A PHASE 1B/2, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB (MSB0010718C) IN COMBINATION WITH EITHER CRIZOTINIB OR PF-06463922 IN PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Pfizer

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A PHASE 1B/2, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, 
EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF 
AVELUMAB (MSB0010718C) IN COMBINATION WITH EITHER CRIZOTINIB
OR PF-06463922 IN PATIENTS WITH ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER 
JAVELIN LUNG 101
Compounds:
MSB0010718C, PF-02341066, PF-06463922
Compound Names:
Avelumab, Crizotinib, PF-06463922
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-001879-43
Protocol Number:
B9991005
Phase:
1b/2
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
26 June 2015
Not applicable (N/A)
Amendment 1
10 August 2015
Per request from the US FDA, add statement that 
patients should have their tumors evaluated for 
EGFR mutations and have exhausted appropriate 
therapy, if positive.
Corrected typographical errors within the 
protocol.
Corrected an error on the SOA referring to 
PF-06463922 PK analysis that was added in 
error.
Corrected an error for hematology and blood 
chemistry collection in the SOA (Both should 
occur on Cycles 1 and 2 on Days 1 and 8).
Clarified efficiency of decision-rules based on 
mTPI design over traditional 3+3 design. 
Removed non-applicable text related to medical 
device safety reporting from the Serious Adverse 
Event section. 
Amendment 2
24 March 2016
Revised Background, PF-06463922 Dose 
Modification and Electrocardiograms sections, 
Exclusion Criteria, and added a new Appendix to 
address any potential cardiac issues related to 
PF-06463922.
Revised exclusion criteria to clarify requirement 
to stop prior ‘cytotoxic’anti cancer therapy at 
least 2 weeks before study entry and provide for 
continuation of TKI therapy closer to study entry 
to mitigate risk of tumor flare.
Clarified in the inclusion criteria (and indication 
section) that Group A patients should be 
previously treated in order to support the primary 
objective for this group.
Modified inclusion criterion #9 regarding renal 
function to only include patients with estimated 
creatinine clearance >30 mL/min based on the 
known avelumab safety profile.

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Clarified modified Toxicity Probability Interval 
(mTPI) dose finding rules including Table 3, and 
removed previous Appendix 2 “Detailed Dose 
Escalation/De-Escalation Scheme for mTPI 
design” as the information was redundant.
 
 
 
Revised procedure information, visit time 
window, and timepoints in the Schedule of 
Activities and Pharmacokinetic Sample 
Collection Table.Clarified that baseline signs and 
symptoms should be collected on the Medical 
History Case Report Form (CRF).
 
 
Changed teratogenic risk of PF-06463922 from 
unknown to known in Section 4.3.
Consolidated information for required Banked 
Biospecimens in Schedule of Assessment and 
Sections 7.4, 7.5, and 7.5.1.
Removed requirement for antineutrophil 
cytoplasmic antibody (ANCA), antinuclear 
antibody (ANA) and rheumatoid factor (RF) 
testing, as these are no longer required in 
avelumab protocols due to the lack of validity 
without a clinical correlate.
Added screening HBV and HCV tests to the 
Schedule of Activities table to be consistent with 
Table 12.
Revised frequency of adrenocorticotropic 
hormone (ACTH), Free thyroxine (FT4), and 
thyroid-stimulating hormone (TSH) assessments, 
based on emerging avelumab data and to be 
consistent with standard of care clinical practice.
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Removed requirement for 2 blood pressure 
readings to be taken 1 hour apart, as these 
assessments did not show blood pressure changes 
throughout the avelumab clinical trial program.
Updated the Recommended Dose Modifications 
section to clarify that dose delays are only 
permitted up to 2 weeks, and rechallenging at the 
original dose after a reduction is only permitted 
on a case-by-case basis.
Updated the Management of Avelumab + 
PF-06463922 Treatment-Related Toxicity 
guidelines.
Combined Sections “Other Prohibited 
Concomitant Medications and Treatments” and 
“Other Prohibited Concomitant Medications and 
Therapies” as the information was overlapping.  
Included additional guidance for Group A.
Additional guidance for use of inhibitors, 
inducers, and substrates of CYP3A enzymes for 
Group A in “Concomitant Medications” was 
provided.
Corrected typographical errors and removed 
duplicate information within the protocol.
Included additional information within the 
Background sections as well as additional 
references.
Included additional abbreviations and removed 
inapplicable abbreviations.
Amendment 3
30 June 2017
The main rationale for the amendment is to 
include Group B Phase 2.
Schedule of Assessments and Pharmacokinetic 
Sample Collection Table: 
 
  Removed 
Follow-up Day 30 avelumab PK sample as it is 
no longer required.  Other clarifications included.
Objectives, Endpoints, Study Overview, Study 
Schema, Sample size calculation, and Efficacy 
Analyses revised for Group B Phase 2.
Inclusion Criterion 2 revised to include 
requirement of no prior treatment for Group B 
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Phase 2.  Inclusion Criterion 6 corrected to state 
“0 to 2” vs “0 or 2”.
Exclusion Criterion 3 revised to not apply for 
Group B Phase 2.  Exclusion Criterion 16 revised 
to update restrictons on cardiovascular disease to 
further protect patient safety in light of potential 
cardiac adverse events.  Exclusion Criterion 
19 updated to restrict listed conditions to within 
the past one year to align with current standards. 
Exclusion Criterion 22 clarified and Exclusion 
criteria 24 and 25 added due to emerging data on 
potential drug interactions with PF-06463922.
Administration section for PF-06463922 revised 
due to emerging food effect data on 
PF-06463922, which allows for more flexibility 
in administration of PF-06463922.
Updated Tables 6 and 7 for the management of 
treatment-related toxicities to harmonize the
management of dose modification instructions 
witht the current avelumab Investigators 
Brochure. 
Added that PF-06463922 treatment should be 
interrupted during palliative radiotherapy, 
stopping 1 day before and resuming treatment 
after recovery from acute radiation toxicities to 
baseline.
Revised Section 5.7.1.2 and Table 8 to remove 
maximum infusion time of 120 minutes as it has 
been determined that this restriction is not 
needed.
Updated guidance for Inhibitors and Inducers of 
CYP Enzymes for Group B due to emerging data 
on potential drug interactions with 
PF-06463922 and to provide further instruction 
re: the types of concomitant medications allowed 
on study.
Clarification added re: steroid use to specify the 
guidelines only apply if patient is still receiving 
avelumab.
Table 12: Required Laboratory Tests revised to 
include corrections and remove redundant 

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language.
Clarification of ECG assessment and eliminated 
redundant language.
Collection of Avelumab Pharmacokinetic 
Samples (Both Groups A and B) and 
Immunogenicity Assessment sections revised to 
provide better guidance on collection of 
avelumab PK and ADA samples, as well as 
proper sample management. 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................13
APPENDICES .........................................................................................................................13
PROTOCOL SUMMARY.......................................................................................................14
SCHEDULE OF ACTIVITIES................................................................................................19
1. INTRODUCTION ...............................................................................................................26
1.1. Indication.................................................................................................................26
1.2. Background and Rationale ......................................................................................26
1.2.1. Non-Small Cell Lung Cancer .....................................................................26
1.2.1.1. ALK Alterations in NSCLC......................................................26
1.2.1.2. Activity of Immune Checkpoint Inhibitors in NSCLC .............27
1.2.2. Pharmaceutical and Therapeutic Background ............................................28
1.2.2.1. Avelumab (MSB0010718C) .....................................................28
1.2.2.2. Crizotinib (XalkoriPF-02341066)..........................................31
1.2.2.3. PF-06463922.............................................................................33
1.2.3. Rationale for Studying Crizotinib in Combination with Avelumab in 
Patients with ALK-Negative NSCLC..............................................................35
1.2.4. Rationale for Studying PF-06463922 in Combination with Avelumab 
in Patients with ALK-Positive NSCLC ...........................................................36
1.2.5. Rationale for Avelumab Starting Dose and Regimen.................................37
1.2.6. Rationale for Starting Crizotinib Dosing Regimen ....................................37
1.2.7. Rationale for Starting PF-06463922 Dosing Regimen...............................37
1.3. Summary of Risk-Benefit Assessment....................................................................37
2. OBJECTIVES AND ENDPOINTS.....................................................................................38
2.1. Objectives................................................................................................................38
2.2. Endpoints.................................................................................................................39
3. STUDY DESIGN.................................................................................................................40
3.1. Study Overview.......................................................................................................40
3.1.1. Phase 1b Evaluation to Determine MTD/RP2D.........................................43
3.1.1.1. Group A.....................................................................................43
3.1.1.2. Group B.....................................................................................45

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3.2. Dose-Limiting Toxicity Definitions........................................................................48
3.3. Maximum Tolerated Dose Definition .....................................................................49
3.4. Recommended Phase 2 Dose Definition.................................................................49
4. PATIENT SELECTION......................................................................................................49
4.1. Inclusion Criteria.....................................................................................................49
4.2. Exclusion Criteria....................................................................................................51
4.3. Lifestyle Guidelines ................................................................................................54
4.3.1. Sunlight Exposure.......................................................................................56
4.4. Sponsor’s Qualified Medical Personnel..................................................................56
5. STUDY TREATMENTS.....................................................................................................56
5.1. Allocation to Treatment ..........................................................................................56
5.2. Patient Compliance .................................................................................................57
5.3. Investigational Product Supplies.............................................................................57
5.3.1. Dosage Form(s) and Packaging..................................................................57
5.3.1.1. Avelumab ..................................................................................57
5.3.1.2. Crizotinib...................................................................................57
5.3.1.3. PF-06463922.............................................................................58
5.3.2. Preparation and Dispensing........................................................................58
5.3.2.1. Avelumab ..................................................................................58
5.3.2.2. Crizotinib...................................................................................58
5.3.2.3. PF-06463922.............................................................................58
5.4. Administration.........................................................................................................59
5.4.1. Avelumab....................................................................................................59
5.4.2. Crizotinib....................................................................................................60
5.4.3. PF-06463922...............................................................................................60
5.4.4. Treatment after Initial Evidence of Radiologic Disease Progression.........61
5.4.5. Treatment after Confirmed Complete Response ........................................61
5.5. Recommended Dose Modifications ........................................................................62
5.5.1. Management of Avelumab + Crizotinib Treatment-Related Toxicity .......63
5.6.1. Management of Avelumab + PF-06463922 Treatment-Related 
Toxicity............................................................................................................77
5.6.1.1. Special Precautions for Avelumab Administration...................90

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5.6.1.2. Management of Avelumab Infusion-Related Reactions ...........90
5.6.1.3. Management of Avelumab-Related Severe 
Hypersensitivity Reactions................................................................91
5.6.1.4. Management of Avelumab Immune-Related Adverse 
Events ................................................................................................91
5.6.2. Crizotinib Dose Modifications ...................................................................92
5.6.2.1. Nausea and Emesis....................................................................92
5.6.2.2. Diarrhea.....................................................................................92
5.6.2.3. Bradycardia ...............................................................................92
5.6.2.4. Pneumonitis/Pneumonia............................................................93
5.6.2.5. Renal Cysts................................................................................93
5.6.3. PF-06463922 Dose Modifications..............................................................94
5.6.3.1. PR Interval Prolongation...........................................................94
5.6.3.2. Pancreatitis ................................................................................94
5.6.3.3. CNS Effects...............................................................................95
5.6.3.4. Lipid Management ....................................................................95
5.7. Investigational Product Storage and Accountability...............................................96
5.7.1. Avelumab....................................................................................................96
5.7.2. Crizotinib....................................................................................................97
5.7.3. PF-06463922...............................................................................................97
5.8. Destruction of Investigational Product Supplies.....................................................97
5.9. Concomitant Treatment(s).......................................................................................98
5.9.1. Inhibitors and Inducers of CYP Enzymes ..................................................98
5.9.1.1. Group A.....................................................................................98
5.9.1.2. Group B.....................................................................................99
5.9.2. Other Anti-Tumor/Anti-Cancer or Experimental Drugs ..........................100
5.9.2.1. Other Prohibited Concomitant Medications and Therapies ....101
5.9.3. Hematopoietic Growth Factors.................................................................101
5.9.4. Concomitant Surgery................................................................................102
5.9.5. Concomitant Radiotherapy.......................................................................102
5.9.6. Clarification About Steroid Use ...............................................................102
6. STUDY PROCEDURES ...................................................................................................103
6.1. Screening...............................................................................................................103

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6.1.1. Tumor Biospecimens................................................................................103
6.1.2. Determination of NSCLC Molecular Status.............................................104
6.2. Treatment Period...................................................................................................104
6.3. End of Treatment/Withdrawal and Follow-Up Visits...........................................104
6.4. Patient Withdrawal................................................................................................104
6.5. Follow-up Visits....................................................................................................105
7. ASSESSMENTS................................................................................................................105
7.1. Safety Assessment.................................................................................................105
7.1.1. Pregnancy Testing ....................................................................................106
7.1.2. Adverse Events.........................................................................................106
7.1.2.1. Avelumab Adverse Events of Special Interest........................106
7.1.3. Laboratory Safety Assessment .................................................................106
7.1.4. Vital Signs and Physical Examinations....................................................107
7.1.5. 12-Lead Electrocardiograms.....................................................................108
7.2. Pharmacokinetics Assessments.............................................................................108
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis .........................109
7.2.2. Collection of Avelumab Pharmacokinetic Samples (Both Groups A 
and B).............................................................................................................109
7.2.3. Collection of Crizotinib Pharmacokinetic Samples (Only Group A).......110
7.2.4. Collection of PF-06463922 Pharmacokinetic Samples (Only Group 
B)....................................................................................................................110
7.3. Immunogenicity Assessment.................................................................................110
7.4. Translational and Pharmacodynamic Assessments...............................................111
7.4.1. Tumor Tissue............................................................................................111
7.6. Tumor Response Assessments ..............................................................................114
8. ADVERSE EVENT REPORTING....................................................................................115
8.1. Adverse Events......................................................................................................115
8.2. Reporting Period ...................................................................................................115
8.3. Definition of an Adverse Event.............................................................................115
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8.4. Medication Errors..................................................................................................116
8.5. Abnormal Test Findings........................................................................................117
8.6. Serious Adverse Events.........................................................................................117
8.6.1. Protocol-Specified Serious Adverse Events.............................................118
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................118
8.7. Hospitalization ......................................................................................................119
8.8. Severity Assessment..............................................................................................121
8.9. Causality Assessment............................................................................................121
8.10. Exposure During Pregnancy................................................................................121
8.11. Occupational Exposure .......................................................................................123
8.12. Withdrawal Due to Adverse Events (See Sections 6.3 and Section 6.4) ............123
8.13. Eliciting Adverse Event Information ..................................................................123
8.14. Reporting Requirements......................................................................................123
8.14.1. Serious Adverse Event Reporting Requirements ...................................123
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................124
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............124
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................124
9.1. Analysis Sets .........................................................................................................124
9.2. Statistical Methods and Properties ........................................................................125
9.2.1. Statistical Methods for Dose De-Escalation/Re-Escalation: mTPI ..........125
9.3. Sample Size Determination...................................................................................126
9.4. Efficacy Analysis ..................................................................................................127
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................129
9.5.1. Analysis of Pharmacokinetics...................................................................129
9.5.1.1. Pharmacokinetic Analysis of Crizotinib, PF-06463922, 
and Avelumab..................................................................................129
9.5.1.2. Immunogenicity Assessment...................................................129
9.5.1.3. Population Pharmacokinetic Analysis.....................................130
9.5.2. Biomarkers................................................................................................130
9.6. Safety Analysis......................................................................................................130
9.6.1. Analysis of the Primary Endpoint.............................................................130
9.6.2. Analysis of Secondary Safety Endpoints..................................................130

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9.8. Data Monitoring Committee .................................................................................132
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................132
11. DATA HANDLING AND RECORD KEEPING ...........................................................133
11.1. Case Report Forms/Electronic Data Record .......................................................133
11.2. Record Retention.................................................................................................133
12. ETHICS............................................................................................................................134
12.1. Institutional Review Board/Ethics Committee....................................................134
12.2. Ethical Conduct of the Study ..............................................................................134
12.3. Patient Information and Consent.........................................................................134
12.4. Patient Recruitment.............................................................................................135
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................135
13. DEFINITION OF END OF TRIAL.................................................................................135
13.1. End of Trial in a Member State...........................................................................135
13.2. End of Trial in All Other Participating Countries...............................................136
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................136
15. PUBLICATION OF STUDY RESULTS........................................................................136
15.1. Communication of Results by Pfizer ..................................................................136
15.2. Publications by Investigators ..............................................................................137
16. REFERENCES ................................................................................................................138
LIST OF TABLES
Table 1.
Crizotinib plus Avelumab Dose Levels................................................................43
Table 2.
Possible Dose Finding Sequences (Group A).......................................................43
Table 3.
Detailed Dose Re-Escalation/De-Escalation Scheme...........................................44
Table 4.
PF-06463922 plus Avelumab Dose Levels (Group B).........................................46
Table 5.
Possible Dose Finding Sequences (Group B).......................................................46
Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity .................63
Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity............77
Table 8.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions...............................................................................................................91
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Table 9.
Crizotinib Dose Levels for Intrapatient Dose Modifications ...............................92
Table 10.
PF-06463922 Dose Levels for Intrapatient Dose Modifications..........................94
Table 11.
Elevated Lipid Management.................................................................................95
Table 12.
Required Laboratory Tests .................................................................................107
Table 13.
Overall Response Derived from Changes in Index, Non-index and New 
Lesions................................................................................................................154
LIST OF FIGURES
Figure 1.
Study Schema .......................................................................................................42
APPENDICES
Appendix 1. Abbreviations and Term Definitions.................................................................143
Appendix 2. ECOG Performance Status................................................................................147
Appendix 3. RECIST Version 1.1 .........................................................................................148
Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................152
Appendix 6. Drugs Known to Prolong PR Interval...............................................................155
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PROTOCOL SUMMARY 
Indication:
For the avelumab/crizotinib combination (Group A): previously treated locally advanced or 
metastatic Anaplastic Lymphoma Kinase (ALK)–negative non-small cell lung cancer 
(NSCLC).
For the avelumab/PF-06463922 combination (Group B): locally advanced or metastatic 
ALK-positive NSCLC.  Group B Phase 2 will be limited to patients who are treatment-naïve. 
Background:
Non-small cell lung cancer is the most common cause of fatal malignancy globally, most 
often diagnosed in advanced stages, where surgery and local radiotherapy are no longer 
curative.9,37 Standard therapy in later stages of disease is primarily palliative in nature, 
involving the use of cytotoxic chemotherapy with or without radiation therapy7,32 or 
immunotherapy.5,28,30,31,42 Despite these advances, patients with NSCLC have a poor 
long-term survival. 
Targeted therapy has been successful in NSCLC patients who have tumors that harbor 
various mutations, including EML4-ALK.  The first approved agent for ALK-positive 
NSCLC is crizotinib.  Although most patients with ALK-positive derive substantial clinical 
benefit from crizotinib, some ALK-positive NSCLC patients will not derive any benefit 
(intrinsic resistance) while other patients who initially derived benefit will develop resistance 
(acquired resistance).  In the case of crizotinib-resistant ALK-positive NSCLC, the rate of 
resistance due to mutations in the ALK kinase domain is typically reported in the range of 
35-40%.6 In response to causes of crizotinib treatment failure, next generation 
ALK/ROS1 tyrosine kinase inhibitor (TKI)s are being developed.  PF-06463922 is a 
selective, brain-penetrant ALK TKI with potent activity against ALK and ROS1 fusions, 
including those harboring resistance mutations.
Recent evidence has shown that tumors also require suppression of the host immune system 
for continued growth and spread.  The development of agents targeting the interaction of 
programmed death receptor-1 (PD-1) and its ligands has shown promise in the treatment of 
various cancers including NSCLC.5,11,31 Promising activity has been seen among patients 
with NSCLC that has progressed after platinum-based chemotherapy when using avelumab.49
It is becoming clear that combination strategies will be one way to enhance antitumor 
activity.45 T cell suppression by immune checkpoint inhibitors may not be sufficient if not 
accompanied by T cell homing to tumor and their activation.1,29 Zhou et al recently 
identified ALK in a screen as one of the genes involved in suppressing T cell infiltrating the 
tumor.46 T cells transduced with pooled short hairpin RNA (shRNA) libraries targeting 
negative regulators of T cell function were injected into B16 melanoma-bearing mice.  Short 
hairpin RNA-driven CD8+ T cell accumulation in tumors was found to be more than doubled 
relative to peripheral lymphoid tissue when ALK was targeted.  These results suggest that the 
same immunostimulatory effect may be achieved with pharmacologic inhibition of ALK. 

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Indeed, preliminary internal Pfizer data demonstrates synergistic activity of both crizotinib 
and PF-06463922 with PD-L1 blockade in a murine ALK-negative colon carcinoma 
syngeneic model, CT26 (Pfizer, data on file). 
Objectives and Endpoints:
Phase 1b Primary Objectives:
•
Group A (ALK-negative): To determine maximum tolerated dose (MTD) and the 
recommended Phase 2 dose (RP2D) of the combination of avelumab with crizotinib;
•
Group B (ALK-positive): To determine the MTD and the RP2D of the combination 
of avelumab with PF-06463922.
Phase 2 Primary Objectives:
•
Group A: To assess Objective response rate (ORR) per Response Evaluation Criteria 
in Solid Tumors (RECIST) v.1.1 in previously treated locally advanced or metastatic 
ALK-negative NSCLC patients treated with the combination of avelumab and 
crizotinib at the RP2D;
•
Group B: To assess ORR and complete response (CR) rate per RECIST v.1.1 in 
previously untreated locally advanced or metastatic ALK-positive NSCLC patients 
treated with the combination of avelumab and PF-06463922 at the RP2D.
Secondary Objectives (both Phase 1b/2):
•
To evaluate the safety and tolerability of avelumab in combination with crizotinib 
(Group A) or with PF-06463922 (Group B); 
•
To assess antitumor activity of avelumab in combination with crizotinib (Group A) or 
with PF-06463922 (Group B);
•
To characterize the PK of avelumab in combination with crizotinib (Group A) or with 
PF-06463922 (Group B);
•
To assess the immunogenicity of avelumab;
•
To evaluate candidate predictive biomarkers of sensitivity or resistance to 
combination therapy in pretreatment tumor tissue.
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Endpoints
Primary Endpoints
Phase 1b:
•
First 2 cycles DLTs for Group A and Group B.
Phase 2: 
•
Confirmed Overall Response (OR) per RECIST v.1.1 for Group A.
•
Confirmed OR and CR per RECIST v.1.1 for Group B.
Secondary Endpoints
•
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Appendix 4); vital signs (blood pressure, pulse rate);
•
Disease Control (DC), Duration of Response (DR), Time to Tumor Response (TTR), 
Progression-Free Survival (PFS) per RECIST v.1.1, and Overall Survival (OS);
•
Pharmacokinetic parameters of crizotinib, its metabolite PF-06260182, and avelumab 
will be determined as data permit:
•
Maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax), area under the plasma concentration-time curve during the dosing interval 
time course (AUCtau), area under the plasma concentration-time curve from time 
of dosing to the last collection time point (AUClast), apparent plasma clearance 
(CL/F), and apparent volume of distribution (V/F) for crizotinib following 
multiple dosing in the presence of avelumab, as data permit; 
•
Cmax, Tmax, AUCtau, metabolite to parent ratio for AUCtau (MRAUCtau), and 
metabolite to parent ratio for Cmax (MRCmax) for PF-06260182 following multiple 
doses in the presence of avelumab;
•
Cmax,  Tmax, AUCtau, AUClast, CL/F, and Vz/F for PF-06463922 following multiple 
dosing in the presence of avelumab, if data permit---; 
•
Single and multiple dose pharmacokinetics (Cmax, Ctrough of avelumab in the 
presence of crizotinib and PF-06463922);
•
Avelumab anti-drug antibodies (ADA; neutralizing antibodies);
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•
Tumor tissue biomarkers, including but not limited to, PD-L1 expression and tumor 
infiltrating CD8+ T cells by immunohistochemistry (IHC).
 
 
 
Study Overview:
This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, pharmacokinetic and 
pharmacodynamic study of Group A and Group B in cohorts of adult patients with locally 
advanced or metastatic NSCLC (see Section 3; Figure 1):
Phase 1b:
Both Group A and Group B will be evaluated to identify the MTD and the RP2D.  Patients 
will be treated at dose level 0 (DL0) of the combination as noted in Table 1 and Table 4.  
Determination of the MTD will be performed using the modified toxicity probability index 
(mTPI) design as described in Section 3.1.1.1.1 and Section 3.1.1.2.1 using dose 
de-escalation from the approved prescribed dose of crizotinib (250 mg BID), dose level 
established to be safe and effective for PF-06463922 (100 mg QD), and the RP2D of 
avelumab (10 mg/kg Q2W).  In Group B, a dose expansion will evaluate an additional 
12 patients at the MTD/RP2D to further assess the safety, pharmacokinetics, 
pharmacodynamics and antitumor activity of the combination.
Phase 2 (Group A )
After the MTD is identified and the RP2D is determined in Group A, the 12 patients treated 
at the RP2D will be considered Stage 1 of Simon’s Optimal Two-Stage design.  If 3 or more 
patients of the 12 in Phase 1b have a confirmed response per RECIST v.1.1, then in 
Phase 2 an additional 33 patients will be enrolled and treated.  If there are fewer than 
3 patients who have a confirmed objective response in the first 12 patients treated at the 
RP2D, then Phase 2 will not be opened for enrollment.  Patients with ALK-negative NSCLC 
who are enrolled and subsequently determined by retrospective central testing to be positive 
for ALK gene rearrangement, ROS1 gene translocation, c-Met gene amplification, or c-Met 
exon 14 deletion may be replaced.  Patients with NSCLC containing epidermal growth factor 
receptor (EGFR) mutations are permitted onto Group A if they have exhausted appropriate 
targeted therapy for these mutations.
Phase 2 (Group B)
Following the identification of the MTD and determination of the RP2D, approximately
30 additional patients who are treatment-naive will be enrolled in the Phase 2 portion to 
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further assess the antitumor activity, safety, pharmacokinetics and pharmacodynamics of the 
combination at the RP2D.
Study Procedures:
For detailed description of the study procedures, please consult the Schedule of Activities.

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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the Schedule of Activities table in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
TREATMENT PERIOD
(1 CYCLE = 14 DAYS)
END of TREATMENT/FOLLOW-UP
CYCLES 1-2
CYCLES ≥3
Visit Identifier
Screening
(28 Days Prior to 
Enrollment)
Day 1
Day 1
End of Treatment / 
Withdrawal25
Follow-up Visits
Day 30, 60, and 
90 Days After 
Last Dose
Survival 
Follow-up26
Visit Time Window
(Cycle 2 3 days)
(3 days)
(+3 days)
(3 days)
(3 days)
Informed Consent
X
Tumor History
X
Medical/Oncology History 
(including prior regimens)
X
Physical Examination
X
X
X
X
Contraception Check1
X
X
X
X
Ophthalmologic Examination 
(Group A only)2
X
X
(Cycle 5 only)
Baseline Signs and Symptoms3
X
Weight
X
X
X
X
Vital Signs4
X
X
X
X
ECOG Performance Status5
X
X
X
X
12-Lead ECG6
X
X
X (Cycle 3 only)
X
Laboratory7
Hematology8
X
X (Cycles 1 and 
2 Days 1 and 8)
X
X
X
Blood Chemistry9
X
X (Cycles 1 and 2 
Days 1 and 8)
X
X
X
Coagulation10
X
X
X
X
ACTH, FT4, and TSH11
X11
X11
X11
X
X
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TREATMENT PERIOD
(1 CYCLE = 14 DAYS)
END of TREATMENT/FOLLOW-UP
CYCLES 1-2
CYCLES ≥3
Visit Identifier
Screening
(≤28 Days Prior to 
Enrollment)
Day 1
Day 1
End of Treatment / 
Withdrawal25
Follow-up Visits
Day 30, 60, and 
90 Days After 
Last Dose
Survival 
Follow-up26
Visit Time Window
(Cycle 2 ±3 days)
(±3 days)
(+3 days)
(±3 days)
(±3 days)
Urinalysis12
X
X
X
Pregnancy Test13
X
X
X
X
X
Registration and Treatment
Registration14
X
Avelumab Administration
(Group A and Group B)15
X
X
Crizotinib Administration 
(Group A) 15
Orally on a 
continuous daily 
dosing schedule
→
PF-06463922 Administration 
(Group B)15
Orally on a 
continuous daily 
dosing schedule
→
Tumor Assessments
CT or MRI Scan or equivalent16
X
X (Q8 weeks)
X
Other Clinical Assessments
Adverse Events17
→
→
X
X
Concomitant and Subsequent 
Treatments18
→
→
X
X
Survival Update
X
Other Samples
Mandatory Archival formalin 
fixed paraffin embedded 
(FFPE) Tumor Tissue19
X
 
 
 
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TREATMENT PERIOD
(1 CYCLE = 14 DAYS)
END of TREATMENT/FOLLOW-UP
CYCLES 1-2
CYCLES ≥3
Visit Identifier
Screening
(≤28 Days Prior to 
Enrollment)
Day 1
Day 1
End of Treatment / 
Withdrawal25
Follow-up Visits
Day 30, 60, and 
90 Days After 
Last Dose
Survival 
Follow-up26
Visit Time Window
(Cycle 2 ±3 days)
(±3 days)
(+3 days)
(±3 days)
(±3 days)
 
Blood for Avelumab PK23
(Group A and Group B)
X
X 
(Up to Cycle 5, 
then Q12wks)
X
Blood for Avelumab ADA and 
Neutralizing antibody 
(Immunogenicity) Testing24
(Group A and Group B)
X
X 
(Up to Cycle 5, 
then Q12wks)
X
X
30 (±3) days after 
last avelumab dose
Blood for Crizotinib 
PK22(Group A)
X (Cycle 2 only)
X (Cycles 4 and 7)
Blood for PF-06463922 PK23
(Group B)
X (Cycle 2 only)
X (Cycles 4 and 7)
Abbreviations: →= ongoing/continuous event; ADAs = anti-drug antibodies; AEs = adverse events; C = cycle; ECG = electrocardiogram, CT = computed 
tomography; MRI = magnetic resonance imaging; PK= pharmacokinetics
Footnotes 
1.
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.  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.
2.
Ophthalmologic Examination (Group A only) (right and left eye): includes best corrected visual acuity (Snellen) and refractive error slit lamp 
biomicroscopy, and ophthalmoscopy and should be performed by an ophthalmologist.  Testing will be performed at screening, on Cycle 5 Day 1, and should 
be repeated during the study whenever a vision disorder AE is observed or CTCAE grade change occurs from the previous visit. 
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3.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry.  Baseline signs 
and symptoms will be recorded on the Medical History case report form (CRF) page.
4.
Vital signs: Blood pressure (BP) and pulse rate to be recorded in seated position.  See Section 7.1.4.
5.
ECOG Performance Status: Use Eastern Cooperative Oncology Group (ECOG) Performance Status– see Appendix 2.
6.
12-Lead ECG: All patients require a single ECG measurement at screening.  For triplicate ECGs, three (3) consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine mean QTc.  Triplicate ECGs should be performed immediately before PK blood draws at respective time points.  
On-treatment triplicate ECGs should be obtained at pre-dose and between 2 and 6 hours following both the morning crizotinib or PF-06463922 and 
avelumab dosing on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1.  If the QTc is prolonged (>500 msec), then the ECG should be re-evaluated by a 
qualified person at the institution for confirmation (such as a cardiologist).  On all other visits, single ECGs should be performed.  Additional ECGs will be 
performed as clinically indicated.  Clinically significant findings seen on follow-up ECGs should be recorded as adverse events.  See Section 7.1.5 for 
further details.
7.
Laboratory Tests: Refer to Assessments Section 7.1.3 for Laboratory Tests list.  On those weeks when no other assessments are required as per the SOA, a 
visit to the clinical site is not required unless the investigator considers it necessary.
8.
Hematology: No need to repeat on Cycle 1 (C1D1) if screening assessment performed within 3 days prior to that date.  See Assessments Section 7.1.3 for 
Laboratory Tests.
9.
Blood Chemistry: Includes all tests marked as components of the Core Chemistry Test in Section 7.1.3.  No need to repeat on Cycle 1 (C1D1) if screening 
assessment performed within 3 days prior to that date.  Patients with liver metastases at baseline should have blood chemistry performed weekly during the 
first 6 weeks of study treatment.
10. Coagulation: No need to repeat on Cycle 1 (C1D1) if screening assessment performed within 7 days prior to that date.  See Assessments Section 7.1.3 for 
Laboratory Tests list.
11. ACTH, FT4, TSH Tests: There is no need to repeat on Cycle 1 Day 1 if screening assessment is performed within 14 days prior to study enrollment. 
At screening, every 8 weeks, EOT visit, 30 days, 60 days and 90 days after last dose of study treatment and if clinically indicated. 
12. Urinalysis: To be done at screening and EOT, and as clinically indicated.  Dipstick is acceptable.  Microscopic analyses should be performed if dipstick 
abnormal and/or if this is the local standard.  No need to repeat on Cycle 1 Day 1 if screening assessment performed within 7 days prior to that date.  In 
Korea, repeat exams should be completed at Day 1 of every cycle and at the end of treatment; all other countries should perform as clinically indicated, for 
example, upon diagnosis of renal cysts.  Reflex Microscopy required if urine dipstick is positive for blood or protein.  See Assessments Section Section 
7.1.3 for Laboratory Tests.
13. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in 
a certified laboratory, will be performed on two occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediately before investigational product administration.  Urine pregnancy tests will also be routinely repeated at every treatment cycle during the active 
treatment period, at the end of study therapy during follow-up (up to 90 days after last study treatment), and additionally whenever one menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review 
board/ethics committee (IRB/ECs) or if required by local regulations.  See Section 7.1.1.

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14. Registration:  Allocation of patients to treatment groups will proceed through the use of an Interactive Response Technology (IRT) System (see 
Section 5.1).
15. Study Treatment Administration: Group A and Group B: Avelumab will be given as a 1-hour infusion every 2 weeks (as described in Section 5.4.1).  
Group A: Crizotinib will be given orally BID (or QD based upon dose level) on a continuous daily dosing schedule (see Section 5.4.2).  
Group B: PF-06463922 will be given orally QD on a continuous daily dosing schedule (as described in Section 5.4.3). 
16. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis CT or MRI 
scans.  Brain scans and bone scans will be performed at baseline if disease is suspected and on study as appropriate to follow disease.  Baseline central 
nervous system (CNS) imaging is required to rule out CNS metastases. CT or MRI scans are to be done starting at Cycle 4/Week 8 (+1 week) then repeated 
every 4 cycles/8 weeks (±1 week).  In case partial response (PR), complete response (CR) or progressive disease (PD) is observed according to RECIST 
v.1.1
 confirmation CT or MRI should be performed no sooner than 4 weeks after the first 
documentation of response or disease progression.  Tumor assessment should be repeated at the End of Treatment visit if more than 4 weeks have passed 
since the last evaluation.  All radiographic images will be collected and may be objectively verified by a BICR independent third-party core imaging 
laboratory as described in the Imaging Manual.  A bone scan (bone scintigraphy) or 18FDG-PET/CT is required at baseline, then every 16 weeks only if 
bone metastases are present at baseline.  Otherwise, bone imaging is required only if new bone metastases are suspected.  Bone imaging is also required at 
the time of CR confirmation for patients who have bone metastases.  Tumor assessments should continue until documented disease progression regardless of 
initiation of subsequent anti-cancer therapy.  See Section 7.6 for additional information.
17. 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 (see Appendix 4).  For SAEs, the active reporting period to Pfizer or its designated 
representative begins from the time that the patients 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 study treatment, through and including 90 calendar days after the last dose of study treatment.  
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 (see Section 8.2).  AEs (serious and non-serious) should be recorded on the case report form (CRF) from the time the patients has taken at least 
1 dose of study treatment 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 study treatment, irrespective of 
any intervening treatment. 
18. Concomitant and Subsequent Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 90 days after the last dose of study treatment (at Days 30, 60, and 90 post-treatment ±3 days).  All concomitant medications should be recorded in the
CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug 
supportive interventions (eg, transfusions).
19. Mandatory Archival FFPE 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; archival tumor tissue collection should be within one year of 
start of study treatment, with no intervening systemic anti-cancer therapy (including neoadjuvant or adjuvant therapy).  If an older archival tumor tissue (ie, 
> 1 year from start of study treatment) is available it can be submitted but will not fulfill the requirement for mandatory tumor tissue.  If an FFPE tumor 
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 FFPE 
block.  If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be obtained (see footnote, De Novo Tumor biospsy) Acquisition of 
the mandatory tumor tissue may be completed prior to the 28-day screening window, but it is required for patient enrollment.  Note that if archival FFPE 
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tumor tissue cannot be provided, FFPE tumor tissue from a de novo tumor biopsy performed at screening must be provided.  Retrospective central testing 
will be performed to confirm ALK status as well as to test for alterations in ROS1, c-Met, and EGFR genes.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23. PK Sampling: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic Samples Collection Table.  Pharmacokinetic 
samples for avelumab will be collected from all patients in the study.  Serial PK samples for crizotinib (Group A) and PF-06463922 (Group B) will be 
collected from all patients in the Phase 1b portion, and sparse sampling will be collected in all patients in the Phase 2 portion of the study.
24. Blood for Avelumab Immunogenicity Testing (anti-avelumab antibodies; anti-drug antibodies [ADAs]) and Neutralizing Antibodies (Nab): All 
samples (3.5 mL) should be drawn within 2 hours before the start of the avelumab infusion.  Additional samples for ADAs will be collected at 30 (±3) days 
after the end of avelumab therapy.  If patient discontinues avelumab treatment and continues crizotinib or PF-06463922 monotherapy, the 30 day follow up 
sample is not required.  All samples that are positive for ADA may also undergo characterization for Nab.
25. End of Treatment: Obtain these assessments if not completed within the prior week, except for tumor assessments, which need not be repeated if performed 
within the prior 4 weeks.
26. Survival Follow-Up: After discontinuation of study treatment, post-study survival status will be collected every 2 months until death or until 24 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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Pharmacokinetic Sample Collection Table
Cycle Identifier 
Cycle 1
Cycles -2
Cycles 3
Post-Treatment 
Study Day
Day 1
Day 8
Day 1
Day 8
Day 1
End of Treatment/
Withdrawal 
Follow-up
Hours Post-Dose
0a
1
0a
1
2
4
6
8
24
0a
PK Blood Samples 
for Avelumabb
(Group A and 
Group B)
X
X
X
X
X
X
Xa
(Up to Cycle 5, 
then every 6 cycles 
thereafter)
X
PK Blood Samples 
for Crizotinibc 
(Group A only)
X
X
X
X
X
X
Xc
Xa
(Cycles 4 and 7)
PK Blood Samples 
for PF-06463922d 
(Group B only)
X
X
X
X
X
X
X
Xa
(Cycles 4 and 7)
PK = pharmacokinetic, ADAs=anti-drug antibodies
a.
Pre-dose.  For crizotinib or PF-06463922 PK samples, just prior to administration of crizotinib or PF-06463922.  For avelumab PK sample, up to 2 hours 
prior to the start of infusion of avelumab. 
b.
One PK blood sample collected at each time point for avelumab.  For patients in Group A and B, blood samples for avelumab PK will be collected (3.5 mL) 
at pre-dose and 1 hour from the start of infusion ( end of infusion) on Day 1, and anytime during the Day 8 clinic visit of Cycles 1 and 2.  Pre-dose samples 
will be collected on Day 1 of Cycles 3 through 5 followed by Day 1 every 6 cycles thereafter.  An additional sample will be collected at the End of 
Treatment. 
c.
Group A only: One PK blood sample (3 mL) collected at each time point for crizotinib.  For all patients enrolled in Phase 1b of Group A, serial blood 
samples for PK of crizotinib will be collected at: pre-dose, 1, 2, 4, 6 and 8 hours post-dose on Day 1 of Cycle 2 only.  Only for patients at DL-2C or 
DL-1A-2C, an additional 24 hour sample (prior to Day 2 dose of crizotinib) post Day 1 of Cycle 2 dose will be obtained.  Sparse blood samples (pre-dose 
only) will be collected on Day 1 of Cycles 4 and 7.  For all patients enrolled in Phase 2, only pre-dose blood samples will be collected on Day 1 of Cycles 2, 
4, and 7 for PK of crizotinib.
d.
Group B only: One PK blood sample collected (4 mL) at each time point for PF-06463922.  For all patients enrolled in Phase 1b of Group B, serial blood 
samples for PK of PF-06463922 will be collected at: pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 PF-06463922 dose) post-dose on Day 1 of 
Cycle 2 only.  Sparse blood samples (pre-dose only) will be collected on Day 1 of Cycles 4 and 7.  For all patients enrolled in Phase 2, only pre-dose blood 
samples will be collected on Day 1 of Cycles 2, 4, and 7 for PK of PF-06463922. 

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1. INTRODUCTION
1.1. Indication 
For the avelumab/crizotinib combination (Group A): previously treated locally advanced or 
metastatic Anaplastic Lymphoma Kinase (ALK)–negative -NSCLC.
For the avelumab/PF-06463922 combination (Group B): locally advanced or metastatic 
ALK-positive NSCLC.  Group B Phase 2 will be limited to patients who are treatment-naïve.  
Following the identification of the MTD and determination of the RP2D, approximately
30 additional patients who are treatment-naive will be enrolled in the Phase 2 portion to 
further assess the antitumor activity, safety, pharmacokinetics and pharmacodynamics of the 
combination at the RP2D.
1.2. Background and Rationale
1.2.1. Non-Small Cell Lung Cancer
NSCLC is the most common cause of fatal malignancy globally, most often diagnosed in 
advanced stages, where surgery and local radiotherapy are no longer curative.9,37 Standard 
therapy in later stages of disease is primarily palliative in nature, involving the use of 
cytotoxic chemotherapy with or without radiation therapy or immunotherapy.5,28,30,31,42
Targeted therapies such as TKIs may be used for appropriate patients.  In spite of these 
treatments, 5-year survival is only about 17.0% for advanced-stage NSCLC patients, 
highlighting the need for novel therapies and treatment regimens.7,32
1.2.1.1. ALK Alterations in NSCLC
A rearrangement 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.40 A subsequent series of studies have described 9 fusion variants of EML4-ALK 
plus additional but less common fusion partners with ALK.23 Currently, there are at least 
27 different ALK fusion variants reported in the literature, the majority of isoforms involve 
EML4-ALK.  ALK-positive NSCLC patients, who represent between 3% and 5% of all 
NSCLC cases, tend to be young (average age 50 years at diagnosis), and light or never 
smokers.27 Oncogenic fusions of ALK and ROS1 define two distinct subsets of human lung 
adenocarcinoma patients and play essential roles in regulation of tumor cell survival, growth, 
and metastasis.
Crizotinib, a potent and selective adenosine triphosphate (ATP) competitive inhibitor of 
ALK, ROS 1, RON, and c-MET receptor tyrosine kinases and relevant oncogenic variants, 
was first studied clinically in ALK-positive NSCLC in an ongoing Phase 1 trial soon after the 
discovery of the EML4-ALK fusion protein oncogenic driver potential in NSCLC.40 The 
clinical benefit of crizotinib led to the US approval of crizotinib (XALKORI) in August 
2011 for the treatment of advanced ALK-positive NSCLC patients (See Section 1.2.2.2).

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Although most patients with ALK-positive tumors derive substantial clinical benefit from 
crizotinib, some patients will not derive any benefit (intrinsic resistance) while other patients 
who initially derived benefit will develop resistance (acquired resistance).  In the case of 
crizotinib-resistant ALK-positive NSCLC, the rate of resistance due to mutations in the ALK 
kinase domain is typically reported in the range of 35-40%.6
Resistance to ALK TKIs may be related to gatekeeper mutations along with activation of 
bypass resistance mechanisms such as germline variations in tumor response pathways.  
Multiple types of ALK kinase domain have been identified in crizotinib-refractory 
patients.6,8,21,44 Additional mechanisms of resistance include mutations in the ALK kinase 
domain, development of bypass mechanisms in the presence of ALK TKI sensitivity that is 
crizotinib-suppressed, failure of drug delivery to the target (such as the central nervous 
system [CNS]), ALK fusion gene amplification, and development of EGFR signaling.6,8,44 In 
response to these causes of crizotinib treatment failure, next generation ALK/ROS1 TKIs are 
being developed. 
PF-06463922 is a selective, brain-penetrant TKI with potent activity against ALK and 
ROS1 fusions, including those harboring resistance mutations.  Activity has been seen in 
previously treated patients with ALK and ROS1 fusion genes (ORR 44% [95% CI 27 – 62]), 
including intracranial responses.50 (See Section 1.2.2.2).
1.2.1.1.1. Potential activity of ALK TKIs in ALK-negative NSCLC
Recently, ALK was identified in a screen as one of the genes involved in suppressing T cell 
infiltrating the tumor.46 Short hairpin RNA-driven CD8+ T cell accumulation in tumors was 
found more than doubled relative to peripheral lymphoid tissue when ALK was targeted.  
These results suggest that the same immunostimulatory effect may be achieved with 
pharmacologic inhibition of ALK. 
Preliminary internal Pfizer data demonstrates synergistic activity of both crizotinib and 
PF-06463922 with PD-L1 blockade in a murine ALK-negative colon carcinoma syngeneic 
model, CT26 (Pfizer, data on file).  More information regarding the background and purpose 
of studying avelumab with crizotinib in ALK-negative patients is found in Section 1.2.3. 
1.2.1.2. Activity of Immune Checkpoint Inhibitors in NSCLC
Recent evidence has shown that tumors require suppression of the host immune system for 
continued growth and spread.  The development of agents targeting the interaction of 
PD-1 and its ligands has shown promise in the treatment of various cancers including 
NSCLC.5,11,31 Substantial clinical activity was observed with anti-PD-1 antibodies, 
nivolumab and pembrolizumab, with ORRs of 15% and 20%, respectively, and long duration 
of response (DR) in heavily pretreated unselected NSCLC patients.4,5,10 Similarly impressive 
activity was observed in the first-line treatment setting with ORRs of 30% and 26% for 
nivolumab and pembrolizumab, respectively.12,33 Anti-PD-L1 antibodies have also been 
studied in pre-treated unselected NSCLC with response rates of 16% to 23% for 
MEDI4736 and MPDL3280a, respectively.3,15

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The initial study of nivolumab in NSCLC reported responses in patients with ALK-positive 
NSCLC; these results are difficult to interpret as the ORR was associated with wide 
confidence intervals.3,15 There were only 7 patients with ALK-positive NSCLC in the 
Phase 3 CheckMate-057 non-squamous NSCLC trial (N=582 for the study), 4 received 
nivolumab and 3 received docetaxel.  ORR, OS, and PFS interpretation could not be 
performed due to the small subset of patients.31 It has been suggested that the use of 
combination therapy of immune checkpoint inhibitors with other agents would be more 
effective in stimulating immune responses.51
1.2.2. Pharmaceutical and Therapeutic Background 
1.2.2.1. Avelumab (MSB0010718C) 
Avelumab (MSB0010718C) is a fully human IgG1 monoclonal antibody directed against the 
Programmed Death Ligand-1 (PD-L1) molecule that is expressed by tumor cells, as well as 
by a number of immune cells.  Avelumab has a calculated molecular weight of 
143,832 Dalton.
Compared with anti-PD-1 antibodies that target T cells, avelumab targets tumor cells.  
Avelumab is expected to have fewer side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2/PD-1 pathway 
intact to promote peripheral self-tolerance.24 For complete details of the in vitro and 
preclinical studies, refer to avelumab Investigator’s Brochure (IB).17
Avelumab is being developed jointly by Pfizer and Merck KGaA.  The clinical development 
program for avelumab currently includes 4 ongoing studies in patients with various solid 
tumors conducted by Merck KGaA (EMR 100070-001, EMR 100070-002, 
EMR 100070-003, and EMR 100070-004).
Trial EMR100070-001 is a Phase 1, open-label, multiple-ascending dose clinical study aimed 
to investigate the safety, tolerability, PK, biological, and clinical activity of avelumab in 
patients with metastatic or locally advanced solid tumors.  This trial consisted of 2 parts, a 
dose escalation phase and a dose expansion phase, which is performed in selected tumor 
indications.  Avelumab was administered intravenously at the assigned dose level as a 1-hour 
intravenous (IV) infusion once every 2 weeks.  The following dose levels (DLs) were 
investigated: 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 20.0 mg/kg.
As of 05 November 2014, a total of 50 patients were treated in the dose escalation phase of 
the trial, with 4, 13, 13, and 20 patients being treated with avelumab of 1, 3, 10, and 
20 mg/kg, respectively.  None of the patients treated with doses up to 10 mg/kg experienced 
a DLT, and the 10 mg/kg dose of avelumab was considered a safe and well-tolerated dose for 
further investigation in the dose expansion cohorts.  One DLT (a Grade 3 immune-related AE 
characterized by increased creatine kinase, myositis, and myocarditis) was observed in 
1 patient at the dose of 20 mg/kg.
A total of 11 expansion cohorts are ongoing and 480 patients have been enrolled and treated 
by the cutoff date with the recommended dose of 10 mg/kg avelumab once every 2 weeks. 

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Of the 480 patients treated in the pooled expansion cohorts, 218 (45.4%) experienced at least 
1 Grade 3 treatment-emergent adverse event (TEAE), and 330 (68.8%) reported 
treatment-related TEAEs, of which 59 (12.3%) reported Grade 3 treatment-related TEAEs.
The most frequently reported (incidence 5%) treatment-related TEAEs (any grade) in the 
pooled expansion cohort are summarized in the avelumab IB.17 The most frequently reported 
(occurring in at least 2 patients) Grade 3 treatment-related TEAEs in the pooled expansion 
cohorts are presented in avelumab IB.17
Overall, 176 of the 480 patients (36.7%) treated in the dose expansion cohorts had serious 
TEAEs.  Of these, 22 (4.6%) patients experienced dyspnea, 19 patients (4.0%) disease 
progression, 12 patients (2.5%) pleural effusion, 11 patients (2.3%) pneumonia, 8 patients 
respiratory failure (1.7%) and 7 patients (1.5%) anemia.  All other serious TEAEs were each 
reported in less than 1.5% of patients.  Of the serious TEAEs considered treatment-related by 
the Investigator (31 patients; 6.5%), the following were reported for 2 or more patients:  
infusion-related reaction (4 patients, 0.8%), pneumonitis (3 patients, 0.6%), and disease 
progression, dyspnea, and hypercalcemia (2 patients each, 0.4%).
As of 05 November 2014, deaths were reported in 134 (27.9%) patients.  The primary cause 
of death was attributed to disease progression in 101 (21.0%) patients.  Seven 
treatment-related AEs with fatal outcome were reported.  Causes of the additional deaths 
were listed as due to AEs unrelated to study treatment, “other,” and “unknown”.  Of the 
137 patients who died, 53 patients (11.0%) died within 30 days of the last administration of 
trial treatment.  The 7 deaths due to TEAEs related to trial treatment were attributed to the 
following events: pneumonitis radiation-induced and dyspnea; acute liver failure associated 
with autoimmune hepatitis (no biopsy/autopsy performed); disease progression; fatal anoxic 
brain injury (not related) after cardiac arrest (related); autoimmune hepatitis with hepatic 
failure and fatigue (no biopsy/autopsy performed); respiratory distress and sepsis; and acute 
respiratory failure, acute exacerbation chronic obstructive pulmonary disease (COPD), and 
leukocytosis (occurred after the end of the on-treatment period). 
A total of 80 patients (16.7%) treated in the dose expansion cohorts withdrew permanently 
from trial treatment due to TEAEs.  In 34 (7.1%) of these patients, the TEAEs leading to trial 
treatment discontinuation were considered related to trial treatment by the Investigator.  The 
most frequent (2 patients) TEAEs leading to trial treatment discontinuation were 
infusion-related reaction (8 withdrawals; 1.7%), GGT increased and rash (3 withdrawals 
each, 0.6%), and aspartate aminotransferase increased, blood creatine phosphokinase 
increased, and disease progression (2 withdrawals each, 0.4%).
Immune-related Adverse Events: As of 05 November 2014, a cumulative review identified 
56 patients with potential immune-related AEs (irAEs) out of 480 patients (11.7%) treated in 
the dose expansion part of trial EMR 100070-001, and 4 cases out of 50 patients 
(8.0%) treated in the dose escalation part of trial EMR 100070-001, for a total of 69 irAEs.  
Of these 69 irAEs, 46 (67%) were assessed as treatment-related by the Investigator, and 
23 (33.3%) were assessed as not treatment-related by the Investigator.  Twenty-six irAEs 
were assessed as Grade 1, 29 as Grade 2, 11 as Grade 3, 2 as Grade 4, and 1 had a fatal 
outcome (radiation pneumonitis) (note: 2 Grade 3 suspected autoimmune hepatitis, not 
confirmed by biopsy, also had a fatal outcome).

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Infusion-Related Reactions: Two suspected unexpected serious adverse reactions (SUSARs; 
anaphylactic reaction and infusion-related reaction) involving 2 patients were reported in 
December 2013 and triggered a cumulative review of serious and non-serious cases of 
infusion-related reactions and hypersensitivity across the avelumab program.  Following 
evaluation of safety signals, infusion-related reactions and hypersensitivity have been 
classified as a newly identified risk (previously classified as a potential risk) and a mandatory 
premedication regimen of a histamine H1 receptor (H1) blocker plus 
acetaminophen/paracetamol was implemented for all trial patients starting 29 January 2014.
As of 05 November 2014, overall 49 (10.2%) of the 480 patients in the expansion cohort 
experienced at least 1 episode of infusion-related reaction when receiving avelumab 
monotherapy.  Most of the events were Grade 1 (8 patients, 1.7%) or Grade 2 (36 patients, 
7.5%) in severity, while Grade 3 (3 patients, 0.6%) and Grade 4 events (2 patients, 0.4%) 
were less frequent.  No Grade 5 events were reported.  Most of the infusion-related reaction 
events had an onset after the first (30 patients, 6.3%) or second (16 patients, 3.3%) avelumab 
infusion.  In 8 patients (1.7%), avelumab treatment was permanently discontinued because of 
infusion-related reaction events.  In addition, 1 patient (2.0%) in the dose escalation cohort 
also experienced an infusion-related reaction event (Grade 2). 
Mandatory premedication with H1 blockers plus acetaminophen/paracetamol was 
implemented for all patients who receive avelumab.  This premedication procedure was 
applied to 28/50 and 440/480 patients in the dose escalation and the pooled treatment 
expansion cohort, respectively.  Under this premedication procedure, 33 of 440 patients 
(7.5%) in the expansion cohort experienced infusion-related reaction events, with 6 patients 
(1.4%) having Grade 1, 26 patients (5.9%) having Grade 2, and 1 patient (0.2%) having 
Grade 3 events.  No infusion-related reaction events were reported in the 28 patients 
premedicated and treated in the dose escalation cohort.
In addition to the aforementioned patients, 1 case of Grade 4 cardiac arrest occurred 
1.5 hours after the third infusion of avelumab (10 mg/kg).  The patient died due to anoxic 
brain injury 7 days later; no autopsy was performed. 
The management of infusion-related reactions and severe hypersensitivity reactions can be 
found in Section 0 and Section 5.6.1.3, respectively.  A complete guideline for the 
emergency treatment of anaphylactic reactions according to the Working Group of the 
Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf.
Avelumab PK and dose proportionality following the first 1-hour infusion have been 
characterized in 57 Caucasian patients treated in the dose escalation and expansion cohorts of 
Study EMR 100070-001 by standard non-compartmental analysis.  This analysis revealed 
that the exposure parameters of Cmax and AUCtau increased in a dose proportionate fashion 
across the 1, 3, 10, and 20 mg/kg doses.  Apparent half-life tended to increase with dose, 
likely due to target mediated disposition at lower doses, but terminal half-life of 10 and 
20 mg/kg doses were similar (106-134 hours).  This likely indicates target mediated 
elimination does not increase at these two doses and target occupancy is very high. 

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Target occupancy (TO) on peripheral blood CD3+ T-cells was investigated in human blood 
in vitro by flow cytometry after spiking of whole blood samples from 8 healthy volunteers 
with avelumab over a concentration of 0.003-10 g/mL. Fifty percent (50%) receptor 
occupancy was observed at a drug concentration of 0.122 g/mL 0.042 g/mL with a 
plateau indicating at least 95% receptor occupancy reached in all blood samples at 1 g/mL.  
PK profiles obtained from the dose escalation phase of Trial EMR 100070-001 found all 
patients at 10 mg/kg dose reached or exceeded the serum level (median Ctrough 20-37 ug/ml) 
of avelumab required for >95% TO.  For patients treated with 3 mg/kg of avelumab, 10 of 
13 patients reached the required serum level (3.7-8.3 ug/ml).
Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab IB.17
1.2.2.1.1. Activity of Avelumab in NSCLC
The clinical efficacy of avelumab in NSCLC is based on data from the unselected NSCLC 
expansion cohort in the ongoing Phase 1 trial EMR 100070-001 using a data cutoff date of 
15 January 2015, 13 weeks after the start of avelumab treatment of the last patient in this 
expansion cohort (a total of 184 treated patients).  This group of NSCLC patients presented 
with a median age of 65 years with Stage IIIB or IV NSCLC that had progressed after at least 
1 line of platinum-containing doublet chemotherapy for locally advanced or metastatic 
disease.  The ECOG PS was 0 in 30% of patients and 1 in 70% of the patients.  The 
histologies treated were adenocarcinoma (62%), squamous cell carcinoma (29%), or other 
(9%).  These patients received avelumab 10 mg/kg Q2weeks.  Promising activity has been 
seen among patients with NSCLC that has progressed after platinum-based chemotherapy 
when using avelumab.17 The median duration of treatment was 12.2 weeks (range 2.0-64.0).  
As of the date of data cutoff, 41 of the 184 patients remained on treatment.  The ORR for the 
NSCLC expansion cohort was 13.6% (95% CI: 9.0 -19.4) including confirmed and 
unconfirmed responses.  One patient (0.5%) had a CR while 24 patients had confirmed and 
unconfirmed PR (13.0%).  The disease control rate (DCR), patients with confirmed and 
unconfirmed CR, PR, and SD, was 50.5%.  The median PFS in the NSCLC expansion cohort 
was 11.6 weeks (95% CI: 8.4 – 13.7) with the proportion of patients alive and 
progression-free at 24 weeks and 48 weeks equal to 26.2% (95% CI: 19.9 – 33.0) and 
18.1% (95% CI: 12.0 – 25.2), respectively.  The median OS in the NSCLC expansion cohort 
was 8.4 months (95% CI: 7.3 – 10.7) with 37.0% of patients alive at 12 months (95% 
CI: 27.1-46.9) in this heavily pretreated group of patients.  The toxicity profile of avelumab 
was noted to be in line with other immune checkpoint inhibitors of PD-1 and PD-L117
1.2.2.2. Crizotinib (XalkoriPF-02341066)
Crizotinib is a selective ATP competitive small molecule inhibitor of ALK, ROS1, RON, and 
c-MET/Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinases and their oncogenic 
variants (eg, ALK or ROS1 fusion proteins or c-MET/HGFR mutant variants).  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 (EML4-ALK or nucleophosmin- [NPM] ALK fusion variants). 

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The PK of crizotinib is explained in detail in the crizotinib IB.18 Oral dosing of crizotinib at 
250 mg BID showed plasma concentrations to reach steady state within 15 days.  The mean 
apparent terminal half-life was 42 hours in cancer patients after a single dose.  Crizotinib is 
absorbed with a peak plasma concentration occurring between 4 and 6 hours under fasted 
condition.  Crizotinib is a substrate of P-glycoprotein and is predominately metabolized by 
CYP3A4/5.  Crizotinib inhibited P-glycoprotein (P-gp), hepatic uptake transporter, organic 
cation transporter 1 (OCT1), and renal uptake transporter, organic cation transporter 
2 (OCT2) in vitro at clinically relevant concentrations.  Elimination of crizotinib was related 
to its hepatic, and possibly gastrointestinal, metabolism with a mean of 63.1% of [14C] 
crizotinib excreted in the feces and 22.2% in the urine.18
Overall, the AEs reported for crizotinib in clinical studies were considered generally 
tolerable and manageable.  For single-agent crizotinib use, 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 
crizotinib250 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 (ILD), and abdominal pain.  The Grade 5 treatment-related AEs that 
occurred most commonly were ILD (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%).18
There are special warnings regarding crizotinib use that must be considered and are described 
in detail in the crizotinib IB.18 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 pneumonitis/ILD and QTc prolongation which both occurred in fewer 
than 2% of patients and bradycardia which occurred in approximately 6% of patients.  
Specific management for these events is noted in Table 6.
Clinical trials using crizotinib showed high rates of objective tumor response that were rapid 
and durable in Studies A8081001 and A8081005.  In Study A8081007 (PROFILE 1007), 
second-line treatment of advanced ALK-positive NSCLC patients (after initial 
platinum-based chemotherapy) with crizotinib demonstrated a significant improvement in 
median PFS when compared to chemotherapy (pemetrexed or docetaxel monotherapy, 
median PFS: 7.7 months vs. 3.0 months, respectively; HR 0.487; 95% CI: 0.371, 0.638; 
P <0.001).  The objective response rates (ORRs) were 65% (95% confidence interval (CI), 
58, 72%) with crizotinib, as compared with 20% (95% CI:14, 26%) with chemotherapy 
(P<0.001)  The duration of response (DR) was 32.1 weeks with crizotinib (95% CI 2.1, 
72.4 weeks), as compared to 24.4 weeks with chemotherapy (95% CI 3.0, 43.6 weeks).52
Validated questionnaires (EORTC QLQ-C30 and QLQ-LC13) showed a significantly greater 

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improvement in patient-reported lung cancer symptoms and global quality of life receiving 
crizotinib as compared with chemotherapy.52 The first-line use of crizotinib was evaluated in 
Study A8081014 (PROFILE 1014) as compared with chemotherapy.  The treatment of 
ALK-positive NSCLC with crizotinib demonstrated significant improvement in median PFS 
and ORR when compared with pemetrexed plus platinum 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).  The DR was 11.3 months with crizotinib (95% CI 
8.1, 13.8), as compared with 5.3 months (95% CI 4.1, 5.8).41
Additional improvements were seen in the use of crizotinib over chemotherapy in patients 
with ROS1 fusion protein-related NSCLC.36
Complete information may be found in the crizotinib IB, which is also to be considered the 
single reference safety document (SRSD) for crizotinib.18
1.2.2.3. PF-06463922
PF-06463922 is a selective, ATP competitive small molecule inhibitor of the ALK and 
ROS1 receptor tyrosine kinases (RTK) that preclinically also potently inhibits ALK kinase 
domain mutations responsible for ALK TKI resistance. 
In vitro, PF-06463922 demonstrated potent, concentration-dependent inhibition in catalytic 
activities of ALK, ALK mutants and ROS1 kinases in recombinant enzyme and cell based 
assays.  PF-06463922 also inhibited ALK- and ROS1-dependent oncogenic functions in 
human NSCLC cell lines, and demonstrated potent and selective growth inhibitory activity 
and induced apoptosis in tumor cell lines exhibiting either non-mutant ALK and 
ROS1 fusion variants or mutant ALK fusions that are acquired and resistant to crizotinib 
treatment.
In vivo, PF-06463922 demonstrated marked cytoreductive activity in mice bearing tumor 
xenografts that express ALK or ROS1 fusion variants, including the crizotinib resistant 
EML4-ALKL1196M or EML4-ALKG1269A mutations.  PF-06463922 treatment considerably 
reduced the tumor size and prolonged animal survival in the orthotopic brain models 
(EML4-ALK and EML4-ALKL1196M in mice.  The anti-tumor efficacy of PF-06463922 was 
dose dependent and demonstrated strong correlations to inhibition of ALK or 
ROS1 phosphorylation. 
As of 24 April 2015, preliminary single-dose PK of PF-06463922 has been evaluated in 
20 patients in doses ranging from 10-200 mg QD in the B7461001 dose-escalation study.  
After a single oral dose in the fasted state, peak plasma concentrations (Cmax) of 
PF-06463922 were achieved at a median time (Tmax) ranging from 1.25-2.0 hours across the 
different doses.  Across the doses, mean Cmax and AUCinf values for PF-06463922 ranged 
from 50.8 to 1201 ng/mL and from 900 to 21429 ng•hr/mL, respectively, and increased in a 
relatively dose-proportionate manner.  Mean estimates of terminal half-life in this study 
ranged from 18.8 to 26.3 hours.  Preliminary steady-state PK of PF-06463922 has been 
evaluated in 26 patients following repeated doses ranging from 10-200 mg QD in the 
B7461001 dose-escalation study.  After multiple doses of PF-06463922 in the fasted state, 

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peak plasma concentrations (Cmax) of PF-06463922 were achieved at a median time (Tmax) 
ranging from 1.0-2.0 hours across the different doses.  Across the doses, mean Cmax and 
AUCτ values for PF-06463922 ranged from 60.3 to 1043 ng/mL and from 713 to 
8057 ng•hr/mL, respectively.  While steady state AUC values at doses greater than 
100 mg QD seem to increase at a less than dose proportional manner, at the time of this 
analysis, the number of patients enrolled at higher doses was small and a definitive 
conclusion regarding dose linearity cannot be made.  Furthermore, doses above 100 mg of 
PF-06463922 are not planned for this study.  Mean estimates of effective half-life in this 
study ranged from 11.8 to 23.4 hours.
A Phase 1 monotherapy study of PF-06463922 in patients with ALK-positive and 
ROS1-positive advanced NSCLC (B7461001; NCT01970865) is currently ongoing.  As of 
the data cutoff date of 20 April 2015, 44 patients were evaluable for safety across all dose 
levels tested.  As of 25 March 2015, 12 patients were treated at 100 mg QD PF-06463922 for 
at least 4 weeks.  No DLTs occurred at this dose level and the safety profile was tolerable.  
One DLT was noted among three patients treated at 200 mg QD.50
PF-06463922 was well tolerated.  In the Phase 1 study, 11 (25%) of patients underwent dose
delays, 8 (18%) had dose reductions, and 1 (2%) required dose discontinuation due to AEs.  
The most common treatment-related AE were hypercholesterolemia (14 patients, 47%), 
peripheral neuropathy (8 patients, 27%), and peripheral edema (7 patients, 23%). A total of 
6 patients had treatment-related Grade 3 AEs, as 3 patients had 
Grade 3 hypercholesterolemia, and 1 patient each had Grade 3 lipase increased, 
hypophosphataemia, and dermatomyositis.  There were no Grade 4 or 5 treatment-related 
AEs.  There were 3 treatment-related serious adverse events: elevated lipase, seizure, and 
dermatomyositis.50 Management of TEAEs related to PF-06463922 is outlined in Sections 
5.6.1 and 
Section 5.4.4.  Other TEAEs are noted in the PF-06463922 IB.19
As of the data cutoff date 20 April 2015, 44 patients (33 with ALK-positive NSCLC and 
11 with ROS1-positive NSCLC) were enrolled across 7 QD dose levels and 3 BID dose 
levels, with total daily doses of 10–400 mg.  18 (41%) patients had one line of prior ALK or 
ROS1 TKI therapy and 19 (43%) having two or more prior lines of TKI therapy.  34 patients 
were evaluable for overall tumor response, and 25 for intracranial response; 27 patients were 
still receiving treatment as of the data cutoff date.  In the 34 patients who were evaluable for 
response, the ORR was 44% (95% CI: 27–62), comprising 1 complete response, 
10 confirmed partial responses, and 4 unconfirmed partial responses.  An additional 
6 patients (18%) had stable disease as their best response.
In 25 patients evaluable for intracranial responses, of whom 14 had CNS lesions as target 
lesions, the intracranial response rate was 36% (95% CI: 18–58), comprising 4 complete 
intracranial responses, 3 confirmed partial intracranial responses, and 2 unconfirmed partial 
intracranial responses (Pfizer, data on file19).
In one healthy volunteer in Study B7461008, the PR interval prolongation was associated 
with one episode of transient second-degree AV block (Mobitz type 1; Wenkebach). In one 
patient on clinical Study B7461001, the PR interval prolongation may have been associated 

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with the progression of pre-existing AV block to complete heart block. When the complete 
heart block was identified, the patient was immediately evaluated and subsequently treated 
by placement of an implanted pacemaker.
In response to the observation of PR interval prolongation, data from all available human 
studies (approximately 100 patients in clinical studies and 45 in single dose healthy volunteer 
studies) was reviewed. Additional instances were identified of asymptomatic increases in the 
PR interval, usually most notable during Cmax (1-2 hours post-dose). Of note, the patients 
with a PR interval > 200 msec were generally those with a baseline value at the upper end of 
the normal range. 
The ECG changes appear limited to the PR interval, with no impact on QRS or QT 
intervals.  This impact on the PR interval is supported by preclinical animal studies, as 
described in the current IB.
Additional information may be found in the PF-06463922 IB19 (2015) which is also to be 
considered the SRSD for PF-06463922.
1.2.3. Rationale for Studying Crizotinib in Combination with Avelumab in Patients 
with ALK-Negative NSCLC
Immune checkpoint inhibitors are demonstrating promising activity in a variety of tumor 
types, including NSCLC.  It is becoming clear that combination strategies will be necessary 
for enhanced antitumor activity.45,51 T cell suppression by immune checkpoint inhibitors 
may not be sufficient if not accompanied by T cell homing to tumor and their activation.1,29,51
Zhou et al recently identified ALK in a screen as one of the genes involved in suppressing 
T cell infiltrating the tumor.46 T cells transduced with pooled shRNA libraries targeting 
negative regulators of T cell function were injected into B16 melanoma-bearing mice.  Short 
hairpin RNA-driven CD8+ T cell accumulation in tumors more than doubled relative to 
peripheral lymphoid tissue when ALK was targeted.  These results suggest that the same 
immunostimulatory effect may be achieved with pharmacologic inhibition of ALK. 
Preliminary internal Pfizer data demonstrates synergistic activity of both crizotinib and 
PF-06463922 with PD-L1 blockade in a murine ALK-negative colon carcinoma syngeneic 
model, CT26 (Pfizer, data on file).  Two independent studies have been conducted in 
CT26 murine model.  In the first study, by Day 25 post-tumor inoculation, no statistically 
significant tumor growth inhibition (TGI) was observed when animals were treated with 
either crizotinib alone or murine anti-PD-L1 alone.  The combination therapy resulted in 
71.8% TGI (P value <0.0001).  In the second study where the animals were treated with 
crizotinib dose escalation (5 mg/kg, 20 mg/kg, 40 mg/kg QD for 12 days) combining fixed 
murine anti-PD-L1 dose, by Day 25 post tumor inoculation no statistically significant TGI 
was observed from either murine anti-PD-L1 alone treatment or any dose of crizotinib alone 
treated groups comparing to isotype control antibody treated group.  Murine anti-PD-L1 in 
combination with 5 mg/kg crizotinib treatment resulted in 59% TGI (P value <0.1), with 
20 mg/kg crizotinib treatment resulted in 75.5% TGI (P value <0.001), and with 40 mg/kg 
crizotinib treatment resulted in 57.5% TGI (P value <0.1).

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A third independent study has been done in MC38 colon carcinoma tumor model by using 
avelumab.  Administration of murine avelumab alone resulted in 49.7% TGI, crizotinib alone 
resulted 48.5% TGI, and combination of murine avelumab with crizotinib led to 65% TGI. 
The data described above suggests that crizotinib may enhance the activity of avelumab 
through an effect on T cell homing to tumor, independent of crizotinib’s effect on tumor cells 
and independent of the presence of the mutation on the tumor parenchyma.  In addition to 
ALK and/or Met, it is possible that other less well characterized targets of crizotinib may also 
contribute to the mechanisms through which crizotinib may enhance anti-tumor immunity.  
Therefore, the objective of Group A in the current study is to assess the safety and efficacy of 
the crizotinib-avelumab combination in a population lacking mutational targets on the tumor 
itself.  In ALK-positive NSCLC, such an “immune-booster” activity of crizotinib would be 
difficult to distinguish from its direct effect on the ALK oncogenic driver in tumor cells.  
Therefore, in the current study, ALK-negative NSCLC patients will be enrolled in Group A, 
and care will be taken to ensure that patients with other known sensitivity mutations to 
crizotinib such as ROS1 or c-MET alterations are excluded or, if not known at the time of 
enrollment, identified retrospectively. 
1.2.4. Rationale for Studying PF-06463922 in Combination with Avelumab in Patients 
with ALK-Positive NSCLC
Despite high response rates observed with crizotinib in the initial treatment of ALK-positive 
NSCLC-, progression of disease invariably occurs over time.  This led to the development 
of-, new therapies.  PF-06463922 is a next generation ALK inhibitor with enhanced activity 
against resistance mutations that arise upon treatment with first (crizotinib) and second 
generation (alectinib, ceritinib) ALK TKIs, as demonstrated in the Phase 1/2 trial presented 
at ASCO 2015.50 (See Section 1.2.2.2).
Immune checkpoint inhibitors are demonstrating promising activity in a variety of tumor 
types, but the challenge remains in identifying optimal combinations with standard-of-care 
therapies including targeted agents.  Tumor-directed therapies such as chemotherapy and 
targeted agents potentially improve tumor antigenicity by inducing cell death, providing the 
basis for potential synergy with immune checkpoint inhibitors.45,47
Additional preclinical data to support the combination of an ALK inhibitor and an immune 
checkpoint inhibitor comes from evaluation of ALK-driven mouse models of lung cancer.  In 
this model, lung tumors containing ALK rearrangements induced an immunosuppressive 
microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells.  
This work suggested that combinations of ALK TKIs and immune checkpoint inhibitor 
therapies might represent an impactful approach for the treatment of ALK-driven NSCLC.53
Based on the promise of complimentary activity of ALK TKIs and immune checkpoint 
inhibitors46,49 the MTD and RP2D of the combination of avelumab with PF-06463922 in 
ALK-positive NSCLC (Group B) will be assessed in the Phase 1b portion of this study.  The 
safety of the combination will be further assessed in the Phase 2 portion as well as 
preliminary information on efficacy (ORR and CR rate).  As the expected activity of 

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PF-06463922 is high in ALK-positive NSCLC in both pretreated and untreated patients, this 
study is not designed to assess the efficacy of the combination compared neither to 
PF-06463922 alone nor to avelumab single agent: the Phase 2 will be single arm, 
non-randomized and open label.  For this reason, biomarker studies will be performed to 
determine whether there are biologic factors that may predict or confirm additive benefits of 
the combination versus single agents as well as all efficacy parameters, including Objective 
Response (OR) (CR, Partial Response (PR)), Disease Control Rate, Duration of response and 
landmark PFS and OS will be carefully assessed to correlate with any biomarker.
1.2.5. Rationale for Avelumab Starting Dose and Regimen
In this clinical trial, the avelumab starting dose will be 10 mg/kg administered as 1-hour 
intravenous (IV) infusions Q2W.  This dose is the RP2D used on a total of 480 patients in the 
ongoing dose-expansion phase of study EMR 100070-001 (see Section 1.2.2.1 for details). 
1.2.6. Rationale for Starting Crizotinib Dosing Regimen
Crizotinib starting dose will be 250 mg BID.  This dose is the approved dose for treatment of 
ALK-positive metastatic NSCLC according to the crizotinib product label.
1.2.7. Rationale for Starting PF-06463922 Dosing Regimen
Based upon the current safety database and PK data, the starting dose for the combination 
will be 100 mg QD (See Section 1.2.2.3).  In the ongoing PF-06463922 Phase 1 study, the 
100 mg QD dose was well-tolerated and associated with antitumor activity.
1.3. Summary of Risk-Benefit Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The risk-benefit relationship has been carefully considered in the planning of the trial.  Based 
upon the avelumab preclinical and Phase 1 clinical data available to date, the conduct of the 
trial with the proposed avelumab dosing regimen is considered justifiable.  The trial shall be
discontinued in the event of any new findings that indicate a relevant deterioration of the 
risk-benefit relationship that would render continuation of the trial unjustifiable.
The clinical safety data available to date for single-agent avelumab in patients with advanced 
solid tumors suggest an acceptable safety profile of the compound.  Most of the observed 
events were either in line with those expected in patients with advanced solid tumors or with 
similar class effects of immune checkpoint inhibitors blocking the PD-1/PD-L1 axis (See 
Section 1.2.2.1 for more details).  Infusion-related reactions including hypersensitivity and 
irAEs/autoimmune disorders have been identified as important risks for avelumab.  
Respective risk mitigation measures have been implemented in all ongoing clinical studies 
with avelumab, including this clinical trial protocol.
Crizotinib is approved multinationally for the single-agent treatment of ALK-positive 
advanced NSCLC.  Overall, the adverse event profile for crizotinib is considered generally 
tolerable and manageable.  The most frequent adverse events include vision disorders, 

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nausea, diarrhea, constipation, vomiting, elevated transaminases, edema, fatigue, and 
decreased appetite.18 Warnings and precautions noted using crizotinib include 
pneumonitis/ILD, transaminitis, QT interval prolongation and bradycardia.18 Pneumonitis, 
diarrhea and liver toxicity represent possible overlapping toxicities with avelumab.  
Respective risk mitigation measures have been included in this protocol (Sections 5.5.1, 
Section 5.6.2 and Table 6).
PF-06463922 is being tested in an ongoing Phase 1 study in ALK-positive or ROS1-positive 
advanced NSCLC patients.  Overall, the adverse event profile for PF-06463922 is 
manageable.  The most frequent treatment-related adverse events were hypercholesterolemia, 
CNS EFFECTS, peripheral edema, peripheral neuropathy, hypertriglyceridemia, fatigue, 
nausea, ALT increase, and constipation.  CNS EFFECTS is a cluster term comprising events 
including cognitive disorder, memory impairment, and slow speech. 
Respective risk mitigation measures have been included in this protocol.  Based on the 
current safety database, no overlapping toxicities with avelumab are anticipated.  Respective 
risk mitigation measures have been included in this protocol (Sections 5.6.1, Section 5.6.3
and Table 7).
As noted above (Sections 1.2.3 and Section 1.2.4), preclinical rationale exists to support 
increased antitumor activity of avelumab in combination with crizotinib and with 
PF-06463922 in patients with ALK-negative NSCLC and ALK-positive NSCLC, 
respectively.  Avelumab demonstrated an acceptable safety profile in the ongoing Phase 1 
trial EMR100070-001.  There is a potential for avelumab in combination with crizotinib and 
in combination with PF-06463922 to become an important therapeutic approach in patients 
with NSCLC.  The projected benefit/risk of avelumab given in combination with crizotinib or 
PF-06463922 is favorable for investigation in this advanced cancer patient population.
2. OBJECTIVES AND ENDPOINTS
2.1. Objectives
Phase 1b Primary Objectives:

Group A (ALK-negative): To determine MTD and the RP2D of the combination of 
avelumab with crizotinib; 

Group B (ALK-positive): To determine the MTD and the RP2D of the combination 
of avelumab with PF-06463922.
Phase 2 Primary Objectives:

Group A: To assess ORR per RECIST v.1.1 in previously treated locally advanced or 
metastatic ALK-negative NSCLC patients treated with the combination of avelumab 
and crizotinib at the RP2D;

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•
Group B: To assess ORR and CR rate per RECIST v.1.1 in previously untreated 
locally advanced or metastatic ALK-positive NSCLC patients treated with the 
combination of avelumab and PF-06463922 at the RP2D.
Secondary Objectives (both Phase 1b/2):
•
To evaluate the safety and tolerability of avelumab in combination with crizotinib 
(Group A) or with PF-06463922 (Group B); 
•
To assess antitumor activity of avelumab in combination with crizotinib (Group A) or 
with PF-06463922 (Group B);
•
To characterize the PK of avelumab in combination with crizotinib (Group A) or with 
PF-06463922 (Group B);
•
To assess the immunogenicity of avelumab;
•
To evaluate candidate predictive biomarkers of sensitivity or resistance to 
combination therapy in pretreatment tumor tissue.
 
 
 
2.2. Endpoints 
Primary Endpoints
Phase 1b:
•
First 2 cycles DLTs for Group A and Group B.
Phase 2: 
•
Confirmed OR per RECIST v.1.1 for Group A.
•
Confirmed OR and CR per RECIST v.1.1 for Group B.
Secondary Endpoints
•
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Appendix 4); vital signs (blood pressure, pulse rate);
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•
Disease Control (DC), Duration of Response (DR), Time to Tumor Response (TTR), 
Progression-Free Survival (PFS) per RECIST v.1.1, and Overall Survival (OS);
•
Pharmacokinetic parameters of crizotinib, its metabolite PF-06260182, and avelumab 
will be determined as data permit:
•
Maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax), area under the plasma concentration-time curve during the dosing interval 
time course (AUCtau), area under the plasma concentration-time curve from time 
of dosing to the last collection time point (AUClast), apparent plasma clearance 
(CL/F), and apparent volume of distribution (V/F) for crizotinib following 
multiple dosing in the presence of avelumab, as data permit; 
•
Cmax, Tmax, AUCtau, metabolite to parent ratio for AUCtau (MRAUCtau), and 
metabolite to parent ratio for Cmax (MRCmax) for PF-06260182 following multiple 
doses in the presence of avelumab;
•
Cmax, Tmax, AUCtau, AUClast, CL/F, and Vz/F for PF-06463922 following multiple 
dosing in the presence of avelumab, if data permit; Single and multiple dose 
pharmacokinetics (Cmax, Ctrough of avelumab in the presence of crizotinib and 
PF-06463922).
•
Avelumab anti-drug antibodies (ADA; neutralizing antibodies);
•
Tumor tissue biomarkers, including but not limited to, PD-L1 expression and tumor 
infiltrating CD8+ T cells by immunohistochemistry (IHC).
 
 
 
 
 
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, pharmacokinetic and 
pharmacodynamic study of Group A and Group B in cohorts of adult patients with locally 
advanced or metastatic NSCLC (See Figure 1).
Phase 1b:
Both Group A and Group B will be evaluated to identify the MTD and the RP2D.  Patients 
will be treated at dose level 0 (DL0) of the combination as noted in Table 1 and Table 4.  
Determination of the MTD will be performed using the mTPI design as described in 
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Sections 3.1.1.1.1 and Section 3.1.1.2.1 using dose de-escalation from the approved 
prescribed dose of crizotinib (250 mg BID), 100 mg QD of PF-06463922, and the RP2D of 
avelumab (10 mg/kg Q2W).  In Group B, a dose expansion will evaluate an additional 
12 patients at the MTD/RP2D to further assess the safety, pharmacokinetics, 
pharmacodynamics and antitumor activity of the combination.
Phase 2 Group A :
After the MTD is identified and the RP2D is determined, the 12 patients treated at the RP2D 
will be considered Stage 1 of Simon’s Optimal Two-Stage design.  If 3 or more patients of 
the 12 (≥ 25%) in Phase 1b have a confirmed objective response, then in Phase 2 an 
additional 33 patients will be enrolled and treated.  If there are fewer than 3 patients 
(< 25%) who have a confirmed objective response in the first 12 patients treated at the RP2D, 
then Phase 2 will not be opened for enrollment.  Patients with ALK-negative NSCLC who 
are enrolled and, subsequently, determined by retrospective central testing to be positive for 
ALK gene rearrangement, ROS1 gene translocation, c-MET gene amplification, or c-MET 
exon 14 deletion may be replaced.  Patients with NSCLC containing EGFR mutations are 
permitted onto Group A if they have exhausted appropriate targeted therapy for these 
mutations.
Phase 2 Group B
Following the identification of the MTD and determination of the RP2D approximately
30 additional patients who are treatment-naive will be enrolled in the Phase 2 portion, to 
further assess the antitumor activity, safety, pharmacokinetics and pharmacodynamics of the 
combination at the RP2D.

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Figure 1.
Study Schema
Phase 1b
Phase 2
Outcomes
Group 
A: 
ALK-
negative 
Dose 
Finding:
crizotinib + 
avelumab 
(Dosing per 
Table 1)
Efficacy Confirmation:
crizotinib + avelumab 
(N=33)
>3/12 
responses 
at RP2D 
+safety 
confirmed
Group 
B: 
ALK-
positive 
Dose 
Finding:
PF-
06463922 
+ avelumab 
(Dosing per 
Table 4)
Dose 
Expansion:
PF-
06463922 + 
avelumab 
(N=up to 
12)
Identify 
MTDs/RP2Ds based 
on safety
Improved Group A 
ORR as compared to 
historical PD-1 
inhibitor controls
Pharmacokinetic and 
biomarker analyses
For Phase 2 Group 
B, assess the 
antitumor activity, 
safety, 
pharmacokinetics 
 
of the combination 
at the RP2D.
Efficacy Confirmation:
PF-06463922 + 
avelumab (N=30)
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3.1.1. Phase 1b Evaluation to Determine MTD/RP2D
3.1.1.1. Group A
The starting dosing regimens (DL-0) for the Group A combination are crizotinib 250 mg BID 
and avelumab 10 mg/kg IV Q2W in 2-week cycles. 
3.1.1.1.1. Group A Dose Finding Criteria
Dose finding in Group A will follow an mTPI design, using dosing regimens of avelumab 
and crizotinib as shown in Table 1.
Table 1.
Crizotinib plus Avelumab Dose Levels
Avelumab
Crizotinib
5 mg/kg IV
10 mg/kg IV
250 mg BID PO
DL-1A*
DL 0 (Start)
200 mg BID PO
DL-1A-1C
DL-1C**
250 mg QD PO
DL-1A-2C
DL-2C**
*-1A denotes dose reduction attributed to avelumab (A=avelumab)
**-1C denotes dose reduction attributed to crizotinib (C=crizotinib), -2C denotes dose reduction attributed to 
crizotinib (C=crizotinib). 
Some of the possible dose finding scenarios based on the tolerability of the starting DL0 are 
illustrated in Table 2.  In this dosing algorithm, there are up to 6 potential DLs.  DL-1A and 
DL-1C will be explored only if the design recommends de-escalation already at DL0.  
DL-1A-1C and DL-2C will be explored only if the design recommends de-escalation at 
DL-1A and DL-1C.  DL-1A-2C will be explored only if the design recommends to 
de-escalation at DL-1A-1C and DL-2C.
There are several potential dose-finding sequences for crizotinib and avelumab.  The specific 
sequence to be followed depends upon the number of patients enrolled in the study and the 
number of DLTs observed at each specific DL combination.  Some possible sequences are 
listed below in Table 2.
Table 2.
Possible Dose Finding Sequences (Group A)
Possible sequences starting at Dose Level 0
DL0
DL0DL-1A and DL-1C
DL0DL-1A and DL-1CDL-1A-1C and/or DL-2C
DL0 DL-1A and DL-1CDL-1A-1C and/or DL-2CDL-1A-2C

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Dosing will begin at DL0 and may possibly be de-escalated to DL-1A and DL-1C according 
to Table 1.  The patients who are enrolled in DL0 will be monitored for 2 cycles (4 weeks) 
for DLTs.  If permitted by mTPI, this dose level will be expanded in cohorts of 3-6 patients 
to a total of 12 patients.  Initially, 3 patients will be assigned to the DL (unless the first 
2 patients experience a DLT) and monitored during the DLT period.  If no more than 1 of the 
3 patients has a DLT at the end of the DLT monitoring period, then, up to 3 more patients 
will be assigned to the same DL and followed for the DLT monitoring period.  This will be 
followed by up to 6 more patients if there are no indications for DL change by the mTPI 
design.  If at any point mTPI requires dose de-escalation, then initially up to 3 patients will 
be enrolled at lower dose levels (unless the first 2 patients experience a DLT) according to 
Table 1.  In this case, both DL-1A and DL-1C may start concurrently.  Dose re-escalation 
will be allowed as long as the next highest dose level has not been determined to have 
exceeded the MTD. 
The re-escalation/de-escalation rules will follow the mTPI method (Section 9.2.1).  Briefly, 
the mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in prior and current cohorts at the same DL to determine where future cohorts should 
involve dose re-escalation, no change in dose, or dose de-escalation.  The detailed 
dose-finding rules based on the mTPI are illustrated in Table 3.
Table 3.
Detailed Dose Re-Escalation/De-Escalation Scheme
Number of Patients Treated at Current Dose
3*
4
5
6
7
8
9
10
11
12
Number of DLTs
0
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
S
E
3
DU
DU
D
D
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
6
DU
DU
DU
DU
DU
DU
D
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
*If the first 2 patients both experience DLTs prior to enrollment of the third patient, then the dose should be de-escalated to 
the next lower dose level, as the current dose level will have exceeded the MTD
E = 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 level.
U = The current dose is unacceptably toxic.
Targeted DLT rate at MTD =30%.

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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 DL (DL0);

2 DLTs de-escalate to DL-1A and DL-1C and allow for possible re-escalation 
back to DL0;

3 DLTs de-escalate to DL-1A and/or DL-1C as DL0 is intolerable.
Rules for dose finding using the mTPI method include the following:

The target enrollment cohort size is 3-6 patients;

The next cohort will be enrolled, if necessary, at the same dose level if allowed by 
mTPI design schema when each patient evaluable for DLT at the current dose cohort 
has been evaluated for the 2 cycles, or experiences a DLT, whichever comes first.  
The next cohort will receive the DL as assigned if a dose modification is required;

If a patient does not receive at least 75% of the first 2 cycles doses of crizotinib or 
does not receive at least 2 infusions of avelumab within the DLT observation period 
(2 cycles = 28 days) for reasons other than study drug-related toxicity, another patient 
will be enrolled to replace that patient at the current dose level;

Phase 1b is completed when 12 DLT-evaluable patients (see Section 9.1) have been 
treated at a DL confirmed to be safe.
3.1.1.1.2. Group A Phase 2
The Phase 1b of Group A will lead to the identification of the MTD or the RP2D.  The first 
12 patients treated at the MTD/RP2D will be assessed for objective response.  If at least 
3 patients (≥25%) achieve confirmed OR, then Phase 2 will be opened, and an additional 
33 patients will be enrolled (45 in total).  If there are <3 patients (<25%) with confirmed 
responses in Phase 1b, then Phase 2 will not open.
3.1.1.2. Group B
The starting dosing regimens (DL 0) for the Group B combination are 
PF-06463922 100 mg QD and avelumab 10 mg/kg IV Q2W in 2 week cycles.
3.1.1.2.1. Group B Dose Finding Criteria
Dose finding for Group B will follow an mTPI design, using a similar algorithm as described 
for Group A.
The starting DL0 for the Group B combination is PF-06463922 100 mg QD and avelumab 
10 mg/kg IV Q2W in 2-week cycles (Table 4).

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Table 4.
PF-06463922 plus Avelumab Dose Levels (Group B)
Avelumab
PF-06463922
5 mg/kg IV
10 mg/kg IV
100 mg QD PO
DL-1A*
DL-0 (Start)
75 mg QD PO
DL-1A*-1P**
DL-1P**
50 mg QD PO
DL-1A*-2P**
DL-2P**
*-1A denotes dose reduction attributed to avelumab (A=avelumab)
**-1P, -2P denotes dose reduction attributed to PF-06463922 (P=PF-06463922) 
Some of the possible dose finding scenarios based on the starting DL0 tolerability are 
illustrated in Table 5.  In this dosing algorithm, there are up to 6 potential DLs.  DL-1A and 
DL-1P will be explored only if the design recommends de-escalation at DL0.  DL-1A-1P and 
DL-2P will be explored only if the design recommends de-escalation at DL-1A and DL-1P.  
DL-1A-2P will be explored only if the design recommends de-escalation at DL-1A-1P and 
DL-2P.  There are several potential dose finding sequences for PF-06463922 and avelumab.  
The specific sequence to be followed depends upon the number of patients enrolled in the 
study and the number of DLTs observed at each specific dose combination.  Some possible 
sequences are listed below in Table 5.
Table 5.
Possible Dose Finding Sequences (Group B)
Possible sequences starting at Dose Level 0
DL0
DL0DL-1A and DL-1P
DL0DL-1A and DL-1PDL-1A-1P and/or DL-2P
DL0 DL-1A and DL-1PDL-1A-1P and/or DL-2PDL-1A-2P
Dosing will begin at DL0 and may be possibly de-escalated to DL-1A and DL-1P according 
to Table 4.  The patients who are enrolled in DL0 will be monitored for 2 cycles for DLTs.  If 
permitted by mTPI, this dose level will be expanded in cohorts of 3-6 patients to a total of 
12 patients.  Initially, up to 3 patients will be assigned to the DL (unless the first 2 patients 
experience a DLT) and monitored during the DLT period.  If no more than 1 of the 3 patients 
has a DLT by the end of the DLT monitoring period, then up to 3 more patients will be 
assigned to the same DL and followed for the DLT monitoring period.  This will be followed 
by up to 6 more patients if there are no indications for a DL change by the mTPI design.  If at 
any point mTPI requires dose de-escalation, then initially 3patients will be enrolled at lower 
dose levels (unless the first 2 patients experience a DLT).  In this case, both DL-1A and 
DL-1C may start concurrently.  Dose re-escalation will be allowed as long as the next highest 
dose level has not been determined to have exceeded the MTD. 
The re-escalation/de-escalation rules will follow the mTPI method as described above in 
Section 3.1.1.1.1 and in Section 9.2.1.  The detailed dose-finding rules based on the mTPI are 
illustrated in Table 3.

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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 DL (DL0);
•
2 DLTs →de-escalate to DL-1A and DL-1P and allow for possible re-escalation back 
to DL0;
•
3 DLTs →de-escalate to DL-1A and DL-1P as DL0 is intolerable.
Rules for dose finding using the mTPI method include the following:
•
The target enrollment cohort size is 3-6 patients; 
•
The next cohort will be enrolled, if necessary, at the same dose level if allowed by 
mTPI design schema when each patient evaluable for DLT at the current dose cohort 
have been evaluated for the 2 cycles, or experiences a DLT, whichever comes first.  
The next cohort will receive the DL as assigned if a dose modification is required;
•
If a patient does not receive at least 75% of the first 2 cycles doses of PF-06463922 or 
does not receive at least 2 infusions of avelumab 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;
•
Phase 1b is completed when 12 DLT-evaluable patients (see Section 9.1) have been 
treated at a DL confirmed to be safe.
These patients will be followed for safety of the combination and to determine whether dose 
modifications of PF-06463922 and/or dose delays of avelumab are needed.  This will allow 
for the determination of the RP2D.
3.1.1.2.2. Group B Expansion
The Phase 1b of Group B will lead to the identification of the MTD or the RP2D.  Group B 
expansion cohort of approximately 12 additional patients will then be enrolled to further 
assess the safety, pharmacokinetics
 and antitumor activity of the 
combination. 
3.1.1.2.3. Group B Phase 2
Following the completion of Phase 1b, approximately 30 additional patients who are 
treatment-naive will be enrolled in the Phase 2 portion to further assess the antitumor 
activity, safety, pharmacokinetics 
 of the combination.
CCI
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3.2. Dose-Limiting Toxicity Definitions
Severity of adverse events will be graded according to NCI CTCAE v4.03 (see Appendix 4).  
For the purpose of dose finding, any of the following adverse events occurring during the 
primary DLT observation period that are attributable to one, the other, or both study drugs 
will be classified as DLTs:
Hematologic:

Grade 4 neutropenia if >7 days in duration;

Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of 38.3 degrees C (101 degrees F) or a sustained temperature of 
38 degrees C (100.4 degrees F) for more than 1 hour; 

Grade 3 neutropenic infection;

Grade 3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia >7 days;

Grade 4 anemia.
Non-Hematologic:
Any Grade 3 toxicity, except for any of the following:

Transient (6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management;

Transient (24 hours) Grade 3 fatigue, local reactions, or headache that resolves 
to Grade 1;

Grade 3 nausea and/or vomiting that resolves to Grade 1 within 7 days with 
appropriate medical management;

Grade 3 diarrhea or Grade 3 skin toxicity that resolves to Grade 1 in less than 7 days 
after medical management (eg, immunosuppressant treatment) has been initiated;

Any Grade 3 amylase or lipase abnormality that is not associated with symptoms or 
clinical manifestations of pancreatitis;

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
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
Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the Investigator, do not have any clinical correlate, and resolve 
to Grade 1 within 7 days with adequate medical management.
Inability to complete at least 75% of crizotinib/PF-06463922 treatment or 2 infusions of 
avelumab during the DLT observation period due to treatment-related toxicity should be 
considered a DLT.
While the rules for adjudicating DLTs in the context of dose finding/dose expansion phases 
are specified above, an AE not listed above, or an AE meeting the DLT criteria above but 
occurring outside of the DLT observation period may be defined as a DLT after consultation 
between Sponsor and Investigator, based on the emerging safety profile.
3.3. Maximum Tolerated Dose Definition
The MTD estimate is the highest dose tested of crizotinib and avelumab or PF-06463922 and 
avelumab associated with the occurrence of DLTs within the first 2 cycles of treatment in 
<33% of patients.
3.4. Recommended Phase 2 Dose Definition
The RP2D is the dose of crizotinib and avelumab or PF-06463922 and avelumab in 
combination chosen for further clinical development.  If the MTD proves to be clinically 
feasible for long-term administration in a reasonable number of patients, this dose may 
become the RP2D.  Further experience in Phase 1b may result in a RP2D dose lower than 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. Diagnosis
Histologically or cytologically proven diagnosis of NSCLC that is locally advanced 
or metastatic: 

Group A: ALK-negative NSCLC based on locally approved testing.  No known 
ROS1 gene translocations, c-MET gene amplification,or c-MET exon 14 deletion 

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predicted to confer sensitivity to crizotinib (ROS1 and c-MET testing is not 
required if not locally available). 

EGFR mutations must also have been evaluated based on locally approved 
testing. Patients with EGFR mutation positive NSCLC will be permitted onto 
this study group if standard treatment options for EGFR mutation positive 
NSCLC have been exhausted.

Group B: ALK-positive NSCLC based on locally approved testing. 
2. Prior Therapy

Group A: At least 1 prior regimen of systemic therapy.

Group B Phase 1b: Any number of prior regimens, including zero.

Group B Phase 2: No prior systemic treatment for advanced or metastatic 
disease (adjuvant and/or neoadjuvant therapies are allowed if completed at 
least 6 months prior to study entry.  No prior tyrosine kinase inhibitor therapy 
is allowed at any time prior to study entry)
3. Mandatory archival FFPE tumor tissue (all patients; see SoA and Section 6.1.1).  If 
tissue is unavailable, a mandatory tumor biopsy must be performed.
4. At least one measurable lesion as defined by RECIST v.1.1 that has not previously 
been irradiated.
5. Age 18 years (≥20 years for Japan). 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 
2 (see Appendix 2).
7. Estimated life expectancy of at least 3 months. 
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 9 g/dL (may have been transfused).
9. Adequate Renal Function as evidenced by:
a.
Estimated creatinine clearance >30 mL/min as calculated using the 
Cockcroft-Gault equation.

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10. Adequate Liver Function, including:
a.
Total serum bilirubin 1.5 x ULN;
b. Aspartate and alanine aminotransferase (AST and ALT) 2.5 x ULN; in all 
patients.
11. Adequate Pancreatic Function, including:
a.
Serum amylase < 1.5 x ULN;
b. Serum lipase < 1.5 x ULN.
12. Serum pregnancy test (for females of childbearing potential) negative at screening.
13. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
throughout the study and for at least 90 days after the last dose of assigned treatment. 
14. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Major surgery 4 weeks or radiation therapy 2 weeks prior to study entry.  Prior 
palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been 
completed 48 hours prior to patient registration. 
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including any 
other antibody or drug specifically targeting T cell co-stimulation or immune 
checkpoint pathways).
3. Systemic cytotoxic anti-cancer therapy ≤2 weeks, or any tyrosine kinase inhibitor 
≤5 half-lives of the drug, before study entry. Any Group B patient who is taking 
PF-06463922 at the time of Screening may continue on that treatment until study 
entry (except for Group B Phase 2 where no prior tyrosine kinase inhibitor therapy is 
allowed).
4. Brain metastases, except:

Patients with previously diagnosed brain metastases are eligible if they have 
completed their treatment and have recovered from the acute effects of radiation 
therapy or surgery prior to study entry, have discontinued corticosteroid treatment 
for these metastases for at least 4 weeks and are neurologically stable (Group A).

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
Patients with asymptomatic brain metastases currently requiring steroid doses less 
than prednisone 10 mg daily or equivalent (Group B). 
5. Persisting NCI CTCAE v4.03Grade >1 toxicity related to prior therapy; however, 
alopecia Grade 2 is acceptable.
6. Diagnosis of any other malignancy within 3 years prior to study entry, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on 
surveillance without any plans for treatment intervention (eg, surgery, radiation, or 
castration).
7. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization, except the following: Intranasal, inhaled, topical steroids, or local 
steroid injections (eg, intra-articular injection); Systemic corticosteroids at 
physiologic doses 10 mg/day of prednisone or equivalent; Steroids as premedication 
for hypersensitivity reactions (eg, CT scan premedication).
8. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible.
9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS) related illness.
10. Rapidly progressive disease (eg, tumor lysis syndrome).
11. Gastrointestinal abnormalities including:

Inability to take oral medication;

Requirement for intravenous alimentation;

Prior surgical procedures affecting absorption including total gastric resection;

Treatment for active peptic ulcer disease in the past 6 months;

Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically 
significant hematemesis, hematochezia or melena in the past 3 months without 
evidence of resolution documented by endoscopy or colonoscopy;

Malabsorption syndromes;

History of pancreatitis.
12. Known prior or suspected hypersensitivity to study drugs or any component in their 
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13. Active infection requiring systemic therapy.
14. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or 
chronic infection. 
15. Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines.
16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication.
Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, uncontrolled atrial 
fibrillation of any grade, bradycardia defined as <50 bpms (unless patient is otherwise 
healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, 
or congenital long QT syndrome.
17. History of extensive disseminated/bilateral or known presence of Grade 3 or 
4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation 
pneumonitis.
18. Participation in other studies involving investigational drug(s) within 2 weeks prior to 
first administration of study combination therapy. 
19. Other severe acute or chronic medical (including severe gastrointestinal conditions 
such as diarrhea, colitis, inflammatory bowel disease, ulcer or pneumonitis) or 
psychiatric condition, including recent (withinthe past year) or active suicidal ideation 
or behavior, or end-stage renal disease or hemodialysis, 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.
20. 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.
21. 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 methods 
of contraception as outlined in this protocol for the duration of the study and for at 
least 90 days after the last dose of investigational product or longer based upon the 
compound’s half-life characteristics.

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22. Current use of food or drugs that are known strong CYP3A4 inhibitors, including 
their administration within 10 days prior to the first dose of PF-06463922 or 
crizotinib (ie: grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville 
oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazle, 
posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir, bocepovir, nefazodone, lopinavir, 
troleandomycin, mibefradil, and conivaptan).  The topical use of these medications (if 
applicable), such as 2% ketoconazole cream, is allowed. 
23. Current use or anticipated need for drugs that are known strong CYP3A4 inducers, 
including their administration within 12 days prior to the first dose (ie, phenobarbital, 
rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine and St. John’s 
Wort).
24. Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, 
such as astemizole*, terfenadine, cisapride*, pimozide, quinidine, tacrolimus, 
cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot 
alkaloids (ergotamine, dihydroergotamine) within 12 days of administration of 
investigational products. [*withdrawn from US market]
25. Current use or anticipated need for drugs that are known P glycoprotein (P-gp)
substrates with a narrow therapeutic index, including their administration within 
12 days prior to study entry (eg, digoxin, dabigatran).
26. Prior organ transplantation including allogenic stem-cell transplantation.
4.3. Lifestyle Guidelines 
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive crizotinib, which has been associated with teratogenic 
risk.  Details are noted in the crizotinib IB.
Preliminary developmental toxicity studies using PF-06463922 have been completed in rats 
and rabbits.  Embryonic and fetal toxicity (including embryo lethality, fewer and smaller 
viable fetuses with some external and visceral malformations) was observed in both species 
at all doses, where the low dose was projected to yield similar exposure as the recommended 
phase 2 dose of 100 mg once daily.  Based on the study results, PF-06463922 induces 
embryonic and fetal toxicity in animals, and the current safety measures to prevent pregnancy 
should remain in place.
The teratogenic risk for avelumab is currently unknown.  Two (2) methods of highly 
effective contraception must be used throughout the study and continue for at least 90 days 
after the last dose.  The investigator or his or her designee, in consultation with the patient, 
will select two appropriate methods of contraception for the individual patient and his/her 
partner from the list of permitted contraception methods (see below) and instruct the patient
in their consistent and correct use.  Patients need to affirm that they meet the criteria for 
correct use of 2 of the selected methods of contraception.  The investigator or his or her 

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designee will discuss with the patient the need to use 2 highly effective contraception 
methods consistently and correctly according to the Schedule of Activities 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. 
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).
6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by 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.

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4.3.1. Sunlight Exposure
Patients treated with crizotinib and PF-06463922 should avoid sunbathing, prolonged 
unprotected sun exposure, or tanning for the duration of the study period.  Patients will be 
advised to report any reaction to sun-exposed skin. 
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 in the Study Binder.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients will be provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational compound identifiers, patient study 
numbers, contact information for the investigational site, and contact details for a contact 
center in the event that the investigational site staff cannot be reached to provide advice on a 
medical question or problem originating from another healthcare professional not involved in 
the patient’s participation in the study.  The contact number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigational site and the study team are not available.  It is, therefore, intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study.  
The contact number is not intended for use by the patient directly, and if a patient calls that 
number, he or she will be directed back to the investigational site.
5. 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).  For the purposes of 
this study, the investigational products are avelumab, crizotinib, and PF-06463922.
5.1. Allocation to Treatment
Allocation of patients to treatment groups will proceed based upon the presence or absence of 
ALK-positive NSCLC.  The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s identification 
(ID) and password, protocol number, the patient number, and the date of birth of the patient.  
The site personnel will then be provided with a treatment assignment and/or dispensable unit 
(DU) or container number when drug is being supplied via the IRT.  The IRT system will 
provide a confirmation report containing the patient number and DU or container number 
assigned. The confirmation report must be stored in the site’s files.

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5.2. Patient Compliance
A patient diary will be provided to the patients to aid in crizotinib or PF-06463922 dosing 
compliance.  The diary will be maintained by the patient to include missed or changed doses.
Patients will be required to return all unused oral study treatments (crizotinib or 
PF-06463922).  The returned oral study medication by the patient will be counted, 
documented, and recorded.  The patient diary may also be used to support this part of the 
crizotinib or PF-06463922 accountability process.
The site will complete required dosage Preparation Record located in the Investigational 
Product (IP) Manual.  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 designated study monitor. 
5.3. Investigational Product Supplies 
Avelumab, crizotinib, and PF-06463922 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 and Proof of Receipt form.  This form will be 
completed, filed, and the shipment confirmed as directed on the bottom of the Drug Shipment 
and 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.
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. Avelumab 
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20 mg/mL solution and will be supplied by the sponsor in single-use glass 
vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable GMP guidelines.  Avelumab will be packed in boxes each containing one vial.  
The information on the trial drug will be in accordance with approved submission 
documents. 
Avelumab will be shipped in transport cool containers (2C to 8C) with temperature 
monitoring devices.
5.3.1.2. Crizotinib
Crizotinib will be supplied for oral administration as capsules containing 200 mg or 250 mg 
of study medication and will be packaged in High-Density Polyethylene (HDPE) bottles.

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5.3.1.3. PF-06463922
PF-06463922 will be supplied for oral administration as 25 mg tablets in High-Density 
Polyethylene (HDPE) bottles with desiccant. 
5.3.2. Preparation and Dispensing
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 
investigational agents.
5.3.2.1. Avelumab 
Avelumab will be administered in 14 day cycles at the investigational site.
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products.
For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection).  Detailed information on infusion bags and medical devices to be 
used for the preparation of the dilutions and subsequent administration will be provided in 
the Investigational Product (IP) Manual. 
Avelumab must not be used for any purpose other than the trial.  The administration of trial 
drug to patients who have not been enrolled into the trial is not covered by the trial insurance.
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
See the IP Manual for instructions on how to prepare the investigational product for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.3.2.2. Crizotinib
Crizotinib will be dispensed at the beginning of every other 14-day treatment cycle (every 
28 days).  Patients should be instructed to keep their medication in the bottles provided and 
not transfer it to any other container.  Crizotinib will be provided in bottles containing 
200 mg or 250 mg capsules.  Site personnel must ensure that patients clearly understand the 
directions for self-medication.  Patients should be given sufficient supply to last until their 
next study visit.  Patients will be provided with Drug Administration Cards and Patient 
Diaries.  In addition, administration instructions will be detailed in the IP Manual.
5.3.2.3. PF-06463922
PF-06463922 will be dispensed at the beginning of every other 14-day treatment cycle (or 
every 28 days).  Patients should be instructed to keep their medication in the bottles provided 
and not transfer it to any other container.  PF-06463922 will be provided in bottles containing 

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25 mg tablets.  Site personnel must ensure that patients clearly understand the directions for 
self-medication.  Patients should be given sufficient supply to last until their next study visit.  
Patients will be provided with Drug Administration Cards and Patient Diaries.  In addition, 
administration instructions will be detailed in the IP Manual.
5.4. Administration
All trial treatments will be administered on an outpatient basis except for avelumab, and 
crizotinib or PF-06463922 on PK sampling visits, which will be administered at the 
Investigational site.  The dose of study drug administered should never be higher than the 
original dose level assigned on Cycle 1 Day 1.
A cycle is defined as 14 days, regardless of missed doses or dose delays. 
5.4.1. Avelumab 
The IP Manual contains specific instructions for avelumab dose calculation, reconstitution, 
preparation of the infusion fluid, and administration.
Avelumab will be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as described in the Schedule of Activities table.  Avelumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.
Avelumab will be administered as a 1-hour IV infusion once every 2 weeks.  In order to 
mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg IV or oral 
equivalent diphenhydramine and 650 mg IV or oral equivalent acetaminophen/paracetamol 
(as per local practice) is mandatory approximately 30 to 60 minutes prior to each dose of 
avelumab.  This may be modified based on local treatment standards and guidelines, as 
appropriate.  Sites should make every effort to target infusion timing to be as close to 1 hour 
as possible.  The exact duration of infusion should be recorded in both source documents and 
CRFs.  Possible modifications of the infusion rate for the management of infusion-related 
reactions are described in Sections 5.6.1.2 and Section 5.6.1.3.
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg).  All patients should be weighed within 3 days prior to 
dosing for every cycle.  If the patient experienced either a weight loss or gain 
>10% compared to the weight used to calculate the prior dose, the amount of study drug 
required for preparation and administration for the current cycle must be recalculated using 
this most recent weight obtained.  Avelumab dose reduction for toxicity management is not 
permitted; however, next cycle administration may be omitted due to persisting toxicity as 
described in Table 6.
There is no change in the concentration of avelumab in the presence of food, thus it can be 
administered with or without food.

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5.4.2. Crizotinib
Crizotinib will be administered orally BID or QD (See Table 1) at approximately the same 
time in the morning and evening 12 hours apart on a continuous daily dosing schedule, ie, 
without a break in dosing in the absence of drug-related toxicity.  Patients must swallow the 
study medication whole and must not manipulate or chew the medication prior to 
swallowing.  On the study day in which both crizotinib and avelumab are administered, 
crizotinib should be taken in the morning prior to the avelumab infusion.  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 1 extra dose during a 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.
On PK sampling days, the crizotinib doses should be taken in the clinic under the supervision 
of the study site personnel.
Oral crizotinib will be administered with at least 8 oz (240 mL) of water with or without 
food. 
5.4.3. PF-06463922
PF-06463922 will be administered orally QD (See Table 4) at approximately the same time 
of the day on a continuous daily dosing schedule, ie, without a break in dosing in the absence 
of drug-related toxicity.  Patients must swallow the study medication whole and must not 
manipulate or chew the medication prior to swallowing.  On the study day in which both 
PF-06463922 and avelumab are administered, PF-06463922 should be taken in the morning 
prior to the avelumab infusion.  A dosing card will be provided to the patients to provide 
guidance for the correct use of PF-06463922.  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.  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.
On PK sampling days, the PF-06463922 dose should be taken in the clinic under the 
supervision of the study site personnel.  The PF-06463922 dose should be administered after 
the 0 hour (pre-dose) pharmacokinetics (PK) sample has been collected.  On 
electrocardiogram (ECG) assessment days, the PF-06463922 dose should be taken in the 
clinic under the supervision of the study site personnel so that timing of assessments is 
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Since no clinically meaningful effect of food on the PK of PF-06463922 has been observed, 
PF-06463922 can be administered with or without food with approximately 8 oz (240 mL) of 
water. 
5.4.4. Treatment after Initial Evidence of Radiologic Disease Progression 
Immune checkpoint inhibitors agents such as avelumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. 
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm the observation.  Assigned study treatment may be continued at the 
Investigator’s discretion while awaiting radiologic confirmation of disease progression. 
Patients may receive study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression; 

No decline in ECOG performance status; 

Absence of rapid progression of disease by radiographic imaging;

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
If repeat imaging no longer shows PD, but rather CR, PR, or SD compared to the initial scan, 
treatment may be continued/resumed.  In determining whether or not the tumor burden has 
increased or decreased, Investigators should consider all target as well as non-target lesions 
(refer to the Study Manual). 
If the repeat imaging confirms PD, patients should be discontinued from study treatment.  
However, according to the Investigator’s clinical judgment and after discussion between the 
Investigator and the Sponsor, if a patient with evidence of PD is still experiencing clinical 
benefit, the patient may be eligible for continued treatment with avelumab and crizotinib or 
avelumab and PF-06463922.  The Investigator’s judgment should be based on the overall 
benefit-risk assessment and the patient’s clinical condition, including performance status, 
clinical symptoms, adverse events and laboratory data. 
5.4.5. Treatment after Confirmed Complete Response
Patients who have experienced a confirmed CR should continue to receive study treatment at 
the discretion of the Investigator.  If the Investigator believes that a patient may benefit from 
avelumab treatment beyond 12 months, further treatment with avelumab may be permissible 
after discussion with the Sponsor.  Patients in CR who have already stopped avelumab 

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treatment before completing the recommended 6 months of treatment after CR confirmation 
can resume treatment with avelumab at the same dose and schedule in order to complete the 
6-month period.  The recommended post-CR confirmation maximum treatment duration of 
12 months applies to avelumab only.  The treatment with crizotinib or PF-06463922 may 
continue without interruption at Investigator discretion.
5.5. Recommended Dose Modifications
Every effort should be made to administer investigational products on the planned dose and 
schedule.  In the event that one of the combination agents is discontinued, the other agent 
may be continued at the discretion of the Investigator in consultation with the Sponsor.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify their investigator at the first 
occurrence of any adverse event.  If due to ongoing treatment-related toxicity and a dose 
delay is still necessary after 2 weeks, study treatment should be permanently discontinued, 
unless there is Investigator discussion of the clinical circumstance with the Sponsor and 
agreement that the patient may resume treatment after a lapse of greater than 2weeks.  If a 
dose reduction is necessary, re-challenging at the original dose will only be permitted on a 
case-by-case basis after discussion and agreement between Investigator and Sponsor. 
For avelumab, no dose modifications are permitted in this study, but doses may be delayed or 
omitted based on persisting toxicity.  Crizotinib or PF-06463922 dose modifications as well 
as infusion omissions/delays for avelumab may occur independently from avelumab dose 
delays according to the guidance provided below and investigator’s medical judgment and 
will be reported in the CRF.  Dose levels for crizotinib and PF-06463922 dose modifications 
are provided in Sections 5.6.1, Section 5.6.2, and Section 5.6.3. 
Some potential immune-related adverse events (irAEs) described with anti-PD-L1 drugs such 
as avelumab may overlap with crizotinib or PF-06463922 toxicities (eg, diarrhea, liver 
function tests increase, or pneumonitis).  Any adverse event suspected to be immune-related 
should be managed according to the guidance for management of irAE as described below.  
For the crizotinib-avelumab combination in ALK-negative NSCLC, avelumab has proven 
clinical activity in this setting, therefore toxicity management guidelines are aimed to 
preserve avelumab dosing.  Crizotinib dose interruptions may be necessary beyond what is 
recommended for single-agent crizotinib so that crizotinib-related toxicity does not lead to 
permanent discontinuation of avelumab.  For the PF-06463922-avelumab combination in 
ALK-positive NSCLC, PF-06463922 has proven activity in this setting.  Therefore, 
avelumab dose interruptions may be necessary to preserve PF-06463922 dosing.  Specific 
guidance on treatment modifications for adverse drug reactions possibly associated to one or 
both of the study drugs including potential immune-related AEs are provided in Table 6 for 
avelumab with crizotinib combination and in Table 7 for avelumab with 
PF-06463922 combination.

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5.5.1. Management of Avelumab + Crizotinib Treatment-Related Toxicity
See Section 5.6.2 for crizotinib dose modification and additional toxicity management 
guidance.
Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
Hematologic 
Abnormalities
Grade 1
Continue avelumab as per schedule.
Continue crizotinib at the 
same dose level
Grade 2
Continue avelumab as per schedule.
Hold crizotinib until 
resolves to Grade 1, then 
resume at the same dose 
level.
Grade 3
Withhold dose until toxicity is Grade 
≤1 (or has returned to baseline), then 
resume treatment
Exceptions are:
Patients who develop Grade 3 or 
4 lymphopenia without other dose 
limiting events (eg, opportunistic 
infection) may continue study treatment 
without interruption.
Withhold crizotinib dose 
until toxicity is Grade ≤1 (or 
has returned to baseline), 
then rechallenge at the same 
dose. 
Exceptions are:
Patients who develop Grade 
3 or 4 lymphopenia without 
other dose limiting events 
(eg, opportunistic infection) 
may continue study 
treatment without 
interruption.
Grade 4
Permanent discontinuation
Exceptions are: 
Single laboratory values out of normal 
range that are unlikely related to 
avelumab according to the Investigator, 
do not have any clinical correlate, and 
resolve to Grade ≤1 within 7 days with 
adequate medical management.
Withhold crizotinib dose 
until toxicity is Grade ≤1 (or 
has returned to baseline), 
then reduce the dose by 
1 dose level.
Avelumab 
infusion-related 
Reaction 
Grade 1-4
See Section 5.6.1.2
Continue crizotinib at the 
same dose level
Avelumab 
hypersensitivity 
reactions
Grade 3-4
See Section 5.6.1.3
Continue crizotinib at the 
same dose level
Potential immune-related adverse events (irAEs)
Liver Test 
Elevation
(NCI-CTCAE v4)
Grade 1
Grade 1 AST or 
ALT >ULN to 
3.0 x ULN 
and/or total 
bilirubin >ULN 
Continue avelumab therapy
Continue liver function monitoring
If worsens: Treat as Grades 2 or 3 to 4
Continue crizotinib at same 
dose level

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
to 1.5 x ULN
Grade 2
AST or ALT 
>3.0 to 5 x 
ULN and / or 
total bilirubin 
>1.5 to 
3 x ULN
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days
If returns to Grade ≤1: 
Resume routine monitoring, resume 
avelumab therapy
If elevations persist >5 to 7 days or 
worsen: Treat as Grade 3 to 4
Hold crizotinib, resume at 
the same dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks;
(2) AST/ALT resolves to 
Grade ≤1;
(3) bilirubin is <2x ULN.
5.6. Grades 
3 to 4
AST or ALT 
>5 x ULN 
and/or total 
bilirubin >3 x 
ULN
Permanently discontinue avelumab 
therapy
Increase frequency of monitoring to 
every 1 to 2 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consult gastroenterologist/hepatologist
Consider obtaining MRI/CT scan of liver 
and liver biopsy if clinically warranted
If returns to Grade ≤1:
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds:
Add mycophenolate mofetil 1 gram (g) 
twice daily
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local 
guidelines.
Permanently discontinue 
crizotinib
Diarrhea/colitis
Grade 1
Diarrhea: < 
4 stools/day over 
Baseline
Continue avelumab therapy
Symptomatic treatment (eg, loperamide)
Continue crizotinib at the 
same dose level.  
Symptomatic care with 
loperamide at the 

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
Colitis: 
asymptomatic
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
immediately
If AE worsens: Treat as Grade 2, 3, or 
4 below
Investigator’s discretion
Grade 2
Diarrhea: 4 to 
6 stools per day 
over Baseline; 
IV fluids 
indicated < 
24 hours; not 
interfering with 
ADL
Colitis: 
abdominal pain; 
blood in stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤ 1:
Resume avelumab therapy
If persists >5 to 7 days or recurs:
Treat as Grade 3 or 4.
Hold crizotinib, resume at 
the same dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) diarrhea has resolved to 
Grade ≤1
Grade 3 or 4
Diarrhea (Grade 
3): ≥ 7 stools 
per day over 
Baseline; 
incontinence; 
IV fluids 
≥24 h; 
interfering with 
ADL
Colitis (Grade 
3):  severe 
abdominal pain, 
medical 
intervention 
indicated, 
peritoneal signs
Grade 4: 
life-threatening, 
perforation
  Withhold avelumab for Grade 3.  
Permanently discontinue avelumab for 
Grade 4 or recurrent Grade 3.
1.0 to 2.0 mg/kg/day prednisone IV or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade ≤1, then 
taper over at least 1 month’ resume 
avelumab therapy following steroids 
taper (for initial Grade 3).
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication).
Note: Infliximab should not be used in 
cases of perforation or sepsis
Hold crizotinib, resume at a 
reduced dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) diarrhea has resolved to 
Grade ≤1
Endocrinopathies 
(hypothyroidism, 
hyperthyroidism, 
adrenal 
Grade 1 or 
Grade 2
Continue avelumab therapy 
Endocrinology consult if needed
Start thyroid hormone replacement 
Continue crizotinib current 
dose level

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
insufficiency, 
type I diabetes 
mellitus)
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as appropriate. 
Rule-out secondary endocrinopathies (ie,
hypopituitarism / hypophysitis)Continue 
hormone replacement/suppression and 
monitoring of endocrine function as 
appropriate.
Grade 3 or 
Grade 4)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as appropriate. 
Rule-out secondary endocrinopathies (ie,
hypopituitarism / hypophysitis)
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 
1 (with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and monitoring 
of endocrine function as appropriate.
.
Hold crizotinib, resume at 
the same dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) AE has resolved to 
Grade ≤1

Refer to endocrinologist for dynamic 
testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women) 

Hormone replacement/suppressive 
therapy as appropriate 

Perform pituitary MRI and visual 
Hold crizotinib, resume at 
the same dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) AE has resolved to 
Grade ≤1

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
field examination as indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI.  Repeat 
the MRI in 1 month

Withhold avelumab if moderate, 
severe or life-threatening symptoms 
of hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at least 
1 month.
Add prophylactic antibiotics for 
opportunistic infections.
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 
1 (with or without hormone 
replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.
Hypopituitarism/
Hypophysitis 
(secondary 
endocrinopathies)
If secondary 
thyroid and/or 
adrenal 
insufficiency is 
confirmed (ie,
subnormal 
serum FT4 with 
inappropriately 
low TSH and/or 
low serum 
cortisol with 
inappropriately 
low ACTH) :
Refer to endocrinologist for dynamic 
testing as indicated and measurement of 
other hormones (FSH, LH, GH/IGF-1, 
PRL, testosterone in men, estrogens in 
women) 
Hormone replacement/suppressive 
therapy as appropriate 
Perform pituitary MRI and visual field 
examination as indicated
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 
1 (with or without hormone 
Hold crizotinib, resume at 
the same dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) AE has resolved to 
Grade ≤1

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
replacement).
Continue hormone replacement/ 
suppression therapy as appropriate.
If hypophysitis 
confirmed:
Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 
1 month
Withhold avelumab if moderate, severe 
or life-threatening symptoms of 
hypophysitis and/or abnormal MRI.  
Consider hospitalization.  Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 
1 month.
Add prophylactic antibiotics for 
opportunistic infections.
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1
(with or without hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone replacement/ 
suppression therapy as appropriate.
Rash
Grade 1 to 2
Covering 30% 
body surface 
area
Continue avelumab therapy
Symptomatic therapy (for example, 
antihistamines, topical steroids) 
If persists >1 to 2 weeks or recurs: 
Withhold avelumab therapy 
Consider skin biopsy 
Consider 0.5 to 1.0 mg/kg/day 
prednisone or equivalent. 
Once improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume avelumab therapy following 
steroids taper.
Continue at the same dose 
level
Symptomatic therapy 
(eg, antihistamines, topical 
steroids) as needed

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
If worsens: 
Treat as Grades 3 to 4
Grades 3
Covering >30% 
body surface 
area; 
Withhold avelumab therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.  Add prophylactic antibiotics 
for opportunistic infections
If improves to Grade 1: 
Taper steroids over at least 1 month; 
Resume avelumab therapy following 
steroids taper.
Hold crizotinib, resume at a 
reduced dose level when all 
of the following conditions 
are met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) rash has resolved to 
Grade ≤1
If recurs, permanently 
discontinue crizotinib
Grade 4
Life threatening 
consequences
Permanently discontinue avelumab for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
Hold crizotinib, then resume 
at a reduced dose level 
when rash has resolved to 
Grade ≤1
If recurs, permanently 
discontinue crizotinib.
Pneumonitis
Grade 1
Radiographic 
changes only
Consider withholding avelumab therapy 
Monitor for symptoms every 2 to 3 days 
Consider Pulmonary and Infectious 
Disease consults
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4
Permanently discontinue 
crizotinib.
Grade 2
Mild to 
moderate new 
symptoms
Withhold avelumab therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization 
1.0 to 2.0 mg/kg/day prednisoneor 
equivalent.  Add prophylactic antibiotics 
Permanently discontinue 
crizotinib.

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
for opportunistic infections 
Consider bronchoscopy, lung biopsy
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month and 
then resume avelumab therapy following 
steroids taper
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4
Grades 3 to 4
Severe new 
symptoms; New 
/ worsening 
hypoxia; 
life-threatening
Permanently discontinue avelumab 
therapy
Hospitalize 
Pulmonary and Infectious Disease 
consults
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung biopsy
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil).
Permanently discontinue 
crizotinib.
Renal irAEs
Grade 1
Creatinine 
increased > 
ULN to 1.5 x 
ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Continue Crizotinib at the 
same dose.
Grade 2 to 3
Creatinine 
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
For Grade 2: Continue 
Crizotinib at the same dose. 

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
increased > 
1.5 and ≤ 6 x 
ULN
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 month, and 
resume avelumab therapy following 
steroids taper.
If worsens: 
Treat as Grade 4
For Grade 3: Withhold 
Crizotinib dose until 
toxicity is Grade 1 (or has 
returned to baseline), then 
reduce the dose by 1 level or 
rechallenge at the same dose
Grade 4
Creatinine 
increased > 6 x 
ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
Withhold Crizotinib until 
toxicity is Grade 1 (or has 
returned to baseline), then 
reduce the dose by 1 level or 
discontinue at the discretion 
of the investigator.
Myocarditis
New onset of 
cardiac signs or 
symotoms 
and/or new 
laboratory 
cardiac 
biomarker 
elevation (eg,
troponin, 
CK-MB, BNP) 
or cardiac 
imaging 
abnormalities 
suggestive of 
myocarditis
Withhold Avelumab.
Hospitalize.
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management.
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.
Guideline based supportive treatment as 
per cardiology consult.
Consider myocardial biopsy if 
recommended per cardiology consult*.
If symptoms improve, and 
immune-mediated etiology is ruled out, 
re-start avelumab therapy.
If symptoms do not imrprove/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is suspected 
or confirmed following cardiology 
consult, manage as immune-mediated 
myocarditis.
Hold crizotinib until 
etiology is confirmed.
If immune-mediated nature 
is excluded and symptoms 
improve to Grade ≤1, 
re-start crizotinib at the 
same or reduced dose based 
on clinical presentation and 
in consultation with the 
cardiologist.
For isolated bradycardia or 
QTc prolongation, see 
dedicated guidelines further 
down in this table.

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
Immune-mediat
ed myocarditis
Permanently discontinue avelumab
Guideline based supportive treatment as 
appropriate as per cardiology consult*.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.  Add prophylactic antibiotocs 
for opportunistic infections.
Once improving, taper steroids over at 
least 1 months.
If no improvement or worsening, 
consider additional immunosuppressants 
(eg, azathioprine, cyclosporine A).
If immune-mediated 
etiology is confirmed, hold 
crizotinib until steroids have 
been initiated and symptoms 
improve to Grade ≤1, then 
re-start crizotinib at the 
same or reduced dose based 
on clinical presentation and 
in consultation with the 
cardiologist.
*Local guidelines, or eg, ESC or AHA guidelines
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Other irAEs (not 
described above)
Grade 2 or 
Grade 3 clinical 
signs or 
symptoms 
suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the diagnosis 
and consider re-starting avelumab therapy
If irAE is confirmed, treat as Grade 2 or 
3 irAE.
Continue at the same dose 
(Grade 2) or hold (Grade 3) 
Crizotinib pending clinical 
investigation. 
If irAE is ruled-out, re-start 
Crizotinib at the same dose 
(for Grade 3)
If irAE is confirmed, treat 
as Grade 2 or 3 irAE
Grade 2 irAE or 
first occurrence 
of Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1:  Taper steroids 
over at least 1 month and resume 
avelumab therapy following steroids 
taper.
Continue at the same dose 
(Grade 2) or hold (Grade 3) 
Crizotinib, depending on 
clinical diagnosis. 
Re-start Crizotinib at the 
same dose (for Grade 3) if 
symptoms improve to Grade 
≤1
Recurrence of 
same Grade 
3 irAEs
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Hold Crizotinib until 
symptoms improve to Grade 
≤1, then re-start Crizotinib 
at the same dose

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month.
Grade 4
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Hold Crizotinib until 
symptoms improve to Grade 
≤1, then re-start Crizotinib 
at the same dose
Requirement 
for 10 mg per 
day or greater 
prednisone or 
equivalent for 
more than 
12 weeks for 
reasons other 
than hormonal 
replacement 
for adrenal 
insufficiency
Persistent 
Grade 2 or 
3 irAE lasting 
12 weeks or 
longer
Permanently discontinue avelumab 
therapy
Specialty consult
Hold Crizotinib until 
symptoms improve to Grade 
≤1, then re-start Crizotinib 
at the same dose
Selected Adverse Drug Reactions Adverse events known to be associated with crizotinib described for 
crizotinib
Visual 
disturbance 
Grade 1/2
Continue avelumab on current schedule
Continue crizotinib at 
current dose level.  Repeat 
ophthalmologic 
examination.  
Grade 3
Hold avelumab and resume when 
recovered to Grade ≤1
Interrupt crizotinib until 
recovery.  Repeat 
ophthalmologic 
examination.  Resume 
treatment by reducing by 
one dose level.

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
Grade 4
Permanently discontinue avelumab.
Discontinue crizotinib 
treatment and do not retreat.  
Repeat ophthalmologic 
examination.  
Bradycardia 
(heart rate less 
than 60 beats per 
minute) in the 
absence of 
suspected or 
confirmed 
immune-mediated 
myocarditis.
If 
immune-mediated 
myocarditis is 
suspected or 
confirmed, treat 
as described 
above
Grade 1
Continue avelumab on current schedule
Continue crizotinib at the 
same dose level
Grade 2/3
Hold avelumab and resume when 
recovered to Grade ≤1
Withhold crizotinib until 
recovery to Grade 1 or to 
heart rate 60.
Evaluate concomitant 
medications known to cause 
bradycardia, as well as 
anti-hypertensive 
medications.
If contributing concomitant 
medication is identified and 
discontinued, or its dose is 
adjusted, resume at previous 
dose upon recovery to 
Grade 1 or to heart 
rate 60.
If no contributing 
concomitant medication is 
identified, or if contributing 
concomitant medications are 
not discontinued or dose 
modified, resume at reduced 
dose upon recovery to 
Grade 1 or to heart 
rate 60.
Grade 4
Hold avelumab and resume when 
recovered to Grade ≤1
Permanently discontinue 
crizotinib if no contributing 
concomitant medication is 
identified.
If contributing concomitant 
medication is identified and 
discontinued, or its dose is 
adjusted, resume at the same 
dose level upon recovery to 
Grade 1 or to heart rate 
60, with frequent 
monitoring.
Permanently discontinue for 
recurrence.
Prolonged QTc , 
in the absence of 
suspected or 
confirmed 
immune-mediated 
myocarditis.
Grade 1
Continue avelumab on current schedule
Continue crizotinib at the 
same dose level
Grade 2
Continue avelumab on current schedule
Continue crizotinib at the 
same dose level.  Assess 
electrolytes and concomitant 
medications.  Correct any 

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
If 
immune-mediated 
myocarditis is 
suspected or 
confirmed, treat 
as described 
above
electrolyte or magnesium 
abnormalities.
Grade 3
Hold avelumab and resume when 
recovered to Grade ≤1
Withhold until recovery to 
Grade 1, then resume at 
the same dose.
In case of recurrence, 
withhold until recovery to 
Grade 1, then reduce 1dose 
level.
Permanently discontinue in 
case of further 
Grade 3 recurrence.
Grade 4
Hold avelumab and resume when 
recovered to Grade ≤1
Discontinue crizotinib 
treatment and do not retreat.
Other Non-Hematologic Toxicities and Laboratory Abnormalities
Grade 1
Continue as per schedule 
Continue at the same dose 
level
Grade 2
If a Grade 2 ADR resolves to 
Grade 1 by the last day of the current 
cycle, avelumab treatment may continue.
If a Grade 2 ADR does not resolve to 
Grade 1 by the last day of the current 
cycle, infusions should not be given on 
the following cycle.  If at the end of the 
following cycle the event has not 
resolved to Grade 1, the patient should 
permanently discontinue treatment 
(except for hormone insufficiencies, that 
can be managed by replacement therapy; 
for these hormone insufficiencies, up to 
2 subsequent doses may be omitted).
Hold crizotinib until 
resolves to Grade 1, then 
resume at the same dose 
level.  If avelumab 
treatment is held and then 
restarted, crizotinib should 
only be restarted when the 
following conditions are 
met: 
(1) avelumab has been 
resumed for at least 
4 weeks, 
(2) toxicity is resolved to 
Grade ≤1.
Grade 3
Permanent discontinuation of avelumab
Exceptions are:
Transient (6 hours) Grade 3 flu-like 
symptoms or fever, which are controlled 
with medical management.
Transient (24 hours) Grade 3 fatigue, 
local reactions, headache, nausea, or 
emesis that resolve to Grade 1. 
Single laboratory values out of normal 
Withhold crizotinib 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.

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Table 6.
Management of Avelumab + Crizotinib Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Crizotinib
Treatment Modification
Treatment Modification
range (excluding Grade 3 liver function 
test increase) that are unlikely related to 
trial treatment according to the 
Investigator, do not have any clinical 
correlate, and resolve to Grade 1 within 
7 days with adequate medical 
management.
Grade 4
Permanent discontinuation of avelumab,
Exceptions are:
single laboratory values out of normal 
range that are unlikely related to trial 
treatment as assessed by the Investigator, 
do not have any clinical correlate, and 
resolve within 7 days with adequate 
medical management.
Withhold crizotinib 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.
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB= creatine kinase muscle and brain b;  CT= 
computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.

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5.6.1. Management of Avelumab + PF-06463922 Treatment-Related Toxicity
See Section 5.6.3 for PF-06463922 dose modification and additional toxicity management 
guidance.
Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
Hematologic 
Abnormalities
Grade 1
Continue avelumab as per schedule.
Continue PF-06463922 at the 
same dose level
Grade 2
Continue avelumab as per schedule 
Continue PF-06463922 at the 
same dose level
Grade 3
Withhold dose until toxicity is Grade 
≤1 (or has returned to baseline), then 
resume treatment.
For lymphopenia: If no evidence of 
infection or other clinically 
significant toxicity, continue at the 
same dose; otherwise, withhold dose 
until toxicity is Grade ≤1 (or 
baseline) then resume treatment
Withhold PF-06463922 dose 
until toxicity is Grade ≤1 (or 
has returned to baseline), then 
rechallenge at the same dose 
For lymphopenia: If no 
evidence of infection or other 
clinically significant toxicity, 
continue at the same dose; 
otherwise, withhold dose until 
toxicity is Grade 1 (or 
baseline) then rechallenge at 
the same dose.
Grade 4
Permanent discontinuation
Exceptions are: 
Single laboratory values out of 
normal range that are unlikely related 
to trial treatment according to the 
Investigator, do not have any clinical 
correlate, and resolve to Grade 
≤1 within 7 days with adequate 
medical management.
Withhold dose until toxicity is 
Grade ≤1 (or has returned to 
baseline), then reduce the dose 
by 1 dose level.
Avelumab 
infusion-related 
Reaction 
Grade 1-4
See Section 5.6.1.2
Continue PF-06463922 at the 
same dose level
Avelumab 
hypersensitivity 
reactions
Grade 3-4
See Section 5.6.1.3
Continue PF-06463922 at the 
same dose level
Potential immune-related adverse events (irAEs)
Liver Test 
Elevation
(NCI-CTCAE v4)
Grade 1
AST or ALT 
>ULN to 3.0 x 
ULN and/or 
total bilirubin 
>ULN to 1.5 x 
ULN
Continue avelumab therapy
Continue liver function monitoring 
If worsens: Treat as Grades 2 or 3 to 
4
Continue PF-06463922 at 
same dose level
Grade 2
Withhold avelumab therapy
Continue PF-06463922 at the 

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
AST or ALT 
>3.0 to 5 x 
ULN and/or 
total bilirubin 
>1.5 to 3 x 
ULN
Increase frequency of monitoring to 
every 3 days
If returns to ≤Grade 1: 
Resume routine monitoring, resume 
avelumab therapy
If elevations persist >5 to 7 days or 
worsen: Treat as Grade 3 or 4. 
same dose level
Grades 3 to 4
AST or ALT 
>5 x ULN 
and/or total 
bilirubin >3 x 
ULN
Permanently discontinue avelumab 
therapy 
Increase frequency of monitoring to 
every 1 to 2 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult 
gastroenterologist/hepatologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted
If returns to Grade ≤1: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram 
twice daily 
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines.
Permanently discontinue 
PF-06463922 -.
Diarrhea/colitis
Grade 1
Diarrhea: < 
4 stools/day 
over Baseline
Colitis: 
asymptomatic
Continue avelumab therapy
Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
Continue PF-06463922 at the 
same dose level.  

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
immediately
If worsens: Treat as Grade 2, 3, or 4
Grade 2
Diarrhea: 4 to 
6 stools per day 
over Baseline; 
IV fluids 
indicated < 
24 hours; not 
interfering with 
ADL
Colitis: 
abdominal pain; 
blood in stool 
Withhold avelumab therapy
Symptomatic treatment 
If improves to Grade ≤1: 
Resume avelumab therapy
If persists >5 to 7 days or recurs: 
Treat as Grade 3 or 4.
Continue PF-06463922 at the 
same dose level. 
Grade 3 to 4
Diarrhea (Grade 
3): ≥ 7 stools 
per day over 
Baseline; 
incontinence; 
IV fluids ≥24 h; 
interfering with 
ADL
Colitis (Grade 
3):  severe
abdominal pain, 
medical 
intervention 
indicated, 
peritoneal signs
Grade 4: 
life-threatening, 
perforation
  Withhold avelumab for Grade 3.  
Permanently discontinue avelumab 
for Grade 4 or recurrent Grade 3.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections. 
Consider lower endoscopy.
If improves: 
Continue steroids until Grade 1, then 
taper over at least 1 month.  resume 
avelumab therapy following steroids 
taper (for initial Grade 3).
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis
Hold PF-06463922 until 
symptoms improve to Grade 1, 
then resume PF -06463922 at 
the same dose level.
If recurs, reduce or discontinue 
PF-06463922 treatment (at 
investigator discretion, upon 
consultation with the sponsor)
Endocrinopathies 
(hypothyroidism, 
hyperthyroidism, 
adrenal 
insufficiency, type 
Grade 1 or 
Grade 2
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
Continue PF 06463922 at 
current dose level

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
I diabetes 
mellitus)
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus), as 
appropriate. 
Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.
Grade 3 or 
Grade 4
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis)
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Continue PF 06463922 at 
current dose level
Hypopituitarism/ 
Hypophysitis 
(secondary 
endocrinopathies)
If secondary 
thyroid and/or 
adrenal 
insufficiency is 
confirmed (ie,
subnormal 
serum FT4 with 
inappropriately 
low TSH and/or 
low serum 
cortisol with 
Refer to endocrinologist for dynamic 
testing as indicated and measurement 
of other hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone in men, 
estrogens in women) 
Hormone replacement/ suppressive 
therapy as appropriate 
Perform pituitary MRI and visual 
Continue PF 06463922 at 
current dose level

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
inappropriately 
low ACTH)
field examination as indicated
Resume avelumab once symptoms 
and hormone tests improve to Grade 
≤ 1 (with or without hormone 
replacement).
Continue hormone 
replacement/suppression therapy as 
appropriate.
If hypophysitis 
confirmed
Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 
1 month
Withhold avelumab if moderate, 
severe or life-threatening symptoms 
of hypophysitis and/or abnormal 
MRI.  Consider hospitalization.  
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at least 
1 month.
Add prophylactic antibiotics for 
opportunistic infections
Resume avelumab once symptoms 
and hormone tests improve to Grade 
≤ 1 (with or without hormone 
replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.
Continue PF 06463922 at 
current dose level
Rash
Grade 1 to 2
Covering 30% 
body surface 
area
Continue avelumab therapy
Symptomatic therapy (for example, 
antihistamines, topical steroids) 
If persists >1 to 2 weeks or recurs: 
Withhold avelumab therapy
Consider skin biopsy 
Continue PF-06463922 at the 
same dose level.  Remind 
patient to avoid sunbathing, 
prolonged unprotected sun 
exposure, or tanning

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
Consider 0.5 to 1.0 mg/kg/day 
prednisone or equivalent.  Once 
improving, taper steroids over at least 
1 month, add prophylactic antibiotics 
for opportunistic infections, and 
resume avelumab therapy following 
steroids taper.
If worsens: 
Treat as Grades 3 to 4
Grade 3
Covering >30% 
body surface 
area
Withhold avelumab therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone  or  
equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade ≤1: 
Taper steroids over at least 1 month; 
Resume avelumab therapy following 
steroids taper (for initial Grade 3).
Hold PF-06463922, resume at 
a reduced dose level when all 
of the following conditions are 
met: 
(1) avelumab has been 
resumed for at least 4 weeks, 
(2) rash has resolved to Grade 
≤1
If recurs, permanently 
discontinue PF-06463922
Grade 4
Life threatening 
consequences
Permanently discontinue avelumab 
therapy for Grade 4 or recurrent 
Grade 3.
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade ≤1: 
Taper steroids over at least 1 month;  
Hold PF-06463922, then
resume at a reduced dose level 
when rash has resolved to 
Grade ≤1
If recurs, permanently 
discontinue PF-06463922
Pneumonitis
Grade 1
Radiographic 
changes only
Consider withholding avelumab 
therapy 
Monitor for symptoms every 2 to 
3 days 
Consider Pulmonary and Infectious 
Continue PF-06463922 at the 
same dose. 

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
Disease consults
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4
Grade 2
Mild to 
moderate new 
symptoms
Withhold avelumab therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization 
1.0 mg/kg/day prednisone or 
equivalent.  Add prophylactic 
antibiotics for opportunistic 
infections. 
Consider bronchoscopy, lung biopsy
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month 
and then resume avelumab therapy 
following steroids taper
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4
Withhold PF-06463922 until 
toxicity has returned to 
baseline.  Then resume 
treatment at one dose level 
lower.  Discontinue 
permanently if pneumonitis 
recurs or if failure to recover 
after 6 weeks of study 
treatment hold and steroid 
treatment.
Grades 3 to 4
Grade 3: Severe 
new symptoms; 
New / 
worsening 
hypoxia; 
Grade 4: 
life-threatening
Permanently discontinue avelumab 
therapy
Hospitalize 
Pulmonary and Infectious Disease 
consults
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung biopsy
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
Permanently discontinue 
PF-06463922.

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or mycophenolate 
mofetil).
Renal irAEs
Grade 1
Creatinine 
increased > 
ULN to 1.5 x 
ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Continue PF-06463922 at the 
same dose. 
Grade 2 to 3
Creatinine 
increased > 
1.5 and ≤ 6 x 
ULN
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 4
For Grade 2: Continue 
PF-06463922 at the same dose. 
For Grade 3: Withhold 
PF-06463922 dose until 
toxicity is Grade 1 (or has 
returned to baseline), then
reduce the dose by 1 level or 
rechallenge at the same dose
Grade 4
Creatinine 
increased > 6 x 
ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Withhold PF-06463922 until 
toxicity is Grade 1 (or has 
returned to baseline), then 
reduce the dose by 1 level or 
discontinue at the discretion of 
the investigator.
Myocarditis
New onset of 
cardiac signs or 
symotoms 
and/or new 
laboratory 
cardiac 
biomarker 
elevation (eg,
Withhold Avelumab.
Hospitalize.
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
Hold PF 06463922 treatment 
until etiology is confirmed..
If symptoms improve to Grade 
≤1, and immune-mediated 
nature is ruled out, re-start 
PF-0463922 at the same or 
reduced dose based on clinical 

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
troponin, 
CK-MB, BNP) 
or cardiac 
imaging 
abnormalities 
suggestive of 
myocarditis
arrhythmia management.
Cardiology consult to establish 
etiology and rule-out 
immune-mediated myocarditis.
Guideline based supportive treatment 
as per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve, and 
immune-mediated etiology is ruled 
out, re-start avelumab therapy.
If symptoms do not improve/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed following 
cardiology consult, manage as 
immune-mediated myocarditis
presentation and in 
consultation with the 
cardiologist.
Immune-mediat
ed myocarditis
Permanently discontinue avelumab
Guideline based supportive treatment 
as appropriate as per cardiology 
consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Once improving, taper steroids over 
at least 1 month and add prophylactic 
antibiotics for opportunistic 
infections.
If no improvement or worsening, 
consider additional 
immunosuppressants (eg,
azathioprine, cyclosporine A).
If immune-mediated etiology 
is confirmed, hold PF 
06463922 until steroids have 
been initiated and symptoms 
improve to Grade ≤1, then 
re-start PF 06463922 at the 
same or reduced dose based on 
clinical presentation and in 
consultation with the 
cardiologist.
*Local guidelines, or eg, ESC or AHA guidelines
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Other irAEs (not 
described above)
Grade 2 or 
Grade 3 clinical 
signs or 
symptoms 
suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
Continue at the same dose 
(Grade 2) or hold (Grade 3) 
PF-06463922 pending clinical 
investigation. 
If irAE is ruled-out, re-start 

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
diagnosis and consider re-starting 
avelumab therapy
If irAE is confirmed, treat as Grade 
2 or 3 irAE.
PF-06463922 at the same dose 
(for Grade 3)
If irAE is confirmed, treat as 
Grade 2 or 3 irAE
Grade 2 irAE or 
first occurrence 
of Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper.
Continue at the same dose 
(Grade 2) or hold (Grade 3) 
PF-06463922, depending on 
clinical diagnosis. 
Re-start PF-06463922 at the 
same dose (for Grade 3) if 
symptoms improve to Grade ≤1
Recurrence of 
same Grade 
3 irAEs
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Hold PF-06463922 until 
symptoms improve to Grade 
≤1, then re-start 
PF-06463922 at the same dose
Grade 4
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Hold PF-06463922 until 
symptoms improve to Grade 
≤1, then re-start 
PF-06463922 at the same dose
Requirement 
for 10 mg per 
day or greater 
prednisone or 
equivalent for 
more than 
12 weeks for 
reasons other 
than hormonal 
Permanently discontinue avelumab 
therapy
Specialty consult
Hold PF-06463922 until 
symptoms improve to Grade 
≤1, then re-start 
PF-06463922 at the same dose

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
replacement for 
adrenal 
insufficiency
Persistent 
Grade 2 or 
3 irAE lasting 
12 weeks or 
longer
Selected Adverse Drug Reactions described for PF-06463922
CNS effects
Grade 1/2
Continue avelumab 
Continue PF-06463922 at the 
same dose or withhold dose 
until recovery to baseline.
Grade 3
Interrupt avelumab until recovery to 
Grade ≤1.
Withhold PF-06463922 dose 
until toxicity is Grade 1.  
Reduce dose to the next lower 
dose level.
Grade 4
Permanently discontinue avelumab.
Discontinue 
PF-06463922 treatment and do 
not retreat
Cholesterol 
increase
(See Table 11 for 
statin 
recommendations)
Grade 1
Continue avelumab 
Continue at the same 
PF-06463922 dose.  Consider 
introducing use of a statin.
Grade 2
Continue avelumab 
Introduce the use of a statin 
and continue at the same dose.
Grade 3
Continue avelumab 
Introduce the use of a statin, or 
increase the dose of the statin, 
or change to a new statin.  
Either continue 
PF-06463922 at the same dose 
without interruption or 
withhold dose until toxicity is 
Grade 2 and then continue at 
the same dose.
Grade 4
Continue avelumab 
Increase the dose of the statin, 
or change to a new statin.  
Withhold dose until toxicity is 
Grade 2 and then reduce the 
PF-06463922 dose by 1 dose 
level or rechallenge at the same 
dose.
Triglyceride 
increase
(See Table 11 for 
statin 
recommendations)
Grade 1
Continue avelumab 
Continue at the same dose.  
Consider introducing use of a 
statin.
Grade 2
Continue avelumab 
Introduce the use of a statin 
and continue at the same dose.

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
Grade 3
Continue avelumab 
Introduce the use of a statin, or 
increase the dose of the statin, 
or change to a new statin.  
Either continue 
PF-06463922 at the same dose 
without interruption or 
withhold dose until toxicity is 
Grade 2 and then continue at 
the same dose.
Grade 4
Continue avelumab 
Increase the dose of the statin, 
or change to a new statin.  
Withhold dose until toxicity is 
Grade 2 and then reduce the 
PF-06463922 dose by 1 dose 
level or rechallenge at the same 
dose.
Pancreatitis
Grade 1
Continue current dose of avelumab
Continue current 
PF-06463922 dose
Grade 2
If elevated enzymes (both amylase 
and lipase are Grade ≥2) are observed 
in the absence of clinical symptoms 
or radiological findings of 
pancreatitis: continue avelumab. 
If elevated enzymes and 
radiologically confirmed pancreatitis, 
permanently discontinue avelumab 
and treat as Grade 3 or 4.
If elevated enzymes (both 
amylase and lipase are 
Grade 2) are observed in the 
absence of clinical symptoms 
or radiological findings of 
pancreatitis: continue at the 
same dose level.  Repeat lipase 
and amylase and obtain 
pancreatic isoenzyme. 
If elevated enzymes and 
radiologically confirmed 
pancreatitis: withhold 
PF-06463922 dose.  Repeat 
radiology and lipase and 
amylase and obtain pancreatic 
isoenzyme and if returned to 
baseline then resume treatment 
at one dose level lower.
Grade 3 or 4
Permanently discontinue avelumab
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Permanently discontinue 
PF-06463922
Other 
Non-hematologic 
Grade 1
Continue as per schedule 
Continue PF-06463922 at the 
same dose level.

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
Toxicities and 
Laboratory 
Abnormalities
Grade 2
If toxicity resolves to Grade 1 by 
the last day of the current cycle, 
treatment may continue.
If toxicity does not resolve to Grade 
1 by the last day of the current 
cycle, infusions should not be given 
on the following cycle. 
If at the end of the following cycle
the event has not resolved to Grade 1, 
the patient should permanently 
discontinue treatment (except for 
hormone insufficiencies, that can be 
managed by replacement therapy; for 
these hormone insufficiencies, up to 
2 subsequent doses may be omitted).
Continue PF-06463922 at the 
same dose level
Grade 3
Permanently discontinue avelumab, 
Exceptions are:
Transient (6 hours) Grade 3 flu-like 
symptoms or fever, which are 
controlled with medical management.
Transient (24 hours) 
Grade 3 fatigue, local reactions, 
headache, nausea, or emesis that 
resolve to Grade 1. 
Single laboratory values out of 
normal range (excluding Grade 
3 liver function test increase) that 
are unlikely related to trial treatment 
according to the Investigator, do not 
have any clinical correlate, and 
resolve to Grade 1 within 7 days 
with adequate medical management.
.
Withhold PF-06463922 dose 
until toxicity is Grade 1 (or 
has returned to baseline), then 
reduce the dose by 1 level or 
rechallenge at the same dose
Patients who develop 
asymptomatic 
Grade 4 hyperuricemia or 
Grade 3 hypophosphatemia 
may continue 
PF-06463922 without dose 
modification at the discretion 
of the investigator.  Nausea or 
vomiting  must persist at 
Grade 3 or 4 despite maximal 
medical therapy to require 
PF-06463922 dose 
modification
Grade 4
Permanently discontinue avelumab 
Exceptions are:
single laboratory values out of 
normal range that are unlikely related 
to trial treatment as assessed by the 
Investigator, do not have any clinical 
correlate, and resolve within 7 days 
Withhold PF-06463922 until 
toxicity is Grade 1 (or has 
returned to baseline), then 
reduce the dose by 1 level or 
discontinue at the discretion of 
the investigator.
Patients who develop 

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Table 7.
Management of Avelumab + PF-06463922 Treatment-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
PF-06463922
Treatment Modification
Treatment Modification
with adequate medical management.
asymptomatic 
Grade 4 hyperuricemia or 
Grade 3 hypophosphatemia 
may continue 
PF-06463922 without dose 
modification at the discretion 
of the investigator.  Nausea or 
vomiting must persist at 
Grade 3 or 4 despite maximal 
medical therapy to require 
PF-06463922 dose 
modification
5.6.1.1. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion related reactions, a premedication regimen of 25 to 
50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent 
acetaminophen/paracetamol (as per local practice) is mandatory approximately 30 to 
60 minutes prior to each dose of avelumab.  This may be modified based on local treatment 
standards and guidelines, as appropriate. 
Following avelumab infusions, patients must be observed for 2 hours post infusion for 
potential infusion related reactions.  Treatment recommendations for the management of 
infusion-related reactions and, severe hypersensitivity reactions, are outlined in 
Sections 5.6.1.2 and Section 5.6.1.3..
Investigators should also monitor patients closely for potential irAEs.  Treatment 
recommendations for the management of irAEs are outlined in Section 5.6.1.4.
5.6.1.2. Management of Avelumab Infusion-Related Reactions
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 8.

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Table 8.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions
NCI CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for 24 hours.
Stop avelumab infusion.
Resume infusion at 50% of previous rate as soon 
as infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any recurrence or worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the avelumab infusion immediately and 
disconnect bag infusion tubing from the patient.
Avelumab treatment must be permanently 
discontinued.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain so for all subsequent infusions.  .
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: In the 
event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 8 (including reducing the infusion 
rate by 50%), the Investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that cycle.  At the next cycle, the Investigator may consider the 
addition of H2-blocker (eg, famotidine or ranitidine), meperidine, or ibuprofen to the 
mandatory premedication.  Prophylactic steroids are NOT permitted.
5.6.1.3. Management of Avelumab-Related Severe Hypersensitivity Reactions
As with all monoclonal antibody therapies, avelumab can induce hypersensitivity reactions, 
including impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, 
hypotension, pale/clammy skin, and cyanosis.
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment, if required.  Patient should be placed on 
monitor immediately and epinephrine injection and dexamethasone infusion should be 
available for immediate access.
5.6.1.4. Management of Avelumab Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of 
irAEs is mainly dependent upon severity (NCI CTCAE grade v4.03).

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Treatment of irAEs should follow guidelines set forth in Table 6 and Table 7.
5.6.2. Crizotinib Dose Modifications
Patients will be monitored closely for toxicity and the dose of crizotinib may be adjusted as 
indicated in Table 9. 
Table 9.
Crizotinib Dose Levels for Intrapatient Dose Modifications
Crizotinib Dose Levels
Modified Dose Level
250 mg BID
200 mg BID
200 mg BID
250 mg QD
250 mg QD
Discontinue crizotinib
Patients requiring more than 2 dose reductions due to treatment-related toxicity will be 
discontinued from the study if these reductions occur during the DLT period.  Otherwise, the 
patient may continue to receive avelumab as monotherapy at the Investigator’s discretion and 
in consultation with the Sponsor.
Investigators are encouraged to employ best supportive care according to local institutional 
clinical practices and according to the guidance for selected adverse events (Table 6 and 
Table 7).
5.6.2.1. Nausea and Emesis
For nausea and emesis, treat with standard anti-emetics such as prochlorperazine or 
ondansetron.  Taking the medication with food may reduce nausea.  The use of prophylactic 
antiemetics should be considered. 
5.6.2.2. Diarrhea
For Grade 1 diarrhea, symptomatic care such as loperamide (Imodium) or no intervention at 
Investigator judgment should be considered.  For Grade 2 diarrhea, loperamide (4 mg at first 
onset, then 2 mg every 2-4 hours until symptom free for 12 hours) should be administered.  
Refer to Table 6. 
5.6.2.3. 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.  See Table 6.

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

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In addition, multitest dipstick urinalysis (should include test for protein and blood) should be 
performed at the time of the renal cysts diagnosis and on Day 1 of each cycle thereafter.  In 
Korea, multitask 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 multitest 
dipstick is positive for blood or protein if this is the local standard. 
5.6.3. PF-06463922 Dose Modifications
Patients will be monitored closely for toxicity, and the dose of PF-06463922 may be adjusted 
as indicated in Table 10.  Patients requiring dose reduction per Table 10 should undergo 
reduction to the next lower dose level as outlined below.
Table 10.
PF-06463922 Dose Levels for Intrapatient Dose Modifications
PF-06463922 Dose Level
Modified Dose Level
100 mg QD
75 mg QD
75 mg QD
50 mg QD
50 mg QD
25 mg QD
25 mg QD
Discontinue PF-06463922
5.6.3.1. PR Interval Prolongation
If patients develop new first-degree AV block up to PR interval of 280 msec, then they 
should be monitored closely. 
If patients develop new second-degree AV block or a PR interval >280 msec, then a timely 
and thorough assessment of concomitant medications and electrolytes should be made. If a 
dose reduction or treatment interruption is considered, then dose reduction may be preferred 
given the pharmacologic auto-induction observed with PF-06463922 and the potential for 
higher exposure of the first dose following a treatment interruption.
Additionally, for patients with PR interval prolongation, the concomitant use of medicinal 
products known to prolong PR interval is not advised and these should be used with caution 
(see Appendix 6).
5.6.3.2. Pancreatitis
Pancreatic acinar atrophy was identified in toxicology studies in both rodent and non-rodent 
species.  Minimal to mild findings at clinically relevant concentrations are non-adverse 
(mid-dose in rats and all doses in dogs from 1-month study).  The pathogenesis is considered 
distinct from acute pancreatitis, lacking inflammation or necrotic cell death.19
In light of these findings, careful monitoring of pancreatic enzymes amylase and lipase are 
recommended.  If elevated enzymes (both amylase and lipase are Grade 2) are observed in 
the absence of radiological findings of pancreatitis, continue at the same dose level.  Repeat 
lipase and amylase and obtain pancreatic isoenzyme. 

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If radiologically confirmed pancreatitis is noted, withhold dose of PF-06463922.  Repeat 
radiology and lipase and amylase and obtain pancreatic isoenzyme and if returned to baseline 
then resume treatment at one dose level lower. 
In the Phase 1 trial of PF-06463922 there was no radiographic findings of pancreatitis and no 
symptomatic pancreatic events.
5.6.3.3. CNS Effects
As potential of CNS effects and cognitive deficit were suggested in safety pharmacology and 
general toxicity studies, close clinical monitoring for signs and symptoms of neurological 
changes are recommended in the Phase 1 study.  Most of the CNS effects, as demonstrated 
by changes in speech, memory, and mood, were mild to moderate in the Phase 1 study.  
Rarely, visual hallucinations have been reported.  These were generally intermittent and 
limited, with management through withholding dose until these events resolved, followed by 
dose reduction.  See Table 7.
5.6.3.4. Lipid Management
In the Phase 1 study, hypercholesterolemia was the most common adverse event.  Elevations 
in lipids usually begin in the first few cycles and, if statins are not introduced, can rise to 
Grade 3 levels by the next treatment cycle.  Therefore, the suggested management is to begin 
a statin for Grade 1 elevations in either cholesterol or triglycerides and to increase the statin 
dose if adequate control is not obtained, as outlined in Table 11 or introduce other lipid 
lowering agent as appropriate based on investigator’s medical judgment as described in 
Table 7.
Members of the statin class of agents are differentially sensitive to CYP3A4 and the 
following table may be used to facilitate management of elevated lipids.
Table 11.
Elevated Lipid Management
STATIN
CYP3A
Potential Effect* of 
PF-06463922 on statin AUC
Recommendation about 
Statin Selection and 
Dose**
Simvastatin (Zocor)
SENSITIVE 
Substrate
50-80% decrease in AUC
Selection not recommended
Lovastatin (Mevacor, 
Altocor)
SENSITIVE 
Substrate
50-80% decrease in AUC
Selection not recommended
Atorvastatin (Lipitor)
Substrate
40 % decrease in AUC
Consider increasing the 
atorvastatin dose 
(eg, 10 -->20 mg)
Pravastatin 
(Pravachol)
Substrate
30-40 % decrease in AUC
Consider increasing the 
pravastatin dose
Pitavavastatin (Livalo)
Not a Substrate
No change expected
No dose change
Rosuvastatin (Crestor)
Not a substrate
No change expected
No dose change
Fluvastatin (Lescol)
Substrate
~25 % decrease in AUC
No dose change
*Estimated based on the reported effect of strong and moderate CYP3A inducers on Statins.
** Dose adjustment to be based on changes in cholesterol levels (eg, worsening by 1 CTCAE grade level).

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5.7. Investigational Product Storage and Accountability
The Investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is stored in a secured area, under specified storage conditions and in 
accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label.  Storage conditions stated in the SRSD (ie, avelumab, crizotinib, or PF-06463922 IBs) 
will be superseded by newer label storage instructions. 
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 take home study 
treatment. 
5.7.1. Avelumab
Avelumab drug product must be stored in accordance with the avelumab investigational 
product label until use, with a temperature log maintained daily.  Medication must be kept in 
a secured locked area at the study site in accordance with applicable regulatory requirements.
Avelumab must not be frozen.  Rough shaking of avelumab must be avoided.  Storage 
conditions stated in the SRSD (ie, IB will be superseded by the label storage).

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5.7.2. Crizotinib
Crizotinib capsules must be stored in accordance with the crizotinib investigational label.  
Medication must be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Patients must be instructed to keep their medication in 
its original container and stored according to the label.  Returned medication for crizotinib 
must be stored separately from medication that needs to be dispensed.  Storage conditions 
stated in the SRSD (ie, IB will be superseded by the label storage).
To ensure adequate records, all study drugs will be accounted for in the CRF and drug 
accountability inventory forms as instructed by the Sponsor.  The investigative site must 
maintain adequate records documenting the receipt, use, loss, or other disposition of the 
investigational product supplies. Unless otherwise authorized by Pfizer, all crizotinib 
supplies unallocated or unused by the patients must be destroyed by procedures approved by 
Pfizer or returned to Pfizer or its designee.  Patients must return all containers to a designated 
study center participant.
5.7.3. PF-06463922
PF-06463922 tablets must be stored in accordance with the PF-06463922 investigational 
product label.  Medication must be kept in a secured locked area at the study site in 
accordance with applicable regulatory requirements.  Patients must be instructed to keep their 
medication in its original container and stored according to the label.  Returned medication 
must be stored separately from medication that is yet to be dispensed.  Storage conditions 
stated in the SRSD (ie, IB will be superseded by the label storage). 
To ensure adequate records, all study drugs will be accounted for in the CRF and drug 
accountability inventory forms as instructed by the sponsor.  The investigative site must 
maintain adequate records documenting the receipt, use, loss, or other disposition of the 
investigational product supplies. Unless otherwise authorized by Pfizer, all 
PF-06463922 supplies unallocated or unused by the patients must be destroyed by procedures 
approved by Pfizer or returned to Pfizer or its designee.  Patients must return all containers to 
a designated study center participant.
5.8. 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.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product/supplies. 

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5.9. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in the Exclusion Criteria are also not 
allowed during the active treatment period, except for administration of the inactivated 
influenza vaccine.
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor, and the patient. 
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
Concomitant medications and treatments will be recorded from 28 days prior to the start of 
study treatment and up to 90 days after the last dose of study treatment.  All concomitant 
medications should be recorded in the CRF including supportive care drugs (eg, antiemetic 
treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, 
and non-drug supportive interventions (eg, transfusions).
Concurrent anticancer therapy with agents other than avelumab, crizotinib or PF-06463922 is 
not allowed.  Medications intended solely for supportive care (ie, antiemetics, analgesics, 
megestrol acetate for anorexia) are allowed.
Recommended medications to treat infusion-related reactions, hypersensitivity reactions, 
flu-like symptoms, tumor lysis syndrome, and immune-related events are reported in 
Sections 5.6.1.2, Section 5.6.1.3, and Section 5.6.1.4.
5.9.1. Inhibitors and Inducers of CYP Enzymes
5.9.1.1. Group A 
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. 

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Additionally, the concurrent use of non prescription drugs, complementary medicines 
(excluding vitamins) or herbal supplements is not recommended.
5.9.1.2. Group B 
The in vitro studies have demonstrated that CYP3A, and UGT1A4 are primarily involved in 
the metabolism of PF 06463922, with additional minor contributions from CYP2C19 and 
CYP2C8.  Inhibition or induction of the above enzymes may result in potential alteration of 
lorlatinib systemic exposure.
Intial in vitro assessment for inhibition and induction drug-drug interaction potential 
indicated that PF 06463922 is a time-dependent inhibitor of CYP 3A and also an inducer of 
CYP3A and CYP2B6.  The net effect of PF-06463922 on CYP3A is currently under 
investigation.  At substantially higher concentrations than those observed clinically, 
PF-06463922 also inhibited CYP2C9 in in vitro studies. 
To protect patient safety, the following action should be exercised until more information is 
available:

Coadministration of strong CYP3A inhibitors (eg, atazanavir, boceprevir, clarithromycin, 
conivaptan, indinavir, itraconazole, miconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
troleandomycin, voriconazole, grapefruit juice or grapefruit/grapefruit related citrus fruits 
[eg, Seville oranges, pomelos]) is not permitted at study entry.  The use of these drugs 
during the study is not recommended and alternate medications should be considered.  If 
absolutely needed during the study, strong CYP3A inhibitors should be used with caution 
and patient closely monitored for safety.  Caution should be excercised exercised when 
coadministering drugs that are moderate CYP3A inhibitors (eg: amprenavir, aprepitant,  
ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir imatinib, 
verapamil).  Closely monitor the safety of patients and reduce the PF-06463922 dose if 
necessary.

Coadministration of strong CYP3A4 inducers (eg, strong inducers: carbamazepine, 
phenobarbital, phenytoin, rifatutin, rifampin, St. John’s Wort) is not permitted at study 
entry.  The use of these and other strong CYP3A4 inducer drugs concomitantly with 
PF-06463922 during the study is strictly prohibited and alternate medications should be 
considered.  If absolutely necessary, administration of PF-06463922 must be stopped 
while receiving the strong inducer and PF-06463922 must not be restarted until 10 days 
after the end of treatment of the strong CYP3A inducer.  Caution should be exercised 
when coadministrating drugs that are moderate CYP3A inducers (eg: nafcillin, modafinil, 
etravirine, efavirenz, bosentab, etc).  Closely monitor the safety of patients and adjust the 
PF-06463922 dose if necessary. 

Caution should be exercised when co-administer co-administering drugs that are sensitive 
CYP2B6 substrates such as bupropion and efavirenz.  The safety of patients should be 
closely monitored and the dose could be adjusted if necessary.

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
PF-06463922 inhibits CYP2C9 (in vitro); caution should be excercised when 
co-administering drugs that are CYP2C9 substrates with narrow therapeutic indices, such 
as warfarin, phenytoin or celecoxib.  The safety of patients should be closely monitored 
and the dose could be adjusted if necessary.

Coadministration of PF-06463922 with CYP3A substrates with a narrow therapeutic 
index, such as alfentanil, astemizole*, cisapride*, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl including transdermal patch, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine* (*withdrawn from US market) is not permitted starting from the 
first PF-06463922 dose and until 12 days after the last PF-06463922 dose.  Alternate 
medications should be considered.  Temporary use (<7 days) of drugs with adjustable 
dosing regimens, such as fentanyl, is allowed during PF-06463922 treatment, but the 
dose should be carefully adjusted to reach therapeutic effect and manage potential side 
effects of the narrow therapeutic index drug.  If there is any interruption or change in 
PF-06463922 treatment, the dose of the CYP3A substrate with narrow therapeutic index 
and adjustable dosing regimen may need to be adjusted down in dose .

The results from in vitro studies showed that PF-06463922 is a P-gp inhibitor.  The 
concurrent use of drugs which are P-gp substrates with narrow therapeutic indices, such 
as digoxin and dabigatran is not permitted at study entry.  The use of these drugs during 
the study is not recommended and alternate medications should be considered.  If 
absolutely needed during the study, caution should be exercised when co-administered 
P-gp substrates with narrow therapeutic indices with PF-06463922.  PF-06463922 may 
increase the plasma concentrations of these drugs and patients should be closely 
monitored for safety and dose of the P-gp substrate with a narrow therapeutic index may 
need to be stopped or adjusted if necessary.

Coadministration of known strong CYP2C19 inhibitors, such as fluconazole, 
fluvoxamine, and ticlopidine should be avoided and alternate drugs should be considered.  
If their use becomes necessary, this should be done with caution since they may increase 
PF-06463922 plasma concentrations. 

Coadministration of known strong CYP2C8 inhibitors, such as gemfibrozil, should be 
avoided.  If their use becomes necessary, this should be done with caution since they may 
increase PF-06463922 plasma concentrations.
Any questions regarding the use of alternative medications should be directed to the Sponsor 
for guidance. 
5.9.2. Other Anti-Tumor/Anti-Cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not 
permitted.

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5.9.2.1. Other Prohibited Concomitant Medications and Therapies 
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy;

Radiation therapy (with the exception noted in the Concomitant Radiotherapy 
Section 5.9.5); 

Immunotherapy, immunosuppressive drugs [unless otherwise indicated for the 
treatment of irAEs (Section 5.9.6.)], or other experimental pharmaceutical products 
(ie, chemotherapy or systemic corticosteroids except for short-term treatment of 
allergic reactions or for the treatment of irAEs);

Any vaccine therapies for the prevention of infectious disease except for inactive 
vaccines ;

Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known 
to potentially interfere with major organ function (eg, hypericin);

Acetaminophen use should be restricted to no more than 2 g/day;

Testosterone replacement therapy is only allowed in Group A in the presence of signs 
and symptoms clearly attributable to hypogonadism in consultation with an 
endocrinologist, who should also exclude any potential confounding effects of 
elevated prolactin and/or estradiol, or a significant recent change in corticosteroid 
dose, before doing so;

The concurrent use of crizotinib (Group A) with medicinal products that are known to 
prolong the QT interval, and/or antiarrhythmics should be used with caution.  The use 
of crizotinib in combination 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 (syncope, dizziness, hypotension). 
5.9.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first 4 weeks (2 cycles) of treatment but they may be used at any time to treat 
treatment-emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines.39
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
investigator in line with local guidelines.  Patients who enter the study on stable doses of 
erythropoietin or darbepoietin may continue this treatment, and patients may start either drug 
during the study at the discretion of the investigator.

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5.9.4. Concomitant Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. 
In case of surgical procedure avelumab treatment should be delayed.  Reinitiation should be 
discussed with the Sponsor.
The appropriate interval of time between surgery, crizotinib, and PF-06463922 required to 
minimize the risk of impaired wound healing and bleeding has not been determined.  
Stopping crizotinib or PF-06463922 is recommended at least 2 days prior to surgery.  
Postoperatively, the decision to reinitiate crizotinib or PF-06463922 treatment should be 
based on a clinical assessment of satisfactory wound healing and recovery from surgery, but 
resumed no sooner than 48 hours after surgery.
5.9.5. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline, otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression. 

Crizotinib must be stopped 24 hours before and at least 24 hours after complete of 
radiation therapy.

PF-06463922 treatment should be interrupted during palliative radiotherapy, stopping 
1 day before and resuming treatment after recovery from acute radiation toxicities to 
baseline.
5.9.6. Clarification About Steroid Use
Data indicate that corticosteroids have an adverse effect on T cell function and that they 
inhibit and damage lymphocytes.22,34 Furthermore, as with all immunotherapies intended to 
augment cell-mediated immunity, there is a risk that concomitant immunosuppressives such 
as steroids will counteract the intended benefit. However, studies with 
anti-CTLA4 compounds indicate that short-term use of steroids may be employed without 
compromising clinical outcomes.  Therefore, if a study patient is still receiving avelumab the 
use of steroids during this trial is restricted as follows:

Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs is permitted according to the modalities indicated in Table 7;

Physiologic use: replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable;

Prophylactic use, eg, for the prevention of acute infusion-related reactions is 
prohibited.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 

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6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see Schedule of Activities and ASSESSMENTS section.
6.1.1. Tumor Biospecimens
Provision of an archival FFPE tumor tissue sample is required from all patients prior to 
registration.  The archival tumor tissue specimen may be from either a primary or metastatic 
lesion, and may represent tissue obtained at the time of, or subsequent to, the initial 
diagnosis.  The archival tumor tissue collection should be within one year of start of study 
treatment, with no intervening systemic anti-cancer therapy (including neoadjuvant or 
adjuvant therapy).  If an older archival tumor tissue (>1 year prior to start of study treatment) 
is available, it might still be submitted but will not fulfill requirement for tumor tissue.  
Archived tumor tissue should be provided as a FFPE tumor tissue block containing sufficient 
tumor tissue to allow if possible for sectioning of 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, a de novo (ie, fresh) tumor sample must be 
obtained in accord with local institutional practice for tumor biopsies.  Archival 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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

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6.1.2. Determination of NSCLC Molecular Status
ALK status will be determined by local standards.  Retrospective central laboratory testing 
for alterations in ROS1, c-Met genes (including ROS1 gene translocation, c-Met gene 
amplification, and c-Met exon 14 deletion), and EGFR will be performed on all tumor tissues 
for validation of mutational status.
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
6.3. End of Treatment/Withdrawal and Follow-Up Visits
For End of Treatment/Withdrawal procedures, see Schedule of Activities (SOA) and 
ASSESSMENTS section.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol- required schedule of study 
visits or procedures at a given study site.
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment per the Investigator will 
be eligible to continue with avelumab in combination with crizotinib or avelumab in 
combination with PF-06463922, provided that the treating physician has determined 
that the benefit/risk for doing so is favorable and discussed with the Sponsor 
(See Table 7);

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
study treatments, the investigator (in discussion with the Sponsor) may continue 
treatment with the other study treatment;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment (follow-up permitted by patient);

Study terminated by sponsor;

Death.

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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.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product(s), request 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 (if 
survival is a secondary endpoint) 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.
6.5. Follow-up Visits
For follow-up procedures see Schedule of Activities and ASSESSMENTS section.
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 and Sponsor 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
examination, 12-lead ECG, laboratory assessments, including pregnancy tests and 
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7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL 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.  Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced and another negative pregnancy test result will then be 
required at the baseline visit before the patient may receive the investigational product.  
Urine pregnancy tests will also be routinely repeated at every treatment cycle prior to dosing, 
during the active treatment period, at the end of study treatment, during follow-up (up to 
90 days after last study treatment) and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  In the case of a positive hCG test, the 
patient will be withdrawn from treatment but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by IRB/ECs or if required by 
local regulations.
7.1.2. 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] 
v4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study will be recorded on the adverse events CRF page.
7.1.2.1. Avelumab Adverse Events of Special Interest
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI).  Specific guidance for the management of irAEs is provided in Section 5.6.1.4.  
AESIs are reported according to the general AE reporting rules specified in Section 8.14.1.
7.1.3. Laboratory Safety Assessment
Haematology, blood chemistry, and urinalysis will be collected at the time points described 
in the Schedule of Activities (SOA) and analyzed at local laboratories.  They may also be 
performed when clinically indicated.  The required laboratory tests are listed in Table 12. 

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Table 12.
Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core 
chemistry test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Protein, glucose and 
blood 
Urine dipstick for 
urine blood: If 
positive, collect 
microscopic urinalysis 
(Reflex Testing)
PT or INR
For female 
patients of 
childbearing 
potential, serum 
or urine 
Platelets
AST*
aPTT
WBC
Alkaline Phosphatase*
Absolute Neutrophils
Sodium*
Absolute Lymphocytes
Potassium*
Absolute Monocytes
Magnesium*
Absolute Eosinophils
Chloride*
Absolute Basophils
Calcium*
Total Bilirubin* 
BUN or Urea*
Creatinine*
Glucose (non-fasted)*
Phosphorus or Phosphate*
Albumin*
Total Protein*
Uric Acid*
Amylase*
Gamma glutamyl 
transferase (GGT)*
Cholesterol*
Creatine kinase*
Lactate dehydrogenase 
(LDH)*
Lipase*
Triglycerides*
HBV, HCV
Thyroid Function Tests:
TSH, free T4
Other Tests: 
ACTH
°Potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time (PT)/INR, alkaline 
phosphatase, and acetaminophen levels.
^ Serum total amylase (pancreatic isoenzyme required if serum total amylase >1.5x ULN per local institutional ranges 
(ie, CTCAE Grade >1)).
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, -free thyroxine (FT4), GGT=gamma-glutamyltransferase, 
HBV= hepatitis B virus, HCV= hepatitis C virus, INR=international normalized ratio, LDH=lactate dehydrogenase, 
RF=rheumatoid factor, TSH=thyroid-stimulating hormone, WBC=white blood cell.
7.1.4. Vital Signs and Physical Examinations
Patients will have a physical examination to include major body systems, weight, blood 
pressure, pulse rate, assessment of ECOG performance status, and height (height will be 
measured at screening only) at the time points described in the Schedule of Activities.  Blood 
pressure and pulse rate should be taken with the patient in the seated position after the patient 
has been sitting quietly for at least 5 minutes.

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7.1.5. 12-Lead Electrocardiograms
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  All 
patients require a single ECG measurement at screening.  Triplicate 12-lead (with a 
10-second rhythm strip) tracing will be used for all other ECGs.  It is preferable that the 
machine used has a capacity to calculate the standard intervals automatically.  At each time 
point (see the Schedule of Activities), 3 consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine mean QTc interval.  If the mean QTc is 
prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate.  If manual reading verifies a QTc of 
>500 msec, immediate correction for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTc 
interval) should be performed.  In addition, repeat ECGs should be immediately performed 
hourly for at least 3 hours until the QTc interval falls below 500 msec.  If QTc interval 
reverts to less than 500 msec, and in the judgment of the investigator(s) and sponsor is 
determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring.  If in that timeframe the QTc intervals rise above 
500 msec the investigational product will be held until the QTc interval decreases to 
500 msec.  Patients will then restart the investigational product at the next lowest dose level 
or dose delayed as appropriate for specific investigational product.  If the QTc interval has 
still not decreased to <500 msec after 2-weeks, or if at any time a patient has a QTc interval 
>515 msec or becomes symptomatic, the patient will be removed from the study.  Clinically 
significant abnormal findings in baseline ECGs will be recorded as medical history.  
Additional ECGs will be performed as clinically indicated.  Clinically significant findings 
seen on the follow up ECGs should be recorded as adverse events.  Prior to concluding that 
an episode of prolongation of the QTc interval is due to investigational product, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by a specialist.
If a patient experiences PR prolongation >200 msec or second-degree or third-degree AV 
block, refer to Section 0.
If a patient experiences any cardiac or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke), an ECG in triplicate should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
7.2. Pharmacokinetics Assessments
Plasma/serum samples will be obtained from patients for PK depending on the treatment 
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7.2.1. Blood Sample Collection for Pharmacokinetic Analysis
Where noted in the Schedule of Activities, blood samples will be collected at approximately 
the same time as other assessments wherever possible.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time of 
blood sample collection and of last dosing prior to PK collection documented in the CRF.
Where noted in the Schedule of Activities, blood samples for study drug concentrations will 
be collected at approximately the same time as other assessments such as pharmacodynamic 
samples, ECGs and bone marrow aspirate collections etc., wherever possible. 
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, the exact time of the sample collection will always be noted on 
the CRF.  If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample time may be re-scheduled with agreement of the clinical investigator, patient, 
and sponsor.
If patient discontinues either PF-06463922/crizotinib or avelumab therapy, PK samples for 
the discontinued drug is no longer necessary. 
PK samples will be assayed using a validated analytical method in compliance with Pfizer 
standard operating procedures.  Details regarding the collection, processing, storage and 
shipping of the blood samples will be provided in the Lab Manual.
7.2.2. Collection of Avelumab Pharmacokinetic Samples (Both Groups A and B)
Blood samples (3.5 mL whole blood) will be collected for PK analysis of avelumab into an 
appropriately labeled serum separator tube (SST) as outlined in the Schedule of Activities.  
PK sampling schedule may be modified based on emerging PK data.  Blood for PK samples 
will be drawn from the arm contralateral to the drug infusion. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, with the exception of samples where nominal time coincides with end of 
infusion, samples obtained within ±10% of the nominal time (eg, within 3 minutes of a 
30 minute sample) will not be captured as a protocol deviation, as long as the exact time of 
the sample collection is noted on the source document and data collection tool (eg, CRF).  
For samples where nominal time coincides with end of infusion, a sample collected within 
10 min post end of infusion will not be captured as a protocol deviation, as long as the exact 
time of the sample collection is noted on the source document and data collection tool (eg, 
CRF).  If the infusion of avelumab is interrupted due to AE, any PK samples scheduled 
during the time the AE is occurring are not required.  If a scheduled blood sample collection 
cannot be completed for any reason, the missed sample time may be re-scheduled with 
agreement of clinical investigators, patient and Sponsor.

Details regarding the collection, processing, storage and shipping of the blood 
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•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
•
 
 
 
7.2.3. Collection of Crizotinib Pharmacokinetic Samples (Only Group A)
Whole blood (3 mL) will be collected into an appropriately labeled K2EDTA tube at the 
designated times as outlines in the Schedule of Activities to provide at least 1 mL of plasma 
for crizotinib PK analysis.  These samples will be analyzed for crizotinib and its metabolite 
PF-06260182. 
Special precaution should be taken to minimize crizotinib samples from exposure to visible 
light, which will cause rapid degradation of crizotinib.
7.2.4. Collection of PF-06463922 Pharmacokinetic Samples (Only Group B)
Whole blood (4 mL) will be collected at the designated times as outlined in the Schedule of 
Activities to provide at least 2 mL of plasma for PF-06463922 PK analysis. 
Special precaution should be taken to minimize PF-06463922 sample from exposure to 
visible light, which will cause rapid degradation of PF-06463922.
7.3. Immunogenicity Assessment
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab 
Anti-Drug Antibodies (ADAs) into an appropriately labeled serum separator tube (SST).  
Predose ADA samples will be collected within 2 hours prior to dosing.  At each assessment, 
a single ADA sample will be separated into two aliquots in order to assess both ADA and 
nAb (if warranted, see below).  Further details can be found in the Lab Manual.  This 
assessment will take place at regular intervals during the treatment and follow-up periods as 
described in the Schedule of Activities. 
A tiered ADA testing strategy will be used: all samples that are positive in the screening 
assay will be confirmed for antibody specificity.  Confirmed positive samples will be further 
characterized for titer and tested in the neutralizing antibody (nAb) assay, if appropriate.
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Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site prior to initiation of the trial.
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
 
 
 
 
7.4. Translational and Pharmacodynamic Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may have predictive value in identifying those patients 
who may benefit from treatment with the combination of avelumab and either crizotinib or 
PF-06463922. 
 
 
7.4.1. Tumor Tissue
Tumor biospecimens from archived tissue samples and/or de novo biopsies (see 
Section 6.1.1) will be used to analyze candidate 
 protein markers, or relevant 
signature of markers, for their ability to identify those patients who are most likely to benefit 
from the study treatment.  
 
 
 
 Markers that may be analyzed include, but may not necessarily be limited to, 
PD-L1 expression and CD8+ TILs. 
Acquisition of the mandatory tumor tissue may be completed prior to the 28 day screening 
window, but it is required for patient enrollment.  Note that if archival FFPE tumor tissue 
cannot be provided, FFPE tumor tissue from a de novo tumor biopsy performed at screening 
must be provided.
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Only core needle or excisional biopsies, collection of malignant pleural effusion cell pellets, 
or resection specimen are suitable (Endobronchial Ultrasound Guided Transbronchial Core 
Needle biopsies are adequate).  Cytologic preparations, such as fine needle aspirate biopsies, 
are not acceptable.  Additional information on tissue collection procedures can be found in 
the Laboratory Manual.
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
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7.6. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging will include 
chest, abdomen, and pelvis CT or MRI scans.  Baseline CNS imaging is required to identify 
asymptomatic brain metastases.  CT or MRI scans are to be done starting at Cycle 
4/Week 8 (+1 week) then repeated every 4 cycles/8 weeks (±1 week).  Bone scans will be 
performed (or bone MRI if preferred by Investigator) at baseline and on study if bony 
metastases are suspected.  Patients with positive results on the bone scans (or bone MRI if 
preferred by Investigator) will have these repeated every 8 cycles/16 weeks (±1 week). 
Tumor assessments must continue until disease progression has been determined by the 
radiologist regardless of initiation of subsequent anti-cancer therapy.  For patients who stop 
study treatment without PD, tumor assessments will be evaluated for delayed tumor response 
by avelumab.  Tumor assessments must continue if the treating physician determines the 
patient would benefit clinically from treatment beyond RECIST (See Appendix 3) 
v.1.1-defined disease progression (see Section 5.4.4).  Both target and non-target lesions are 
to be followed using the same modality used at baseline and interval unless clinically 
indicated.  Tumor assessments should be repeated after at least 4 weeks to confirm response 
and disease progression, and at the End of Treatment visit if more than 4 weeks have passed 
since the last evaluation.  CR and PR must be confirmed with repeated imaging performed at 
least 4 weeks after initial documentation of response.  If radiologic imaging shows 
progressive disease (PD), then tumor assessment should be repeated after at least 4 weeks to 
confirm PD.
All radiographic images will be collected and may be objectively verified by a blinded 
independent third-party core imaging laboratory as described in the Imaging Manual.
 
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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 non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. 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 90 calendar days after the last 
administration of the investigational product.  -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 non-serious) 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 non-serious 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 treatment.
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;

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
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 CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

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
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 AEs are captured on an AE CRF page. 
The guidance on reporting of medication errors also applies to the reporting of overdose.
For purposes of this study, an overdose of avelumab is defined as an increase 5% than the 
planned avelumab dose for that particular administration.
As for crizotinib and PF-06463922, an overdose is defined as a dose greater than the 
prescribed dose.
There is no specific treatment for avelumab, crizotinib, or PF-06463922 overdose.  In the 
event of overdose with any of these study drugs, the patient should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided as clinically 
indicated. 
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 outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
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;

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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as 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 CTCAE) Grade 5 (see the section on 
Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other 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 (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
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
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 × ULN, or 
8 × ULN (whichever is smaller);
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 × ULN or 
if the value reaches 3 × 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 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;

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
Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of 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 
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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 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 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship 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 the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
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. 
For combination treatments, causality assessment will be performed for each of the 
individual drugs included in the combination.
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 
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product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If 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 an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
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.

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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 form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Sections 6.3 and 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.  In addition, each study patient 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 
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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 
designated representative. 
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 trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Analysis Sets 
The following patient populations will be assessed:

Full analysis set: includes all enrolled patients who receive at least 1 dose of study 
treatment.  If a patient received more than one study treatment the patient will be 
classified according to the first study treatment received.  This will be the primary 
analysis set for all efficacy endpoints in both Phase 1b and 2;

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
Safety analysis set: includes all enrolled patients who receive at least 1 dose of study 
treatment.  If a patient received more than one study treatment the patient will be 
classified according to the first study treatment received.  In this non-randomized 
study the Full analysis set and the Safety analysis set are identical.  This will be the 
primary analysis set for all safety endpoints in both Phase 1b and 2;

DLT-evaluable analysis set includes all patients enrolled in Phase 1b who are in the 
safety analysis set, and either experience DLT during the first 2 cycles, or complete 
the observation period for the first 2 cycles of treatment.  If there is a patient without 
DLTs and who does not receive at least 75% of the first 2 cycles doses of crizotinib 
or PF-06463922 or who do not receive at least 2 infusions of avelumab for reasons 
other than study drug-related toxicity will be replaced;

PK analysis set: includes all patients in the safety analysis set who have sufficient 
concentration data to estimate at least 1 of the PK parameters of interest;

Biomarker analysis set: includes all patients in the safety analysis set who have at 
least 1 screening biomarker assessment, and have received at least 1 dose of any 
study drug.  Analysis sets will be defined separately for blood-based and tumor 
tissue-based biomarkers.
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 design 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.  As shown by Ji and Wang, mTPI design is 
more efficient and safer than 3+3 design.53 They considered 42 scenarios to cover a wide 
range of practical dose-response shapes, and concluded that the 3 + 3 design was more likely 
to treat patients at toxic doses above the MTD and less likely to identify the true MTD than 
the mTPI design.  For example, the 3 + 3 design exhibited a lower overall toxicity percentage 
than the mTPI design in only one of 42 scenarios.
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.20 Thus, compared to 

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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.20
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0, pT-e1), the overdosing interval (pT+e2,1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of crizotinib and avelumab, 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 
underdosing interval corresponds to a dose re-escalation (RE), overdosing 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 underdosing 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.20 Simulations 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). 
The Phase 1b dose finding evaluation of the trial is completed when 12 DLT-evaluable 
patients have been treated at the highest dose associated with a DLT rate 33% or if the 
combinations are deemed to toxic, as determined by the DLT rate and/or lower than expected 
doses of the study treatments.  In case de-escalation is required from the initial starting DL0, 
it is estimated that up to approximately 42 DLT-evaluable patients will need to be enrolled to 
estimate MTD for the crizotinib plus avelumab combination.  For the PF-06463922 plus 
avelumab combination, up to approximately 36 patients may be enrolled.
9.3. Sample Size Determination
For Phase 1b of this study, due to the dynamic nature of the Bayesian allocation procedure, 
the exact sample size of the “Up-and-Down” matrix design using the mTPI approach cannot 
be determined in advance
For Group A, it is expected that from approximately 12 to 36 patients will need to be enrolled 
in Phase 1b using the mTPI approach.  At least 12 patients will be treated at the MTD in 
Phase 1b to further determine the RP2D (See Sections 3.3 and Section 3.4) according to the 
safety of the combination.  These patients will also be monitored to assess objective response 
in order to determine the expansion into Phase 2, an additional 33 patients enrolled at the 
RP2D in Stage 2 (Phase 2).  The sample size determination is based on Simon's Optimal 
Two-Stage design.38 The null hypothesis that the true ORR does not exceed 15% will be 
tested at =0.025 (one-sided) against the alternative: 

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H0: ORR15% versus Ha: ORR>15%  
The first 12 patients treated at the RP2D during dose-finding stage will be included as 
Stage 1 of Simon’s Optimal Two-Stage design.  If there are 3 or more patients with 
confirmed objective response in the first 12 patients treated at the RP2D, then an additional 
33 patients will be enrolled and treated at that dose level.  The null hypothesis will be 
rejected if there are 12 patients with confirmed CR or PR among 45 patients treated at the 
RP2D.  The study will have at least 80% power to reject the null hypothesis when the true 
response rate ORR is at least 35% (Ha: ORR35%). 
For Group B, it is expected that from approximately 12 to 36 patients will need to be treated 
in the dose-finding stage of Phase 1b using the mTPI approach.  Up to 12 additional patients 
may be enrolled at the MTD to further characterize safety and tolerability and determine the 
RP2D (See Section 3.3 and Section 3.4).
For the Phase 2 of Group B, approximately 30 treatment-naïve patients will be enrolled.  This 
will allow estimating the ORR and CR rate with a maximum standard error of 9.1%.  
Table 13 provides the exact binomial 90% and 95% confidence intervals for the ORR and 
CR rate based on different bserved responses among 30 patients.
Table 13.
Sample Size and Exact 90% and 95% CI for ORR and CR rate for Phase 
2 of Group B
Sample 
Size
Number of 
Responders/
Complete Responders
ORR/ CR 
Rate
90% CI
95% CI
30
6
20%
(9.1%, 35.7%)
(7.7%, 38.6%)
30
9
30%
(16.6%, 46.5%)
(14.7%, 49.4%)
30
12
40%
(25.0%, 56.6%)
(22.7%, 59.4%)
30
15
50%
(33.9%, 66.1%)
(31.3%, 68.7%)
30
18
60%
(43.4%, 75.0%)
(40.6%, 77.3%)
30
21
70%
(53.5%, 83.4%)
(50.6%, 85.3%)
30
24
80%
(64.3%, 90.9%)
(61.4%, 92.3%)
30
25
83.3%
(68.1%, 93.2%)
(65.3%, 94.4%)
30
26
86.7%
(72.0%, 95.3%)
(69.3%, 96.2%)
30
27
90%
(76.1%, 97.2%)
(73.5%, 97.9%)
30
28
93.3%
(80.5%, 98.8%)
(77.9%, 99.2%)
30
29
96.7%
(85.1%, 99.8%)
(82.8%, 99.9%)
9.4. Efficacy Analysis
The Full analysis set will be used for all efficacy analyses.  Summaries of efficacy will be 
presented separately for Group A (including Phase 1b and Phase 2 patients at the RP2D) and 
Group B (including Phase 1b and Phase 2 patients at the RP2D).  Within Group A and 
Group B, patients treated at doses other than RP2D will be summarized separately by study 
treatment (dose).  Within Group B, the patients enrolled in Phase 2 will also be summarized 
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Objective response is defined as a CR or PR per RECIST v.1.1 from the date of first dose of 
study treatment until disease progression or death due to any cause.  Both CR and PR must 
be confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.  Otherwise, the patient will be counted as a non responder in the 
assessment of ORR.  ORR is defined as the proportion of patients with a confirmed CR or 
confirmed PR per Investigator’s assessment according to RECIST v.1.1.  The CR rate is the 
proportion of patients with CR.
Disease Control (DC) is defined as objective response (CR or PR) or stable disease (SD) per 
RECIST v.1.1 from the date of first dose of study treatment until disease progression or death 
due to any cause.  The DC rate (DCR) is the proportion of patients with DC.
PFS is defined as the time from the date of first dose of study treatment to the date of disease 
progression by RECIST v.1.1 or death due to any cause, whichever occurs first.  PFS data 
will be censored on the date of the last adequate tumor assessment for patients who do not 
have an event (PD or death), for patients who start new anti-cancer treatment prior to an 
event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor
assessments will be censored on the date of first dose of study treatment unless death 
occurred on or before the time of the second planned tumor assessment in which case the 
death will be considered an event.
OS is defined as the time from the date of first dose of study treatment to the date of death 
due to any cause.  Patients last known to be alive will be censored at date of last contact.
DR is defined for patients who have confirmed objective response as the time from the first 
documentation of objective tumor response (CR or PR) to the first documentation of 
objective disease progression or to death due to any cause, whichever occurs first. 
TTR is defined for patients who have confirmed objective response as the time from the date 
of first dose of treatment to first documentation of objective tumor response (CR or PR).
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 and DCR will be calculated along with the corresponding exact 2-sided 
95% confidence intervals.  For Group B Phase 2 patients, the CR rate will also be calculated 
along with the corresponding exact 2-sided 95% confidence interval. 
 
 
 
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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, PF-06463922, and Avelumab
Standard plasma PK parameters for crizotinib and PF-06463922 will be estimated using 
non-compartmental analysis.  For crizotinib and PF-06463922, standard PK parameters will 
include maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax), area under the plasma concentration-time curve during the dosing interval time course 
(AUCtau), area under the concentration-time curve from time of dosing to the last collection 
time point (AUClast), trough plasma concentration (Ctrough), apparent plasma clearance 
(CL/F), and apparent volume of distribution (V/F), if data permit.  Dose-normalized 
parameters (eg, CDN-Cmax, DN-AUC) will be reported as appropriate.
For PF-06260182, standard PK parameters will include Cmax, Tmax, Ctrough, metabolite to 
parent ratio for area under t, he plasma concentration versus time curve during the dosing 
interval time course (MRAUC-), and the metabolite to parent ratio for Cmax (MRCmax).  
Descriptive statistics for the PK parameters for crizotinib and PF-06260182 and 
PF--06463922 will be provided by dose, cycle, and day of assessment in tabular form. 
Crizotinib, PF-06260182, and PF-06463922 plasma concentrations will be summarized 
descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean, its 
associated CV, and 95% confidence interval) by dose, cycle, day and nominal time.  
Individual patient and median profiles of crizotinib, PF-06260182, and 
PF-06463922 concentration-time data will be plotted by dose, cycle and day using nominal 
times.  Median crizotinib, PF-06260182, and PF-06463922 profiles will be presented on both 
linear-linear and log-linear scales.
Ctrough and Cmax for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
dose, cycle, and day.  The trough concentrations for avelumab will be plotted for each dose
using a box-whisker plot by cycle and day in order to assess the attainment of steady-state.
Crizotinib and PF-06463922 at steady state when combined with avelumab will be compared 
to PK of crizotinib and PF-06463922 when administered alone in a similar patient population 
from historical data. 
9.5.1.2. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by dose and overall incidence.  For patients with positive 
ADA or neutrolizing antibodies, the magnitude (titer), time of onset, and duration of ADA or 
neutrolizing antibodies response will also be described, if data permit. 
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.

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9.5.1.3. Population Pharmacokinetic Analysis
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab exposure and biomarkers, efficacy endpoints, or significant 
safety endpoints.  The results of these analyses, if performed, may be reported separately.
9.5.2. Biomarkers
Biomarkers will be assessed separately for whole blood, serum, plasma, archival tumor 
tissue, and de novo tumor tissue biospecimens.  In each case, summaries of baseline levels, 
changes from baseline (where appropriate), expression and genetic alterations will be 
reported.  For continuous variables, summary statistics may include the mean, ratio to 
baseline, standard deviation, 25th, median, and 75th quartile, %CV and minimum/maximum 
levels of biomarker measures; for categorical variables, summary may include number and 
percentage, odds ratio, frequency statistics, as appropriate.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
 
  
9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the DLT-evaluable 
analysis set.  All other summaries and analyses of safety parameters will be based on the 
safety analysis set. Safety data will be summarized by dose level using appropriate 
tabulations and descriptive statistics (pooling together patients treated at the MTD from both 
phases of the study).
9.6.1. Analysis of the Primary Endpoint
Dose-Limiting Toxicity (DLT) is the primary endpoint of the study Phase 1b portion.  The 
occurrence of DLTs during the first 2 cycles of treatment, as well as during the anytime 
throughout the trial in determining the RP2D, observed in the dosing cohorts is used to 
estimate the MTD as described in the STUDY DESIGN section (Section 3).  Adverse Events 
constituting DLTs will be listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
The Safety Analysis Set will be used for all secondary safety evaluations.  Summaries of AEs 
and other safety parameters will be presented separately for Group A (including Phase 1b and 
Phase 2 patients at the RP2D) and Group B at the RP2D.  Within Group A and Group B, 
patients treated at doses other than RP2D will be summarized separately by study treatment 
(dose). 
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Adverse Events
AEs will be graded by the investigator according to the CTCAE v4 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of study treatment.  The number and percentage of patients who 
experienced any AE, SAE, treatment-related AE, and treatment-related SAE will be 
summarized according to worst toxicity grades.  These summaries will present AEs both on 
the entire study period and by cycle (Cycle 1 and Cycles >1). 
Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v4 severity grade whenever 
applicable.  The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test. 
The analyses will summarize laboratory test results both on the entire study period and by 
cycle (Cycle 1 and Cycles >1). 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
Shift tables will be provided to examine the distribution of laboratory abnormalities.
Electrocardiograms 
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.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post-baseline corrected QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically-relevant morphological ECG changes will be summarized (including 
frequency and percentage).

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9.8. Data Monitoring Committee 
An external Data 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 will include 
surveillance for SAEs according to regulatory guidelines.
Discussions between the investigators and the sponsor of AEs and laboratory abnormalities 
seen at each dose level in an ongoing manner at regular teleconferences and/or meetings to 
determine the safety profile and make a benefit/risk assessment to decide if further patient 
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.
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.
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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.
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 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. 

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

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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 Last Patient Last Visit.
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 
avelumab, crizotinib and/or PF-06463922 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 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date 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 

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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.
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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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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16. REFERENCES
1.
Antonia, SJ, Larkin, J, Ascierto, PA.  Immuno-oncology combinations: a review of 
clinical experience and future prospects.  Clin Cancer Res. 2014; 20: 6258 68.
2.
Awad MM, Katayama R, McTigue M, et al. Acquired Resistance to Crizotinib from a 
Mutation in CD74–ROS1. N Engl J Med. 2013; 368: 2395-401.
3.
Brahmer JR, Rizvi NA, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, 
an anti–PD-L1 antibody, in patients with NSCLC. J Clin Oncol 2014; 32:5s (suppl; 
abstr 8021).
4.
Brahmer JR, Horn L, Gandhi L, et al. Nivolumab (anti–PD-1, BMS- 936558, ONO 
4538) in patients (pts) with advanced non–small-cell lung cancer. J Clin Oncol. 2014; 
32: 5s (suppl; abstr. 8112). 
5.
Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced 
squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; DOI: 
10.1056/NEJMoa1504627.
6.
Camidge DR, Pao W & Sequist LV. Acquired resistance to TKIs in solid tumours: 
learning from lung cancer. Nat Rev Clin Onc. 2014; 11: 473-481.
7.
Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. 
Version 5.2015. www.nccn.org. 
8.
Doebele R, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in 
patients with ALK gene rearranged non-small-cell lung cancer. Clin Cancer Res. 2012; 
18: 1472-82.
9.
Ferlay J, Soerjomataram I, Dikshit R, et al.  Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136: 
E359-86. 
10.
Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in 
previously treated patients (pts) with non–small cell lung cancer (NSCLC). J Clin 
Oncol. 2014; 32: 5s (suppl; abstr. 8020). 
11.
Gettinger SN and Herbst R.  B7-H1/PD-1 blockade therapy in non-small cell lung 
cancer: current status and future direction.  Cancer J. 2014; 20: 281-9. 
12.
Gettinger SN, Shepherd FA, Antonia SA, et al. First-line nivolumab (anti-PD-1; BMS 
936558; ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and 
correlation of outcomes with PD-L1 status. J Clin Oncol. 2014; 32:5s (suppl; abstr. 
8024).

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13.
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody 
blockade of cytotoic T lymphocyte-associated antigen 4 in previously vaccinated cancer 
patients. Proc Natl Acad Sci USA. 2008; 105:3005-10.
14.
Hoos A, Egermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst. 2010; 102:1388-97.
15.
Horn L, Herbst R, Spiegel D, et al. An analysis of the relationship of clinical activity to 
baseline EGFR status, PD-L1 expression and prior treatment history in patients with 
non–small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A 
(anti-PD-L1). J Thorac Oncol. 2013; 8 (suppl. 2): S364 (abstr. MO18.01).
16.
Howard SC, Jones DP, and Pui CH. The tumor lysis syndrome. N Engl J Med. 2011; 
364:1844-54.
17.
Investigator’s Brochure of avelumab (MSB0010718C), dated February 2014.
18.
Investigator’s Brochure of crizotinib dated May 2014.
19.
Investigator’s Brochure of PF-06463922 dated July 2015.
20.
Ji Y, Lui P, Li Y, et al. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010; 7: 653-63.
21.
Katayama, R., Lovly, C.M., & Shaw, A.T.  Therapeutic targeting of anaplastic 
lymphoma kinase in lung cancer: a paradigm for precision cancer medicine.  Clin Canc 
Res. 2015; 21: 2227-35.
22.
Khan MM. Immunosuppressive agents. In: Khan MM (ed) Immunopharmacology.  
Springer Science + Business Media, New York, 2008; pp 87-105.
23.
Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of 
an ALK kinase inhibitor in lung cancer. Clin Canc Res. 2008; 14: 4275-4283. 
24.
Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and 
inhibits T cell activation. Nat Immunol 2001; 2(3): 261-68.
 
 
26.
Nishino M, ---Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesion impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Cancer. 2014; 2:17 
doi:10.1186/2051-1426-2-17.
CCI

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27.
Ou S-H I, Bartlett CH, Mino-Kenudson M, et al. Crizotinib for the Treatment of 
ALK-rearranged non-small cell lung cancer: a success story to usher in the second 
decade of molecular targeted therapy in oncology. Oncologist. 2012; 17:1351-75. 
28.
Papadimitrakopoulou V, Patnaik A, Borghaei H, et al. Pembrolizumab (pembro; 
MK-3475) plus platinum doublet chemotherapy (PDC) as front-line therapy for 
advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohorts A and C. 
J Clin Oncol. 2015; 33: (suppl; abstr. 8031)
29.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev 
Cancer. 2012; 12: 252-64. 
30.
Patnaik A, Socinski MA, Gubens MA, et al. Phase 1 study of pembrolizumab (pembro; 
MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell 
lung cancer (NSCLC): KEYNOTE-021 cohort D. J Clin Oncol. 2015; 33: (suppl; abstr. 
8011).
31.
Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of 
nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous (non-SQ) 
non-small cell lung cancer (NSCLC). J Clin Oncol. 2015; 33: (suppl; abstr. LBA109).
32.
Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): 
ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2014; 25 (suppl. 3): ii27-ii39.
33.
Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial 
therapy in patients with advanced non–small cell lung cancer (NSCLC). J Clin Oncol. 
2014; 32:5s (suppl; abstr 8007).
34.
Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol. 1984; 132:266-71.  
35.
Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non–small-cell lung 
cancer. N Engl J Med. 2014; 370:1189-97.
36.
Shaw AT, Ou, S-H.I., Bang, Y.J., et al. Crizotinib in ROS1-rearranged non–small-cell 
lung cancer. N Engl J Med. 2014; 371: 1963-71.
37.
Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014; 64: 9-29.
38.
Simon R. Optimal two-stage designs for phase II clinical trials.  Control Clin Trials 
1989; 10: 1-10. 
39.
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. J 
Clin Oncol. 2015; 33: 3199-212

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40.
Soda, M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK 
fusion gene in non–small-cell lung cancer. Nature. 2007;  448: 561–6.
41.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in 
ALK-positive lung cancer. N Engl J Med. 2014; 371: 2167-77.
42.
Spira AI, Park K, Mazieres J, et al. Efficacy, safety and predictive biomarker results 
from a randomized phase II study comparing atezolizumab (MPDL3280A) vs docetaxel 
in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015; 33: (suppl; abstr. 8010).
43.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 
15:7412-20.
44.
Yamada T, Takeuchi S, Nakade J, et al. Paracrine receptor activation by 
microenvironment triggers bypass survival signals and ALK inhibitor resistance in 
EML4-ALK lung cancer. Clin Cancer Res. 2012; 18: 3592-3602.
45.
Zamarin D and Postow MA. Immune checkpoint modulation: rational design of 
combination strategies.  Pharmacol Ther. 2015; 150: 23-32. 
46.
Zhou, P, Shaffer DR, Alverez Arias DA, et al. In vivo discovery of immunotherapy 
targets in the tumor microenvironment. Nature 2014; 506: 52–57. 
47.
Zitvogel L, Galluzzi L, Smyth MJ, et al. Mechanism of action of conventional and 
targeted anticancer therapies: reinstating immunosurveillance Immunity 2013; 39: 
74-88.
48.
Chiarle R, Martinengo C, Mastini C, et al. The anaplastic lymphoma kinase is an 
effective oncoantigen for lymphoma vaccination. Nat Med. 2008; 14: 676-80.
49.
Voena C, Menotti M, Mastini C, et al. Efficacy of a cancer vaccine against 
ALK-rearranged lung tumors. Cancer Immunol Res 2015; 3(12):1333-43.Gulley JL, 
Spigel D, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in 
advanced NSCLC patients: a phase 1b, open-label expansion trial in patients 
progressing after platinum-based chemotherapy. J Clin Oncol. 2015; 33: (suppl; abstr. 
8034).
50.
Shaw AT, Bauer TM, Felip E, et al. Clinical activity and safety of PF-06463922 from a 
dose escalation study in patients with advanced ALK+ or ROS1+ NSCLC. J Clin 
Oncol. 2015; 33: (suppl; abstr. 8016).
51.
Sharma P and Allison JP. The future of immune checkpoint therapy. Science. 2015; 
348: 56-61.
52.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med. 2013; 368: 2385-94.

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53.
Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol. 2013; 
31:1785-1791. Ota K, Azuma K, Kawahara A, et al. Induction of PD-L1 expression by 
the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung 
cancer. Clin Cancer Res. 2015; 21: 4014-21.
54.
Nada A, Gintant GA, Kleiman R, et al. The evaluation and management of drug effects 
on cardiac conduction (PR and QRS intervals) in clinical development. Am Heart J 
2013;165:489-500.

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Appendix 1. Abbreviations and Term Definitions
Abbreviation
Term
Ab
Antibody
ACRIN
American College of Radiology Imaging Network
ADA
anti drug antibodies
AE
adverse event
ADCC
Antibody-dependent cellular cytotoxicity
AIDS
acquired immunodeficiency syndrome
ALK
Anaplastic Lymphoma Kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BP
blood pressure
BUN
blood urea nitrogen
C
Cycle
C
Concentration
CDS
core data sheet
CHF
congestive heart failure
CI
confidence interval
CL
Clearance
Cmax
Maximum plasma concentration
CNS
central nervous system
CR
complete response
CRR
Complete Response Rate
CRF
case report form
CRM
Continuous Reassessment Method
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
D
Day
DL
Dose level
DLI
Donor Lymphocyte Infusion
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid

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Abbreviation
Term
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
EFS
Event-Free Survival
EML4
echinoderm microtubule-associated protein-like-4
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 
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GnRH
gonadotropin-releasing hormone agonist
GVHD
graft versus host disease
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HR
heart rate
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
Identification
Ie
that is
IND
investigational new drug application
INR
international normalized ratio
irAE
immune-related adverse events
IRB
institutional review board
IRT
Interactive Response Technology
CCI
CCI

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Abbreviation
Term
IUD
intrauterine device
IV
Intravenous
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LFT
liver function test
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
mTPI
modified toxicity probability interval
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
N/A
not applicable
nAB
Neutralizing Antibodies
NCI 
National Cancer Institute 
NSCLC
non-small cell lung cancer
OR
Overall Response
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 ligand 1
PET
positron emission tomography
PFS
Progression-Free Survival
P-gp
P glycoprotein
PK
Pharmacokinetics
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
Q
every
QD
every day
ORR
Objective response rate
QT
time between the start of the Q wave and the end of the T wave
R
Ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan

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Abbreviation
Term
SC
Subcutaneous
SD
Stable disease
SPC
Summary of Product Characteristics
SRSD
single reference safety document
SST
serum separator tube
T
Time
T1/2
terminal elimination half-life
TCR
T-Cell receptor
TKI
tyrosine kinase inhibitor
TLS
tumor lysis syndrome
Tmax
time to maximum plasma concentration
TTP
time to progression
ULN
upper limit of normal
UPM
unit probability mass
US
United States
USPI
United States Package Insert
V
volume of distribution
WBC
white blood cell count

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Appendix 2. ECOG Performance Status 
Score
Definition
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 self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
5
Dead

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Appendix 3. RECIST Version 1.1
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation. 
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable: 
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable:  All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered 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 during treatment.  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 target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 
diameter to be used as reference to further characterize the objective tumor response of the 

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measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent”.
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Definitions of Tumor Response
Target Lesions
Complete response (CR) is defined as the disappearance of all target lesions.  Any
pathological lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
Partial response (PR) is defined as a 30% decrease in the sum of the longest dimensions of 
the target lesions taking as a reference the baseline sum longest dimensions.
Progressive disease (PD) is defined as a 20% increase in the sum of the longest dimensions 
of the target lesions taking as a reference the smallest sum of the longest dimensions 
recorded since the treatment started, or the appearance of one or more new lesions.  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase
of at least 5 mm.
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the smallest sum of the longest dimensions 
since the treatment started. 
Non-Target Lesions
Complete response (CR) is defined as the disappearance of all non-target lesions.  All
lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.
Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of 1 new lesion.

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The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease.
Confirmation of Tumor Response
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.
Response Evaluation Criteria in Solid Tumors
Target Lesions1
Non-Target Lesions2
New Lesions3
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
1 Measurable lesions only.
2 May include measurable lesions not followed as target lesions or non-measurable lesions.
3 Measurable or non-measurable lesions.
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  For CR and PR, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 6 weeks.
NOTE: Patients with a global deterioration of health status requiring 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 the objective 
progression even after discontinuation of treatment.  It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation to 
document whether or not objective tumor progression has occurred. 

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In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy before 
confirming the complete response status. 

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Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:
http://ctep.cancer.gov/reporting/ctc.html

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CCI
CCI
CCI
CCI
CCI

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Lesions
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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Appendix 6. Drugs Known to Prolong PR Interval
The following are examples and should not be considered all-inclusive listing.54