTPI algorithm. Since this protocol specifies a DLT rate 
<33% in 10 patients, all entries on the row with 4 toxicities are fixed to DU since 4/10 would be ≥33%.   
** This further modification will allow re-escalatation and exposure of up to 10 patients at the higher dose if 
≤3 out of 10 patients with a DLT at the current dose and assuming the previous higher dose was not already a 
DU.
RE = Re-escalate to the next higher dose or if current dose level is DL0 stay on DL0
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
NA = Not applicable. The first three patients will have to be evaluable for DLT before assigning DL for the 
next patient
Targeted DLT rate at MTD <33%


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As an example, if the total number of patients treated at DL0 is 3, then the following dosing 
rules are to be applied:

0 - 1 DLT remain at the same dose (DL0);

2 DLTs
de-escalate to DL-1 and allow for possible escalation back to DL0;

3 DLTs
de-escalate to DL-1 as DL0 is intolerable.
If the dose is de-escalated to DL-1 and the total number of patients then treated at DL-1 is 
3, the following dosing rules are to be applied:

0 DLTs  escalate back to DL0 if DL0 was not considered intolerable;

1 DLT  remain at the same dose (DL-1);

2 DLTs  de-escalate to DL-2 and allow for possible escalation back to DL-1;

3 DLTs  de-escalate to DL-2 as DL-1 is intolerable.
Rules for dose-finding, using the mTPI method, include the following:

The target enrollment cohort size is 3 patients.  The first 3 patients treated at each 
dose level will initiate dosing sequentially, at least 2 days apart from each other.

The next cohort will be enrolled when all patients at the current dose cohort have 
been evaluated for 6 weeks (ie, the first 2 treatment cycles), or experience a DLT, 
whichever comes first.  The next cohort will receive the dose level as assigned by 
Table 5.

If a patient does not receive at least 80% of the planned first 2 cycles of crizotinib 
dosing or both infusions of pembrolizumab within the DLT observation period for 
reasons other than study drug-related toxicity, another patient will be enrolled to 
replace that patient at the current dose level.

The Dose Finding Phase is completed when 10 DLT-evaluable patients (see
Section 9.2) have been treated at the highest dose associated with DLT rate <0.33.  
This will be considered the MTD of the combination.  It is estimated that 
approximately 30 DLT-evaluable patients will need to be enrolled to estimate the 
MTD. 
The proposed doses and, schedules may be reconsidered and amended during the study based 
on the emerging safety and pharmacokinetic data.
The RP2D will be confirmed in the Dose Expansion Phase, taking into account the MTD 
determination from the Dose Finding Phase, and other factors related to safety, efficacy, and 
PK/PD involving all available data from test cohorts.


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3.1.2. Tumor Assessments
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
then at Week 9, and every 6 weeks, thereafter, using RECIST v1.1 [See Schedule of 
Activities (SOA) – Table 1, and Table 3].  In addition, radiological tumor assessments will 
also be conducted to confirm a best response of CR or PR at ≥4 weeks after initial 
assessment of response, whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the time of End of Treatment/Withdrawal (if not performed in the 
previous 6 weeks.  In determining whether or not the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as non-target lesions and 
new lesions according to RECIST v1.1 (See Appendix 6).
Brain CT or MRI scans are required for all patients at baseline and subsequently while on 
treatment.  These are to be repeated every 6 weeks along with the CT/MRI scan of the chest, 
abdomen, and pelvis.  Bone scans will be performed at baseline.  Patients with positive 
results on the bone scans will have these repeated every 12 weeks (±1 week).  Bone imaging 
is also required at the time of confirmation of response for patients who have known bone 
metastases.
3.1.3. Pharmacokinetic Assessment
Crizotinib and pembrolizumab do not have competing elimination/metabolism pathways, 
hence an overt PK interaction between the 2 drugs is not anticipated.  However, PK
assessments (Section 7.2 and Table 2, and Table 4) will be performed in this study to confirm 
the absence of pembrolizumab effects on crizotinib metabolism.  Crizotinib has a mean 
terminal half-life of 42 hours after single-dose administration.  Pembrolizumab has a long 
plasma half-life (21 to 28 days) and trough concentrations increase with successive doses 
until steady state is reached (expected within 3.5-4.5 months of initial pembrolizumab 
dosing).  The administration of pembrolizumab monotherapy has not been evaluated for this 
patient population.  Except for DL-1, all doses of crizotinib and pembrolizumab will be given 
concurrently.  With the exception of the lead-in period for DL-1, steady-state crizotinib PK 
data determined following concurrent administration of pembrolizumab will be compared to 
historical crizotinib data. In the event that DL-1 is evaluated, the crizotinib lead-in period
will permit a within study comparison of steady state crizotinib PK given alone (Day 15 of 
lead-in period) versus crizotinib plus pembrolizumab (Cycle 2 Day 1). As this study does not 
include administration of pembrolizumab as a single agent, the effect of crizotinib on 
pembrolizumab can only be evaluated by comparing pembrolizumab PK at steady-state in the 
presence of crizotinib with those reported for pembrolizumab monotherapy in KEYNOTE-
001. In order to obtain data that adequately characterizes PK at the potential RP2D, PK 
assessments will be done in at least 8 patients from the Dose Expansion Phase.  
The schedule for pharmacokinetic collections is included in Table 2, and Table 4.
  
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3.1.5. Tumor Biopsy Requirements and Translational Studies
All patients will be required to provide archived or de novo FFPE tumor tissue (see
Section 6.1.1). Acquisition of the mandatory tumor tissue sample may be completed outside 
the 28-day screening time window.  This mandatory tumor tissue will be used for 
retrospective  biomarker assessments including as a first priority evaluation of tumor PD-L1 
expression by IHC
 
 as described in Section 7.3.
3.2. Dose-Limiting Toxicity Definition
Severity of adverse events will be graded according to NCI CTCAE version 4.03. For the 
purpose of dose de-escalation, any of the following adverse events occurring in the first 
2 cycles of treatment (6 weeks) which are attributable to crizotinib, pembrolizumab or both 
will be classified as DLTs:
Hematologic toxicities:

Grade 4 neutropenia;

Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38°C or a sustained temperature of >38°C for more than one 
hour;

Grade ≥3 neutropenic infection;

Grade ≥3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.
Non-hematologic toxicities:

Grade ≥3 toxicities (non-laboratory);

Grade ≥3 nausea, vomiting, or diarrhea despite maximal therapy;

Non-hematologic Grade ≥3 laboratory value if medical intervention is required to 
treat the patient or the abnormality leads to hospitalization.
Other

Inability to complete at least 80% of the first 2 cycles doses of crizotinib or both
infusions of pembrolizumab within the DLT observation period due to treatment-
related toxicity.
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3.3. Maximum Tolerated Dose Definition
The MTD estimate is the highest DL of crizotinib in combination with pembrolizumab from 
Table 5 associated with the occurrence of DLTs in <33% of patients. 
3.4. Recommended Phase 2 Dose Definition
The RP2D is the dose of crizotinib and pembrolizumab in combination for further clinical 
development.  Additional safety experience in the Dose Expansion Phase may result in an
RP2D at or below the MTD.  
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
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 
study:  
1. Histologically or cytologically proven diagnosis of locally advanced, recurrent, or 
metastatic non-squamous NSCLC that is not suitable for local treatment with curative 
intent.
2. ALK-positive NSCLC as determined by a test that is approved or validated for use as a 
companion diagnostic test in accordance with applicable local regulatory and practice 
guidelines.
3. Able to provide formalin-fixed, paraffin-embedded (FFPE) tumor tissue (see
Section 6.1.1). 
4. No prior systemic therapy for metastatic disease.  
a.
Any prior adjuvant chemotherapy for Stage I to III disease or combined modality 
chemoradiotherapy for locally advanced disease must have been completed 
>12 months prior to study enrollment.
5. Tumors must have measurable disease as per RECIST (version 1.1); see Appendix 6.
6. Age ≥18 years (or ≥20 years for Japan).
7. ECOG PS must be:
a.
0 or 1 for the Dose Finding Phase.


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b. 0, 1, or 2 for the Dose Expansion Phase.  
8. Adequate Bone Marrow Function, including:
a.
Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
b. Platelets ≥100,000/mm3 or ≥100 x 109/L;
c.
Hemoglobin ≥8 g/dL.
9. Adequate Renal Function, including:
a.
Serum creatinine <2x upper limit of normal (ULN).
10. Adequate Liver Function, including:
a.
Total serum bilirubin ≤1.5 x ULN;
b. AST and ALT ≤2.5 x ULN (≤5.0 x ULN if there is liver involvement secondary 
to tumor); 
c.
Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone metastasis). 
11. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
a.
Male patients able to father children and female patients of childbearing potential 
and at risk for pregnancy must agree to use 2 highly effective method(s) of 
contraception throughout the study and for 90 days after the last of crizotinib or 
120 days after the last dose of pembrolizumab, whichever is later (see
Section 4.3.1).
12. Evidence of a personally signed and dated informed consent document indicating that the 
patient or legally acceptable representative has been informed of all pertinent aspects of 
the study.
13. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior exposure to ALK receptor tyrosine kinase inhibitors, anti-PD-1, anti-PD-L1, anti-
PD-L2, Anti-CD137, or anti-CTLA-4 monoclonal antibodies (including ipilimumab or
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways).


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2. Current treatment on another clinical trial.
3. Major surgery, adjuvant chemotherapy, radiotherapy, any investigational agents, or other 
anticancer therapy within 2 weeks prior to study enrollment or has not yet recovered 
(ie,Grade ≤1 or at baseline) from related acute adverse events more than 4 weeks earlier.
4. History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial 
fibrosis or any grade of interstitial lung disease, including a history of any of the
following conditions: pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, 
interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis, but not history 
of prior radiation pneumonitis.
5. Active autoimmune disease that has required systemic treatment in the past 3 months (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or corticosteroids at physiologic doses for 
eg. thyroid, pancreatic or adrenal insufficiency is acceptable.
6. Known carcinomatous meningitis or leptomeningeal disease. Patients with brain 
metastases are only eligible if treated and neurologically stable with no ongoing 
requirement for corticosteroids, eg, dexamethasone, for at least 2 weeks and are not 
taking contraindicated medications.
7. History of malignancy within the past 3 years (with the exceptions of non-squamous 
NSCLC, in situ cervical cancer, colon polyps, prostate carcinoma in situ or status post-
resection or radiotherapy, ductal carcinoma in situ of the breast, papillary thyroid cancer 
(resected and treated with curative intent), or resected/treated squamous cell or basal cell 
carcinoma of the skin).
8. Active infection requiring systemic therapy.
9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness.
10. Known diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  
11. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected). 
12. Administration of a live vaccine within 30 days prior to the first dose of trial treatment.
13. Any of the following within the 3 months prior to starting study treatment: myocardial 
infarction, severe/unstable angina, congestive heart failure, coronary/peripheral artery 
bypass graft, or cerebrovascular accident including transient ischemic attack.  
Appropriate treatment with anticoagulants is permitted.


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14. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial fibrillation 
of any grade, or machine-read ECG with QTc interval >470 msec.
15. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular 
disease or previous gastric resection or lap-band.  Gastroesophageal reflux disease under 
treatment with proton-pump inhibitors is allowed.
a.
For Japan only: patients who have following complications or symptoms:
1. Serious wound such as chronic wound, or Grade ≥3 gastrointestinal ulcer.
2. Serious gastrointestinal symptoms such as Grade ≥3 diarrhea.
16. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
17. 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.
18. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant male patients able to father children and female patients of 
childbearing potential who are unwilling or unable to use 2 highly effective method(s) of 
contraception as outlined in this protocol for the duration of the study and for at least 90 
days after the last dose of crizotinib or 120 days after the last dose of pembrolizumab, or 
longer based upon the compound’s half-life characteristics..  
19. Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to 
study enrollment, including but not limited to atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin, voriconzole, and grapefruit or grapefruit juice.  The topical use of these 
medications (if applicable), such as 2% ketoconazole cream, may be allowed.
20. Use of drugs that are known potent CYP3A4 inducers within 12 days prior to study 
enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, and St. John’s wort.
21. 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). 


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4.3. Lifestyle Guidelines 
4.3.1. Contraception
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive crizotinib with is associated with teratogenic risk and 
pembrolizumab, a compounds for which the teratogenic risk is currently unknown.  Those 
who, in the opinion of the investigator, are sexually active and at risk for pregnancy, must 
agree to use two (2) methods of highly effective contraception throughout the study and 
continue for at least 90 days after the last dose of crizotinib or 120 days after the last dose of 
pembrolizumab, whichever is later.  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 and his/her partner 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 at least 2 of the 
selected methods of contraception.  The investigator or his/her designee will discuss with the 
patient the need to use highly effective contraception consistently and correctly according to 
the Schedule of Activities (SOA – Table 1 and Table 3) and document such conversation in 
the patient’s chart.  In addition, the investigator or his/her designee will instruct the patient to 
call immediately if one or both selected contraception methods are 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 the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal methods of 
contraception is allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, or 
suppository).  For countries where spermicide is not available or condom plus spermicide 
is not accepted as highly effective contraception, this option is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Female patients of non childbearing potential must meet at least one of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 


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
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
within the laboratory’s reference range for postmenopausal women.
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.
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 of crizotinib or 120 days after the last dose of pembrolizumab, whichever is later.
4.3.2. Sunlight Exposure
Patients treated with crizotinib should avoid sunbathing, prolonged unprotected sun 
exposure, or tanning for the duration of the study period. Sun exposure responses to 
pembrolizumab are unknown.  Patients will be advised to report any reaction to sun exposed 
skin.  
4.3.3. Food Limitations
Crizotinib is predominately metabolized by CYP3A4.  Because grapefruit and grapefruit 
juice are strong CYP3A4 inhibitors, these should be avoided in this study.  
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list on the team’s Sharepoint site.  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.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference 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).
5.1. Patient Compliance
Patients will be required to return all unused crizotinib at the beginning of each cycle.  The 
number of crizotinib capsules returned by the patient at the end of the cycle will be counted, 
documented, and recorded.
The site will complete required dosage with preparation record located in the study manual
for pembrolizumab.  The use of the Preparation Record is preferred but it does not preclude 
the use of an existing appropriate clinical site documentation system.  The existing clinical 
site's documentation system should capture all pertinent /required information on the 
preparation and administration of the dose.  This may be used in place of the Preparation 
Record after approval from the Pfizer monitor. 
5.2. Investigational Product Supplies
Crizotinib and pembrolizumab will be supplied for the study by Pfizer Global Clinical
Supply, Worldwide Research and Development. Drug supplies will be shipped to the study
sites with a Drug Shipment & Proof of Receipt form. This form will be completed, filed, and
the shipment confirmed as directed on the bottom of the Drug Shipment & Proof of Receipt
form. The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage 
of investigational product in accordance with the protocol and any applicable laws and 
regulations.
5.2.1. Dosage Form(s) and Packaging
5.2.1.1. Crizotinib
Crizotinib will be supplied as 200 and 250 mg capsules for oral administration and will be
packaged in HDPE bottles.
5.2.1.2. Pembrolizumab
Pembrolizumab will be supplied in single-use vials containing 100 mg/4 mL sterile solution 
for intravenous administration. Each vial is sealed with a coated stopper and oversealed and
labeled according to local regulatory requirements.


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5.2.2. Preparation and Dispensing  
Crizotinib should be dispensed at each visit per the schedule of treatment (Section 5.3).  
Dispensing will be by a qualified staff member in bottles provided, in quantities appropriate 
for the study visit schedule.  The patient/caregiver should be instructed to maintain the 
product in the bottle provided throughout the course of dosing and return the bottle to the site 
at the next study visit. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
Pembrolizumab will be administered at the investigational site as indicated in Section 5.3.2.
Specific preparation and dispensing instructions are provided in the Dosage Administration 
Instructions located in the Study Manual.
5.3. Administration
Every effort should be made to administer study treatment on the planned dose and schedule.  
However, in the event of significant treatment-related toxicity, administration of the study 
drug may need to be adjusted as described in the following sections.  Depending on the 
nature of the toxicity observed, treatment interruption may be required for 1 or both study 
drugs in the combination.  In the event treatment interruption is deemed necessary for just 
1 of the study drugs in the combination, treatment with the other study drug will continue as 
planned.
The start of a cycle is defined as the day when crizotinib and pembrolizumab administration 
begins, starting with the first crizotinib dose at Cycle 1 Day 1, except for DL-1 where the 
start of Cycle 1 follows the 3-week lead-in period of crizotinib monotherapy.  In case of 
crizotinib dosing interruptions, administration of prembrolizumab will continue according to 
the pre-planned schedule.  
5.3.1. Crizotinib Administration
Crizotinib will be administered orally BID or QD (depending on the DL; see Table 5) at 
approximately the same time in the morning +/- evening on a continuous daily dosing 
schedule, ie, without a break in dosing in the absence of drug-related toxicity.  Crizotinib 
should be taken in the morning prior to the pembrolizumab infusion.  On the study day in 
which both crizotinib and pembrolizumab are administered, crizotinib capsules (on the BID 
schedule) are to be taken approximately 12 hours apart.  Patients must swallow the 
investigational product whole and must not manipulate or chew the investigational product
prior to swallowing.  A dosing card will be provided to the patients to provide guidance for 
the correct use of crizotinib.  Patients must be instructed that should they miss a dose or 
vomit any time after taking a dose, they must not “make it up” with an extra dose.  Instead, 
resume the subsequent doses as originally prescribed.  Any missed dose may be taken up to 
6 hours prior to the next scheduled dose, otherwise it should be skipped and dosing resumed 
with subsequent doses as prescribed.  If a patient inadvertently takes 1extra dose during a 


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day, the patient should not take the next dose.  The patient must be instructed to record all 
doses (including missed or vomited) in a dosing diary supplied by the site.  If doses are 
missed or vomited, this must be indicated in the source documents and CRFs.
During the PK analysis evaluation period, the crizotinib dose should be taken in the clinic 
under the supervision of the study site personnel.
5.3.2. Pembrolizumab Administration
Pembrolizumab will be administered intravenously on Day 1 of every 3-week.  Treatment 
with pembrolizumab may be administered up to 2 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons (such as holidays).  
Pembrolizumab will be administered as a 30 minute IV infusion.  Sites should make every 
effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of (-) 5 minutes and (+) 10 minutes
is permitted (ie, infusion time of 25 to 40 minutes are acceptable).
For purposes of this trial, an overdose will be defined as ≥1000 mg (5 times the standard 
dose) of pembrolizumab. No specific information is available on the treatment of overdose 
of pembrolizumab.  In the event of overdose, the patient should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
Discontinuation from pembrolizumab treatment may be considered at the investigator’s 
discretion for patients who have attained a confirmed CR, have been treated for at least 
24 weeks with pembrolizumab, and have received at least 2 pembrolizumab infusions beyond 
the date the initial CR was declared.  Crizotinib treatment may continue in these patients.  
Patients who then experience radiologic disease progression will be eligible for re-treatment 
with pembrolizumab at the discretion of the investigator if 1) no cancer treatment was 
administered other than study drugs since the last dose of pembrolizumab, 2) the patient 
meets the safety parameters listed in the Inclusion /Exclusion criteria, and 3) the trial is still
open.  Patients will resume therapy at the same dose and schedule in use at the time of initial 
discontinuation.  Pembrolizumab treatment will be administered for up to one additional 
year. Patients who continue to experience radiologic disease progression per RECIST 1.1 or 
have global deterioration of health status requiring discontinuation, will be discontinued from 
trial see Section 6.4.
5.3.3. Food Requirements
Both crizotinib and pembrolizumab may be administered without regard to meals. 
5.3.4. Recommended Dose Modifications
Dose level assignments for the combination therapy will follow the recommendations in
Table 5.  Every effort should be made to administer both investigational products on the 
planned dose and schedule.  Intra-patient dose modifications will be permitted with either 
drug individually, based upon any AEs as described in Table 8.  In the event of significant 
toxicity, dosing may be interrupted, delayed, and/or reduced as described below.  Patients are 
to be instructed to notify investigators at the first occurrence of any AE.


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Dose modifications may occur in 2 ways:

Within a cycle (for crizotinib only): dosing interruption until adequate recovery and 
dose reduction, if required, during a given treatment cycle; 

Between cycles (for pembrolizumab only): next cycle administration may be delayed 
due to persisting toxicity when a new cycle is due to start.  
Dose modifications will be reported in the CRF.
5.3.4.1. Intra-Patient Crizotinib Dose Modifications
In the Dose Finding Phase, crizotinib intra-patient dose reduction is permitted but the adverse 
event leading to the dose modification may be considered a DLT if this occurs during the 
first 2 cycles of the study during this phase, if the investigator grades the treatment-related 
AE as Grade ≥3 and in consultation with the Sponsor (see Table 8).  In the Dose Expansion 
Phase, crizotinib intra-patient dose reduction or escalation is permitted and based upon 
treatment-related adverse events observed.
Patients in the Dose Expansion Phase who tolerate crizotinib below the 250 mg BID dose 
level and have no Grade >2 treatment-related adverse events for 3 consecutive weeks 
(1 treatment cycle) have the option to increase the dose of crizotinib 1 dose level according to
Table 7.  As long as crizotinib is tolerated, crizotinib may be increased up to 250 mg BID.
Table 7.
Crizotinib Dose Modifications
Treatment Level
Crizotinib Dose
0
250 mg BID
-1
200 mg BID
-2
200 mg QD
Below -2
Discontinue crizotinib
5.3.4.1.1. Bradycardia
For a heart rate <40 beats per minute, the patient should be evaluated fully including an 
assessment of concomitant medications.  The dosage of any medication known to be 
associated with bradycardia, eg, beta blockers, should be adjusted accordingly.  If the 
bradycardia is symptomatic at any time or does not improve within 7 days of adjusting the 
concomitant medications, hold crizotinib dosing until recovery.  Patient may continue 
treatment only with the agreement of both the sponsor and investigator.  Concurrent use of 
crizotinib with other bradycardic agents (eg, beta-blockers, non-dihydropyridine calcium 
channel blockers such as verapamil and diltiazem, clonidine, digoxin) should be avoided to 
the extent possible due to the increased risk of symptomatic bradycardia.  Heart rate and 
blood pressure should be monitored regularly.  Dose modification is not required in case of 
asymptomatic bradycardia. For management of patients who develop symptomatic 
bradycardia (see Table 8).


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5.3.4.1.2. Pneumonitis
Investigators must evaluate thoroughly patients who demonstrate potential signs/symptoms 
of pneumonitis/pneumonia.  If a patient has a potential diagnosis of pneumonitis or drug-
related lung injury, the following evaluations/procedures should be considered to support or 
exclude the diagnosis of pneumonitis during this period:

A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, 
protozoal, and mycobacteria; 

Blood culture should be performed in febrile patients;

Thoracentesis if pleural fluid is present (examined for same pathogens as sputum);

Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate.  The BAL fluid 
should be sent for culture and cytology (same pathogens as above);

Lung biopsy (eg, open or thorascopic preferable, bronchoscopy with transbronchial 
biopsy) if appropriate;

A plasma sample for 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 crizotinib (see Table 8).
5.3.4.1.3. Renal Cysts
The development of complex renal cysts has been reported in some patients with NSCLC 
treated with crizotinib.  These cysts may be symptomatic or asymptomatic, and have 
developed from 2 to 6 months after starting crizotinib.  The precise nature and significance of 
these cysts is unclear; however, while no evidence of malignancy has been found based on 
aspiration of cyst fluid and biopsy in the reported cases, complex renal cysts may be 
associated with renal malignancy, and thus consultation with a urologist or suitable alternate 
medical expert is recommended.  
Active surveillance with appropriate imaging (contrast-enhanced CT scanning or magnetic 
resonance imaging) should be performed at the time of the renal cysts diagnosis and as 
scheduled per protocol (as indicated in Table 1 and Table 3) Investigators should also review 
retrospectively all CT/MRIs for any prior occurrence of complex renal cysts.  


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In addition, dipstick urinalysis should be performed at the time of the renal cysts diagnosis 
and on Day 1 of each cycle thereafter; in Korea, dipstick urinalysis should be performed in 
all patients at screening and on Day 1 of each cycle thereafter.  
Urine reflex microscopy is required whenever urine dipstick is positive for blood or protein.
Dose modifications based on specific treatment-related AEs are described in Table 8.
5.3.4.2. Intra-Patient Pembrolizumab Dose Modifications
Pembrolizumab is a humanized monoclonal antibody.  Patients should be monitored for 
potential AEs during antibody infusion and throughout the study.  In the event that a patient 
experiences an infusion reaction to pembrolizumab, , refer to Section 5.7.8 Pembrolizumab 
Infusion Reaction Treatment Guidelines and Table 9.  
Intra-patient pembrolizumab dose modifications are not permitted.  Permanently discontinue
pembrolizumab for any severe or Grade ≥3 drug-related AE that recurs or any life-
threatening treatment related adverse event. Rechallenge after delay due to pembrolizumab 
toxicities may be allowed once for some specific toxicity, but if it recurs, it will require 
permanent discontinuation.  Refer to the ECI Guidance Document for supportive care 
guidance and Section 5.3.4.2.2 Supportive Care Guidance for irAEs Following 
Pembrolizumab Dosing. Management of treatment-related toxicity is described in Table 8.
Table 8.
Crizotinib and Pembrolizumab Dose Modifications for Treatment-Related 
Toxicity
Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
Hematological 
Toxicity
1/2
Continue at the same treatment 
level
If considered related to 
pembrolizumab, refer to the ECI 
Guidance Document for supportive 
care guidance.
3
Withhold dose until toxicity is 
Grade ≤2, or has returned to 
baseline, then resume treatment at 
the same treatment level or reduce 
the dose by 1 treatment level after 
discussion with the Sponsor. †
If considered related to 
pembrolizumab, refer to the ECI
Guidance Document for supportive 
care guidance.
4
Withhold until toxicity is Grade ≤2 
or has returned to baseline, then 
reduce by 1 treatment level
If considered related to 
pembrolizumab, refer to the ECI 
Guidance Document for supportive 
care guidance.
Non-hematological 
toxicity and/or 
Other Drug Related 
Toxicities b
1/2
Continue at the same treatment 
level
Refer to the ECI Guidance Document 
for supportive care guidance.
3
Continue at the same treatment 
level or reduce by 1 treatment level
Withhold until toxicity is Grade ≤1 or 
baseline.  Discontinue pembrolizumab 
if the AE does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroids to ≤10 mg of 
prednisone or equivalent per day 


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
within 12 weeks. Follow the ECI 
Guidance Document for supportive 
care guidance.
4
Withhold until toxicity is Grade ≤1 
or has returned to baseline, then 
reduce by 1 treatment level
Discontinue pembrolizumab.
Follow the ECI Guidance Document 
for supportive care guidance.
ALT or AST 
elevation possibly 
related with total 
bilirubin <2x ULN
1
Continue crizotinib at the same 
treatment level.
Continue at the same dose level. If 
considered related to pembrolizumab, 
refer to the ECI Guidance Document 
for supportive care guidance.
2
Continue crizotinib at the same 
treatment level
Repeat ALT or AST and total 
bilirubin when patient is 
symptomatic or within 7 days if not 
symptomatic.  Monitor weekly.
Withhold until resolution of ALT or 
AST to Grade ≤1 or baseline. 
Discontinue if toxicity does not resolve 
within 12 weeks of last dose or 
inability to reduce corticosteroid to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
3 
Withhold dose until toxicity is 
Grade ≤ 1, or has returned to 
baseline, then resume treatment by 
reducing by one treatment level.  If 
Grade 3 ALT or AST elevation 
recurs reduce further (at most by 2 
treatment levels if starting dose is 
treatment level 0).  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 treatment 
level increments up to the initial 
dose level.
Discontinue pembrolizumab.  For 
patients with liver metastasis who 
begin treatment with Grade 2 AST or 
ALT, if AST or ALT increases by 
greater than or equal to 50% relative to 
baseline and lasts for at least 1 week 
then patients should be discontinued.
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
4
Discontinue crizotinib
Discontinue pembrolizumab. For 
patients with liver metastasis who 
begin treatment with Grade 2 AST or 
ALT, if AST or ALT increases by 
greater than or equal to 50% relative to 
baseline and lasts for at least 1 week 
then patients should be discontinued.
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
ALT or AST 
elevation and total 
bilirubin ≥ 2x ULN 
(in the absence of 
1
Continue crizotinib at the same 
treatment level
Repeat ALT or AST and total 
bilirubin within 48 hours and 
Continue pembrolizumab.  If 
considered related to pembrolizumab, 
refer to the ECI Guidance Document 
for supportive care guidance.


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
cholestasis or 
hemolysis)
monitor every 48 hours until 
Grade <1.
2
Discontinue crizotinib
Withhold until resolution to Grade ≤1
or baseline. 
Discontinue if toxicity does not resolve 
within 12 weeks of last dose or
inability to reduce corticosteroid to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks. Refer to 
pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
3/4
Discontinue crizotinib
Discontinue pembrolizumab. For 
patients with liver metastasis who 
begin treatment with Grade 2 AST or 
ALT. If AST or ALT increases by 
greater than or equal to 50% relative to 
baseline and lasts for at least 1 week 
then patients should be discontinued.
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
Pneumonitis
1
Discontinue crizotinib
If considered related to 
pembrolizumab, refer to the ECI 
Guidance Document for supportive 
care guidance.
2
Discontinue crizotinib
Withhold pembrolizumab until toxicity 
is Grade ≤1 or returns to baseline. 
Discontinue if toxicity does not resolve 
within 12 weeks of last dose or 
inability to reduce corticosteroids to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.  
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
3/4
Discontinue crizotinib
Discontinue pembrolizumab
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
Diarrhea/Colitis
1
Continue crizotinib at the same 
treatment level
Start supportive care with 
loperamide if clinically appropriate.
Continue pembrolizumab at the same 
treatment level
Refer to the ECI Guidance Document 
for supportive care guidance.
2
Continue crizotinib at the same 
level 
Start loperamide at 4 mg at onset 
then 2 mg every 2-4 hours until 
symptom free for 12 hours.
Withhold pembrolizumab until toxicity 
resolves to Grade ≤1 or baseline.
Discontinue if toxicity does not resolve 
within 12 weeks of last dose or 
inability to reduce corticosteroid to 
≤10 mg of prednisone or equivalent per 


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
day within 12 weeks.
Refer to pembrolizumab ECI Guidance 
Document for supportive care 
guidance.
3
Grade 3: Withhold dose until 
toxicity is Grade ≤1, or has 
returned to baseline, then resume 
treatment at the same dose level or 
reduce the dose by 1 level at the 
discretion of the investigator 
(despite use of loperamide).
Withhold pembrolizumab until toxicity 
resolves to Grade ≤1 or baseline.
Discontinue if toxicity does not resolve 
within 12 weeks of last dose or 
inability to reduce corticosteroid to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
4
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then reduce the dose by 1 
level and resume treatment, or 
discontinue at the discretion of the 
investigator (despite use of 
loperamide).
Withhold pembrolizumab.
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
Bradycardia (Heart 
rate less than 60 
bpm)
1
Continue crizotinib at the same 
treatment level
Continue pembrolizumab
There are no specific recommendations
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
2/3
Withhold until toxicity is Grade ≤1 
or heart rate ≥60 bpm, then reduce 
by 1 treatment level.
Evaluate concurrent medications 
and serum electrolytes.
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
Continue pembrolizumab
There are no specific recommendations
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
4
Discontinue crizotinib if no 
contributing concomitant 
There are no specific recommendations 
– please consult the non-hematologic 


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
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 or discuss with sponsor.
Permanently discontinue for 
recurrence.
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
Left ventricular 
systolic 
dysfunction
1 / 2
Continue crizotinib at the same 
treatment level
Continue pembrolizumab
There are no specific recommendations 
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
3 / 4
Discontinue crizotinib
There are no specific recommendations 
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
Prolonged QTc 
interval
1 / 2
Continue crizotinib at the same 
treatment level
For Grade 2 only:  assess 
electrolytes and concomitant 
medications
Correct any electrolyte or 
magnesium abnormalities.
Continue pembrolizumab
There are no specific recommendations 
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
3
Interrupt crizotinib until recovery 
to Grade ≤1, then resume at a lower 
dose level. 
Assess and correct electrolytes and 
concomitant medications. 
In case of recurrence, withhold 
until recovery to Grade ≤1, then 
resume at 250 mg once daily or 
discuss with sponsor.
Permanently discontinue in case of 
further Grade ≥3 recurrence.
There are no specific recommendations 
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
4
Discontinue crizotinib and do not 
retreat
There are no specific recommendations 
– please consult the non-hematologic 
guidelines for recommendations and 
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
Visual disturbance
1 / 2
Continue crizotinib at the same 
treatment level
Obtain an ophthalmology 
consultation
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
3
Interrupt crizotinib until recovery 
to Grade ≤1.
Obtain an ophthalmologic 
consultation
Resume treatment by reducing the 
dose by one dose level upon 
recovery to Grade ≤1.
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
4
Discontinue crizotinib and do not 
retreat
Obtain an ophthalmology 
consultation
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
Type 1 diabetes 
mellitus (if new 
onset) or 
hyperglycemia
1/2
Continue crizotinib at the same 
dose level
Continue pembrolizumab and refer to 
the ECI Guidance Document for 
supportive care guidance.
3 / 4
Grade 3: Withhold dose until 
toxicity is grade 1, or has returned 
to baseline, then resume treatment 
at the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4
hyperglycemia associated with 
evidence of beta cell failure. Resume 
Pembrolizumab when patients are 
clinically and metabolically stable.
Refer to pembrolizumab ECI Guidance 


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
Grade 4: Withhold dose until 
toxicity is grade 1, or has returned 
to baseline, then reduce the dose by 
1 level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Document for supportive care.
Hypophysitis
1
Continue crizotinib at the same 
dose level
Continue pembrolizumab. Follow the 
ECI Guidance Document for 
supportive care guidance.
2
Continue crizotinib at the same 
treatment level
Discontinue if toxicity does not 
resolves within 12 weeks of last dose 
or inability to reduce corticosteroids to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.
Hold treatment until toxicity resolves 
to Grade ≤1 or baseline.  Therapy with 
pembrolizumab may continue while 
endocrine replacement therapy is 
instituted.  
Refer to the ECI Guidance Document 
for supportive care guidance.
3 / 4
Grade 3: Withhold dose until 
toxicity is grade 1, or has returned 
to baseline, then resume treatment 
at the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
Grade 4: Withhold dose until 
toxicity is grade 1, or has returned 
to baseline, then reduce the dose by 
1 level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Discontinue if toxicity does not 
resolves within 12 weeks of last dose 
or inability to reduce corticosteroids to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.
Hold treatment until toxicity resolves 
to Grade ≤1 or baseline, therapy with 
pembrolizumab may continue while 
endocrine replacement therapy is 
instituted.  
Refer to the ECI Guidance Document 
for supportive care guidance.
Hyperthyroidism
1/2
Continue crizotinib at the same 
dose level
Continue pembrolizumab
3
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then resume treatment at 
the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
Hold treatment until toxicity resolves 
to Grade ≤1 or baseline. 
Discontinue if toxicity does not 
resolves within 12 weeks of last dose 
or inability to reduce corticosteroids to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks.
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
4
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then reduce the dose by 1 
level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Permanently discontinue
pembrolizumab.
Refer to pembrolizumab ECI Guidance 
Document for supportive care.


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Toxicity
Severity 
Grade
Crizotinib 
Dose Modification
Pembrolizumab 
Dose Modificationa,    
Renal Failure or 
Nephritis
1
Continue crizotinib at the same 
dose level
Continue pembrolizumab. Refer to the 
ECI Guidance Document for 
supportive care guidance.
2
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then resume treatment at 
the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
Hold treatment until toxicity resolves 
to Grade ≤1 or baseline.
Discontinue if toxicity does not 
resolves within 12 weeks of last dose 
or inability to reduce corticosteroids to 
≤10 mg of prednisone or equivalent per 
day within 12 weeks
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
3/4
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then reduce the dose by 1 
level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Permanently discontinue
Refer to pembrolizumab ECI Guidance 
Document for supportive care.
a.
Intra-patient pembrolizumab dose modifications are not permitted.  Permanently discontinue 
pembrolizumab for any severe or Grade ≥3 drug-related AE that recurs or any life-threatening treatment 
related adverse event. Re-challenging after delay due to pembrolizumab toxicities may be allowed once for
some specific toxicities as in the ECI document but if it recurs, it will require permanent discontinuation.  
Refer to the ECI Guidance Document for supportive care guidance and Section 5.3.4.2.2.  
b.
Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue pembrolizumab for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
†  Patients who develop Grade 3 or 4 lymphopenia without other dose-limiting events (eg, 
opportunistic infection) may continue study treatment without interruption.
In case toxicity does not resolve to Grade <1 or does not return to baseline within 12 weeks 
after the last dose of either crizotinib or pembrolizumab, either treatment or both may be 
discontinued, after consultation with the Sponsor.  With investigator and Sponsor agreement, 
patients with a laboratory adverse event that remains Grade >2 after 12 weeks may continue 
treatment in the trial only if asymptomatic and controlled. Patients who experience a 
recurrence of the same severe or life-threatening event at the same grade or greater with re-
challenge of either crizotinib or pembrolizumab should be discontinued from the study
treatment after consultation with the Sponsor.
5.3.4.2.1. Immune-Related Adverse Events 
An immune-related adverse event (irAE) may occur after the first dose to several months 
after starting pembrolizumab treatment.  This will need to be monitored by the investigator 
and Sponsor throughout the time that patients remain on the study.  Mild irAEs are treated 
symptomatically and do not require dosing delays or discontinuation.  For irAE management, 
consult Table 8.


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5.3.4.2.2. Supportive Care Guidelines for irAEs Following Pembrolizumab Dosing
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document).  Refer to Table 8 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document.
5.3.4.2.2.1. Pneumonitis 

For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade ≤1, steroid taper should be started and continued over no less than 4 weeks.

For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed.

Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration.
5.3.4.2.2.2. Diarrhea/Colitis 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  

All patients who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade ≥2 diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis.

For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 


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
For Grade 3 or 4 diarrhea/colitis that persists >1 week, treat with IV steroids followed by 
high-dose oral steroids.  

When symptoms improve to Grade ≤1, steroid taper should be started and continued over 
no less than 4 weeks.
5.3.4.2.2.3. Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
5.3.4.2.2.4. Hypophysitis

For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade ≤1, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade ≤1, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
5.3.4.2.2.5. Hyperthyroidism or Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 2 hyperthyroidism and Grade 2, 3 and 4 hypothyroidism events:
For hyperthyroidism, non-selective beta-blockers (eg, propranolol) are suggested as initial 
therapy.

For hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade ≤1, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.


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5.3.4.2.2.6. Hepatic Events
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly).

Treat with IV or oral corticosteroids.
For Grade 3-4 events, 

Treat with intravenous corticosteroids for 24 to 48 hours. 
Monitor liver function tests more frequently until returned to baseline value (consider 
weekly).  When symptoms improve to Grade ≤1, a steroid taper should be started and 
continued over no less than 4 weeks.
5.3.4.2.2.7. Renal Failure or Nephritis

For Grade 2 events, treat with corticosteroids.

For Grade 3-4 events, treat with systemic corticosteroids.
When symptoms improve to Grade ≤1, steroid taper should be started and continued over no 
less than 4 weeks.
5.3.5. Dosing Interruptions
See Table 8 for AEs that require dosing interruptions for crizotinib, respectively. 
Appropriate follow-up assessments should be done until adequate recovery as assessed by the 
investigator.  
Doses may be held as needed until toxicity resolution as described in Section 5.3.4.2 (Table 
8).  Depending on when the AE resolved, an interruption of crizotinib treatment may lead to 
the patient missing all subsequent planned doses within that same cycle or even to delayed
initiation of the subsequent cycle. 
If pembrolizumab is to be held according to toxicities described in Section 5.3.4 (Table 8), 
this will lead to a delay in the initiation of the subsequent cycle or dose modification 
according to Table 5.
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing of crizotinib in that cycle is allowed.  Doses omitted for toxicity are not replaced 
within the same cycle.  Dose modification for pembrolizumab will only involve an increase 
in the time between infusions and will follow the recommendations in Table 8 as the dose 
pembrolizumab cannot be modified.  If the crizotinib dose reduction occurs during the cycle, 
the patient will need to return to the clinical site to receive a new bottle of crizotinib drug 
supply.


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5.3.6. Pembrolizumab Dosing Delays
Pembrolizumab dosing delays should follow the recommendations in Table 8. If the adverse 
events are due to crizotinib (per investigator assessment), pembrolizumab may be continued 
according to the aforementioned tables.  If the adverse events are due to pembrolizumab (per 
investigator assessment), crizotinib may be continued according to the aforementioned tables.
5.3.7. Crizotinib Dosing Reductions
Following dosing interruption or cycle delay due to toxicity, the crizotinib dose may need to 
be reduced when treatment is resumed.  See Table 7 and Table 8 for guidelines.
5.4. Allocation to Treatment
Dose level allocation will be performed by the Sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will
email a complete Registration Form to the designated sponsor study team member.  The 
sponsor will assign a patient identification number, which will be used on all Case Report 
Form (CRF) pages and other study-related documentation or correspondence referencing that 
patient and email to the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

confirmation of the patient’s enrollment;

specification of the dose level for that patient; and 

permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
drug label.
Storage conditions stated in the single reference safety document (SRSD) (eg. IB) will be 
superseded by the storage conditions stated in the labeling. 


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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  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 upon discovery. The site should actively pursue options for 
returning the product to the storage conditions as described in the labeling, 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, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site. 
Site staff will instruct patients on the proper storage requirements for crizotinib. 
5.6. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. Crizotinib must be returned to the 
investigator by the patient.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer,  and all destruction must be adequately documented.
5.7. Concomitant Treatments
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the investigator.
All concomitant treatments, blood products, as well as non-drug interventions received by 
patients from screening until the end of study visit will be recorded on the CRF.  
Concurrent anticancer therapy with agents other than crizotinib and pembrolizumab is not 
allowed. 


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5.7.1. Prohibited Medications When Using Crizotinib
The metabolism of crizotinib is predominantly mediated by the CYP3A isozymes in human 
liver microsomes and hepatocytes.  Coadministration with drugs that are CYP3A inhibitors 
and inducers may change the plasma concentrations of crizotinib in humans.  The concurrent 
use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, telithromycin, 
troleandomycin, saquinavir, voriconazole, and grapefruit or grapefruit juice, are not allowed 
in the study.  The topical use of medications, such as 2% ketoconazole cream, may be 
allowed when discussed with the Sponsor.  The concurrent use of potent CYP3A inducers, 
including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, 
and St. John’s wort, are not allowed in the study.
Coadministration of crizotinib with CYP3A4 substrates with narrow therapeutic indices 
including, but not limited to, dihydroergotamine, ergotamine, pimozide, astemizole*, 
cisapride*, and terfenadine* (* withdrawn from U.S. market) must be avoided from the time 
of the first dose of crizotinib until treatment discontinuation.  
Additionally, the concurrent use of non prescription drugs, complementary medicines 
(excluding vitamins) or herbal supplements is not recommended.
5.7.2. Prohibited Medications When Using Pembrolizumab
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than pembrolizumab.

Radiation therapy (see Section 5.7.3).

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (eg, Flu-Mist®) are live 
attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
Note:  Inhaled steroids are allowed for management of asthma.


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Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Patients may receive other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.7.3. Supportive Care 
Palliative and supportive care for disease-related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.  
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions
provided that the lesions were known at the time of study enrollment and the investigator 
clearly indicates that the need for palliative radiotherapy is not indicative of disease 
progression.  
5.7.4. Hematopoietic Growth Factors
Primary use of granulocyte-colony stimulating factors (G-CSF) or 
erythropoietin/darbopoietin is not permitted during Cycles 1 and 2 of the Dose Finding Phase 
(the DLT evaluation period).  G-CSF may be used to treat treatment emergent neutropenia as 
indicated by the current American Society of Clinical Oncology (ASCO) guidelines.  If 
approved and available for use per country regulations, erythropoietin or darbopoeitin may 
be used at the investigator’s discretion for the supportive treatment of anemia in both the 
Dose Finding and Dose Expansion Phases.
5.7.5. Anti-Emetic, Anti-Diarrheal Therapy
Supportive care including premedication with anti-emetics to limit treatment-related nausea 
and vomiting should be considered as consistent with the IBs of crizotinib and 
pembrolizumab, respectively, and local standards of care.  Patients may receive prophylaxis 
against treatment-induced diarrhea for crizotinib or pembrolizumab.
All patients with diarrhea should be advised to increase oral intake of clear fluids.  If 
sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion.  In particular, for pembrolizumab, patients should be carefully monitored for colitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and for 
bowel perforation (such as peritoneal signs and ileus).  Colitis may be related to crizotinib, 
pembrolizumab or both.  The recommended therapy for colitis is described in Table 8.


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5.7.6. Other Concomitant Medications
Anti-inflammatory or narcotic analgesics may be offered as needed.  Due to the AE of 
hypothyroidism from pembrolizumab, patients in this study may be supported with 
appropriate hormone replacement therapy for hypothyroidism and monitored for any changes 
in thyroid function.
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.
The concurrent use of crizotinib with other bradycardic agents, medicinal products that are 
known to prolong the QT interval, and/or antiarrhythmics should be avoided.
5.7.7. Surgery
5.7.7.1. Crizotinib Guidelines
The effect of crizotinib on wound healing is not known and has not been investigated; 
therefore, caution is advised on theoretical grounds (potential antiangiogenic effect).  In the 
event elective surgery is necessary during study participation, crizotinib dosing should be 
stopped 48 hours before surgery and resumed no sooner than 48 hours after surgery.  
5.7.7.2. Pembrolizumab Guidelines
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy such as elective surgery, unrelated medical events, patient 
vacation and holidays. Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for the 
interruption should be documented..
5.7.8. Pembrolizumab Infusion Reaction
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion Table 9 below shows treatment 
guidelines for patients who experience an infusion reaction associated with administration of 
pembrolizumab.


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Table 9.
Pembrolizumab Infusion Reaction Treatment Guidelines
Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, NSAID, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluid
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the patients is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the infusion rate (eg, from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration.
Patients may be premedicated 
1.5 hour (30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3;
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor of ventilatory 
support indicated
Stop infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Patient is permanently discontinued from further 
trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
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6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see Schedule of Activities and ASSESSMENTS section (Table 1
and Table 3 and Section 7).
6.1.1. Mandatory Tumor Biospecimen
Provision of an archival tumor tissue biospecimen is mandatory for all patients, including 
patients in either the Dose Finding or the Dose Expansion Phases. The archived tumor tissue 
specimen may be from either a primary or a metastatic lesion, and may represent tissue 
obtained at the time of, or subsequent to, the initial diagnosis. The most recently obtained 
archival tissue is preferred.
Archived tumor tissue should be provided as a formalin-fixed, paraffin-embedded (FFPE) 
tumor tissue block containing sufficient tumor tissue to allow if possible for fifteen (15) 
slides each containing a 5-micron tissue section.  If a tissue block cannot be provided, sites 
should try to obtain 15 unstained slides each containing a 5-micron tissue section cut serially 
from the same block. If archived FFPE tissue is not available, every effort should be made to 
collect a de novo (ie, fresh) tumor sample in accordance with local institutional practice for 
tumor biopsies.  Archived or de novo tumor tissue from cytologic sampling (eg, fine needle 
aspiration, including FFPE cell pellet material), is not adequate and should not be submitted
(see Section 7.3.1). Additional information on tumor tissue specimen collection procedures 
is included in the study laboratory manual. Acquisition of the mandatory tumor tissue can be 
completed outside the 28-day screening window.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section
(Table 1, Table 3, Table 2 and Table 4).
6.3. End of Treatment/Withdrawal and Follow-up Visit
For follow-up procedures see Schedule of Activities and ASSESSMENTS section (Table 1
and Table 3 and Section 7).
At least 28 days but no more than 35 days after the last dose of study treatment, patients will 
return to undergo review of concomitant medications, vital signs, body weight, and 
assessment of resolution of any treatment-related toxicity.  Any toxicity that continues should 
be followed at least every 4 weeks until resolution or or new anticancer therapy is started.  
Any irAEs should be reported to the Sponsor up to 12 months after the last dose of 
pembrolizumab, or until a new immunologic therapy is started.
Hematology, Blood Chemistry, and Urinalysis: Required tests are listed in Appendix 1 of 
protocol. 


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Where possible, laboratory tests should be performed preferably at the clinical site’s local 
laboratory, and, when not possible, patients will provide the laboratory test results copy 
(from the non-clinical site laboratory) 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. 
If ALT or AST becomes Grade ≥3 or ALT or AST  Grade ≥2 and total bilirubin Grade ≥2, 
then liver function tests need to be repeated every 48-72 hours until ALT/AST and total 
bilirubin recover to Grade <2.
Patients will be followed for post-study survival every 2 months until death or until 
18 months after enrollment of the last patient, whichever occurs first.  Collection of 
information on subsequent anti-cancer therapy and the patient’s disposition by telephone is 
acceptable.
Once the primary endpoint for the study has been summarized and reported, ongoing patients 
on single-agent crizotinib will only need to visit the clinic every other cycle for study 
assessments instead of every cycle. Hematology and blood chemistry tests are still required 
in the non-visit cycle ie, approximately 3 weeks after previous laboratory testing. Enough 
study medication until the next clinic visit will be dispensed at each clinic visit. During the 
non-visit cycle, patients must telephone the clinical site to provide an update of AEs and 
concomitant medications, and to provide results of the laboratory tests.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site.  
Reasons for withdrawal of study treatment may include:

Objective disease progression; unless the patient is considered to be deriving clinical 
benefit by the investigator;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Refusal of further treatment;

Study terminated by sponsor;


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
Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  Telephone contact is acceptable.  All attempts to contact the patient and information 
received during contact attempts must be documented in the patient’s medical record. In any 
circumstance, every effort should be made to document patient outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the patient return all 
unused crizotinib capsules, request that the patient return for a final visit, if applicable, and 
follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examinations, ECGs, laboratory assessments, including pregnancy tests and verification of 
concomitant treatments.  For details, refer to the SOA –Table 1, Table 3, Table 2 and 
Table 4.
7.1.1. Pregnancy Testing
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 the start of screening and once at the 


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baseline visit, immediately before investigational product administration. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a further negative pregnancy test result will then be required at the baseline visit before 
the patient may receive the investigational product. Pregnancy tests will also be routinely 
repeated at every treatment cycle during the active treatment period, at the end of study 
treatment, and additionally whenever 1 menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  In the case of a positive confirmed pregnacy test, the 
patient will be withdrawn from administration of investigational product and will be 
withdrawn from the study.  
Additional pregnancy tests may also be undertaken if requested by IRB/ECs or if required by 
local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the adverse events CRF page.
7.1.2.1. Events of Clinical Interest (ECI): Pembrolizumab
Events of clinical interest (ECI) are non-serious and serious adverse events that may or may 
not be irAEs. Information on how to identify and report ECIs can be found in the Study
Reference Manual.  
Events of clinical interest for this trial include:
1. An overdose of Sponsor's product, as defined in Section 5.3, Administration, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT values that is ≥3X the upper limit of normal and an elevated 
total bilirubin value that is ≥2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is <2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Study Reference Manual (or equivalent).
A separate guidance document has been provided entitled “MK-3475 Events of Clinical 
Interest and Immune-Related Adverse Event Guidance Document”. This guidance document 
can be found in the Study Reference Manual and provides guidance regarding identification, 
evaluation and management of ECIs and irAEs.  Additional ECIs are identified in this 
guidance document and also need to be reported.


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Patients should be assessed for possible ECIs prior to each dose.  Laboratory results should 
be evaluated and patients should be asked for signs and symptoms suggestive of an immune-
related event.  Patients who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If laboratory results or symptoms 
indicated a possible immune-related ECI then additional testing should be performed to rule 
out other etiologic causes.  If no other cause was found, then it is assumed to be immune-
related.
ECIs that occur to any patient from the date of first dose through 90 days following cessation 
of pembrolizumab treatment, or the initiation of a new anticancer therapy, whichever is 
earlier, whether or not related to the Sponsor's product, must be reported within 24 hours of 
the investigator awareness of the event see Section 8.14. Reporting Requirements. Sponsor 
Contact information can be found in the Study Reference Manual.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the SOA 
(Table 1 and Table 3) and analyzed at local laboratories.
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT
PT or INR
Urine dipstick 
including urine 
protein or urine blood 
at screening only.  If 
positivie collect a 
microscopic (Reflex 
testing)
For female patients 
of childbearing 
potential,  serum or 
urine (to be 
specified in the 
protocol)
Platelets
AST
PTT
WBC
Alk Phos
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Absolute Eosinophils
Chloride
Absolute Basophils
Total Calcium
Total Bilirubin***
BUN or Urea
Creatinine
Uric Acid
Glucose (fasted or 
non-fasted)
Albumin
Phosphorous or 
Phosphate
Thyroid Function 
Tests: TSH, T3, and 
Free T4 
*** For Hy's law potential cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin 
time (PT)/INR, and alkaline phosphatase.  
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examinations to include body weight, vital signs, ECG 
assessments, and height; height will be measured at baseline only.


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7.1.5. ECOG Performance Status
ECOG performance status will be performed at baseline and on Day 1 of each study cycle.
7.1.6. (12-Lead) Electrocardiogram
All patients require a single ECG measurement at screening.  Triplicate ECGs measurements 
(approximately 2 minutes apart) will be measured at all other time points with all 
3 measurements obtained within a 10 minute time window for each timepoint.  ECGs should 
be performed immediately before PK blood draws at respective time points. See Schedule of 
Activities Table 1 and Table 3 for more details.  Additional ECGs will be performed as 
clinically indicated
7.2. Pharmacokinetics Assessments
Plasma/serum samples will be obtained from patients for PK analysis of crizotinib, the 
crizotinib metabolite PF-06260182, pembrolizumab and anti-pembrolizumab-antibodies 
depending on the treatment cohort that they belong to. Serum samples for pembrolizumab
PK
 will be collected from all patients in the study. Plasma samples for crizotinib
PK will be collected from all patients in the Dose Finding Phase and at least 8 patients in the 
Dose Expansion Phase. The PK sampling schedule may be modified based on emerging PK 
data.
7.2.1. Blood Sample Collection for Pharmacokinetic 
 Analysis
Where noted in the Schedule of Activities (SOA – Table 1 and Table 3), blood samples will 
be collected at approximately the same time as other assessments wherever possible. 
Blood samples for crizotinib and PF-06260182 PK, pembrolizumab PK,
 will be 
collected as outlined in Table 2 and Table 4. 
Table 2 indicates PK blood sampling time points for crizotinib given in combination with 
pembrolizumab at DL0, DL-2, and DL-3.  For DL-1 Table 4 indicates PK blood sampling 
time points for when crizotinib is administered alone and in combination with 
pembrolizumab. On the days of crizotinib PK sample collection, patients should be 
instructed to hold morning crizotinib dosing until the pre-dose sample has been drawn. For 
all collections, the actual time of crizotinib and pembrolizumab dosing, as well as actual 
times of PK collections will be recorded in the source documents and CRF. 
In addition to samples collected at the scheduled times, additional blood samples for 
crizotinib concentrations and pembrolizumab concentrations
 should be collected 
from patients experiencing unexpected and/or SAEs.  The date and time of sample collection 
and of last dosing prior to PK collection should be documented in the CRF. All efforts will 
be made to obtain the pharmacokinetic samples at the scheduled nominal time relative to 
dosing. However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) will be considered protocol complaint, and the exact time of the sample 
collection noted on the CRF. If a scheduled blood sample collection cannot be completed for 
any reason, the missed sample collection may be rescheduled with agreement of the clinical 
investigator, patient, and Sponsor.
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PK samples will be assayed for crizotinib, PF-06260182, pembrolizumab
using validated analytical method in compliance with Pfizer standard operating procedures. 
Additional details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the study manual. As part of the understanding of the 
pharmacokinetics of the study drug, samples may be used for potential qualitative and/or 
quantitative metabolite analyses and/or evaluation of the bioanalytical methods for crizotinib, 
pembrolizumab,
 
7.2.2. Collection of Crizotinib PK Samples
At each crizotinib time point, a 3 mL whole blood sample will be collected into an 
appropriately labeled K2EDTA tube to provide a minimum of 1 mL plasma for 
pharmacokinetic analysis.
7.2.2.1. Processing, Storage and Shipment of Crizotinib PK Samples
Special precaution should be taken to minimize crizotinib samples from exposure to visible 
light, which will cause rapid degradation of crizotinib.  The blood collection tube should be 
covered completely immediately after sample collection.  Gently invert the covered tube 
8-10 times to mix the blood with the anticoagulant. Place the tube in an ice bath (2C to 
8C) until sample can be centrifuged.  Centrifuge for 10 to 15 minutes at 1700 x g at 4C or 
lower to separate the plasma. Plasma should be transferred rapidly to an amber cryovial, 
with the collection tube covered during the plasma transfer.  Place plasma aliquot in an ice
bath (2C to 8C) until frozen storage.  Harvested plasma should be frozen within 1 hour of 
collection at -20C or lower in an opaque box to protect from light exposure.  If a sample is 
inadvertently exposed to light (for at least 5 minutes), the sponsor should be notified so that 
the sample can be flagged for possible spurious results.  Once frozen, samples should not be 
allowed to thaw until assayed.
7.2.3. Collection of Pembrolizumab Pharmacokinetic Samples
At each pembrolizumab timepoint, a 3 mL whole blood sample will be collected into an 
appropriately labeled Serum Separator Tube (SST) tube to provide a minimum of 1 mL 
serum for PK analysis.
7.2.3.1. Processing, Storage and Shipment of Pembrolizumab PK Samples
PK sample collection must be from the opposite arm to that used for pembrolizumab
infusion.  If pembrolizumab was administered via a central venous catheter, the sample 
collection should be from a different site. Collect 3 mL of blood into a 3.5 mL SST at the 
designated collection timepoints.  The tube should be inverted 5-6 times without shaking.  
Leave the tube upright at room temperature for 30 minutes but less than 60 minutes to allow 
coagulation.  Centrifuge for 10 to 15 minutes at 1100 to 1300 x g at room temperature until 
clot and serum are separated.  Serum should be aliquoted equally into 2 polypropylene 
cryovials (at least 0.5 mL per aliquot).  Place serum aliquot in an ice bath (2C to 8C) until 
frozen storage.  Serum samples should be frozen within 30 minutes of centrifugation at –
70°C or colder (alternatively –20°C is acceptable for up to 1 month) and maintained in the 
frozen state until assayed.
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7.3. Pharmacodynamic Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3.1. Archival Tumor Tissue and Optional De Novo End of Treatment Tumor Biopsies
 
 
Specifically, tumor expression of PD-L1 will be measured by anti-PD-L1 IHC. 
 
 
 
 
 
 
 
 
The optional end-of-treatment tumor biopsy will also be used to investigate the biomarkers 
described above with the objective being to determine change from pre-treatment baseline to 
begin to define potential mechanisms of resistance to treatment with the combination of 
crizotinib and pembrolizumab.
 
 
 
 
 
 
 
 
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7.4. Tumor Response Assessments
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
then at Week 9 , and every 6 weeks, thereafter, using RECIST v 1.1 (See SOA – Table 1 and
Table 3).  In addition, radiological tumor assessments will also be conducted to confirm a 
best response of CR or PR at ≥4 weeks after initial assessment of response, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of End of 
Treatment/Withdrawal (if not performed in the previous 6 weeks).  In determining whether or 
not the tumor burden has increased or decreased, investigators should consider all target 
lesions as well as non-target lesions and new lesions according to RECIST v 1.1 (see 
Appendix 6). The same imaging technique used to characterize each identified and reported 
lesion at baseline will be employed in the following tumor assessments.
If radiologic imaging shows PD and the patient is perceived to be experiencing clinical 
benefit, repeat tumor assessment is to be performed ≥4 weeks later in order to confirm tumor 
status;  study treatment may be continued at the investigator’s discretion.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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7.6. Patient-Reported Outcomes
Patient-reported lung cancer specific disease/treatment-related symptoms, functioning  and 
global quality of life will be assessed using the European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30),69, 70 and its 
corresponding module for lung cancer (QLQ-LC13).71 The visual disturbances experienced 
by the patient will be characterized using the visual symptom assessment questionnaire 
(VSAQ-ALK).  
Patients will complete the EORTC QLQ-C30, the QLQ-LC13 and VSAQ-ALK on Cycle 1 
Day 1 (baseline)  and Day 1 of each subsequent cycle until End of Treatment/Withdrawal 
The EORTC QLQ-C30, QLQ-LC13 and VSAQ-ALK should be completed by patients prior 
to any testing, treatment, or discussion with the physician or clinic personnel.
7.6.1. EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ-C30 (Version 3.0) and the QLQ-LC13 module (Appendix 3 and
Appendix 4, respectively) are validated and reliable self-report measures.69, 70, 71  The 
EORTC QLQ-C30 consists of 30 questions which assess 5 functional domains (physical, 
role, cognitive, emotional, and social domains); global quality of life and disease/treatment-
related symptoms (fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep 
disturbance, constipation, and diarrhea).69, 70, 71
The QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess the specific 
symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, 
dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer patients 
receiving chemotherapy.71 The EORTC QLQ-C30 and the QLQ-LC13 module require about 
15 minutes to complete and are available in many languages.
7.6.2. VSAQ-ALK
The VSAQ-ALK is a self-report measure that was developed to assess and better understand 
the visual symptoms that some patients reported experiencing upon starting treatment in a 
crizotinib monotherapy trial (Appendix 5). These visual symptoms may include the 
appearance of overlapping shadows and after images; shimmering, flashing or trailing lights; 
strings, streamers, or floaters; as well as hazy or blurry vision.  The VSAQ-ALK consists of 
7 items which assess the frequency, duration, bother, and impact of visual disturbances on 
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activities of daily living.  Translation of the VSAQ-ALK into different languages is 
available.  However, if the VSAQ-ALK is not available in the patient’s preferred language, 
the patient does not need to complete this assessment.  The VSAQ-ALK should take less than 
5 minutes to complete.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for classification 
as an SAE requiring immediate notification to Pfizer or its designated representative.  For all 
AEs, sufficient information should be obtained by the investigator to determine the causality 
of the AE.  The investigator is required to assess causality.  Follow-up by the investigator 
may be required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the 
administration of crizotinib or 90 calendar days after the last administration of 
pembrolizumab, whichever is later, and before initiation of a new anti-cancer treatment.  The 
prolonged follow-up is due to the pharmacokinetic properties of pembrolizumab.  SAEs 
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 SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the sponsor.
AEs (serious and nonserious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
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8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs 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;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;
Worsening of signs and symptoms of the malignancy under study should be reported as AEs
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. 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 AE page, and on the SAE 
form when appropriate.  In the event of medication dosing error, the sponsor should be 
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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(s);

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated adverse event(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 AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing  or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
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;


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
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 5 (see Section 8.8 Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. 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 preexisting ALT OR AST OR total bilirubin values above the ULN, 
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 value ≥2 times the baseline values and ≥3 X ULN, or ≥8 X ULN
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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, 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, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected. Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time, should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs. Such potential Hy’s 
law cases should be reported as SAEs.
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;

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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting
purposes, as defined by the sponsor (see Section 8.14 Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE 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 women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on anSAE Report Form and Exposure During 
Pregnancy (EDP) supplemental form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a 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 AE has occurred and within 24 hours of 
awareness of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer 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
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the 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 AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE Report 
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8.12. Withdrawal Due to Adverse Events (See also the Section on Patient Withdrawal
(Section 6.4))
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient or legally acceptable representative.  In addition, each study patient or 
legally acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames 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 SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE 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 
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8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Analysis sets 
The following patient populations will be assessed:

Safety analysis population: includes all enrolled patients who receive at least 1 dose 
of crizotinib or pembrolizumab. This will also be the primary population for the 
efficacy endpoints of PFS and OS.

DLT-evaluable population: includes all patients enrolled in the Dose Finding Phase 
who are in the safety analysis population, and either experience DLT during the first 
2 cycles, or complete the observation period for the first 2 cycles of treatment.  
Patients who do not receive at least 80% of the planned first 2 cycles of crizotinib 
dosing or both infusions of pembrolizumab within the DLT observation period due to 
reasons other than treatment-related AEs will not be evaluable for DLT.

Response-evaluable population: includes all patients in the safety analysis population
who have an adequate baseline tumor assessment. This will be the primary population 
for the efficacy endpoints of ORR, DR and TTR.

PK analysis population: includes all patients in the safety analysis population who 
have sufficient concentration data to estimate at least 1 of the PK parameters of 
interest.

PRO-evaluable population: includes all patients in the safety analysis population who 
have completed the patient reported questionnaires both at baseline and at least 1 on-
treatment assessment.


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
 
9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose De-escalation/Re-Escalation: mTPI
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation studies that improve its accuracy, efficiency and statistical validity. 
The mTPI design72 uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of 3 dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target probability (pT) rate
(pT = 0.30). If the toxicity rate of the currently used dose level is far smaller than pT, the 
mTPI will recommend escalating the dose level; if it is close to pT, the mTPI will recommend 
continuing at the current dose; if it is far greater than pT, the mTPI will recommend de-
escalating the dose level. These rules are conceptually similar to those used by the
3+3 design, except the decisions of an mTPI design are based on posterior probabilities 
calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose re-escalation 
and de-escalation decisions for different studies with different toxicity parameters. More 
importantly, all the dose re-escalation/de-escalation decisions for a given study can be pre-
calculated under the mTPI design and presented in a 2-way table (see Table 6). Thus, 
compared to other advanced model-based designs published in the literature, the mTPI 
design is logistically less complicated and easier to implement. Recently, a phase 1 study 
based on the mTPI design has been published.73
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the proper-
dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions. Based on the safety 
profile of crizotinib and pembrolizumab, e1 is selected as 0.05, and e2 is selected as 0.03. 
Therefore, the target interval for the DLT rate is (0.25, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions. The under-
dosing interval corresponds to a dose re-escalation (RE), over-dosing corresponds to a dose
de-escalation (D), and proper-dosing corresponds to staying at the current dose (S). Given a 
dosing interval and a probability distribution, the UPM of that dosing interval is defined as 
the probability of a patient belonging to that dosing interval divided by the length of the 
dosing interval. The mTPI design calculates the UPMs for the 3 dosing intervals, and the 
1 with the largest UPM informs the corresponding dose-finding decision, which is the dose 
level to be used for future patients. For example, if the under-dosing interval has the largest 
UPM, the decision will be to escalate, and the next cohort of patients will be treated at the 
next higher dose level. Ji et al.72  have demonstrated that the decision based on UPM is 
optimal in that it minimizes a posterior expected loss (ie, minimizes the chance of making a 
wrong dosing decision). 
CCI


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The Dose Finding Phase of the trial is completed when 10 DLT-evaluable patients have been 
treated at the highest dose associated with a DLT rate <0.33. For this reason, a modification 
has been applied to the original mTPI decision algorythm so that if 4 DLTs are observed at 
any dose level, that dose level is considered unacceptable and never used again in the 
remainder of the study since 4/10 patients with DLTs would be a ≥33% rate. In addition, a 
further modification will allow re-escalatation and exposure of up to 10 patients at the higher 
dose in case of ≤3 out of 10 patients experience DLTs.
In case a de-escalation is required from the initial starting DL0, it is estimated that 
approximately up to 30 DLT-evaluable patients will need to be enrolled to estimate MTD.
9.2.2. Statistical Method for Estimating the MTD
As previously described in Section 9.2.1, the estimated MTD is the highest tested dose level 
with DLT rate <0.33 in 10 DLT-evaluable patients. It is unknown whether higher doses of 
either crizotinib or pembrolizumab result in higher toxicity rates.  But, due to the relatively 
low number of patients that may be potentially allocated to any dose combination, this 
assumption may be violated.
For example, at the end of the study, the dose combination (crizotinib 200 mg BID, 
pembrolizumab 200 mg Q3weeks) may have a higher proportion of DLTs than, say, 
(crizotinib 250 mg BID, pembrolizumab 200 mg Q3weeks), and this variability may be 
simply related to small cohort size alone.  To overcome this potential problem, a bivariate 
isotonic regression is used to smooth the resulting toxicity surface to a monotonically 
increasing one.  The determination of the MTD contour is accomplished using the 
Dykstra-Roberston algorithm.73 Once a monotonically increasing toxicity surface is obtained 
(either observed or smoothed according to the bivariate isotonic regression algorithm), the 
MTD combinations closest to the targeted DLT rate of 0.30 but still <0.33 are calculated.  
Clinical judgment will be exercised in taking forward combinations to the Dose Expansion 
Phase, in case no clear choice exists between more than 1 competing MTD combination. 
While the limited sample size may result in up to 2 dose combinations of equal potential anti-
tumor activity, under the circumstances of this study, likely only 1 will be chosen for the 
Dose Expansion Phase. This decision will be based upon the combination of data related to 
safety, available antitumor activity, and clinical judgment of the investigators and the 
Sponsor
9.3. Sample Size Determination
The sample sizes planned for the study arise from logistic feasibility and past experience with 
Phase 1b studies in Oncology and are not entirely driven by statistical considerations. It is 
expected that approximately 70 patients will be required to achieve all study objectives.
As far as the Dose Finding Phase of this study is concerned, due to the dynamic nature of the 
Bayesian allocation procedure, the sample size of the “Up-and-Down” matrix design using 
the mTPI approach cannot be determined in advance.  It is estimated that 30 DLT evaluable 
patients will be enrolled in the dose escalation stage in order to have a reliable and accurate 
estimate of the MTD and determine the RP2D. 


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Subsequent patients will then enter the Dose Expansion Phase aimed at evaluating safety, 
antitumor activity and PK at the MTD.
The planned sample size for the Dose Expansion Phase is 50 patients (including 10 patients 
from the Dose Finding Phase of the study treated at the MTD).  Fifty patients will allow to 
test the hypothesis that the true 18-month PFS probability is ≥50% vs. 32% for historical 
control (data from the crizotinib arm of Study 10148) with 85% power, an alpha
= 0.05 (1-sided), and based on normal approximation. 
9.4. Efficacy Analysis
Efficacy analyses will be presented in the form of statistical summaries and data listings for 
the Dose Expansion Phase (including the 10 patients from the Dose Finding Phase of the 
study treated at the MTD). For the Dose Finding Phase only data listings will be presented.  
PFS and OS will be analyzed in the safety analysis population, whereas ORR will be 
determined in the response-evaluable population, and DR and TTR will be assessed in the 
subgroup of responding patients.
PFS is defined as the time from the date of the first dose of crizotinib or pembrolizumab to 
first documentation of objective disease progression or to death due to any cause, whichever 
occurs first.  Six, 12, and 18-month PFS probabilities are defined as the probabilities of being 
alive and progression free at 6, 12 and 18 months, respectively, after the first dose of the 
combination treatment based on the Kaplan-Meier estimate.
OS is defined as the time from the date of first dose of crizotinib or pembrolizumab to the 
date of death due to any cause. Twelve and 18-month survival probabilities are defined as 
the probabilities of survival at 12-months and 18-months, respectively, after the first dose of 
the combination treatment based on the Kaplan-Meier estimate.
ORR is defined as the percent of patients with confirmed CR or PR according to RECIST 
v1.1 relative to the response-evaluable population. Confirmed responses are those that 
persist on repeat tumor assessments for at least 4 weeks after initial documentation of
response.  
DR is defined as the time from the first documentation of objective tumor response (CR or 
PR) that is subsequently confirmed to the first documentation of objective disease 
progression or to death due to any cause, whichever occurs first. 
TTR is defined as the time from the date of first dose of crizotinib or pembrolizumab to first 
documentation of objective tumor response (CR or PR) that is subsequently confirmed
PFS, OS, and DR will be analyzed by the Kaplan-Meier method while TTR will be 
summarized with descriptive statistics. Best overall response (BOR) will be summarized and 
ORR will be calculated along with the corresponding exact 2-sided 95% confidence intervals 
using the exact method based on the F-distribution. 


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9.5. Analysis of Pharmacokinetics and Pharmacodynamics
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Pharmacokinetic Analysis of Crizotinib and Pembrolizumab
Standard plasma PK parameters for crizotinib will be estimated using non-compartmental 
analysis. For crizotinib, standard PK parameters will include; Cmax, Tmax, Ctrough, AUC0-8, 
AUCtau , and oral plasma clearance (CL/F). For PF-06260182 PK parameters will include; 
Cmax, Tmax, Ctrough, AUC0-8, AUCtau, MRAUCtau, and MRCmax. Descriptive statistics for the 
PK parameters for crizotinib and PF-06260182 will be provided by dose level, cycle and day 
of assessment in tabular form. 
All plasma/serum concentrations will be summarized descriptively (n, mean, SD, CV, 
median, minimum, maximum, geometric mean, its associated CV, and 95% confidence 
interval) by dose level, cycle, day and nominal time. Individual patient and median profiles 
of the concentration-time data will be plotted by dose level, cycle and day using nominal 
times. Median profiles will be presented on both linear-linear and log-linear scales.
Trough concentrations for pembrolizumab will be plotted for each dose using a box-whisker 
plot by cycle and day in order to assess the attainment of steady-state.
In addition, Non-linear Mixed Effects Modeling (NONMEM) approaches will be explored to 
further describe the PK profile of pembrolizumab in combination with criztoinib(See also 
Section 9.5.1.4).
9.5.1.2. Effect of Pembrolizumab on Crizotinib Pharmacokinetics
For DL-1, the effect of pembrolizumab on crizotinib PK will be evaluated using steady-state 
crizotinib AUCtau and Cmax after crizotinib is administered as a single agent (Cycle -1 
Day 15, Reference) and in combination with  pembrolizumab (Cycle 6 Day 1, Test), 
respectively, as the primary pharmacokinetic parameters.  The AUCtau and Cmax will be log 
transformed and analyzed using a mixed effect model with treatment as the fixed effect and 
patient as the random effect.  Ninety percent confidence interval for the ratio of geometric 
means of AUCtau and Cmax (crizotinib + pembrolizumab/ crizotinib  alone) will be computed 
to assess the effect magnitude.For the other dose levels that do not incorporate a crizotinib 
lead-in period, the effect of repeated pembrolizumab doses on crizotinib PK will be evaluated 
by comparing the steady-state crizotinib and PF-06260182 PK to that observed in prior 
single-agent crizotinib studies.
 
CCI
CCI


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9.5.2. Analysis of Patient-Reported Outcomes 
The PRO-evaluable population will be the primary population for the analysis of PROs. 
Change from baseline scores over treatment will be evaluated in the PRO evaluable 
population.  
At each time point, the number and percentage of patients who completed the QLQ-C30, 
QLQ-LC13 and VSAQ-ALK will be summarized.  A questionnaire is considered complete if 
at least 1 item was answered by the patient.  Scoring and handling of missing data for the 
EORTC QLQ-C30 and QLQ-LC-13 was implemented in line with the scoring manual.72  
Summary statistics (mean, standard deviation, median, range, and 95% CI) of actual scores 
and change from baseline at each time point will calculated for all scales of the EORTC 
QLQ-C30 and QLQ-LC13 scores.  The number and proportion of patients who improved, 
worsened, or remained stable as compared to baseline will also be summarized for all of the 
symptom and functional domains, global QOL, and single items of the EORTC QLQ-C30 
and QLQ-LC-13.  If less than half of the constituent items on the QLQ-C30 and QLQ-LC13
have been answered for a multi-item subscale, that subscale will be considered missing. 
Single-item subscales will be considered missing if the constituent item is incomplete. For 
the VSAQ-ALK questions not answered will be considered missing items and will not be 
utilized.
Frequency analyses will be performed and reported for each item of the VSAQ.
 
 
 
 
 
 
 
 
 
 
 
9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the DLT-evaluable  
analysis population. All other summaries and analyses of safety parameters will be based on
the safety analysis population. Safety data will be summarized by dose level using 
appropriate tabulations and descriptive statistics (pooling together patients treated at the 
CCI


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MTD from both phases of the study). If applicable, safety data collected during 
the crizotinib lead-in period for patients who are treated at DL-1 will be reported
separately.  
9.6.1. Primary Endpoint Analysis
The occurrence of DLTs observed in the Dose Finding Phase will be used to estimate the 
MTD as described in (Section 3.3 and Section 9.2.1).  Adverse events meeting the DLT
definition in Section 3.2 will be listed per dose level.  The RP2D will be based upon a DLT 
rate <33% as well as the tolerance of the dose in the Dose Expansion Phase.
9.6.2. Secondary Safety Endpoint Analysis
9.6.2.1. Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the NCI CTCAE 
version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
The focus of AE summaries will be on treatment-emergent AEs, those with initial onset or 
increasing in severity after the first dose of study treatment.  The number and percentage of 
patients who experienced any treatment-emergent AE, treatment-emergent SAE, treatment-
related AE, and treatment-related SAE will be summarized according to worst toxicity 
grades.  The summaries will present AEs both on the entire study period and by cycle 
(Cycle 1, Cycle 2, and Cycles ≥2).  In DL-1, the summaries will present AEs during the lead-
in period, overall, and by cycle (Cycle 1, Cycle 2, and Cycles ≥2).
9.6.2.2. Laboratory Tests Abnormalities
The number and percentage of patients who experience laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests during the lead-in period (only applicable to DL-1), 
overall, and by cycle (Cycle 1, Cycle 2, and Cycles ≥2).  Shift tables will be provided to 
examine the distribution of laboratory abnormalities.
For laboratory tests without CTCAE Grade definitions, results will be categorized as normal, 
abnormal, or not done.   
9.6.3. Electrocardiograms
The analysis of ECG results will be based on data collected during the first 3 cycles in all 
patients except in DL-1 where ECG collection will be performed during the crizotinib lead-in
period.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.


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QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s [QTcF; default correction], or Bazett’s [QTcB]).  Data will be summarized and 
listed for  HR, RR interval, PR interval, QRS complex, QTcF and QTcB, and by dose level.  
Categorical analysis of the ECG parameters will be performed as follows:

The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (<30, 30- 60, and ≥60 ms).

The number of and percentage patients with maximum post-dose QTcF/QTcB 
(<450, 450-<480, 480- <500, and ≥500 ms).

PR changes from baseline ≥50% if absolute baseline value was <200 ms, and ≥25% if 
absolute baseline value was ≥200 ms.

QRS changes from baseline ≥50% if absolute baseline value was <100 ms, and ≥25% 
if absolute baseline value was ≥100 ms.
Shift tables will be provided for baseline vs. worst on treatment for QTcF and QTcB using 
maximum CTCAE Grade.
9.6.4. Vital signs
Vital signs will be categorized according to the maximum/minimum change from baseline 
and/or according to the maximum/minimum values on treatment.  
9.7. Data Safety Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for this study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases. Procedures include:

Surveillance for SAEs according to regulatory guidelines;

Discussions between the investigators and the sponsor of AEs and laboratory test
alterations, vital signs, and ECGs abnormalities observed at each dose level in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety 
profile and benefit/risk ratio to decide if further enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion.


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During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
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 will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative 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.


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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, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board /Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.


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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 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 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 must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements,  the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse) and that the patient’s assent was obtained, or waived.  If assent is obtained verbally it 
must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative, before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent document.


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12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.  
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
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 that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as the last patient last visit in the 
Dose Expansion Phase of the study.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of
combination crizotinib and pembrolizumab at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 7 business days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer 
product.However, to ensure against inadvertent disclosure of confidential information or 
unprotected inventions, the investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure of the results of the study (collectively, 
“Publication”) before it is submitted or otherwise disclosed.


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The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the  
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Galluzzi L, Senovilla L, Zitvogel L, et al. The secret ally: immunostimulation by 
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Talmadge JE, Donkor M and Scholar E. Inflammatory cell infiltration of tumors: Jekyll 
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Usubütün A, Ayhan A, Uygar MC, et al. Prognostic factors in renal cell carcinoma. J 
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17. APPENDICES
Appendix 1. Required Laboratory Tests 
Conventional Units
Conversion Factor
SI Units
Hematology
Hemoglobin (Hgb)
g/dL
x 10
g/L
Platelet count (Plt)
103/mm3
x 109
1012/L
White blood count (WBC)
103/mm3
x 106
109/L
White blood cell differential
%
x 0.01
fraction
Chemistry
Total bilirubin
mg/dL
x 17.1
mol/L
Alanine aminotransferase (ALT)
U/L
N/A
U/L
Aspartate aminotransferase (AST)
U/L
N/A
U/L
Alkaline phosphatase
U/L
N/A
U/L
Total protein
g/dL
x 10
g/L
Albumin
g/dL
x 10
g/L
Sodium
MEq/L
x 1.0
mmol/L
Potassium
MEq/L
x 1.0
mmol/L
Chloride
MEq/L
x 1.0
mmol/L
Calcium
mg/dL
x 0.25
mmol/L
Phosphorus
mg/dL
x 0.323
mmol/L
Blood urea nitrogen (BUN)*
mg/dL
x 0.357
mmol/L
Urea*
Na
Na
mmol/L
Creatinine
mg/dL
x 88.4
mol/L
Uric acid
mg/dL
x 0.059
mmol/L
Magnesium
mg/dL
x 0.41
mmol/L
Glucose
mg/dL
x 0.055
mmol/L
LDH 
U/L
N/A
U/L
Urinalysis
Microscopy and Dipstick for Protein/ Blood
(unitless)
N/A
(unitless)
For France only: FibroTest*
(unitless)
N/A
(unitless)
Coagulation
Protime INR
(unitless)
N/A
(unitless)
* either/or
In cases of suspected Drug-Induced Liver 
Injury (DILI) - values eventually to be 
reported on SAE form and eCRF AE page 
if appropriate
Creatine kinase  (aka CPK)
U/L
N/A
U/L
Indirect bilirubin
mg/dL
x 17.1
mol/L
Direct bilirubin
mg/dL
x 17.1
mol/L
Gamma-glutamyl transferase (GGT)
U/L
N/A
U/L
Acetaminophen  level
g/mL
6.62
mol/L
Thyroid Functions
TSH
µU/mL
T3
Pg/dL
Free T4
ng/dL
* For France only, FibroTest: the FibroTest score is calculated from the results of the following blood tests: Alpha-2 
macroglobulin, Haptoglobulin, Apolipoprotein A1, Gamma-glutamyl transpeptidase (GGT), Total bilirubin, and ALT.


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


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Appendix 3. EORTC QLQ-C30 Questionnaire


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Appendix 4. EORTC QLQ-LC13 Questionnaire


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Appendix 5. Visual Symptom Assessment Questionnaire (VSAQ-ALK)  
We would like to ask some questions about problems you may be experiencing with your eyesight. These 
problems are called visual disturbances and may include but are not limited to the appearance of the 
following: overlapping shadows or after images; shimmering, flashing or trailing lights; streamers, strings, 
or floaters in your peripheral vision; as well as hazy or blurry vision.
Please select the response that best applies to your experience of visual disturbances in the past three weeks. 
1)   In the past three weeks, have you experienced any visual disturbances? 
 Yes        If yes go to Question 2.
 No
      If no, thank you and please return the questionnaire. 
2)  In the past three weeks, how often did you experience a visual disturbance? 
 One day a week or less often. 
 Two or three days a week. 
 Four to six days a week. 
 Seven days a week.
3)   In the past three weeks, when did you experience a visual disturbance? (Check all that apply)
 Morning.
 Afternoon (from 12 PM -4 PM).
 Evening.
4)   In the past three weeks, how long did each visual disturbance last on average? (Check only one)  
  30 seconds or less.  
   More than 30 seconds but not longer than one minute. 
   More than one minute but not longer than five minutes. 
   More than five minutes but not longer than ten minutes. 
   More than ten minutes. 
   Don’t remember. 
5)   In the past three weeks, how often did you experience a visual disturbance when adjusting to changes 
in lighting (eg, coming indoors on a bright sunny day)? 
 Never.
 Rarely.
 Sometimes. 
 Often.
 Always.


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6)   In the past three weeks, how much have you been bothered by. . . (Check one box on each line below):
Did not 
experience Not at all
A little
Moderately Quite a bit
Extremely 
a. Visual disturbances? 
□
□
□
□
□
□
 b. Appearance of overlapping 
shadows or after images?
□
□
□
□
□
□
c. Appearance of shimmering, 
flashing, or trailing lights?
□
□
□
□
□
□
d. Appearance of streamers, strings, 
or floaters? 
□
□
□
□
□
□
e. Difficulty seeing at night? 
□
□
□
□
□
□
f. Hazy or blurry vision?
□
□
□
□
□
□
g. Difficulty adapting to bright lights 
(e.g., going out on a bright day)?
□
□
□
□
□
□
h. Difficulty adapting to dim light (eg,
entering a darkened room)?
  □ 
    □        □        □         □          □
7)   During the past three weeks, how much did visual disturbances affect your ability to do your regular 
daily activities?
By regular activities, we mean the usual activities you do, such as work around the house, shopping, child care, 
exercising, studying, etc.  Think about times you were limited in the amount or kind of activities you could do 
and times you accomplished less than you would like.  If visual disturbances affected your activities only a little, 
choose a low number.  Choose a high number if visual disturbances affected your activities a great deal.
Visual 
disturbances had 
no effect on my 
daily activities
Consider only how much visual disturbances affected
your ability to do your regular daily activities
Visual disturbances 
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER


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Appendix 6. RECIST version 1.1 Tumor Assessment Criteria
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below (see Table 11):
Measurable Lesions
Lesions that can be accurately measured in at least 1 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 1 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 1 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 1 or more new lesions is also considered 
progression).
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or stable disease and progressive 
disease.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF.  Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF. 
New Lesions 
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
The use of FDG-PET is sometimes reasonable to complement a CT scan assessment of a PD 
(particularly for possible ‘new’ disease).  New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm: 

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up. 

No FDG-PET at baseline and a positive FDG-PET at follow-up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.


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Final Protocol, 22 April 2015  
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Confirmation of Tumor Response 
Confirmation of response is required for non-randomized trials with primary endpoint of 
response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data.
Determination of Overall Response by RECIST v1.1
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 11.
Table 11.
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).


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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.

SAP_001.pdf: 
Protocol A8081054
Statistical Analysis Plan
Page 1
PROTOCOL A8081054
A PHASE 1B STUDY OF CRIZOTINIB IN COMBINATION WITH 
PEMBROLIZUMAB (MK-3475) IN PATIENTS WITH UNTREATED ADVANCED 
ALK-TRANSLOCATED NON-SMALL CELL LUNG CANCER
Statistical Analysis Plan
(SAP)
Version: 1.0
Author: 
Date: June 26, 2015
PPD


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Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................5
2.2.1. Primary Objective.........................................................................................5
2.2.2. Secondary Objectives ...................................................................................5
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING.................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS SETS .................................................................................................................7
5.1. Safety Analysis Set....................................................................................................7
5.2. Per Protocol Analysis Set (DLT-evaluable population)............................................7
5.3. Response Evaluable Analysis Set .............................................................................7
5.4. PK Analysis Set.........................................................................................................7
5.5. PRO Analysis Set......................................................................................................8
5.7. Treatment Misallocations..........................................................................................8
5.8. Protocol Deviations...................................................................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoints ....................................................................................................8
6.2. Safety Endpoints .....................................................................................................11
6.2.1. Dose Limiting Toxicity (DLT) (Primary Endpoint for Dose Finding 
Cohorts)............................................................................................................11
6.2.2. Adverse Events...........................................................................................11
6.2.3. Laboratory Abnormalities...........................................................................11
6.2.4. Other Safety Endpoints...............................................................................11
6.3. PK Endpoints...........................................................................................................11
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6.5. PRO Endpoints........................................................................................................12
6.6. Covariates................................................................................................................12
7. HANDLING OF MISSING VALUES ................................................................................13
7.1. Missing Dates..........................................................................................................13
7.2. Missing Efficacy Endpoint Values..........................................................................13
7.3. Pharmacokinetics ....................................................................................................13
7.5. Patient Reported Outcomes.....................................................................................14
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................14
8.1. Statistical Methods ..................................................................................................14
8.1.1. Statistical Methods for Dose De-Escalation: Up-and-Down Matrix 
Design with the mTPI Method.........................................................................14
8.1.2. Methods for Estimating the MTD...............................................................16
8.1.3. Sample Size Determination ........................................................................16
8.2. Statistical Methods for Different Types of Endpoints ............................................17
8.3. Statistical Analyses .................................................................................................17
8.3.1. Standard Analyses ......................................................................................17
8.3.2. Analysis of Efficacy Endpoints ..................................................................18
8.3.3. Analysis of Safety Endpoints......................................................................19
8.3.3.1. Analysis of Primary Endpoint...................................................19
8.3.3.2. Analysis of Secondary Safety Endpoint....................................19
8.3.4. Analysis of Pharmacokinetics.....................................................................23
8.3.4.1. Pharmacokinetic Analysis of Crizotinib and 
Pembrolizumab..................................................................................23
8.3.4.2. Effect of Pembrolizumab on Crizotinib Pharmacokinetics.......24
8.3.5. Analysis of Patient-Reported Outcomes.....................................................25
8.4. Summary of Secondary Efficacy Analyses.............................................................28
9. REFERENCES ....................................................................................................................29
10. APPENDICES ...................................................................................................................30
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LIST OF TABLES
Table 1.
Response Evaluation Criteria in Solid Tumors ....................................................38
APPENDICES
Appendix 1. Programming Specifications for AE Analyses ...................................................30
Appendix 2. Study Specific Information for Efficacy.............................................................34
Appendix 3. RECIST 1.1.........................................................................................................35
Appendix 4. Detailed Dose Re-Escalation/De-Escalation Scheme .........................................39
Appendix 5. Visit Windows for the analysis of PRO endpoints..............................................40


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Not applicable.
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol A8081054.  This 
analysis plan is meant to supplement the study protocol. In this document, any text taken 
directly from the protocol is italicized. 
Any deviations from this analysis plan will be described in the Clinical Study Report. 
2.1. Study Design
This is a Phase 1b, open-label, multicenter, multiple-dose, dose-finding, safety, and 
pharmacokinetic study of crizotinib in combination with pembrolizumab in sequential 
cohorts of adult patients with previously untreated ALK-positive advanced NSCLC with 
2 phases (Dose Finding Phase and Dose Expansion Phase).  
Approximately 70 total patients are expected to be enrolled in this study.  The first phase of 
the study, the Dose Finding Phase, will utilize the mTPI method to determine the MTD of the 
combination regimen.  The second phase, the Dose Expansion Phase, will further evaluate 
the combination regimen at the MTD to determine whether or not the MTD will also be the 
RP2D. The Dose Finding Phase of the trial will be completed when 10 DLT-evaluable 
patients have been treated at the highest DL associated with a DLT rate of <0.33 Crizotinib 
will be given orally (PO) either BID or QD, with or without food on a continuous daily 
dosing schedule.  Pembrolizumab will be given as a 30-minute intravenous (IV) infusion 
Q3-weeks.  Patients will continue with combination crizotinib and pembrolizumab treatment 
until RECIST-defined progression of disease and investigator decision that the patient is no 
longer experiencing clinical benefit, or unacceptable toxicity, death, or consent withdrawal, 
whichever occurs first.  
2.2. Study Objectives 
2.2.1. Primary Objective

To assess safety and tolerability of crizotinib in combination with pembrolizumab 
in the first-line treatment of patients with ALK-positive advanced non-squamous 
NSCLC in order to identify the Maximum Tolerated Dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 
2.2.2. Secondary Objectives

To evaluate the overall safety profile of crizotinib in combination with 
pembrolizumab;

To document the anti-tumor activity of crizotinib in combination with 
pembrolizumab in previously untreated ALK-positive advanced NSCLC patients;

To characterize the pharmacokinetics (PK) of crizotinib and pembrolizumab and to 
assess the effect of pembrolizumab on the PK of crizotinib;


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
To evaluate tumor PD-L1 expression, as assessed by PD-L1 immunohistochemistry, 
as a predictor of anti-tumor activity.
 
 
 
 

To evaluate the impact of combination therapy of crizotinib and pembrolizumab on 
patient-reported lung cancer symptoms (such as dyspnea, cough and pain) and 
global Quality of Life (QOL) per the validated cancer specific EORTC QLQ-C30, 
and its lung cancer module, QLQ-LC-13, and visual symptoms per the Visual 
Symptom Assessment Questionnaire (VSAQ-ALK).
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING
This is an open label, single-arm trial for which no formal interim analysis is planned.  The 
final analysis of efficacy will be performed approximately 18 months after enrollment of the
last patient; however, earlier analyses of the data may be performed for publication and 
regulatory reporting purposes.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The emphasis of the final analyses will be on estimation of key summary statistics rather than 
hypothesis testing.
4.2. Statistical Decision Rules
Up-and-Down Matrix Design with the mTPI Method
The dose escalation/de-escalation rules will follow the modified toxicity probability interval 
(mTPI) method (see Section 8 for a detailed description).  Briefly, the mTPI method relies 
upon a statistical probability algorithm, calculated using data from all patients treated at the 
same dose level (and not simply those in the current cohort) to determine whether future
cohorts should involve dose de-escalation, no change in dose, or dose escalation.
Maximum Tolerated Dose Definition
The MTD estimate is the highest dose of crizotinib and pembrolizumab associated with the
occurrence of DLTs in <33% of previously untreated ALK-positive advanced NSCLC
patients.
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Dose Expansion Phase Cohort
Once the MTD (or the RP2D) for the combination has been defined, up to additional 
40 patients with previously untreated ALK-positive advanced NSCLC will be enrolled and 
treated in the Expansion Phase (for a total of 50 patients treated at the MTD).  The expansion
phase will confirm the safety and tolerability as well as explore the anti-tumor activity of
crizotinib in combination with pembrolizumab in patients with previously untreated 
ALK-positive advanced NSCLC.
5. ANALYSIS SETS
5.1. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least 1 dose of crizotinib 
or pembrolizumab.  This is the primary population for all standard analyses and is also the 
primary population for the efficacy endpoints of PFS and OS.  
5.2. Per Protocol Analysis Set (DLT-evaluable population)
The per protocol analysis set includes all patients enrolled in the Dose Finding Phase who are 
in the safety analysis population, and either experience DLT during the first 2 cycles, or 
complete the observation period for the first 2 cycles of treatment.  Patients who do not 
receive at least 80% of the planned first 2 cycles of crizotinib dosing or both infusions of 
pembrolizumab within the DLT observation period due to reasons other than treatment-
related AEs will not be evaluable for DLT.
5.3. Response Evaluable Analysis Set
The response-evaluable population includes all patients in the safety analysis population who 
have an adequate baseline tumor assessment. This is the primary population for the efficacy 
endpoints of ORR, DR and TTR.
In addition, at any interim reporting of the data, patients also need to meet one of the 
following 2 criteria:

have at least one post-baseline disease assessment

withdraw from the trial or experience progression/death at any time on study
The post-baseline disease assessment must be at least 6 weeks from first dose
(Cycle 1 Day 1)
5.4. PK Analysis Set
The PK concentration population is defined as all patients in the safety analysis population 
who have at least 1 concentration of crizotinib, its metabolite PF-06260182, or 
pembrolizumab. 


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The PK parameter analysis population is defined as all patients in the safety analysis 
population who have at least 1 of the PK parameters of crizotinib, its metabolite 
PF-06260182, or pembrolizumab.
5.5. PRO Analysis Set
The PRO-evaluable population includes all patients in the safety analysis population who 
complete the patient reported questionnaires for at least one of the item both at baseline and 
at least 1 post baseline assessment.
 
 
 
 
 
5.7. Treatment Misallocations
Not applicable.
5.8. Protocol Deviations
The full list of protocol deviations will be compiled and presented in the study report.  All 
deviations related to the statistical analyses or analyses populations will be described.  As 
appropriate, sensitivity analyses may be conducted by excluding patients with specific 
protocol deviations.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints 
Investigator assessment of tumor response will be made using RECIST version 1.1.3
Tumor assessments will include all known or suspected disease sites.  Imaging will include 
chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scans for patients with known 
or suspected brain metastases; bone scans for patients with known or suspected bone 
metastases.
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The same imaging technique used to characterize each identified and reported lesion at 
baseline should be employed in the following tumor assessments.
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
then at Week 9, and every 6 weeks, thereafter.  In addition, radiological tumor assessments 
will also be conducted to confirm a best response of CR or PR at ≥4 weeks after initial 
assessment of response, whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the time of End of Treatment/Withdrawal (if not performed in the 
previous 6 weeks.
The primary efficacy summaries of tumor related data for this study will be based on a
programmatic approach to derive tumor response/progression, using RECIST version 1.1.3
As described in Appendix 3 of this document, the derived tumor assessment will be based on 
the target lesion measurements, non-target lesion assessments, and new lesion records 
provided by the Investigator. 

Progression Free Survival (PFS) is defined as the time from the date of the first 
dose of crizotinib or pembrolizumab to the date of the first documentation of 
objective tumor progression or death on-study due to any cause, whichever occurs 
first. If tumor progression data include more than 1 date, the first date will be used. 
PFS (in months) will be calculated as (first event date − first dose date +1)/30.44.
PFS will be summarized in the safety analysis population
Patients with inadequate baseline assessments (adequate baseline is defined in 
Appendix 2) will have their event time censored on the date of first dose.  Patients 
lacking an evaluation of tumor response after the date of the first dose or for whom the 
first on-study assessment of disease progression occurs after Week 17 (the first 2 tumor 
assessments + 2 weeks of allowance window), will also have their event time censored on 
the date of first dose unless death occurs within (and including) Week 17 (in which case 
the death is an event)
If patients have at least 1 on-study disease assessment, PFS data will be censored on the 
date of the last evaluable tumor assessment documenting absence of progressive disease 
for patients:

Who are alive, on study and progression free at the time of the analysis;

Who discontinue treatment without documented disease progression and who 
do not die on study;

Who have documentation of disease progression or death on study after 
2, consecutive missed tumor assessments (ie, >14 weeks after last on-study 
tumor assessment, 2 tumor assessments + 2 weeks of allowance window);

Who are given anti-tumor treatment other than the study medication while on 
study and prior to documented disease progression or death on study.  In this 
case, the last evaluable tumor assessment prior to start of the anti-tumor 


Protocol A8081054
Statistical Analysis Plan
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treatment will be used.  One exception to this rule is for patients who have 
documented PD or death within (and including) 14 days of anti-tumor 
treatment, in which case, the PD or death will be considered an event.

Eighteen-month PFS is defined as the probability of being alive and progression-
free at 18 months after the date of first dose based on the Kaplan Meier2 estimate. 
The 18-month PFS rate is summarized as a product limit estimator based on the 
Kaplan-Meier method to account for censored events. Six-month and 12-month
PFS are defined similarly. 

Objective Response Rate (ORR) is defined as the percent of patients with 
confirmed complete response (CR) or confirmed partial response (PR) according to 
RECIST v1.1, (Appendix 3) relative to the response evaluable population. 
Confirmed responses are those that persist on repeat imaging study at least 4 weeks 
after initial documentation of response. Patients who do not have on-study 
radiographic tumor re-evaluation or who die, progress, or drop out for any reason 
prior to reaching a CR or PR will be counted as non-responders in the assessment 
of ORR.  A patient who initially meets the criteria for a PR and then subsequently 
becomes a confirmed CR will be assigned a best response of CR.

Time to Response (TTR) is defined as the time from first dose of crizotinib or 
pembrolizumab to the first documentation of objective tumor response (CR or PR) 
that is subsequently confirmed.  TTR will only be calculated for the subgroup of 
patients with a confirmed objective tumor response.
TTR (weeks) = [first date of Objective response (OR) – date of first dose +1]/7.02

Duration of Response (DR) is defined as the time from first documentation of 
objective tumor response (CR or PR) that is subsequently confirmed, to the first 
documentation of objective tumor progression or to death on study due to any 
cause, whichever occurs first. If tumor progression data include more than 1 date, 
the first date will be used.  Censoring for DR is identical to the censoring rules 
presented for PFS when patients have at least 1 on-study disease assessment. DR 
will only be calculated for the subgroup of patients with a confirmed objective 
tumor response.
DR (weeks) = [progression/death date – first date of OR +1]/7.02

Overall Survival (OS) is defined as the time from the first dose of crizotinib or 
pembrolizumab to the date of death due to any cause. OS will be summarized in 
the safety analysis population.  For patients still alive at the time of the analysis, the 
OS time will be censored on the last date they were known to be alive.  Patients 
lacking data beyond the day of first dose of study treatment will have their survival 
times censored at 1 day.
OS (months) = [date of death – date of first dose +1]/30.44


Protocol A8081054
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
Eighteen-month OS is defined as the probability of being alive at 18 months after 
the date of first dose based on the Kaplan Meier estimate. The 18-month OS rate is 
summarized as a product limit estimator based on the Kaplan-Meier method to 
account for censored events. Twelve-months OS is defined similarly.
6.2. Safety Endpoints
6.2.1. Dose Limiting Toxicity (DLT) (Primary Endpoint for Dose Finding Cohorts)
Severity of AEs will be graded according to NCI CTCAE v 4.03. AEs meeting one of the 
definition criteria in Study Protocol Section 3.2 and occurring in the first 2 cycles of 
treatment (6 weeks) which are attributable to crizotinib, pembrolizumab or both will be 
classified as DLTs
6.2.2. Adverse Events
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 4.03),
timing, seriousness and relationship to study treatment.
Treatment Emergent Adverse Events
The focus of AE summaries will be on treatment-emergent AEs, those with initial onset or 
increasing in severity after the first dose of study treatment, through and including 
28 calendar days after the last administration of crizotinib or 90 calendar days after the last 
administration of pembrolizumab, whichever is later, and before initiation of a new anti-
cancer treatment.
Treatment Related Adverse Events
Treatment-related AEs are those judged by the Investigator to be at least possibly related to 
the study drugs (crizotinib and/or pembrolizumab) [with a cause related to study drug as
indicated on the case report form (CRF)], or for which relatedness is recorded as “unknown” 
by the Investigator. 
6.2.3. Laboratory Abnormalities
Laboratory abnormalities will be characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing. For laboratory tests without NCI CTCAE Grade 
definitions, results will be categorized as normal, abnormal, or not done.
6.2.4. Other Safety Endpoints
Descriptive statistics and categorical analyses will be presented for ECG results and vital 
signs data.
6.3. PK Endpoints
The following PK parameters of crizotinib, its metabolite PF-06260182, and pembrolizumab 
will be determined as data permits: 


Protocol A8081054
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
Maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax), pre-dose concentration (Ctrough), area under the plasma concentration time 
curve from 0 to 8 hours (AUC0-8), area under the plasma concentration time curve 
over the dosing interval (AUCtau), and apparent plasma clearance (CL/F) for 
crizotinib; 

Cmax, Tmax, Ctrough, AUC0-8, AUCtau, metabolite to parent ratio for AUCtau 
(MRAUCtau), and metabolite to parent ratio for Cmax (MRCmax) for PF-06260182;

Ctrough for pembrolizumab;

Population-based PK parameters for crizotinib and pembrolizumab (if performed, 
will be presented in a separate report); 

 
 
 
 
 
6.5. PRO Endpoints

Overall change from baseline patient-reported lung cancer symptom, functioning, 
and global QOL scores using the EORTC QLQ-C30 and QLQ-LC-13 
questionnaires;

Frequency of occurrence and degree of bothersomeness of visual disturbances as 
reported by the patients on the VSAQ-ALK questionnaire.
6.6. Covariates
None.
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7. HANDLING OF MISSING VALUES
7.1. Missing Dates
In compliance with Pfizer standards, imputation methods apply to partial dates.  If the day of 
the month is missing for a start date used in a calculation, the 1st of the month will be used to 
replace the missing date.  Similarly, if both the day and month are missing, the first day of 
the year is used.  For stop dates, the last day of the month, or last day of the year is used if the 
day or both day and month are missing, respectively.  These rules are used unless the 
calculations result in negative time durations (eg, date of resolution cannot be prior to date of 
onset).  In these cases, the dates resulting in 0 time duration will be used. For PFS, TTR, DR
and OS, if conventions result in a negative duration, durations will be reset to 1 day.
7.2. Missing Efficacy Endpoint Values
For all efficacy analyses no values will be imputed for missing data, except as specified in 
Section 6.1, where for time to event endpoints, non-event observations will be censored and 
for ORR, patients with no post-baseline tumor evaluations will be counted as non-responders.  
7.3. Pharmacokinetics
Concentrations below the limit of quantification:
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In 
log-linear plots these values would not be represented. The BLQ values will be excluded 
from calculations of geometric means and their confidence intervals. A statement similar to 
“all values reported as BLQ have been replaced with zero” will be included as a footnote to 
the appropriate tables and figures.
Deviations, missing concentrations and anomalous values:
For summary tables and plots of median profiles, appropriate summary statistics will be 
calculated.  Concentrations will be set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
as anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than
50% of the data are missing. For analysis of PK concentrations, no values will be imputed 
for missing data.  
Pharmacokinetic parameters:
Actual PK sampling times (and where possible the actual dosing information) will be used in 
the derivation of PK parameters. If a PK parameter cannot be estimated from a patient’s 
concentration data, the parameter will be coded as NC (ie, not calculated). (Note that NC 
values will not be generated beyond the day that a patient discontinues).


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In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will not be presented for a particular treatment if more than 50% of the data are NC. For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all of the study drug is absorbed in the body), 
this will be footnoted in summary tables and will not be included in the calculation of
summary statistics or statistical analyses.
For PK analysis, patients will be required to have at least one quantifiable concentration of 
each study drug to be included in the concentration summary.  
For evaluation of changes in PK of crizotinib when administered alone vs in combination 
with pembrolizumab, as assessed in patients who receive Dose Level -1 (DL-1), only patients 
with a matching pair of PK assessments under both conditions will be included in the 
PK summary. Patients who have been treated with crizotinib for whom drug plasma 
concentrations (from both PK visits, when administered alone and in combination) are 
available will be included in average concentration summary.
 
 
 
  
 
7.5. Patient Reported Outcomes
For the EORTC QLQ-C30, QLQ-LC13 and VSAQ-ALK in cases where multiple answers 
are given to one item, the more severe answer (higher score for QLQ-C30, QLQ-LC13 and 
VSAQ-ALK) will be counted.  If less than half of the constituent items have been answered 
for a multi-item subscale, that subscale will be considered missing.  Single-item subscales
will be considered missing if the constituent item is incomplete.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Statistical Methods for Dose De-Escalation: Up-and-Down Matrix Design with the 
mTPI Method
The modified toxicity probability interval (mTPI) design uses a Bayesian statistics 
framework and a beta/binomial hierarchical model to compute the posterior probability of 
three dosing intervals that reflect the relative difference between the toxicity rate of each 
dose level to the target rate (pT = 0.30).  If the toxicity rate of the currently used dose level is 
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far smaller than pT, the mTPI will recommend escalating the dose level; if it is close to pT, 
the mTPI will recommend continuing at the current dose; if it is far greater than pT, the mTPI 
will recommend de-escalating the dose level.  These rules are conceptually similar to those 
used by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different trials with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given trial can be pre-calculated under the 
mTPI design and presented in a two-way table (Appendix 4).  Thus, compared to other 
advanced model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of crizotinib and pembrolizumab, e1 is selected as 0.05, and e2 is selected as 
0.03.  Therefore, the target dosing interval for the DLT rate is (0.25, 0.33).
The three dosing intervals are associated with three different dose-escalation decisions.  The 
under-dosing interval corresponds to a dose re-escalation (RE), over-dosing corresponds to a 
dose de-escalation (D), and proper-dosing corresponds to staying at the current dose (S).  
Given a dosing interval and a probability distribution, the unit probability mass (UPM) of 
that dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval.  The mTPI design calculates the UPMs for the 
three dosing intervals, and the one with the largest UPM informs the corresponding 
dose-finding decision, which is the dose level to be used for future patients.  For example, if 
the under-dosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Ji and collaborators have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision).4
The Dose Finding Phase of the trial is completed when 10 DLT-evaluable patients have been 
treated at the highest dose associated with a DLT rate <0.33.  For this reason, a modification 
has been applied to the original mTPI decision algorithm so that if 4 DLTs are observed at 
any dose level, that dose level is considered unacceptable and never used again in the 
remainder of the study since 4/10 patients with DLTs would be a 33% rate.  In addition, a 
further modification will allow re-escalation and exposure of up to 10 patients at the higher 
dose in case of 3 out of 10 patients experience DLTs.
In case a de-escalation is required from the initial starting DL0, it is estimated that 
approximately up to 30 DLT-evaluable patients will need to be enrolled to estimate MTD


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8.1.2. Methods for Estimating the MTD
The estimated MTD will be the highest tested dose level with a DLT rate <0.33 in 10 DLT 
evaluable patients.  We assume that higher doses of crizotinib result in higher toxicity rates.  
But, due to the relatively low number of patients that may be potentially allocated to any 
dose combination, this assumption may be violated.  For example, at the end of the study, the 
dose combination (crizotinib 200 mg BID, pembrolizumab 200 mg Q3weeks) may have a 
higher proportion of DLTs than, say, (crizotinib 250 mg BID, pembrolizumab 200 mg 
Q3weeks), and this variability may be simply related to small cohort size alone.  To 
overcome this potential problem, we will use a bivariate isotonic regression to smooth the 
resulting toxicity surface to a monotonically increasing one.  The determination of the MTD 
contour is accomplished using the Dykstra-Roberston algorithm.5  Once a monotonically 
increasing toxicity surface is obtained (either observed or smoothed according to the 
bivariate isotonic regression algorithm), the MTD combinations closest to the targeted DLT 
rate of 0.3 but still <0.33 are calculated.  Clinical judgment will be exercised in taking 
forward combinations to the Dose Expansion Phase, in case no clear choice exists between 
more than 1 competing MTD combination.  While the limited sample size may result in up to 
2 dose combinations of equal potential anti-tumor activity, under the circumstances of this 
study, likely only 1 will be chosen for the Dose Expansion Phase.  This decision will be 
based upon the combination of data related to safety, available anti-tumor activity, and 
clinical judgment of the investigators and the Sponsor.
8.1.3. Sample Size Determination
The sample size planned for the study arise from logistic feasibility and past experience with 
Phase 1b studies in Oncology and are not entirely driven by statistical considerations.  It is 
expected that approximately 70 patients will be required to achieve all study objectives.
As far as the Dose Finding Phase of this study is concerned, due to the dynamic nature of the 
Bayesian allocation procedure, the sample size of the “Up-and-Down” matrix design using 
the mTPI approach cannot be determined in advance.  It is estimated that 30 DLT evaluable 
patients will be enrolled in the dose escalation stage in order to have a reliable and accurate 
estimate of the MTD and determine the RP2D. 
Subsequent patients will then enter the Dose Expansion Phase aimed at evaluating safety, 
anti-tumor activity and PK at the MTD.
The planned sample size for the Dose Expansion Phase is 50 patients (including 10 patients 
from the Dose Finding Phase of the study treated at the MTD) and was calculated using the 
1-sample survival method.  Assuming enrollment over 3 months and 18 months follow-up, 
50 patients will allow to test the hypothesis that the true 18-month PFS probability is 
≥50% vs. ≤32% for historical control (data from the crizotinib arm of Study A8081014)10
with 85% power, alpha = 0.05 (1-sided), and based on exponential assumption.


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8.2. Statistical Methods for Different Types of Endpoints
Listings and standard summary statistics will be used to summarize data from this study.  
Analysis of Time-to-Event Endpoints
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate. Median event times (and other quartiles) and corresponding 
2-sided 95% confidence interval (CI) will be provided (Brookmeyer R and Crowley JJ).1
Analysis of Binary Endpoints
Binary endpoints will be summarized by percentages along with the 95% CIs using an exact 
method based on the F-distribution.
Analysis of Continuous Endpoints
Continuous endpoints will be summarized by descriptive statistics, including the mean, 
standard deviation, median, minimum, and maximum values.
 
Analysis of Categorical Endpoints
The number and percentage of patients in each category will be provided for categorical 
variables.
8.3. Statistical Analyses
8.3.1. Standard Analyses

Study Conduct and Patient Disposition - an accounting of the study patients in the 
SA population will be provided.  Patients not completing the study will be listed 
along with the reason for their discontinuation.  Reasons for discontinuation will be 
summarized.

Baseline Characteristics – for patients in the SA population, characteristics such as 
age, gender, height, weight, ethnicity, ECOG performance status, smoking history, 
prior anti-cancer therapy, histopathological classification, stage at diagnosis, extent 
of disease, and medical history at study entry will be summarized in frequency 
tables, and descriptive statistics will be provided for quantitative variables.

Treatment Administration/Compliance – Administration of study medication will 
be presented for the SA population, by medication administered and will be 
described in terms of the total number of cycles administered, the median (range) of 
cycles administered, dose intensity, dose modifications, dose interruptions, dose 
delays.
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8.3.2. Analysis of Efficacy Endpoints
Efficacy analyses will be presented in the form of statistical summaries and data listings for 
the Dose Expansion Phase (including the 10 patients from the Dose Finding Phase of the 
study treated at the MTD).  For the Dose Finding Phase, only data listings will be presented.  
For the Dose Expansion Phase, PFS and OS will be summarized in the safety analysis 
population; ORR will be summarized in the response-evaluable population; DR and TTR will 
be summarized for the subgroup of responding patients.
PFS, OS, and DR will be analyzed by the Kaplan-Meier method. The median event time 
(and other quartiles) and corresponding 2-sided 95% CI will be provided for each endpoint.  
Six, 12-, and 18-month PFS probabilities will be summarized as a product limit estimator 
based on the Kaplan-Meier method to account for censored events, together with the 
corresponding 2-sided 95% CI.  The 2-sided 95% CI for the log[-log(6-, 12, 18-month PFS 
probabilities)] will be calculated using normal approximation and then back transformed to 
give the CIs for the respective PFS probabilities.  Twelve- and 18-month OS probabilities
will be calculated similarly.
TTR will be summarized with descriptive statistics.  Best overall response (BOR) will be 
summarized and ORR will be calculated along with the corresponding exact 2-sided 95% CI
using the exact method based on the F-distribution
Analysis Sets

Response-evaluable population for ORR (Dose Expansion Phase including the 
10 patients from the Dose Finding Phase of the study treated at the MTD).

Safety analysis population for PFS and OS (Dose Expansion Phase including the 
10 patients from the Dose Finding Phase of the study treated at the MTD).

Patients with an overall objective response of CR or PR in the response-evaluable 
population for DR and TTR (Dose Expansion Phase including the 10 patients from 
the Dose Finding Phase of the study treated at the MTD).
Listings or/and tables (when applicable) will be sorted by dose level.
Tumor Response

The best overall response is the best response (CR, PR, SD, PD, Early Death or 
IND) recorded during the “on-study” period (as defined in Appendix 2 of this 
document). 

Best overall response is determined from the sequence of objective responses.  

A patient’s best overall response will be Early Death if the patient died within 
42 days of treatments start and prior to having sufficient evaluations for overall 
response.


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For BOR, if a patient has not achieved an objective response, but remained stable for at least 
6 weeks after starting treatment, then the BOR for such a patient will be SD. 
8.3.3. Analysis of Safety Endpoints
Analysis Set 

Summaries and analyses of the primary safety endpoint will be based on the 
DLT-evaluable analysis population.  All other summaries and analyses of safety 
parameters will be based on the safety analysis population.  Safety data will be 
summarized by dose level and/or by dose level within dosing regimen using 
appropriate tabulations and descriptive statistics (pooling together patients treated 
at the MTD from both phases of the study).  If applicable, safety data collected 
during the crizotinib lead-in period for patients who are treated at DL-1 will be 
reported separately.  
8.3.3.1. Analysis of Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the study. The occurrence of DLTs 
observed in the Dose Finding Phase will be used to estimate the MTD as described in Study 
Protocol Section 3.2.  Adverse events constituting DLTs will be listed per dose level.
DLT-related listings will be produced by dose level and will include:

Patient ID;

DLT term;

Date at which DLT occurred;

Time from treatment start to onset of DLT;

Time to resolution of DLT to Grade 1 or baseline;

Action(s) taken due to DLT (stopped temporarily, permanently discontinued, no 
action taken, Dose/Infusion interruption etc).
8.3.3.2. Analysis of Secondary Safety Endpoint
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the NCI CTCAE 
version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
The focus of AE summaries will be on treatment-emergent AEs, those with initial onset or 
increasing in severity after the first dose of study treatment. 


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Because the frequency of certain medical concepts or conditions may be underestimated by 
reliance on single MedDRA preferred terms, certain preferred terms will be analyzed in 
aggregate using clustered terms.  Patients having more than 1 AE preferred term within a 
clustered term will contributed 1 event to the clustered term at the highest grade observed.  
Clustered terms to be used for summary of data from this study will be defined prior to data 
summary based on information included in the current Safety and Risk Plan maintained by 
the Sponsor.
The number and percentage of patients who experienced any treatment-emergent AE, 
treatment-emergent SAE, treatment-related AE, and treatment-related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1, Cycle 2, and Cycles ≥3).  In DL-1, the summaries 
will present AEs during the lead-in period, overall, and by cycle (Cycle 1, Cycle 2, and 
Cycles ≥3).

An overall summary of AEs will be provided.  The number and percentage of 
patients who experienced any AE, who experienced any SAE, who experienced any 
treatment-related AE, who experienced any treatment-related SAE, and with
permanent/temporary discontinuation or dose reduction, if applicable, because of an 
AE will be presented.  

All treatment-emergent AEs (all causality) will be summarized by MedDRA 
preferred term (PT) and/or clusters of MedDRA PT. A summary of AEs by 
preferred term/clustered term and maximum CTCAE grade will be presented, in 
decreasing order of frequency.  A summary of AEs by preferred term/clustered 
term and maximum CTCAE grade group (Grade 1-2, Grade 3-4, and Grade 5) will 
also be presented, in decreasing order of frequency. Treatment-emergent AEs will 
be summarized by dose level.

Treatment-related AEs, all-causality SAEs and treatment-related SAEs will be 
summarized similarly to all causality treatment-emergent AEs. Displays of 
treatment related events will include events judged by the Investigator to be at least 
possibly related/unknown to one of the study drugs (crizotinib and/or 
pembrolizumab). Displays will not be focused on crizotinib-related only events or 
pembrolizumab-related only events. 

Treatment-emergent AEs associated with permanent/temporary discontinuation of 
the study drug or with dose reduction, if applicable, will be summarized (taking 
into consideration the action taken from the CRF AE page).

Deaths will be summarized by two time periods: 1: within 28 days of last dose of 
crizotinib and/or within 90 days of last dose of pembrolizumab and 2: >28 calendar 
days after the last administration of crizotinib and > 90 calendar days after the last 
administration of pembrolizumab, and cause of death. Deaths that occurred within 
28 days after the last dose of crizotinib and/or within 90 days of last dose of 
pembrolizumab are defined as on-treatment deaths. Death data will also be listed.


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Additional analyses may be performed for AEs of special interest: Time to AE onset (in 
days), Duration of AE (in days) and Prevalence of AE (definitions for time to AEs, duration 
of AEs and prevalence of AEs are provided in Appendix 1 of this document). 
Duration of AE (days) will be summarized using the Kaplan-Meier method.  The median and 
other quartiles, as appropriate, will be presented along with associated 95% CIs. Descriptive 
statistics will be presented for time to AE onset (days) and duration of AEs for the subgroup 
of subjects with the AE, if the number of events is small for reliable use of the Kaplan-Meier 
method. The prevalence of AEs of special interest will be summarized by maximum CTC 
severity grade. Programming specifications for AE analyses are described in Appendix 1.
Laboratory Tests
The number and percentage of patients who experience laboratory test abnormalities will be 
summarized according to the worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests during the lead-in period (only applicable to DL-1), 
overall, and by cycle (Cycle 1, Cycle 2, and Cycles 3).  Shift tables will be provided to 
examine the distribution of laboratory abnormalities.
For laboratory tests without CTCAE Grade definitions, results will be categorized as normal, 
abnormal, or not done.   

Hematology and blood chemistry results will be graded according to the NCI
CTCAE Version 4.03.  A shift summary of baseline grade by maximum post-
baseline CTCAE grade will be presented, as appropriate. Shift tables may also be 
summarized separately for Cycle 1, Cycle 2, and > Cycle 2.
Patients who 
developed toxicities of grade 3 will be listed.

E-DISH scatter plots of maximum ALT and maximum AST vs. maximum total 
bilirubin on-study will be presented

Other Laboratory Tests – Individual patient test results will be listed.
ECG
The analysis of ECG results will be based on data collected during the first 3 cycles for all 
patients except in DL-1 where ECG collection will also be performed during the crizotinib 
lead-in period. In this case baseline assessment will be the one obtained prior to start of
crizotinib.
ECG measurements (an average of the triplicate measurements) will be used for all data 
presentations.  Any data obtained from ECGs repeated for safety reasons after the nominal 
time points will not be averaged along with the preceding triplicates.  Interval measurements 
from repeated ECGs will be included in the outlier analysis (categorical analysis) as 
individual values obtained at unscheduled time points.


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QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s [QTcF; default correction], or Bazett’s [QTcB]).  Data will be summarized and 
listed for HR, RR interval, PR interval, QRS complex, QTcF and QTcB, and by dose level.  
Categorical analysis of the ECG parameters will be performed as follows:

The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (<30, 30- 60, and 60 ms);

The number of and percentage patients with maximum post-dose QTcF/QTcB 
(<450, 450-<480, 480- <500, and 500 ms);

PR interval changes from baseline 50% if absolute baseline value was <200 ms, 
and 25% if absolute baseline value was 200 ms;

QRS complex changes from baseline 50% if absolute baseline value was <100 ms, 
and 25% if absolute baseline value was 100 ms;
Shift tables will be provided for baseline vs. worst on study QTcF and QTcB using maximum 
CTCAE Grade.
Vital Signs
The number and percent of patients in each of the following minimum and maximum blood 
pressure, body weight and pulse rate categories will be presented:
Vital Sign
Category
Blood
Pressure
Maximum Change from baseline (increase or decrease) in SBP of 
40 mmHg
Maximum Change from baseline (decrease) in SBP of 60 mmHg
Maximum Change from baseline in DBP (increase or decrease) of 
20 mmHg
Maximum Change from baseline in DBP (decrease) of 40 mmHg
Body
Weight
Maximum change from baseline body weight (increase or decrease)
≥10%
Pulse Rate
Minimum Pulse Rate <50 bpm
Maximum Pulse Rate > 120 bpm
Maximum Change from baseline (increase or decrease) 30 bpm
In addition, the baseline and the change from baseline in blood pressure and pulse rate will be 
summarized using descriptive statistics by visit. For DL-1 baseline assessment will be the 
one obtained prior to start of crizotinib.
ECOG Performance Status 
ECOG performance status data will be summarized with a shift table of the baseline and the 
worst on study status.


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Concomitant Medications and Non-drug Procedure/Treatments 
All drug medications will be coded by the World Health Organization (WHO) medical 
dictionary. Non-drug procedure/treatments will be coded by the MedDRA dictionary. All 
medications with a start date prior to study start are considered previous medications. All 
ongoing medications at study start or with start date after study start are considered 
concomitant medication. If a medication satisfies both the definition of previous and 
concomitant medication, it will be considered both previous and concomitant medication.
The number of patients with any concomitant drug/non-drug treatment will be summarized. 
Listings of prior and concomitant drug/non-drug treatment will be provided separately.  If 
any prior or concurrent surgery or radiation therapy is given, these data will be listed for each 
patient. Furthermore, prior and follow-up systemic therapy for the primary diagnosis will be 
listed for each patient and summarized as appropriate.
Data Safety Monitoring Committee
A Data Safety Monitoring Committee will not be established for the study.  However, Pfizer 
procedures for periodic safety review will be applied, as described in Section 9.7 of the study 
protocol.
8.3.4. Analysis of Pharmacokinetics
Analysis Set: PK
8.3.4.1. Pharmacokinetic Analysis of Crizotinib and Pembrolizumab
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean 
and its associated %CV, and 95% confidence interval) for all plasma/serum concentrations of 
crizotinib (plasma) and pembrolizumab (serum) will be presented in tabular form by dose 
level, visit (cycle/day), and nominal time. 
When applicable, plots of mean and median crizotinib and pembrolizumab plasma/serum 
concentrations by nominal time will be presented by dose level, visit (cycle/day) on both 
linear-linear and log-linear scales. Similarly, individual patient profiles of 
concentration-time data will be plotted by treatment, dose level, cycle, and day, using 
nominal times. 
Steady state trough plasma concentration (Ctrough,ss) of crizotinib and its metabolite 
PF-06260182 is defined as predose plasma concentration following at least 14 consecutive 
days of the prescribed dose without dosing interruption.  Individual mean steady state 
predose concentration (Ctrough, ss, mean) of crizotinib and metabolite PF-06260182 will be 
obtained by using the arithmetic mean of all Ctrough, ss values for each patient. Presentations 
for Ctrough,ss and Ctrough, ss, mean of crizotinib and its metabolite PF-06260182 were to include, 
but not limited to: 

Summary of Ctrough,ss by visit (Cycle/Day) and by ethnicity and race group (Asians 
versus Non-Asians) using descriptive statistics;


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
Summary of Ctrough,ss,mean by ethnicity and race group (Asians versus Non-Asians ) 
using descriptive statistics;

Linear plots of median/mean Ctrough,ss against visit (Cycle/Day) by ethnicity and 
race group (Asians versus Non-Asians).
For DL-1, standard plasma PK parameters for crizotinib and its metabolite PF-06260182 will 
be estimated using non-compartmental methods for PK concentration data collected on Cycle 
-1 Day 15 (when crizotinib given alone) and Cycle 6 Day 1 (in combination with 
pembrolizumab). PK parameters for crizotinib will include: Cmax, Tmax, Ctrough, AUC0-8, 
AUCtau , and oral plasma clearance (CL/F). PK parameters for PF-06260182 will include: 
Cmax, Tmax, Ctrough, AUC0-8, AUCtau, MRAUCtau, and MRCmax. PK parameters will be listed 
and summarized in tabular form by visit (Cycle/Day) or treatment (when given alone and in 
combination), using descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, 
geometric mean and its associated %CV, and 95% confidence interval). For Tmax, the range 
(min, max) will also be provided. All calculations will follow the Pfizer Clinical 
Pharmacology Guidance “Pharmacokinetic Data Handling and Non-Compartmental Analysis 
Conventions”.  Box plots for AUCtau and Cmax for crizotinib and PF-06260182 (when given 
alone and in combination with pembrolizumab) will be generated, respectively. Individual 
data points, the geometric mean and the median of the parameter in each treatment will be 
overlaid on the box plots.
Trough concentrations for pembrolizumab will be plotted for each dose using a box-whisker 
or linear plots by visit (cycle/day) in order to assess the attainment of steady-state.
In addition, Non-linear Mixed Effects Modeling (NONMEM) approaches will be explored to 
further describe the PK profile of pembrolizumab in combination with crizotinib.
Additional tables, listings, and figures for post-hoc analyses may be included in the final 
CSR.
8.3.4.2. Effect of Pembrolizumab on Crizotinib Pharmacokinetics
For DL-1, the effect of pembrolizumab on crizotinib PK will be evaluated using steady-state 
crizotinib AUCtau and Cmax as the primary pharmacokinetic parameters after crizotinib is 
administered as a single agent (Cycle -1 Day 15 [Reference]) and in combination with  
pembrolizumab (Cycle 6 Day 1 [Test]). The AUCtau and Cmax will be log transformed and 
analyzed using a mixed effect model with treatment as the fixed effect and patient as the 
random effect. The ninety percent confidence interval for the ratio of geometric means of 
AUCtau and Cmax (Test/Reference) will be computed to assess the effect magnitude. The 
effect of pembrolizumab on the PK of PF-06260182 may also be assessed using this method.
For the other dose levels that do not incorporate a crizotinib lead-in period, the effect of 
repeated pembrolizumab doses on crizotinib PK will be evaluated by comparing the 
steady-state crizotinib and PF-06260182 PK to that observed in prior single-agent crizotinib 
studies, as appropriate.


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8.3.5. Analysis of Patient-Reported Outcomes 
The PRO-evaluable population will be the primary population for the analysis of PROs.  
Change from baseline scores over treatment will be evaluated in the PRO evaluable 
population.  Visit windows will be applied for the analysis of the PRO endpoints.  Further 
details are described in Appendix 5.
PRO Scoring Procedure
The subscales of the EORTC QLQ-C30 and the QLQ-LC13 will be scored based on the 
EORTC scoring manual. In summary, each scale of the EORTC QLQ-C30 and the QLQ-
LC13 will be transformed so that scale scores will range from 0 to 100. The transformation 
will proceed in two steps. First, the average of the items contributing to a subscale will be 
calculated to compute the raw score of the scale. Next, a linear transformation will be 
applied to ‘standardize’ the raw score. After scores are transformed, higher scores on the 
EORTC QLQ-C30 or the QLQ-LC13 will represent higher (“better”) levels of functioning 
and/or a higher (“worse”) level of symptoms.6,7,8
For the VSAQ-ALK questionnaires descriptive statistics will be used to evaluate each item. 
Item 7 was developed based on question 6 (impairment on daily activities) of the Work 
Productivity Questionnaire (WPAI SHP). Item 7 will be scored according to the WPAI SHP 
guideline for question 6.
Instrument Compliance Rates
At each time point, the number and percentage of patients who completed the QLQ-C30, 
QLQ-LC13 and VSAQ-ALK will be summarized.  A questionnaire is considered complete if 
at least 1 item was answered by the patient.  Scoring and handling of missing data for the 
EORTC QLQ-C30 and QLQ-LC-13 will be implemented in line with the scoring manual. 
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Global QOL, Functioning and Lung Cancer Symptoms.
Summary statistics (mean, standard deviation, median, range, and 95% CI) of actual scores 
and change from baseline at each time point will calculated for all scales of the EORTC 
QLQ-C30 and QLQ-LC13 scores.  
The number and proportion of patients who improved, worsened, or remained stable as 
compared to baseline will also be summarized for all of the symptom and functional domains, 
global QOL, and single items of the EORTC QLQ-C30 and QLQ-LC-13. Patients will be 
classified as improved, stable or deteriorated according to a 10-point or greater change in 
score from baseline as this is perceived by patients as being clinically significant on the 
EORTC QLQ-C30 (Osoba).9
If less than half of the constituent items on the QLQ-C30 and QLQ-LC13 have been 
answered for a multi-item subscale, that subscale will be considered missing.  Single-item 
subscales will be considered missing if the constituent item is incomplete.  
VSAQ-ALK (Visual Symptoms)
Frequency analyses will be performed and reported for each item of the VSAQ. For the 
VSAQ-ALK questions not answered will be considered missing items and will not be 
utilized.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4. Summary of Secondary Efficacy Analyses 
Endpoint
Analysis 
Population
Statistical Method
Missing Data
Analysis 
Type/Timing
ORR
Response 
Evaluable
Exact method based on 
F-distribution (95% CI)
(Section 8.3.2)
See Section 6.1
Secondary 
analysis
DR
Subgroup of 
pts with OR 
from the 
Response 
Evaluable
Population
K-M method (median 
and 95% CI) (Section 
8.3.2)
See Section 6.1
Secondary 
analysis
TTR
Subgroup of 
pts with OR 
from the 
Response 
Evaluable
Population
Univariate (median and 
range) (Section 8.3.2)
See Section 6.1
Secondary 
analysis
PFS
Safety 
Analysis
K-M method (median, 6-
, 12-, 18-month PFS and 
95% CIs)
(Section 8.3.2)
Censor patients on 
the day of the last 
evaluable tumor 
assessment 
documenting 
absence of disease 
progression for … 
(See Section 6.1)
Secondary 
analysis 
OS
Safety 
Analysis
K-M method (median, 
12- and 18-month OS 
and 95% CIs)
(Section 8.3.2)
Censor patients on 
the day last known 
to be alive (See 
Section 6.1)
Secondary 
analysis 
CI: Confidence intervals; DR: Duration of Response; K-M: Kaplan-Meier; OR: Objective Response; ORR: 
Objective Response Rate; PFS: Progression-free Survival; TTR: Time to Response; OS: Overall Survival


Protocol A8081054
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9. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
3.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
4.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials 2010; 7:653 663.
5.
Dykstra R, Robertson T. An algorithm for isotonic regression for two or more 
independent variables. Ann Stat. 1982;10:708-716.
6.
Aaronson NK et al. The European Organization for Research and Treatment of Cancer 
QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology.  J Natl Cancer Inst. 85:365-76, 1993.
7.
Aaronson NK et al. The European Organization for Research and Treatment of Cancer 
(EORTC) modular approach to quality of life assessment in oncology: an update, in 
Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd Ed.  S. B, Editor.  Raven 
Press: New York.  179-89, 1996.
8.
Bergman B et al. The EORTC QLQ-LC13: a modular supplement to the EORTC Core 
Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC 
Study Group on Quality of Life.  Eur J Cancer. 30A:635-42, 1994.
9.
Osoba D et al, Interpreting the significance of changes in health related quality of life 
scores. J. Cin Oncology. 1998. 16:139-144.  
10.
Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed-cisplatin or
pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous
non-small cell lung cancer (PROFILE 1014). J Clin Oncol. 2014 ; 32 : 5s (suppl ; abstr.
8002).


Protocol A8081054
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10. APPENDICES
Appendix 1. Programming Specifications for AE Analyses
a. Time to AE onset
1. Definition
Time to AE onset (days) will be calculated as first AE start date – first dose date +1.  
AE start date
The Date of Onset for the first occurrence of the AE based on the Log AE CRF page.  
First dose date
The date of the starting dose: The date of first dose of study medication based on the 
Dosing CRF page.
b. Duration of AE
1. Definition
Duration of AE (days) is defined as the cumulative duration across episodes of the
specific AE (by preferred terms) where duration for each episode is calculated as 
AE-end date – AE start date +1 excluding any overlap. Duration of AE is defined for 
patients with the AE.
AE start date
The Date of Onset based on the Log AE CRF page. 
AE end date
The Date Resolved based on the Log AE CRF page.
2. Censoring
AE resolution is considered an event (censoring variable=1).  If a patient has an AE 
that was ongoing (does not have to be the last AE) at the time of analysis, the time is 
censored (censoring variable=0) at the last available on study visit date.  Patients who 
die prior to resolution of the AE will be censored at the date of death. If the date of 
death is the same as the date of the resolution of the AE, the patient will be censored 
at that date (ie, resolution will not be considered an event) and only if the AE is the 
AE that resulted in death will it be counted as an event.
Date of death
Death date is based on the Notice of Death CRF page.


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3. Clustered Events
For clustered events, a patient could have multiple events in the cluster which may 
overlap.  In this case, AE duration will be summed across all events in the cluster 
accounting for the overlap (ie, overlapping periods between events in the same cluster 
are not double-counted).  Lags between events in the same cluster are not included in 
the duration.
The following scenarios provide examples of the calculation for 2 events in the same 
cluster.  The extension to 3 or more events of the same cluster is similar.

TWO EVENTS OF THE SAME CLUSTER WHERE ONE EVENT 
COMPLETELY CONTAINS THE OTHER EVENT
    event 1                  [------------------------------]
   
            startdate1                     enddate1
    event 2                      [------------------------]
                                    startdate2            enddate2
   duration = enddate1-startdate1+1

CERTAIN PORTIONS OF TWO EVENTS IN THE SAME CLUSTER 
OVERLAP
    event 1                  [------------------------------]
          
            startdate1                     enddate1
    event 2                                          [------------------------]
            
                                   startdate2            enddate2
    duration = enddate2-startdate1+1

TWO EVENTS OF THE SAME CLUSTER ARE CONTIGUOUS TO EACH 
OTHER  
event 1                 [------------------------------]
            
         startdate1                     enddate1
    
event 2                                                           [------------------------]
            
                                                  startdate2           enddate2
duration = enddate2-startdate1+1


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
TWO EVENTS OF THE SAME CLUSTER ARE NON-OVERLAPPING 
    
event 1                  [------------------------------]
            
          startdate1                     enddate1
event 2                                                                 [------------------------]
                                                                                     startdate2    enddate2
    
duration = (enddate1-startdate1+1) + (enddate2-startdate2+1)
c.
AE Prevalence
1. Definition
AE prevalence is defined as the number of patients with an AE in a particular time 
period (including both new cases with an onset date during the specified time period 
AND cases with an AE continued from a previous time period) divided by the 
number of patients at risk during the specified time period.  The number of patients at 
risk includes all patients except those who either have discontinued or died prior to 
the specified time period.
AE prevalence may be presented separately for Cycle 1, Cycle 2, Cycle 3, Cycle 4, 
Cycle 5, Cycle 6, and Cycle >6, and Lead-in period, for DL-1.
2. Assumptions

Patients are counted for an AE in each cycle up until the cycle where the AE 
resolved.  Thus, the calculation conservatively assumes that if the AE resolved in a 
cycle, it resolved at the end of the cycle.

For DL-1 and for lead-in period, a patient is counted in the numerator if the patient 
has an onset date of the AE during the Lead-in period.

For Cycle 1, a patient is counted in the numerator if the patient has an onset date of 
the AE during Cycle 1 OR an onset date during the Lead-in period, for DL-1, that is 
still ongoing in Cycle 1 (ie, did not have a resolution date in the Lead-in phase).

For Cycle 2, a patient is counted in the numerator if the patient has an onset date of 
the AE during Cycle 2 OR an onset date during the Lead-in period, for DL-1, or 
Cycle 1 that is still ongoing in Cycle 2 (ie, did not have a resolution date in the 
Lead-in phase or Cycle 1). The calculation for Cycles 3, 4, 5, and 6 is similar.

For Cycles > 6, a patient is counted in the numerator if the patient has an onset date 
in Cycles > 6 OR an onset date in an earlier cycle that is still ongoing (ie, did not 
have a resolution date in Cycle 6 or earlier cycle).


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
The denominator for a particular time period will include patients who are at risk 
prior to the time period.  The number at risk includes all patients except those who 
either have discontinued both study drugs (based on the ‘Subject Summary End of 
Treatment Crizotinib’ and on the ‘Subject Summary End of Treatment 
Pembrolizumab’ CRF) or died prior to the specified time period (ie, Death Date 
based on ‘Notice of Death’ CRF is prior to start of time period). 


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Appendix 2. Study Specific Information for Efficacy 

Baseline:  is defined as the last observation within 28 days prior to the first dose of study 
treatment

Adequate Baseline: 

Baseline tumor evaluations must be performed within 4 weeks (28 days) prior to 
the first dose of study treatment;  tumor scans performed outside this window will 
be reviewed and might be considered acceptable on a case by case basis.; 

Presence of at least one measurable lesion per RECIST version 1.1;

All lesions recorded at baseline must have an associated status recorded on the 
CRF;

Baseline lesions must be assessed with an acceptable method that includes: 
Conventional CT Scan, Spiral CT Scan, MRI, Physical Exam, Bone Scan and 
Other. Note: If based on data review “unacceptable” methods (eg, ultrasound, 
etc) are noted under “Other”, then this category will not be considered acceptable 
(on a case by case basis).

“On-study” period for efficacy: is defined as the period from the date of the first dose 
until patient death, progression of disease, patient no longer willing to participate, start of
other anti-cancer treatment, or 28 days after last administration of crizotinib (or 90 days 
after last administration of pembrolizumab, whichever is later), whichever is earlier.

Subsequent anti-tumor treatment: includes any systemic anticancer therapy (other than 
study medication), radiation and surgery for removal of target or non-target lesions 
(resected or partially resected).


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Appendix 3. RECIST 1.1
The determination of anti-tumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST vesion 1.1 system of unidimensional evaluation.  
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable:
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable:  All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques. 
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals after baseline.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  
The longest diameter will be recorded for each non-nodal target lesions and the short axis
dimension will be used for each target lymph node.  The sum of the longest diameter for 
target lesions/short axis dimension for target lymph nodes will be calculated and recorded as 
the baseline sum of lesion dimensions (SLD) to be used as reference to further characterize 
the objective tumor response of the measurable dimension of the disease during treatment.  


Protocol A8081054
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All measurements should be performed using a caliper or ruler and should be recorded in
metric notation in centimeters.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent.”
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the anti-tumor effect of a treatment.
Definitions of Tumor Response
Target Lesions
Complete Response (CR) is defined by the disappearance of all non-lymph node target 
lesions (where all target lesions are recorded with a length of 0 mm on the “Target Lesions” 
eCRF).  Any pathological lymph nodes (recorded as target lesion) must have reduction in 
short axis to <10 mm.  Note: the SLD may not be zero if lymph nodes are included as target 
lesions.
Partial Response (PR) is defined by a 30% or more decrease in SLD of target lesions, taking 
as reference the baseline SLD.
Progressive Disease (PD) is defined by a 20% or more increase in the SLD of target lesions 
relative to baseline or the smallest SLD (nadir) recorded since first dose.  In addition to the 
relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm 
(5 mm) relative to baseline or the smallest SLD (nadir) recorded since first dose.
Stable Disease (SD) is assigned when neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD is observed, taking as reference the smallest sum 
diameters while on study.
Indeterminate (IND) is assigned if any individual target lesion is evaluated as
“Indeterminate” or if inconsistent methods are used for post-baseline lesion assessment for 
any lesion, or if one or more target lesions are not assessed.
Non-Target Lesions
Complete response (CR) is defined as the disappearance of all non-target lesions.  All
lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.


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Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of 1 new lesion. PD is assigned if any non-target lesion is marked
“Increased” on the “Non-Target Lesion” eCRF.  However, in an effort to programmatically
define “unequivocal progression” of non-target lesions, the derived non-target lesion response 
will also take into account the “Non-Target Lesions” assessment from the IOTA eCRF.
Indeterminate (IND) is assigned if any individual non-target lesion is evaluated as 
“Indeterminate” or if inconsistent methods are used for post-baseline lesion assessment for 
any lesion, or if one or more non-target lesions are not assessed
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease.
Confirmation of Tumor Response
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.


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Table 1.
Response Evaluation Criteria in Solid Tumors
Target Lesion Response
Non-Target Lesion
Response
Overall Response
CR
CR
CR
CR
Non-CR/Non-PD
PR
CR
PD
PD
CR
IND
PR
PR
CR
PR
PR
Non-CR/Non-PD
PR
PR
PD
PD
PR
IND
PR
SD
CR
SD
SD
Non-CR/Non-PD
SD
SD
PD
PD
SD
IND
SD
PD
Any Response
PD
IND
PD
PD
IND
Non-PD
IND
CR/PR/SD/PD/IND
Not Collected at Baseline
CR/PR/SD/PD/IND
CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease,
IND=Indeterminate.
Note: If non-target (or target) lesions are not collected at baseline, then the overall response is equivalent to
the target (or non-target) lesions response.
Best Overall Response Evaluation for Each Patient:

The best overall response is the best response (CR, PR, SD, Early Death, PD or 
IND) recorded during the “on-study” period for each patient.

Best overall response is derived from the sequence of objective responses.

A patient’s best overall response will be Early Death if the patient died within 
42 days of date of the first dose and prior to having sufficient evaluations for 
overall response.

Assessments done after PD or after “anti-tumor treatment” but prior to PD will not 
be considered for evaluation of best overall response.

For a patient to qualify for a best response of SD, the overall response evaluation 
must have met the stable disease criteria at least once since the date of the first dose 
at a minimum interval of 6 weeks (42 days).

Unconfirmed CR and PR will be classified as a best response of SD provided it 
meets the 42 days requirement.

Indeterminate (IND) is assigned for a patient who has only a baseline assessment, or 
a response assessment of CR/PR/SD at an interval less than 6 weeks and has no 
subsequent disease evaluation, or has all overall response evaluations assessed as
IND.


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Appendix 4. Detailed Dose Re-Escalation/De-Escalation Scheme
Number of Patients Treated at Current Dose
1
2
3
4
5
6
7
8
9
10
Number of tDLTs
0
NA
NA
RE
RE
RE
RE
RE
RE
RE
RE
1
NA
NA
S
S
S
RE
RE
RE
RE
RE
2
NA
D
S
S
S
S
S
RE**
RE**
3
DU
DU
D
D
S
S
S
RE**
4*
DU
DU
DU
DU
DU
DU
DU
5
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU
*A modification has been applied to the original mTPI algorithm. Since this protocol specifies a DLT rate 
<33% in 10 patients, all entries on the row with 4 toxicities are fixed to DU since 4/10 would be 33%. 
** This further modification will allow re-escalation and exposure of up to 10 patients at the higher dose if 
3 out of 10 patients with a DLT at the current dose and assuming the previous higher dose was not already a 
DU.
RE = Re-escalate to the next higher dose or if current dose level is DL0 stay on DL0.
S = Stay at the current dose.
D = De-escalate to the next lower dose.
U = The current dose is unacceptably toxic.
NA = Not applicable. The first three patients will have to be evaluable for DLT before assigning DL for the 
next patient.
Targeted DLT rate at MTD <33%.


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Appendix 5. Visit Windows for the Analysis of PRO Endpoints
The following visit label and visit windows will be applied for the analysis of PRO 
endpoints.
A Questionnaire is considered complete if at least one question is answered regardless of 
whether DONE/ NOT DONE is checked on the case report form.
In the case of multiple records for a patient within a particular visit window, then the average 
of the response values will be taken.
Visit Label
Visit Window (inclusive)
Target Day
Width (days)
Cycle 1 Day 1
<= 1
Cycle 2
12 to 32
22
21
Cycle 3
33 to 53
43
21
Cycle 4
54 to 74
64
21
Cycle 5
75 to 95
85
21
Cycle 6
96 to 116
106
21
Cycle 7
117 to 137
127
21
Cycle 8
138 to 158
148
21
Cycle 9
159 to 179
169
21
Cycle 10
180 to 200
190
21
Cycle 11
201 to 221
211
21
Cycle 12
222 to 242
232
21
Cycle 13
243 to 263
253
21
Cycle 14
264 to 284
274
21
Cycle 15
285 to 305
295
21
Cycle 16
306 to 326
316
21
Cycle 17
327 to 347
337
21
Cycle 18
348 to 368
358
21
Cycle 19
369 to 389
379
21
Cycle 20
390 to 410
400
21
……
……
End of Treatment
End of Patient’s Treatment