Clinical trial NCT02584634
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer NSCLC ALK avelumab crizotinib PF-06463922
Sponsor: Pfizer
Start date: 2015-12-18; Completion date: 2022-07-13
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of avelumab when combined with either crizotinib or PF-06463922.

Detailed description:
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.

Arms: arm 1: ALK negative Non-Small Cell Lung Cancer arm 2: ALK positive Non-Small Cell Lung Cancer
Interventions: intervention 1: Avelumab intervention 2: PF-06463922 intervention 3: Crizotinib
Intervention descriptions: intervention 1: Administered by IV once every two weeks in doses of either 5 mg/kg or 10 mg/kg intervention 2: Tablets taken orally once every day in doses of either 100mg, 75mg, or 50mg. intervention 3: Capsules. Taken orally once or twice every day in doses of either 200mg or 250mg.

Protocol documents:
Prot_000.pdf: 
MSB0010718C, PF-02341066, PF-06463922
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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 
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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 
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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 
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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 
formulations.


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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 
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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 
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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 
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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.
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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 
verification of concomitant treatments.


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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.

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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: 

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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);

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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 
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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 
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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 
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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 
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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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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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Lesions
 
 
 
 
 
 
 
 
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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

SAP_001.pdf: 
Avelumab
B9991005 (MSB0010718C, PF-02341066, PF-06463922) Statistical Analysis Plan    
PFIZER CONFIDENTIAL
Page 1
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
STATISTICAL ANALYSIS PLAN – B9991005
Compounds:
MSB0010718C
PF-02341066
PF-06463922
Compound Name:
Avelumab
Crizotinib
PF-06463922
Version:
3.0
Date:
12-Jul-2019
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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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION ...............................................................................................................11
2.1. Study Objectives .....................................................................................................11
2.2. Study Design ...........................................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoints...................................................................................................13
3.2. Secondary Endpoints...............................................................................................15
3.2.1. Safety endpoints..........................................................................................15
3.2.2. Efficacy endpoints ......................................................................................15
3.2.3. Pharmacokinetic endpoints.........................................................................15
3.2.4. Immunogenicity endpoints .........................................................................16
3.2.5. Biomarker endpoints...................................................................................16
3.4. Baseline Variables...................................................................................................17
3.4.1. Study drug, study treatment and baseline definitions.................................17
3.4.2. Baseline characteristics...............................................................................18
3.5. Safety Endpoints .....................................................................................................19
3.5.1. Adverse events............................................................................................19
4. ANALYSIS SETS ...............................................................................................................19
4.1. Full Analysis Set .....................................................................................................19
4.2. Safety Analysis Set..................................................................................................19
4.3. Other Analysis Set...................................................................................................20
4.3.1. DLT-evaluable set ......................................................................................20
4.3.2. PK analysis sets ..........................................................................................20
4.3.3. Biomarker analysis set................................................................................20
4.3.4. Immunogenicity analysis set.......................................................................20
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................20
5.1. Hypotheses and Decision Rules ..............................................................................20
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5.1.1. Hypotheses and sample size determination................................................20
5.1.2. Decision rules .............................................................................................22
5.2. General Methods .....................................................................................................24
5.2.1. Data handling after the cut-off date............................................................25
5.2.2. Pooling of centers .......................................................................................25
5.2.3. Presentation of continuous and qualitative variables..................................25
5.2.4. Definition of study day...............................................................................26
5.2.5. Definition of start of new anti-cancer drug therapy....................................26
5.2.6. Definition of start of new anti-cancer therapy............................................26
5.2.7. Definition of on-treatment period...............................................................27
5.2.8. Standard derivations and reporting conventions.........................................27
5.2.9. Unscheduled visits......................................................................................27
5.2.10. Adequate baseline tumor assessment........................................................28
5.2.11. Adequate post-baseline tumor assessment................................................28
5.3. Methods to Manage Missing Data ..........................................................................28
5.3.1. Missing data................................................................................................28
5.3.1.1. Pharmacokinetic concentrations................................................28
5.3.1.2. Pharmacokinetic parameters .....................................................29
5.3.2. Handling of incomplete dates .....................................................................29
5.3.2.1. Disease history ..........................................................................29
5.3.2.2. Adverse events ..........................................................................29
5.3.2.3. Prior and concomitant medications...........................................30
5.3.2.4. Exposure....................................................................................30
5.3.3. Imputation rules for date of last contact and efficacy assessments ............31
5.3.3.1. Date of last contact....................................................................31
5.3.3.2. Death date..................................................................................31
5.3.3.3. Tumor assessments....................................................................32
5.3.3.4. Date of start of new anti-cancer therapy ...................................32
6. ANALYSES AND SUMMARIES ......................................................................................34
6.1. Primary Endpoints...................................................................................................34
6.1.1. DLT for Phase 1b (Group A and Group B) ................................................34
6.1.1.1. Primary analysis ........................................................................34
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6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 
(Group A and Group B)...................................................................................34
6.1.2.1. Primary analysis ........................................................................34
6.2. Secondary Endpoint(s) ............................................................................................36
6.2.1. Safety endpoints..........................................................................................36
6.2.2. Efficacy endpoints ......................................................................................36
6.2.2.1. Tumor shrinkage from baseline.................................................37
6.2.2.2. Disease control ..........................................................................37
6.2.2.3. Duration of response .................................................................37
6.2.2.4. Time to response .......................................................................39
6.2.2.5. Progression-free survival...........................................................39
6.2.2.6. Overall Survival ........................................................................41
6.2.3. Pharmacokinetic endpoints.........................................................................42
6.2.4. Population pharmacokinetic endpoints.......................................................43
6.2.5. Biomarker endpoints...................................................................................44
6.2.6. Endpoints for immunogenicity data of avelumab.......................................44
6.2.6.1. Time to and Duration of ADA response ...................................45
6.2.6.2. ADA titer...................................................................................46
6.2.6.3. Analysis of PK and safety by immunogenicity status...............46
6.4. Subset Analyses.......................................................................................................50
6.5. Baseline and Other Summaries and Analyses.........................................................50
6.5.1. Baseline summaries ....................................................................................50
6.5.1.1. Demographic characteristics .....................................................50
6.5.1.2. Medical history..........................................................................52
6.5.1.3. Disease characteristics...............................................................52
6.5.1.4. Prior anti-cancer therapies.........................................................52
6.5.2. Study conduct and patient disposition........................................................53
6.5.2.1. Patient disposition .....................................................................53
6.5.2.2. Protocol deviations....................................................................54
6.5.3. Study treatment compliance and exposure .................................................55
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6.5.3.1. Exposure to avelumab ...............................................................56
6.5.3.2. Exposure to Crizotinib ..............................................................56
6.5.3.3. Exposure to PF-06463922.........................................................57
6.5.3.4. Dose reductions.........................................................................58
6.5.3.5. Dose interruptions .....................................................................58
6.5.3.6. Dose delays ...............................................................................59
6.5.3.7. Infusion rate reductions.............................................................59
6.5.3.8. Infusion interruptions ................................................................59
6.5.4. Concomitant medications and non-drug treatments ...................................59
6.5.5. Subsequent anti-cancer therapies................................................................60
6.6. Safety Summaries and Analyses .............................................................................60
6.6.1. Adverse events............................................................................................61
6.6.1.1. All adverse events .....................................................................62
6.6.1.2. Adverse events leading to dose reduction.................................63
6.6.1.3. Adverse events leading to interruption of study treatment .......63
6.6.1.4. Adverse events leading to discontinuation of study 
treatment............................................................................................64
6.6.2. Deaths .........................................................................................................64
6.6.3. Serious adverse events................................................................................65
6.6.4. Other significant adverse events.................................................................65
6.6.5. Laboratory data...........................................................................................66
6.6.5.1. Hematology and chemistry parameters.....................................66
6.6.5.2. Other laboratory parameters......................................................69
6.6.6. Vital signs...................................................................................................69
6.6.7. Electrocardiogram.......................................................................................69
6.6.8. Physical examination..................................................................................71
6.6.9. ECOG performance status..........................................................................71
7. INTERIM ANALYSES.......................................................................................................71
7.1. Introduction .............................................................................................................71
7.2. Interim Analyses and Summaries............................................................................71
8. REFERENCES ....................................................................................................................72
9. APPENDICES .....................................................................................................................73


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LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
PK Parameters to be Determined for Avelumab, Crizotinib, its 
metabolite PF-06260182, and PF-06463922............................................16
Table 3. 
Biomarker Definition and Determination.................................................17
Table 4.
Sample Size and Exact 90% and 95% CI for ORR and CR rate for 
Phase 2 of Group B...................................................................................22
Table 5.
Study Summaries and Tabulations ...........................................................25
Table 6.
Outcome and Event Dates for DR Analyses.............................................38
Table 7. 
DR Censoring Reasons and Hierarchy .....................................................39
Table 8.  
Outcome and event dates for PFS analysis...............................................40
Table 9.    
PFS Censoring Reasons and Hierarchy....................................................41
Table 10.   
OS Censoring Reasons and Hierarchy......................................................42
Table 11. 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................45
    
Table 13.    
Case Definition for irAEs.........................................................................73
Table 14.   
Case Definition for IRRs – IV Study Drugs Administered Alone 
Or In Combination With Non-IV Study Drugs ........................................75
LIST OF FIGURES
Figure 1.
Study Design Schema...............................................................................13
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................73
Appendix 2. Infusion Related Reactions .................................................................................75
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991005 is based on the Protocol
Amendment 03 dated 30-Jun-2017.  
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version Date
Summary of Changes
3
12-Jul-2019
Section 3.2.3 “Pharmacokinetic endpoints” – metabolite to parent ratio for CL/F 
and Vz/F for PF-06260182 following multiple doses are added. Plasma 
concentration at the end of dosing interval of avelumab is added.
Section 3.5.1 “Adverse events” and Section 6.6.1 “Adverse events” – updated 
the definition of treatment-emergent adverse event to remove the requirements 
for worsening from baseline or first onset during the on-treatment period.
 
Section 5.2 “General Methods” – Table 5 was updated to remove summaries of 
Group B Phase 2 data alone due to the small number of patients enrolled (N=3).
Section 6.2.2.3 “Duration of response” – added details regarding censoring for 
duration of response since “no adequate baseline assessment” which is used in 
censoring for PFS analyses is not applicable to analyses of duration of response 
for patients with objective response.
Section 6.2.3 “Pharmacokinetic endpoints” – the box whisker plots of trough 
concentrations for avelumab, crizotinib and PF-06463922 are removed.
Duplication of analysis was removed. Analysis of Ctrough was added as 
appropriate. It was added that observed concentration of avelumab, crizotinib and 
PF-06463922 from this study may be compared with historical observed 
concentrations when each drug is administered alone.
Section 6.2.6 “Endpoints for immunogenicity data of avelumab” – detailed 
analyses of ADA/nAb were added, including patients characterization based on 
anti-drug antibody results, definition and analysis of time to and duration of 
ADA response, analysis of patients who are ADA ever positive and patients with 
treatment-induced ADA, and analyses of PK and safety by immunogenicity 
status.
 
Section 6.5.1.3 “Baseline summaries” – delete detailed analysis pertaining to 
smoking exposure and years since quitting.
Section 6.5.3 “Study treatment compliance and exposure” and Section 6.5.3.1
“Exposure to avelumab” – removed by-cyce summaries for exposure to 
avelumab.
Section 6.5.3.5 “Dose interruptions” – corrected the definition to align with the 
eCRF data collection.
Section 6.5.3.6 “Dose delays” – aligned the intervals to match the protocol-
allowed window for dosing. 
Section 6.6.1 “Adverse events” and Section 6.6.1.3 “Adverse events leading to 
interruption of study treatment” –added that IRRs will be excluded in the 
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analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion. 
Section 6.6.1.1 “All adverse events” – added summary of TEAE leading to 
interruption of avelumab, crizotinib and PF-06463922 respectively; removed 
summary of TEAE excluding SAEs with frequency ≥5% in any treatment group 
by SOC and PT.
Section 6.6.4 “Other significant adverse events” – given the nature of immune-
related AEs, summaries of irAE leading to discontinuation of crizotinib, PF-
06463922, any study drug and all study drug were removed.
Section 6.6.5.1 “Hematology and chemistry parameters” – added summary for 
patients with newly occurring or worsening laboratory abnormalities; removed 
lab data summaries by actual values; changed the listing for liver function tests to 
include only patients with potential Hy’s Law.
Section 6.6.7 “Electrocardiogram” – removed the summaries based on a 
population linear regression method.
Appendix 1 “Immune-related Adverse Events” – deleted H02C (since ATC code 
is associated with anti-corticosteroids rather than corticosteroids) and provided 
additional ATC codes for concomitant medications in Step 4 of the case 
definition for irAEs. Minor editorial and consistency changes throughout the 
document.
2
31-Oct-2017
With protocol amendment 03, a Phase 2 portion is included for Group B. 
Sections 2.1, 2.2, 3.1, 3.2.2, 5.1, 6.1.2, 6.4 have been modified accordingly.  In 
addition, the following updates were made.
Section 2 “Introduction” – updated cut-off date for primary analysis.
Section 3.4.1 “Study drug, study treatment and baseline definitions” – added 
definition of end date of study treatment; clarified definition of baseline applies 
to all analyses; referred to RR instead of heart rate in ECG baseline derivations 
since the ECG eCRFs collect RR rather than heart rate.
Section 3.5.1 “Adverse events” – clarified that the start of anti-cancer drug 
therapy is used in the definition. Updated that irAE and IRR derivation rules are 
documented in Appendices.
Section 5.1.2 “Decision rules” – clarified that combinations are deemed too toxic 
as determined by the DLT rate and/or lower than expected doses of the study 
treatments.
Section 5.2 “General Methods” – added a Table 5 “Study Summaries and 
Tabulations” for overview of the summaries and the tabulations in this study.
Section 5.2.8 “Standard derivations and reporting conventions”, Section 6.5.1.1
“Demographic characteristics” – removed derivation of BSA since it is not 
applicable to this study. 
Section 5.2.5 “Definition of start of new anti-cancer drug therapy”, Section 5.2.6 
“Definition of start of new anti-cancer therapy”, Section 5.2.10 “Adequate 
baseline tumor assessment”, Section 5.2.11 “Adequate post-baseline tumor 
assessment” were added to provide the details associated with derivations used to 
define the on-treatment period and censoring in efficacy analyses.
Section 5.3.2.4 “Exposure” – deleted the last step in the imputation “The imputed 
date will be compared with start date of study drug”. 
Section 5.3.3.2 “Death date” – deleted the last step in the imputation “if the day 
is missing from the date of last contact it will be imputed to 1st day of the month 


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and year of last contact only if derived from the ‘Survival Follow-up’ eCRF 
page” since not needed.
Section 5.3.3.4 “Date of start of new anti-cancer therapy” was added to provide 
details of imputation rules for incomplete dates for start date of new anti-cancer 
therapy (drug therapy, radiation, surgery).
Section 6.1.2 “Objective response as assessed by the Investigator per RECIST 
v1.1 (Group A and Group B)” – added definition of BOR of non-CR/non-PD for 
patients without measurable disease at baseline; included additional reasons for 
NE associated with no baseline assessment and death prior to first post-baseline 
tumor assessment.
Section 6.1.2.1 “Primary analysis”, Section 6.2.2 “Efficacy endpoints” –clarified
tumor-related endpoints will be analyzed based on investigator assessment.
Section 6.1.2.1 “Primary analysis”, Section 6.2.2 “Efficacy endpoints”, Section 
6.2.3 “Pharmacokinetic endpoints”, Section 6.2.5 “Biomarker endpoints”, 
Section 6.2.6 “Endpoints for immunogenicity data of avelumab”, 
 
 Section 6.5.1 “Baseline summaries” , Section 6.5.2
“Study conduct and patient disposition”, Section 6.5.3 “Study treatment 
compliance and exposure”, Section 6.5.4 “Concomitant medications and non-
drug treatments”, Section 6.5.5 “Subsequent anti-cancer therapies”, Section 6.6
“Safety Summaries and Analyses” – clarified summaries and tabulations will be 
done as described in Table 5.
Section 6.2.2.2 “Disease control” – updated definition for disease control to 
include non-CR/non-PD as per BOR updated definition.
Section 6.2.2.5 “Progression-free survival” – updated the allowable time window 
for tumor assessment to align with protocol amendment 3; provided more details 
on the analysis of PFS and Time of Follow-Up for PFS; provided more details 
and hierarchy associated with the derivation of reasons for censoring; also 
referred consistently to adequate baseline assessments rather than just baseline 
assessments in censoring rules.
Section 6.2.2.6 “Overall Survival” – provided more details on analysis of Time 
of Follow-Up for OS; provided more details and hierarchy associated with the 
derivation of reasons for censoring.
Section 6.2.5 “Biomarker endpoints” – provided more details on analysis of 
biomarker endpoints.
 
 
Section 6.4 “Subset Analyses” – clarified ORR and DR (if meaningful) will be 
summarized by prior anti-cancer therapy (including drug therapy, radiotherapy 
and surgery).
Section 6.5.1.1 “Demographic characteristics” – added Middle East as another 
possible geographic region and changed the geographic region Australia to 
Australasia.
Section 6.5.1.4 “Prior anti-cancer therapies” – added “not applicable” as a 
possible outcome category for best response; clarified that prior anti-cancer 
therapies will be listed together with concomitant and follow-up therapies but 
with a flag to identify them as prior therapies.
Section 6.5.2.1 “Patient disposition” – aligned the wording and summaries to the 
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information collected in the disposition pages of the eCRF.
Section 6.5.3 “Study treatment compliance and exposure” – provided details 
regarding cycle derivations and provided formulas for exposure derivations 
overall and by cycle.
Section 6.5.3.4 “Dose reductions” – added dose reduction definition for 
crizotinib and PF-06463922.
Section 6.5.3.5 “Dose interruptions” was added.
Section 6.5.3.6 “Dose delays” – added further derivation details; split the 
summary for no delays from 1-2 days delays.
Section 6.5.3.7 “Infusion rate reductions” – added further derivation details.
Section 6.5.3.8 “Infusion interruptions” was added.
Section 6.5.5 “Subsequent anti-cancer therapies” – updated eCRF pages that will 
be used for the summary of subsequent anti-cancer therapies. 
Section 6.6.1 “Adverse events” – added definition of adverse events leading to 
dose reduction and adverse events leading to interruption of study treatment.
Section 6.6.1.1 “All adverse events”, Section 6.6.1.4 “Adverse events leading to 
treatment discontinuation” – added summaries of AEs leading to discontinuation 
of all study drugs. 
Section 6.6.1.2 “Adverse events leading to dose reduction” and Section 6.6.1.3
“Adverse events leading to interruption of study treatment” were added.
Section 6.6.1.1 “All adverse events”, Section 6.6.4 “Other significant adverse 
events” – removed tabulation for treatment-related irAEs and IRRs; added 
tabulations for irAEs and IRRs leading to study drug discontinuation.
Section 6.6.2 “Deaths” – removed references to primary cause of death since not 
collected in the eCRF.
Section 6.6.5 “Laboratory data” and subsections – changed the formula for 
corrected calcium to be expressed in SI units; clarified that the denominator to 
calculate percentages for each laboratory parameter is the number of patients 
evaluable for the particular summary.
Section 6.6.7 “Electrocardiogram” – clarified that the denominator to calculate 
percentages for each ECG parameter is the number of patients evaluable for the
particular summary.
Section 6.6.8 “Physical examination” – added details on the summary of physical 
examination results.
Section 8 “References” updated.
Section 9 “Appendices” – added appendices with the irAE and IRR derivation 
rules; deleted data derivation details since included with more details in the 
exposure section.
Minor editorial and consistency changes throughout the document.
1
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B9991005.  This document may modify the plans outlined in the protocol;
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetic (PK) data, centrally assessed ALK, ROS1 status, other biomarker data). The 
primary analysis will include all data up to a cut-off date corresponding to the earliest of 24 
months after the last patient receives the first dose of study treatment, death, withdrawal of 
consent or lost to follow-up. The final analysis of the data will be performed after last patient 
last visit (LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
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 ORR per RECIST v1.1 in previously treated locally advanced or 
metastatic ALK-negative non-small cell lung cancer (NSCLC) patients treated with the 
combination of avelumab and crizotinib at the RP2D;

Group B: To assess ORR and CR rate per RECIST v1.1 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 and 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;


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•
To evaluate candidate predictive biomarkers of sensitivity or resistance to combination 
therapy in pretreatment tumor tissue.
 
 
2.2. Study Design
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. Determination of the MTD will be 
performed using the modified toxicity probability interval (mTPI) design 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,
 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 of the 12 patients in Phase 1b have a confirmed objective response, then an
additional 33 patients will be enrolled and treated in Phase 2. 
•
If ≤2 of the 12 patients in Phase 1b who have a confirmed objective response, 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 Phase 2, to further assess the 
antitumor activity, safety, pharmacokinetics 
 of the combination at 
the RP2D.
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Figure 1.
Study Design Schema 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
Phase 1b:
•    First 2 cycles dose-limiting toxicities (DLTs) for Group A and Group B.
      Severity of adverse events (AEs) will be graded according to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. For 
the purpose of dose finding, any of the following AEs 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;
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
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 
known or suspected tumor;

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.
Phase 2:
Confirmed Overall Response (OR) per RECIST v1.1 for Group A.

Confirmed OR and complete response (CR) per RECIST v1.1 for Group B.
OR is defined as CR or partial response (PR) according to RECIST v1.1 from the date of 
first dose of study treatment until the date of the first documentation of progressive 
disease (PD). Both CR and PR must be confirmed by repeat assessments performed no 
less than 4 weeks after the criteria for response are first met.


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3.2. Secondary Endpoints
3.2.1. Safety endpoints

AEs and laboratory abnormalities as graded by NCI CTCAE v4.03; vital signs (blood 
pressure, pulse rate).
AEs will be graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for
Regulatory Activities (MedDRA).
3.2.2. Efficacy endpoints

Disease Control (DC), Duration of Response (DR), Time to Tumor Response (TTR), 
Progression-Free Survival (PFS) per RECIST v1.1, and Overall Survival (OS);
DC is defined as CR, PR, non-CR/non-PD or SD.  Both CR and PR must be confirmed 
by repeat assessments performed no less than 4 weeks after the criteria for response are 
first met. Criteria for SD and non-CR/non-PD must have been met at least 6 weeks after 
the date of first dose of study treatment.
DR is defined, for patients with OR, as the time from first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.  
TTR is defined, for patients with an OR, as the time from the date of first dose of study 
treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
PFS is defined as the time from the date of first dose of study treatment to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.
3.2.3. Pharmacokinetic endpoints

Pharmacokinetic parameters of crizotinib, its metabolite PF-06260182, and avelumab 
will be determined as data permit:
o
Maximum plasma concentration (Cmax), time to Cmax (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;
o
Cmax, Tmax, AUCtau, metabolite to parent ratio for AUCtau (MRAUCtau), metabolite to 
parent ratio for Cmax (MRCmax), CL/F, and Vz/F for PF-06260182 following multiple 
doses in the presence of avelumab;
o
Single and multiple dose pharmacokinetics (Cmax and Ctrough, plasma concentration at 
the end of dosing interval) of avelumab in the presence of crizotinib and PF-
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Table 2.
PK Parameters to be Determined for Avelumab, Crizotinib, its 
metabolite PF-06260182, and PF-06463922 
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCsd,τ
AUCss,τ
Area under the plasma concentration-time 
profile after single dose from time zero to 
the time of next dose (after single dose and 
at steady state)
Linear/Log trapezoidal method
Cmax
Maximum observed plasma concentration 
Observed directly from data
Tmax
Time to Cmax
Observed directly from data as time of 
first occurrence
t½
a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear regression 
of the log-linear concentration-time curve.  
Only those data points judged to describe 
the terminal log-linear decline were used 
in the regression.
Ctrough
Observed plasma concentration at the end 
of  dosing interval 
Observed directly from data
CL/F
Apparent clearance
Dose / AUCτ for steady state
Vz/Fa
Apparent volume of distribution
Dose / (AUCτ ·kel) for steady state
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
AUCinf(dn)a
Dose normalized AUCinf
AUCinf / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
MRAUCtau
a
Metabolite to parent ratio for AUCtau
Metabolite AUCtau/parent AUCtau
MRCmax
a
Metabolite to parent ratio for Cmax
Metabolite Cmax/parent Cmax
a If data permit
3.2.4. Immunogenicity endpoints

Avelumab anti-drug antibodies (ADA; neutralizing antibodies).
ADA / Neutralizing antibodies (nAb) titers for avelumab given in combination with 
crizotinib or PF-06463922. 
3.2.5. Biomarker endpoints

Tumor tissue biomarkers, including but not limited to, PD-L1 expression and tumor 
infiltrating CD8+ T cells by immunohistochemistry (IHC).


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Table 3.
Biomarker Definition and Determination
Parameter
Definition
Method of Determination
PD-L1 expression
The number of PD-L1 positive cells and/or 
qualitative assessment of PD-L1 staining on 
tumor and inflammatory cells in regions of 
interest that are defined by tumor cell 
morphology and the presence or absence of 
CD8+ 
 cells
Pathologist, assisted by image 
analysis
Tumor infiltrating 
CD8+ lymphocytes
The number of CD8+ cells per unit area and 
the percent of counted cells that are scored as 
CD8+
Pathologist, assisted by image 
analysis
 
 
 
 
 
 
 
 
 
3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab, crizotinib or PF-06463922 and ‘study 
treatment’ (or ‘treatment group’) refers to one of the following.
Possible dose combinations for Group A (all dose combinations may not be explored):
•
DL0: avelumab 10 mg/kg IV Q2W in combination with crizotinib 250 mg PO BID
•
DL-1A: avelumab 5 mg/kg IV Q2W in combination with crizotinib 250 mg PO BID
•
DL-1C: avelumab 10 mg/kg IV Q2W in combination with crizotinib 200 mg PO BID
•
DL-1A-1C: avelumab 5 mg/kg IV Q2W in combination with crizotinib 200 mg PO BID
•
DL-2C: avelumab 10 mg/kg IV Q2W in combination with crizotinib 250 mg PO QD
•
DL-1A-2C: avelumab 5 mg/kg IV Q2W in combination with crizotinib 250 mg PO QD
Possible dose combinations for Group B (all dose combinations may not be explored):
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
DL0: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 100 mg PO QD

DL-1A: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 100 mg PO QD

DL-1P: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 75 mg PO QD

DL-1A-1P: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 75 mg PO QD

DL-2P: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 50 mg PO QD

DL-1A-2P: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 50 mg PO QD
Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline characteristics
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 


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are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6. 
3.5. Safety Endpoints
3.5.1. Adverse events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 
Appendix 2, respectively.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The full analysis set (FAS) will include all patients who receive at least one dose of study 
drug.  Patients will be classified according to the study treatment actually received.  If a 
patient receives more than one treatment the patient will be classified according to the first 
study treatment received. 
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first 
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical. 


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4.3. Other Analysis Set
4.3.1. DLT-evaluable set
The DLT-evaluable set is the primary analysis set for the Phase 1b and will include all 
patients enrolled in Phase 1b who are in the safety analysis set, and either experience DLT 
during the first 2 cycles (28 days), or complete the observation period for the first 2 cycles of 
treatment.
A patient without DLT will be replaced if, for reasons other than drug-related toxicity,
a) the patient does not receive at least 75% of the planned doses of the first 2 cycles for 
crizotinib or PF-06463922, or
b) the patient does not receive at least 2 infusions of avelumab.
4.3.2. PK analysis sets
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for avelumab or crizotinib or PF-06463922. 
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for avelumab, crizotinib or PF-
06463922.
4.3.3. Biomarker analysis set 
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least 1 screening biomarker assessment. Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers:
•
Tumor IHC analysis set;
  
4.3.4. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and sample size determination
Phase 1b:
There is no formal hypothesis testing in this phase. The objective of the dose-finding phase is 
to determine MTD or RP2D. 
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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.
Group A 
For Group A, it is expected that 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 according to the safety of the combination.
Group B 
For Group B, it is expected that from approximately 12 to 36 patients will need to be treated 
in the dose-finding stage using the mTPI approach including at least 12 patients treated at the 
MTD. Up to 12 additional patients may be enrolled at the MTD (24 patients in total) to 
further characterize safety and tolerability and determine the RP2D.
Phase 2:
Group A
The sample size determination is based on Simon's Optimal Two-Stage design.
The first 12 patients treated at the RP2D during dose-finding stage in Phase 1b 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 that the true ORR does not exceed 15% will be tested at the 1-sided 
significance level α=0.025 against the alternative: 
H0: ORR≤15% versus Ha: ORR>15% 
With 45 patients total, the study will have at least 80% power to reject the null hypothesis if 
the true ORR is ≥35%.
Group B
For Phase 2 of Group B, approximately 30 treatment-naïve patients will be enrolled. This
will allow estimation of the ORR and CR rate with a maximum standard error of 0.091.
Table 4 provides the exact binomial 90% and 95% confidence intervals (CIs) for the ORR 
and CR rate based on different observed responses among 30 patients.
No formal hypothesis will be tested.


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Table 4.
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%)
5.1.2. Decision rules
Phase 1b:
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. 
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. Thus, compared to other 
advanced model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement. 
Decision rules in the mTPI design are based on calculating unit probability mass (UPM) of 3 
dosing intervals corresponding to under, proper, and overdosing in terms of toxicity. 
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
the underdosing interval is defined as (0, pT-e1), 

the overdosing interval is defined as (pT+e2,1), and 

the proper-dosing interval is defined as (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), 

the overdosing interval corresponds to a dose de-escalation (D), and 

the proper dosing interval 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. 
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).
For both Group A and Group B, the Phase 1b dose finding evaluation 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 too toxic, as determined by the DLT rate and/or lower 
than expected doses of the study treatments. 
Phase 2:
Group A
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 patients with confirmed OR out of 12 patients treated at the RP2D, then 
an additional 33 patients will be enrolled and treated at that dose level (Stage 2). 

if there are ≤2 patients with OR out of 12 patients treated at the RP2D and the remaining 
patients either discontinued or completed at least 12 months of treatment, then the study 
will not proceed to Stage 2 of Simon’s Optimal Two-Stage design. 
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
if there are ≥ 12 patients with confirmed OR out of 45 patients treated at the RP2D, the null 
hypothesis will be rejected. 

if there are ≤11 patients with OR out of 45 patients treated at the RP2D, then it will be 
declared that the null hypothesis cannot be rejected. 
Group B
There are no formal decision rules for Phase 2 of Group B.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ is defined below.
Possible dose combinations for Group A (all dose combinations may not be explored):

DL0: avelumab 10 mg/kg IV Q2W in combination with crizotinib 250 mg PO BID

DL-1A: avelumab 5 mg/kg IV Q2W in combination with crizotinib 250 mg PO BID

DL-1C: avelumab 10 mg/kg IV Q2W in combination with crizotinib 200 mg PO BID

DL-1A-1C: avelumab 5 mg/kg IV Q2W in combination with crizotinib 200 mg PO BID

DL-2C: avelumab 10 mg/kg IV Q2W in combination with crizotinib 250 mg PO QD

DL-1A-2C: avelumab 5 mg/kg IV Q2W in combination with crizotinib 250 mg PO QD
Possible dose combinations for Group B (all dose combinations may not be explored):

DL0: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 100 mg PO QD

DL-1A: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 100 mg PO QD

DL-1P: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 75 mg PO QD

DL-1A-1P: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 75 mg PO QD

DL-2P: avelumab 10 mg/kg IV Q2W in combination with PF-06463922 50 mg PO QD

DL-1A-2P: avelumab 5 mg/kg IV Q2W in combination with PF-06463922 50 mg PO QD
Table 5 provides an overview of the summaries and the tabulations for this study taking into 
account the fact that at the time of this amendment only DL0 was studied (RP2D) and no 
other doses will be explored.  Given the small number of patients (N=3 in Group B and N=0 
in Group A since the pre-specified statistical criterion to proceed to Phase 2 was not met) 
who received study drug in Phase 2, summaries for Phase 2 alone will not be performed.


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Table 5.
Study Summaries and Tabulations
Summaries
Analysis 
Population
Phase 1b
Phase 1b and Phase 2 combined
Baseline characteristics 
and disposition
FAS
ND
Separately for Group A and Group B
DLTs
DLT-evaluable set
Group A 
and Group B
separately
ND
Efficacy data 
FAS
ND
Separately for Group A and Group B
Other safety data, 
exposure data, 
concomitant medications, 
non-drug treatment
Safety analysis set
ND
Separately for Group A and Group B
PK data for avelumab
PK analysis sets
ND
Separately for Group A and Group B
PK data for crizotinib
PK analysis sets
ND
Group A
PK data for PF-06463922
PK analysis sets
ND
Group B
Biomarker data
Biomarker analysis 
set
ND
Separately for Group A and Group B
Immunogenicity data
Immunogenicity 
analysis set
ND
Separately for Group A and Group B
ND: Not done.
5.2.1. Data handling after the cut-off date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center.
5.2.3. Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.


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5.2.4. Definition of study day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg,
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages

Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’ 

Surgery date recorded in ‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages 
when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘Concomitant Surgery’, 
and ‘Follow-up Surgery’ eCRF pages.


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5.2.7. Definition of on-treatment period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 

BMI (kg/m2) = weight (kg)/[height (m)]2
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.


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5.2.10. Adequate baseline tumor assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 31 days prior to and including the date of first 
dose of study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.2.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic concentrations
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
as anomalous by the clinical pharmacologist.


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Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.
5.3.1.2. Pharmacokinetic parameters
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter 
cannot be derived from a patient’s concentration data, the parameter will be coded as NC (ie, 
not calculated).  NC values will not be generated beyond the day that a patient discontinues.
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses.
 
 
 
5.3.2. Handling of incomplete dates
5.3.2.1. Disease history
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:
•
If the day is missing, it will be imputed to the 15th day of the month. 
•
If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.
•
If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 
•
If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse events
Incomplete AE-related dates will be imputed as follows:
CCI


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
If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment.

If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.

If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and concomitant medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.

If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 

If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:


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
If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date

If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
5.3.3. Imputation rules for date of last contact and efficacy assessments
5.3.3.1. Date of last contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:

All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments)

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation

AE start and end dates

Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)

Study drug start and end dates

Randomization date

Withdrawal of consent date

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date.
5.3.3.2. Death date
Missing or partial death dates will be imputed based on the last contact date:

If the date is missing it will be imputed as the day after the date of last contact 

If the day or both day and month is missing, death will be imputed to the maximum of the
full (non-imputed) day after the date of last contact and the following:


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-
Missing day:
1st day of the month and year of death
-
Missing day and month:
January 1st of the year of death
5.3.3.3. Tumor assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg,
X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of start of new anti-cancer therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment.

The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is
o
completely missing then it will be ignored in the imputations below
o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy
o
partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy

For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below. 


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
If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows:
o
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy]
o
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = 01JANYYYY
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY ;
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 


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THEN 
imputed start date = 01 MMM YYYY;
ELSE IF
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology. 
6.1. Primary Endpoints
6.1.1. DLT for Phase 1b (Group A and Group B)
6.1.1.1. Primary analysis
The following analyses will be based on the DLT-evaluable set for patients in Phase 1b.  
DLTs will be listed and summarized by treatment group as described in Table 5.
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 (Group A 
and Group B)
6.1.2.1. Primary analysis
The following analyses will be based on the FAS by treatment group as described in Table 5. 
Assessment of response will be made using RECIST v1.1.  Assessments below refer to 
investigator assessment.  
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of
disease progression.
BOR Based on Confirmed Responses:

CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD


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
PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR) 

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (and not qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (and not qualifying for CR or 
PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment
(and not qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set, and CR rate is the proportion of patients with CR in the analysis 
set.
For Group A, to account for the properties of the 2-stage Simon design, estimates of the 
response rates using uniform minimum variance unbiased estimator (UMVUE) will be 
provided (Porcher and Desseaux, 2012 5).


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where m=1 is stopping stage 1 and m=2 is stopping stage 2, S=number of responses observed 
in stage 1 if m=1 and S=total number of responses observed if m=2, n1= number of subjects 
in stage 1 and n2 is the number of subjects in stage 2. The symbol ∩ implies minimum and 
the symbol  implies maximum.
ORR will also be calculated along with the 2-sided 95% CI using the Clopper-Pearson 
method 2 (exact CI for a binomial proportion as computed by default by the FREQ procedure 
using the EXACT option). 
For Group B, ORR and the CR rate will be calculated along with the 2-sided 95% CI using 
the Clopper-Pearson method 2. 
In addition, for both Group A and Group B, the frequency (number and percentage) of 
patients with a confirmed BOR of CR, PR, SD, non-CR/non-PD (applicable only to patients 
with non-measurable disease at baseline), PD and NE will be tabulated. Patients with 
confirmed BOR of NE will be summarized by reason for having NE status. The following 
reasons will be used:
•
No baseline assessment 
•
No post-baseline assessments due to death 
•
No post-baseline assessments due to other reasons
•
All post-baseline assessments have overall response NE
•
New anti-cancer therapy started before first post-baseline assessment
•
SD of insufficient duration (<6 weeks after the date of first dose of study treatment
without further evaluable tumor assessments)
•
PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD of insufficient duration’.
6.2. Secondary Endpoint(s)
6.2.1. Safety endpoints
Refer to Section 6.6.
6.2.2. Efficacy endpoints
The following analyses will be based on the FAS by treatment group as described in Table 5. 
Assessment of response will be made using RECIST v1.1. Tumor-related endpoints will be 
analyzed based on investigator assessment.  


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6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameter 
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.2. Disease control
Disease Control (DC) is defined as BOR of CR, PR, non-CR/non-PD or SD.   DC rate (DCR) 
is the proportion of patients with DC.
DCR will be summarized by frequency counts and percentages.
6.2.2.3. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are described in Table 6.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 6.
Outcome and Event Dates for DR Analyses
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
No PD and no death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rates at 3, 6, 12, 18 and 24 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 and the CIs for the survival function estimates at the time 
points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc LIFETEST)
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 7 following the hierarchy shown.


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Table 7. 
DR Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
Start of new anti-cancer therapy   
Start of new anti-cancer therapy
2 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after 2 or more missing 
assessments a
3
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up] 
Withdrawal of consent
4
No event and lost to follow-up in any disposition page 
Lost to follow-up
5
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
6 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The DR time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
6.2.2.4. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – date of first dose of study treatment
+1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.5. Progression-free survival
Progression-Free Survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD 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 a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment 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 (ie ≤ 16 weeks after the date of first dose of study treatment) in which case 
the death will be considered an event. 


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In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and at Week 8 (+1 week) and every 8 weeks (± 1 week) thereafter 
until PD regardless of initiation of subsequent anti-cancer therapy.  The censoring and event 
date options to be considered for the PFS analysis are presented in Table 8.  
PFS (months) = [date of event or censoring– date of first dose of study treatment
+1]/30.4375
Table 8.  
Outcome and event dates for PFS analysis
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study 
treatment a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
after 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
No PD and no death
Date of last adequate tumor
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived based on 
documented progression 
only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
a However if the patient dies ≤16 weeks after the date of first dose of study treatment the death is an event with 
date on death date
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided
95% CIs.  In particular, the PFS rates at 3, 6, 9, 12, 18 and 24 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 and the CIs for the survival function estimates at the time 
points defined above will be derived using the log-log transformation according to 


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Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc LIFETEST)
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 9 following the hierarchy shown.
Table 9.    PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of first dose of study treatment
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Subject 
refused further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators.  Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
group together with a summary of associated statistics including the median time of follow-
up for PFS with 2-sided 95% CIs.   In particular, the rates at 3, 6, 9, 12, 18 and 24 months 
will be estimated with corresponding 2-sided 95% CIs.
6.2.2.6. Overall Survival
Overall survival (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.
OS (months) = [date of death or censoring– date of first dose of study treatment
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Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rates at 3, 6, 9, 12, 18, and 24 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 and the CIs for the survival function estimates at the time 
points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc LIFETEST)
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 10 following the hierarchy shown.
Table 10.   OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Subject 
refused further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 9 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators.    Kaplan-
Meier estimates (product-limit estimates) will be presented by treatment group together with 
a summary of associated statistics including the median time of follow-up for OS with 2-
sided 95% CIs.  In particular, the rates at 3, 6, 9, 12, 18, and 24 months will be estimated 
with corresponding 2-sided 95% CIs.
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group as described in Table 5.
Ctrough and Cmax for avelumab, crizotinib and PF-06463922 will be summarized descriptively
(n, mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and
95% CI) by treatment group, cycle, and day. Dose-normalized parameters for avelumab, 
crizotinib and PF-06463922 (CDN-Ctrough and CDN-Cmax) will be reported as appropriate.


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Other standard parameters including, but not limited to Tmax, AUClast, Tlast, AUC sd,, t1/2, CL,
and Vz will be calculated for crizotinib and PF-06463922 as data permit.
Pharmacokinetic parameters for avelumab, crizotinib and PF-06463922 will be calculated
from observed values or derived from plasma concentration-time data as described in Section 
3.2.3.
Presentation of pharmacokinetic data will include:

Linear-linear plots of mean and median plasma concentrations by nominal time for 
crizotinib and PF-06463922 will be presented for PK sampling days by treatment group, 
cycle, and study day. Similar plots will be presented for each individual patient 
concentrations. Patients who have undergone intrapatient dose reduction or escalation 
will be excluded from the median plasma concentration-time plots.

Pharmacokinetic parameters for avelumab, crizotinib and PF-06463922 will be listed and 
summarized by treatment group/dose level, cycle and study day using descriptive 
statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean and its 
associated %CV, and 95% CI). For Tmax, the range (min, max) will also be provided. PK 
parameters with zero values will be excluded from the calculation of geometric means 
and its associated %CV. If an intrapatient dose escalation or reduction occurs, dose-
dependent PK parameters (Ctrough, Cmax and AUC) for that patient may be dose-
normalized when it is known that the drug exhibits linear PK within the dose range and 
other PK parameters will be reported as estimated; or may only be included in descriptive 
statistics and summary plots up to the time of the dose change. In addition, dose-
normalized Ctrough, Cmax and AUC parameters will be summarized (as described above) 
using data pooled across treatment groups in which different crizotinib and PF-06463922 
doses were administered.

Box plots for Ctrough and Cmax for avelumab, crizotinib and PF-06463922 will be 
generated. Individual data points, the geometric mean and the median of the parameter in 
each treatment will be overlaid on the box plots. If a treatment group has limited 
evaluable PK data (n<4), matchstick plots showing changes in Ctrough, Cmax and AUC for 
each drug in individual patients will then be generated. The geometric mean of the 
parameter in each treatment will be overlaid in the plots. In addition, box plots for dose-
normalized avelumab Ctrough, Cmax , and AUC parameters will be created using data 
pooled across treatment groups in which different avelumab doses were administered.

Ctrough and Cmaxfor avelumab will be plotted for each treatment group using a box-
whisker plot by cycle and day within cycle in order to assess the attainment of steady-
state.

Observed concentrations of avelumab, crizotinib and PF-06463922 from this study may 
be compared with the historical observed concentrations when each drug is administered 
alone.
6.2.4. Population pharmacokinetic endpoints
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 


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association between avelumab, crizotinib and PF-06463922 exposure and biomarkers or 
significant safety/efficacy endpoints. The results of these analyses, if performed, may be 
reported separately.
6.2.5. Biomarker endpoints
The following biomarker analyses will be based on the relevant biomarker analysis sets by 
treatment group as described in Table 5. 
Descriptive summary statistics (mean, SD, median, Q1, Q3, coefficient of variation, minimum, 
and maximum), at each timepoint and ratio to baseline at each visit (if appropriate) will be 
provided for continuous biomarker variables, including CD8, CD68 and PD-L1 tumor analyses, 
as applicable. Non-continuous variables will be summarized using frequencies at each timepoint.
For each biomarker or set of biomarkers, patients may be classified as positive, negative, or 
some other category according to scoring algorithms and cut-offs established from external 
sources. If no external standards exist, biomarkers may be stratified using the median: ≤
median and > median, and by quartile. Percent of patients in each category will be tabulated.
Correlations of biomarker results with pharmacokinetic parameters and measures of anti-
tumor efficacy may be assessed through statistical and graphical methods.
BOR will be summarized for each biomarker category if appropriate. The number of 
responders (patients with BOR of CR or PR) will be tabulated relative to biomarker 
classifications using a contingency table and a Fisher’s exact test may be performed.
The relationship of the biomarkers (individually) at baseline with DR, PFS and OS may be 
explored using graphical methods such as box plots, as applicable.
6.2.6. Endpoints for immunogenicity data of avelumab 
The following analyses of immunogenicity data will be based on the Immunogenicity analysis set 
by treatment group as described in Table 5.
Blood samples for avelumab immunogenicity testing will be collected as outlined in the 
“Schedule for Pharmacokinetic Sample Collection” table of the Schedule of Assessments 
section in the protocol. 
Patients will be characterized into different ADA categories based on the criteria defined in 
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Table 11. Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable.
The number and percentage of patients in each ADA category will be summarized. 
6.2.6.1. Time to and Duration of ADA response 
The ADA analyses described below will include patients with treatment-induced ADA.  
Time (weeks) to ADA response is defined as:
(Date of first positive ADA result – date of first dose of avelumab + 1)/7. 
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).  
Duration (weeks) of ADA response is defined as:
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 

the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or


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
the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment is after the cut-off date.
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley
(1982)1 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided.
6.2.6.2. ADA titer
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory. 
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored. 
6.2.6.3. Analysis of PK and safety by immunogenicity status
The following ADA status will be used for the analyses described below.
ADA 

ADA ever-positive versus ADA never-positive 

ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive
Data listings will include immunogenicity data together with relevant PK and safety data.
PK parameters and immunogenicity status
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.  Blood samples for avelumab PK will be collected as outlined in the 


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“Schedule for Pharmacokinetic Sample Collection” table of the Schedule of Assessments 
section of the protocol.
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum,
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear plots of mean and median for Ctrough and Cmax over nominal time and by 
ADA status will be presented. 
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
Ctrough and Cmax have any changes before and after the first positive ADA assessment. To be 
included in this analysis, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as:
(PK assessment nominal day) – (first positive ADA assessment nominal day).
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -28. Linear-linear plots of mean and 
median for Ctrough and Cmax over relative PK day will be presented. 
Safety and immunogenicity status
The following analyses will include patients in the immunogenicity analysis set.
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status.
•
TEAEs, by SOC and PT 
•
TEAEs leading to discontinuation of avelumab, by SOC and PT
•
Grade ≥ 3 TEAEs, by SOC and PT
•
SAEs, by SOC and PT
•
IRRs, by PT
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.  
 
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6.4. Subset Analyses
The following subset analyses will be performed and presented separately for Group A and 
Group B (including Phase 1b and Phase 2 patients at the RP2D).
ORR and DR (if meaningful) will be summarized by prior anti-cancer therapy (Yes, No). 
A listing of patients (along with their OR) whose ALK status determined centrally differs from 
their ALK status determined locally will also be presented.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS overall and separately by treatment group
as described in Table 5.
6.5.1.1. Demographic characteristics
Demographic characteristics and physical measurements will be summarized by treatment 
group using the following information from the ‘Screening/Baseline Visit’ eCRF pages.
•
Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other, Unknown
-
Ethnic origin: 

Hispanic or Latino 

Not Hispanic or Latino
-
Age (years): summary statistics 
-
Age categories: 
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
< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years
-
Pooled Geographical Region (as applicable): 

North America 

Europe

Asia

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the 
overall treated population)
-
Geographic Region (as applicable):

North America

Latin America

Western Europe

Eastern Europe

Middle East

Australasia

Asia

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 

Physical measurements
-
Height (cm)
-
Weight (kg)
-
Body Mass Index (BMI) (kg/m2)
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2) and ECOG performance status.
In addition, the following summaries will also be presented, as applicable. 

ALK status from local versus central labs (yes, no, unknown) 

ROS1 gene translocation status from central labs 

c-MET gene amplification status 

c-MET exon 14 deletion status 


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A listing of the above data will also be presented.
6.5.1.2. Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
6.5.1.3. Disease characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
RECIST eCRF pages will be summarized overall and by treatment group. Summary statistics 
will be presented for the following.
From the ‘Primary Diagnosis’ eCRF page:

Site of primary tumor

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)

Time since initial diagnosis to date of first dose of study treatment (months), defined as 
(date of first dose of study treatment – date of initial diagnosis)/30.4375

Time since diagnosis of locally advanced or metastatic disease (months), defined as (date 
of first dose of study treatment – date of diagnosis of locally advanced or metastatic 
disease)/30.4375
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No)

Involved tumor sites at baseline
From the ‘Substance Use’ eCRF page:

Smoking history (never smoker vs current vs former smoker)
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.


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The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy

Patients with at least one prior anti-cancer drug therapy

Patients with at least one prior anti-cancer radiotherapy

Patients with at least one prior anti-cancer surgery
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy

Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4

Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced - Metastatic

Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived 
from the last treatment regimen.
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used.
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages.

Listing of anti-cancer drug therapies 

Listing of anti-cancer radiotherapy 

Listing of anti-cancer surgeries
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group as described in Table 5. 
6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall

Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation


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
Number and percentage of treated patients in each of the analysis sets defined in Section 
4

Number and percentage of patients with study drug ongoing (separately for each study 
drug)

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug)

Number and percentage of patients who entered follow-up

Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation

Number and percentage of patients who entered long-term follow-up

Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation
In addition the following will be summarized:

Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia, Africa), by 
country within region 

Number and percentage of treated patients by center.
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with crizotinib or PF-
06463922 will also be provided. 
6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria

Patients who develop withdrawal criteria whilst on the study but are not withdrawn

Patients who receive the wrong treatment or an incorrect dose

Patients who receive an excluded concomitant medication

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.


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6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment group as 
described in Table 5. 
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit)

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 14 days – 1 day
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.  
Exposure may be summarized as dose received (cumulative dose, actual dose intensity) and 
as dose received relative to intended dose (relative dose intensity [RDI]).  
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily).  
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination.
The derivations below are provided for the following:

Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg or 5 mg/kg once 
every 2 weeks in 2-week cycles. 

Crizotinib administered orally BID as 250 mg or 200 mg or QD as 250 mg. 

PF-06463922 administered orally QD as 100 mg, 75 mg or 50 mg. 
Analysis of exposure will be based on the calculated actual dose levels 

Avelumab - total dose / weight 


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
Crizotinib – total dose 

PF-06463922 – total dose 
6.5.3.1. Exposure to avelumab 
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg). The 
last available weight of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 14 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 14)/7  
Cumulative dose is the sum of the actual doses of avelumab received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/kg/2-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/2].  
Relative Dose Intensity (RDI)  

Intended DI (mg/kg/2-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 2-weeks in a cycle] = [d (mg/kg)] / [1 (2-week cycle)]  
= d (mg/kg/2-week cycle)

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]  
= 100 ×  [overall actual DI] / [d (mg/kg/2-week cycle)] 
where d = 5 or 10.
The summary of treatment exposure and compliance for avelumab will include the following 
information: 

Treatment duration (weeks) 

Total number of infusions received 

Cumulative dose (mg/kg) 

Dose intensity (mg/kg/cycle) 

Relative dose intensity (%). 
6.5.3.2. Exposure to Crizotinib
The dose level is calculated as actual dose administered (mg/day).  
Intended duration of treatment with crizotinib (weeks) =(end date – date of first dose of 
crizotinib +1)/7, 


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where end date = date of last dose of crizotinib.
Duration of exposure to Crizotinib (weeks) = 
(last dose date of crizotinib – first dose date of crizotinib + 1)/7  
Cumulative dose is the sum of the actual doses of crizotinib received in the study.  
Actual Dose Intensity (DI)

Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]   
Relative Dose Intensity (RDI)  

RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of study drug] 
= 100 × [overall cumulative dose] / [7 × d × duration of exposure to crizotinib in weeks]
where d can be 500, 400, 250.
The summary of treatment exposure and compliance for crizotinib will include the following 
information: 

Treatment duration (weeks) 

Cumulative dose (mg) 

Dose intensity (mg/week) 

Relative dose intensity (%).
6.5.3.3. Exposure to PF-06463922
The dose level is calculated as actual dose administered (mg/day).  
Intended duration of treatment with PF-06463922 (weeks) =(end date – date of first dose 
of PF-06463922 +1)/7, 
where end date = date of last dose of PF-06463922.
Duration of exposure to PF-06463922 (weeks) = 
(last dose date of PF-06463922 – first dose date of PF-06463922 + 1)/7  
Cumulative dose is the sum of the actual doses of PF-06463922 received in the study.  
Actual Dose Intensity (DI)

Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]   
Relative Dose Intensity (RDI)  


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
RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of study drug] 
= 100 × [overall cumulative dose] / [7 × d × duration of exposure to PF-06463922 in 
weeks]
where d can be 100, 75, 50.
The summary of treatment exposure and compliance for PF-06463922 will include the following 
information: 

Treatment duration (weeks) 

Cumulative dose (mg) 

Dose intensity (mg/week) 

Relative dose intensity (%).
6.5.3.4. Dose reductions 
Dose reduction for avelumab is defined as actual non-zero dose < 90% of the planned dose. 
Dose reduction for crizotinib and PF-06463922 is defined as a change to a non-zero dose 
level lower than that planned in the protocol.
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.5. Dose interruptions
Applicable to crizotinib and PF-06463922.  
An interruption is defined a 0 mg dose administered on one or more days for crizotinib and
PF-06463922. What follows defines how dose interruptions will be counted in the case of 
multiple dose interruptions.

If an interruption occurs consecutively for at least two days, then it will be counted only 
once (example: If the actual dose on days 1-3 is 50 mg and actual dose on days 4-5 is 0 
mg and dose interruption on days 4-5 is due to AE, then the total number of dose 
interruptions is 1).

If an interruption occurs for more than one day but the days are not consecutive, ie there 
is at least one dosing day in between, then each dose interruption will be counted as a 
different occurrence (example: If the actual dose on days 1, 3 and 5, is 50 mg and actual 
dose on days 2 and 4 is 0 mg, and dose interruptions on day 2 and 4 are both due to 
dosing error, the total number of dose interruptions is 2). 
A dose interruption is not considered a dose reduction.
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized.


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6.5.3.6. Dose delays 
Applicable to avelumab.
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – 14. 
Dose delays will be grouped into the following categories: 

No delay 

1-3 days delay

4-6 days delay

7 or more days delay
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab  administration date will be on Day 15; however, 
if the patient receives avelumab on Days 16, 17 or 18, this is considered as 1-3 days delay.
No delay and 1-3 days delay will also be summarized together.
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.7. Infusion rate reductions
Applicable to avelumab.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.
6.5.3.8. Infusion interruptions
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment group as 
described in Table 5. 
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 


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those started during the on-treatment period. Prior medications are medications, other than 
study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment. 
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately
from the ‘Pre-Medication Treatment’ eCRF page.
Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes. The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page. A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’. 
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page.
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment group as described in Table 5.
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, and 
‘Follow-up Surgery’ eCRF pages. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of
AEs and other safety parameters will be based on the safety analysis set by treatment group
as described in Table 5. 


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6.6.1. Adverse events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period as defined in Section 3.5.1.
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.

Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’). Related AEs are those related to any study drug (ie, 
at least one of the study drugs).

Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced).

Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted).
The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.

Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).

Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).  

Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan [SRP] and finalized for analysis of the current 
studies data prior to DB lock)

Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
SRP and finalized for analysis of the current studies data prior to DB lock.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 


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strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All adverse events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 

The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to interruption of avelumab
-
TEAEs leading to interruption of crizotinib
-
TEAEs leading to interruption of PF-06463922
-
TEAEs leading to discontinuation of avelumab
-
TEAEs leading to discontinuation of crizotinib
-
TEAEs leading to discontinuation of PF-06463922  
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs
-
Related TEAEs leading to discontinuation of avelumab
-
Related TEAEs leading to discontinuation of crizotinib
-
Related TEAEs leading to discontinuation of PF-06463922
-
Related TEAEs leading to discontinuation of any study drug
-
Related TEAEs leading to discontinuation of all study drugs
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death


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-
irAEs
-
IRRs 

TEAEs by SOC and PT and worst grade

TEAEs related to avelumab by SOC and PT and worst grade

TEAEs related to crizotinib by SOC and PT and worst grade

TEAEs related to PF-06463922 by SOC and PT and worst grade

TEAEs related to any study drug by SOC and PT and worst grade

TEAEs leading to death by SOC and PT

Related TEAEs leading to death by SOC and PT

TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related TEAEs 
/ Grade ≥3 TEAEs / Related Grade ≥3 TEAEs
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group:

TEAEs leading to dose reduction of avelumab by SOC and PT

TEAEs leading to dose reduction of crizotinib by SOC and PT

TEAEs leading to dose reduction of PF-06463922 by SOC and PT
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information. 
6.6.1.3. Adverse events leading to interruption of study treatment
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay). 
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding 

IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.6). These IRRs will be considered as IRRs leading to 
interruption of infusion.

IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.6)


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The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group:

TEAEs leading to interruption of avelumab by SOC and PT

TEAEs leading to interruption of crizotinib by SOC and PT

TEAEs leading to interruption of PF-06463922 by SOC and PT
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information.
6.6.1.4. Adverse events leading to discontinuation of study treatment
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment group:

TEAEs leading to discontinuation of avelumab by SOC and PT

Related TEAEs leading to discontinuation of avelumab by SOC and PT

TEAEs leading to discontinuation of crizotinib by SOC and PT

Related TEAEs leading to discontinuation of crizotinib by SOC and PT

TEAEs leading to discontinuation of PF-06463922 by SOC and PT

Related TEAEs leading to discontinuation of PF-06463922 by SOC and PT

TEAEs leading to discontinuation of any study drug by SOC and PT

Related TEAEs leading to discontinuation of any study drug by SOC and PT

TEAEs leading to discontinuation of all study drugs by SOC and PT

Related TEAEs leading to discontinuation of all study drugs by SOC and PT
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment group.  

All deaths 

Deaths within 30 days after last dose of study treatment

Reason for Death 
-
Disease progression
-
Study treatment toxicity


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-
AE not related to study treatment
-
Unknown
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5), 

Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT

Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other significant adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:

irAEs leading to death, by Cluster and PT

irAEs, by Cluster and PT

irAEs, Grade ≥ 3, by Cluster and PT

irAEs leading to discontinuation of avelumab, by Cluster and PT 

Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:

IRRs leading to death, by PT

IRRs, by PT

IRRs, Grade ≥ 3, by PT

IRRs leading to discontinuation of avelumab, by PT 

Serious IRRs, by PT


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
Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later)
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory data
6.6.5.1. Hematology and chemistry parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Abnormalities classified according to NCI-CTCAE toxicity grading v4.03 will be described 
using the worst grade. For those parameters which are graded with two toxicities such as 
potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. Low 
direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 when 
the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), and vice 
versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 800/mm3

Neutrophil count decreased 
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows


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Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group:

ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN

AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN

(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN

TBILI ≥ 2×ULN

Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing)
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN . 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) will be 
provided.
Parameters with NCI-CTC grades available: 


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The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).

The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period.

The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)).
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:

Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased).

Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase 
(CPK 
increased), 
Potassium 
(hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).
Parameters with NCI-CTC grades not available:
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 

shifts from baseline normal to at least one result above normal during on-treatment period 

shifts from baseline normal to at least one result below normal during on-treatment 
period
In this study, these apply to the following parameters: 

Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils


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
Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH)
6.6.5.2. Other laboratory parameters
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF. 

Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (INR).

Urinalysis: all urinalysis parameters

Other parameters: hormone, and immunology parameters

Pregnancy test.
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing. 
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided.
6.6.6. Vital signs
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Weight will not be collected at End of Treatment. Height will 
be measured at screening only.
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline. 
6.6.7. Electrocardiogram
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing. QTcB and QTcF will be derived based on RR and QT (see below). The 
average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point.


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Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  Although Bazett’s correction is the historical standard, it does not perform 
well when heart rate fluctuates. Fridericia’s formula may perform better under these 
conditions. 
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category.

Pearson correlation between QT and HR, QTc (QTcB, QTcF) and HR using individual 
(non-averaged) baseline assessments 

For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point 

Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:  
-
QT/QTc increase from baseline >30 ms,  >60 ms
-
QT/QTc > 450 ms, > 480 ms, > 500 ms
-
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm
-
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm
-
PR ≥ 220 ms and increase from baseline ≥ 20 ms
-
QRS ≥ 120 ms 


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Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters.
6.6.8. Physical examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.9. ECOG performance status
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing.
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.


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8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934.
3.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience, 2002.  
4.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
5.
Porcher R, Desseaux K. What inference for two-stage phase II trials? BMC Med Res 
Methodol. 12:117, 2012.


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 13.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.  
Table 13.    
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) OR C) below are met then the AE is in for 
the next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB, 
L04AC, L04AD, L04AX, A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated with 
“Immune-mediated endocrinopathies”
C)
conmed ATC code is A10A and AE PT is in the 
irAE cluster associated with “Immune-mediated 
endocrinopathies: Type I Diabetes Mellitus”


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5
A) No clear etiology (other than immune 
mediated etiology)
B) Histopathology / biopsy consistent with 
immune-mediated event
Event is in if 
[Answer to 5B1 and 5B2 is YES  (regardless 
of answer to 5A)]
OR
[Answer to 5B1 is YES AND answer to 5B2 
is NO AND answer to 5A is NO] 
OR
[Answer to 5B1 is NO AND answer to 5A is 
NO]
A) From the AE eCRF page
Is the AE clearly related to an etiology other than 
immune-mediated etiology?    Yes / No
If answer is Yes, check all that apply:
Underlying malignancy / progressive disease.
Other medical conditions. 
Prior or concomitant medications / procedures.  
Other.  Specify.
B) From the AE eCRF page
B1) Was there a pathology /histology evaluation 
performed to investigate the AE?  Y/N
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text)
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses.


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Appendix 2. Infusion Related Reactions
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 

All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset. 

All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of  resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 14
and will be identified for IV drugs only.     
Table 14.   
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs
Condition
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)]  then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2

AE onset date = date of infusion of study drug AND

AE timing related to study drug (‘DURING’, ‘AFTER’) AND

AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND

AE  end date – AE onset date ≤2 
3
PT is included in the ‘IRRs CORE’ list 
4A

AE onset date = date of infusion of study drug AND

AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion