A Phase 2 Study of Neoadjuvant Cemiplimab for Stage II to IV (M0) Cutaneous Squamous Cell Carcinoma (CSCC)
Phase: PHASE2
Conditions: Cutaneous Squamous Cell Carcinoma
Sponsor: Regeneron Pharmaceuticals

EudraCT No. 2019-003007-35 
IND No. 127100 
Clinical Study Protocol 
Regeneron Phannaceuticals, Inc. 
A PHASE 2 STUDY OF NEOADJUVANT CEMIPLIMAB FOR STAGE II 
TO IV (MO) CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) 
Compound: 
Clinical Phase: 
Protocol Number: 
Protocol Version: 
Date of Issue: 
Medical /Study Director: 
Cemiplimab (REGN2810) 
2 
R2810-ONC-1901 
R2810-ONC-1901 Original 
See appended electronic signature page 
Regeneron Phannaceuticals, Inc. 
777 Old Saw Mill River Road 
Tanytown, NY 10591 
VV-RIM-00078797-1.0 Approved - 16 Jul 2019 GMT-5:00
NCT04154943

Clinical Study Protocol 
R2810-ONC-1901 Original 
Regeneron Pharmaceuticals, Inc. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition of Term 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
BAL 
Bronchoalveolar lavage 
BID 
Twice daily 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CR 
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid  
DFS 
Disease free survival 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDM 
Epidermotropic metastasis 
EFS 
Event free survival 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 
EORTC Quality of Life Questionnaire-Core 30 
EOT1 
End of treatment in Part 1 (neoadjuvant) 
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Abbreviation 
Definition of Term 
EOT2 
End of treatment in Part 2 (adjuvant) 
FAS 
Full analysis set 
FFPE 
Formalin-fixed paraffin-embedded 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HBsAg+  
Hepatitis B virus surface antigen positive 
HCV 
Hepatitis C virus 
HCV Ab+ 
Hepatitis C virus antibody positive  
HCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HN 
Head and neck 
HRQoL  
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG4P 
Immunoglobulin G subclass 4 (serine to proline mutation in the hinge region) 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IPRC 
Independent pathology review committee 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ISC 
Independent surgical committee 
ITM 
In-transit metastasis 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LFT 
Liver function test 
M stage 
Metastatic stage (M1 indicates presence of distant metastases) 
Mb 
Megabase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPR 
Major pathologic response 
MRI 
Magnetic resonance imaging 
N stage 
Nodal stage 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
Non-small cell lung cancer 
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Abbreviation 
Definition of Term 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
pCR 
Pathologic complete response 
PD 
Progression of disease 
PD-1 
Programmed death-1 (receptor) 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
R0 
Microscopically margin-negative resection; no gross or microscopic tumor 
remaining in the primary tumor bed 
R1 
Removal of all macroscopic disease; microscopic margins are positive for 
tumor 
R2 
Gross disease after surgery; macroscopically positive surgical margins 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Stable disease 
SOC 
System organ class 
SPT 
Second primary tumor 
SUSAR 
Suspected unexpected serious adverse reaction 
T stage 
Tumor stage  
TEAE 
Treatment-emergent adverse event 
TMB 
Tumor mutation burden 
TNM 
Tumor, Node, Metastasis  
TSH 
Thyroid-stimulating hormone 
UICC 
Union for International Cancer Control 
ULN 
Upper limit of normal 
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Abbreviation 
Definition of Term 
US 
United States 
USPI 
United States Prescribing Information 
UV 
Ultraviolet 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Background on Cutaneous Squamous Cell Carcinoma ..............................................19 
1.2. 
Background on Cemiplimab .......................................................................................19 
1.3. 
Efficacy of Cemiplimab in Advanced CSCC .............................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................20 
2.1. 
Primary Objective .......................................................................................................20 
2.2. 
Secondary Objectives .................................................................................................20 
2.3. 
Exploratory Objectives ...............................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................21 
3.1. 
Hypothesis ..................................................................................................................21 
3.2. 
Rationale .....................................................................................................................21 
3.2.1. 
Rationale for Dose Selection ......................................................................................21 
3.2.2. 
Rationale for Neoadjuvant Cemiplimab in Locally Advanced Patients with 
CSCC Who Are Candidates for Surgery ....................................................................21 
3.2.3. 
Rationale for Adjuvant Cemiplimab Following Surgery............................................23 
3.2.4. 
Rationale for Study Population ...................................................................................24 
3.3. 
Risk-Benefit ................................................................................................................24 
3.3.1. 
Benefit .........................................................................................................................24 
3.3.2. 
Risk .............................................................................................................................25 
4. 
ENDPOINTS ..............................................................................................................26 
4.1. 
Primary Endpoint ........................................................................................................26 
4.2. 
Secondary Endpoints ..................................................................................................26 
4.3. 
Exploratory Endpoints ................................................................................................26 
5. 
STUDY VARIABLES................................................................................................27 
5.1. 
Demographic and Baseline Characteristics ................................................................27 
5.2. 
Efficacy Variables ......................................................................................................27 
5.2.1. 
Disease Response and Disease Recurrence ................................................................27 
5.2.2. 
Changes in Planned Surgery and Post-Surgical Management (Per 
Investigator and Per Independent Review) .................................................................27 
5.2.2.1. 
Management Plan During the Screening Period .........................................................27 
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5.2.2.2. 
Actual Management on the Study ...............................................................................28 
5.2.2.3. 
Estimated Costs of Treatment .....................................................................................29 
5.3. 
Safety Variables ..........................................................................................................29 
5.4. 
Pharmacokinetic Variables .........................................................................................29 
5.5. 
Immunogenicity Variables ..........................................................................................29 
5.6. 
Exploratory Pharmacodynamic and Biomarker Variables .........................................30 
5.7. 
Patient Reported Outcomes Variables ........................................................................30 
6. 
STUDY DESIGN .......................................................................................................30 
6.1. 
Study Description and Duration .................................................................................30 
6.1.1. 
Screening ....................................................................................................................31 
6.1.2. 
Treatment in Part 1 (Neoadjuvant) .............................................................................31 
6.1.3. 
Treatment in Part 2 (Adjuvant) ...................................................................................32 
6.1.4. 
Post-Treatment Follow-Up .........................................................................................32 
6.1.5. 
Description of Study Cohorts and Dose Escalation ....................................................32 
6.1.6. 
End of Study Definition ..............................................................................................32 
6.1.7. 
Informed Consent .......................................................................................................32 
6.2. 
Interim Analysis ..........................................................................................................32 
6.3. 
Study Committees .......................................................................................................33 
6.3.1. 
Independent Central Pathology Review Committee ...................................................33 
6.3.2. 
Independent Surgical Committee ...............................................................................33 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............33 
7.1. 
Number of Patients Planned .......................................................................................33 
7.2. 
Study Population .........................................................................................................33 
7.2.1. 
Inclusion Criteria ........................................................................................................33 
7.2.2. 
Exclusion Criteria .......................................................................................................34 
7.3. 
Premature Withdrawal from the Study .......................................................................37 
7.4. 
Replacement of Patients .............................................................................................37 
8. 
STUDY TREATMENT ..............................................................................................37 
8.1. 
Investigational Treatment ...........................................................................................37 
8.2. 
Dose Modification ......................................................................................................37 
8.3. 
Study Drug Discontinuation .......................................................................................38 
8.3.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................38 
8.3.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................38 
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8.3.3. 
Immune-related Adverse Events and Study Drug Discontinuation ............................38 
8.3.3.1. 
Identification of Immune-Related Adverse Events ....................................................38 
8.3.3.2. 
Management of Immune-related Adverse Events ......................................................39 
8.3.4. 
General Guidance for Management of Adverse Events .............................................40 
8.3.5. 
Study Drug Discontinuation Due to Disease State .....................................................41 
8.3.6. 
Resumption of Study Drug .........................................................................................41 
8.3.7. 
Clinical Assessments Following Study Drug Discontinuation ...................................42 
8.4. 
Management of Acute Infusion-Related Reactions ....................................................42 
8.4.1. 
Identification of Acute Infusion-Related Reactions ...................................................42 
8.4.2. 
Interruption of the Infusion .........................................................................................42 
8.4.3. 
Termination of the Infusion ........................................................................................43 
8.5. 
Method of Treatment Assignment ..............................................................................44 
8.5.1. 
Blinding ......................................................................................................................44 
8.6. 
Treatment Logistics and Accountability .....................................................................44 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................44 
8.6.2. 
Supply and Disposition of Treatments .......................................................................44 
8.6.3. 
Treatment Accountability ...........................................................................................44 
8.6.4. 
Treatment Compliance ................................................................................................45 
8.7. 
Concomitant Medications and Procedures .................................................................45 
8.7.1. 
Prohibited Medications and Procedures .....................................................................45 
8.7.2. 
Permitted Medications and Procedures ......................................................................45 
9. 
STUDY SCHEDULES OF EVENTS AND PROCEDURES ....................................46 
9.1. 
Schedules of Events ....................................................................................................46 
9.1.1. 
Footnotes for Table 2: Schedule of Events for Screening, Neoadjuvant 
Cemiplimab, and Surgery (Part 1 of the Study) .........................................................48 
9.1.2. 
Footnotes for Table 3: Schedule of Events for Adjuvant Cemiplimab (Part 2 
of the Study) ...............................................................................................................51 
9.1.3. 
Footnotes for Table 4:  Schedule of Events for Follow-Up After Part 2 of the 
Study ...........................................................................................................................52 
9.1.4. 
Early Termination Visit ..............................................................................................52 
9.1.5. 
Visit Schedule for Patients Who Discontinue Study Drug .........................................53 
9.1.5.1. 
Visit Schedule for Patients Who Discontinue Neoadjuvant Cemiplimab ..................53 
9.1.5.2. 
Visit Schedule for Patients Who Discontinue Adjuvant Cemiplimab ........................53 
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9.1.6. 
Visit Schedule for Patients Who Receive Adjuvant Radiation Therapy or 
Observation Only ........................................................................................................53 
9.1.7. 
Survival Follow-Up ....................................................................................................54 
9.1.8. 
Unscheduled Visits .....................................................................................................54 
9.2. 
Study Procedures ........................................................................................................54 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................54 
9.2.2. 
Efficacy Procedures ....................................................................................................54 
9.2.2.1. 
Pathologic Assessment of Tumor Response ...............................................................54 
9.2.2.2. 
Change in Surgical Plan and Post-Surgical Management (Treatment 
Management Plan Assessment) ..................................................................................55 
9.2.2.3. 
Imaging Studies ..........................................................................................................55 
9.2.2.4. 
Characterization of New Skin Lesions (Disease Recurrence) or SPT 
Following Surgery ......................................................................................................56 
9.2.2.5. 
Definitions for Patterns of Disease Recurrence Following Surgery ...........................57 
9.2.2.6. 
Date of Disease Recurrence Following Surgery .........................................................58 
9.2.2.7. 
Biopsies to Document Disease Recurrence or SPT Following Surgery .....................59 
9.2.3. 
Safety Procedures .......................................................................................................59 
9.2.3.1. 
Vital Signs ..................................................................................................................59 
9.2.3.2. 
Physical Examination .................................................................................................59 
9.2.3.3. 
Electrocardiogram .......................................................................................................60 
9.2.3.4. 
ECOG Performance Status .........................................................................................60 
9.2.3.5. 
Laboratory Testing ......................................................................................................60 
9.2.4. 
Survival Data Collection .............................................................................................62 
9.2.5. 
Anti-Drug Antibody and Pharmacokinetic Procedures ..............................................62 
9.2.5.1. 
Anti-Drug Antibody Measurements and Samples ......................................................62 
9.2.5.2. 
Drug Concentration Measurements and Samples .......................................................62 
9.2.6. 
Exploratory Pharmacodynamic and Biomarker Procedures .......................................62 
9.2.6.1. 
Tumor Biopsy .............................................................................................................63 
9.2.6.2. 
Circulating Tumor DNA .............................................................................................63 
9.2.6.3. 
Peripheral Blood Mononuclear Cells for Exploratory Immune Monitoring ..............64 
9.2.6.4. 
Whole Blood for DNA Analysis (Mandatory Sample) ..............................................64 
9.2.7. 
Genomics Sub-study (Optional Sample) ....................................................................64 
9.2.8. 
Future Biomedical Research (Optional Use of Samples) ...........................................65 
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9.2.9. 
Patient Reported Outcomes ........................................................................................65 
10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................65 
10.1. 
Obligations of Investigator .........................................................................................65 
10.2. 
Obligations of Sponsor ...............................................................................................65 
10.3. 
Definitions ..................................................................................................................66 
10.3.1. 
Adverse Event .............................................................................................................66 
10.3.2. 
Serious Adverse Event ................................................................................................66 
10.3.3. 
Adverse Events of Special Interest .............................................................................67 
10.3.4. 
Infusion Reactions ......................................................................................................67 
10.4. 
Recording and Reporting Adverse Events ..................................................................67 
10.4.1. 
Adverse Events ...........................................................................................................67 
10.4.2. 
Serious Adverse Events ..............................................................................................67 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................68 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................68 
10.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................68 
10.4.6. 
Follow-up ....................................................................................................................69 
10.5. 
Evaluation of Severity and Causality .........................................................................69 
10.5.1. 
Evaluation of Severity ................................................................................................69 
10.5.2. 
Evaluation of Causality ...............................................................................................70 
10.6. 
Safety Monitoring .......................................................................................................71 
10.7. 
Investigator Alert Notification ....................................................................................71 
11. 
STATISTICAL PLAN................................................................................................71 
11.1. 
Statistical Hypothesis ..................................................................................................72 
11.2. 
Justification of Sample Size........................................................................................72 
11.3. 
Subgroup Analyses .....................................................................................................73 
11.4. 
Analysis Sets ...............................................................................................................73 
11.4.1. 
Efficacy Analysis Sets ................................................................................................73 
11.4.2. 
Safety Analysis Set .....................................................................................................73 
11.4.3. 
PK Analysis set ...........................................................................................................73 
11.4.4. 
Immunogenicity Analysis Sets ...................................................................................73 
11.4.5. 
Exploratory Pharmacodynamic and Biomarker Analysis Set ....................................73 
11.5. 
Statistical Methods ......................................................................................................74 
11.5.1. 
Patient Disposition ......................................................................................................74 
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11.5.2. 
Demography and Baseline Characteristics .................................................................74 
11.5.3. 
Efficacy Analyses .......................................................................................................74 
11.5.3.1. 
Primary Efficacy Analysis ..........................................................................................74 
11.5.3.2. 
Secondary Efficacy Analysis ......................................................................................74 
11.5.4. 
Control of Multiplicity ................................................................................................75 
11.5.5. 
Safety Analysis ...........................................................................................................75 
11.5.5.1. 
Adverse Events ...........................................................................................................75 
11.5.5.2. 
Other Safety ................................................................................................................76 
11.5.5.3. 
Treatment Exposure ....................................................................................................76 
11.5.5.4. 
Treatment Compliance ................................................................................................76 
11.5.6. 
Analysis of Anti-Drug Antibody Data ........................................................................76 
11.5.7. 
Analysis of Drug Concentration Data .........................................................................77 
11.5.8. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data ..............................77 
11.5.9. 
Analysis of Patient-Reported Outcomes Data ............................................................77 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........77 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
12.1. 
Data Management and Electronic Systems ................................................................78 
12.1.1. 
Electronic Systems ......................................................................................................78 
12.2. 
Study Monitoring ........................................................................................................78 
12.2.1. 
Monitoring of Study Sites ...........................................................................................78 
12.2.2. 
Source Document Requirements ................................................................................78 
12.2.3. 
Case Report Form Requirements ................................................................................79 
12.3. 
Audits and Inspections ................................................................................................79 
12.4. 
Study Documentation .................................................................................................79 
12.4.1. 
Certification of Accuracy of Data ...............................................................................79 
12.4.2. 
Retention of Records ..................................................................................................80 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................80 
13.1. 
Good Clinical Practice Statement ...............................................................................80 
13.2. 
Informed Consent .......................................................................................................80 
13.3. 
Patients Confidentiality and Data Protection ..............................................................81 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................81 
13.5. 
Clinical Study Data Transparency ..............................................................................81 
14. 
PROTOCOL AMENDMENTS ..................................................................................82 
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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................82 
15.1. 
Premature Termination of the Study ...........................................................................82 
15.2. 
Close-out of a Site ......................................................................................................82 
16. 
CONFIDENTIALITY ................................................................................................82 
17. 
FINANCING AND INSURANCE .............................................................................83 
18. 
PUBLICATION POLICY ..........................................................................................83 
19. 
REFERENCES ...........................................................................................................84 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................88 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................89 
 
LIST OF TABLES 
Table 1: 
General Guidelines for Management of Treatment-Related AEs ...............................40 
Table 2: 
Schedule of Events for Screening, Neoadjuvant Cemiplimab, and Surgery 
(Part 1 of the Study) ....................................................................................................47 
Table 3: 
Schedule of Events for Adjuvant Cemiplimab (Part 2 of the Study) .........................50 
Table 4: 
Schedule of Events for Follow-Up After Part 2 of the Study .....................................52 
Table 5: 
Grading System for Adverse Events Not Listed in NCI-CTCAE ..............................69 
Table 6: 
The 95% Binomial Exact Confidence Intervals for Observed pCR with a 
Sample Size of 76 Patients .........................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................31 
 
LIST OF APPENDICES 
Appendix 1. Eastern Cooperative Oncology Group Criteria ......................................................90 
Appendix 2. Guidelines for Management of Selected Immune-Related Adverse Events ..........91 
Appendix 3. Guidelines For Exploratory Biopsies ...................................................................101 
Appendix 4. Response Evaluation Criteria in Solid Tumors: RECIST Guideline 
(Version 1.1) ........................................................................................................102 
Appendix 5. Digital Photographic Procedures ..........................................................................107 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2 Study of Neoadjuvant Cemiplimab for Stage II to IV (M0) 
Cutaneous Squamous Cell Carcinoma (CSCC) 
Site Location(s) 
Approximately 20 sites in North America, Europe, and Asia-Pacific 
Principal Investigator 
Neil Gross, MD, FACS 
Objective(s) 
 
 
Primary Objective 
To evaluate the efficacy of neoadjuvant cemiplimab as measured by pathologic 
complete response (pCR) rate per independent central pathology review. 
 
Secondary Objectives 
The secondary objectives of the study are: 
 
To evaluate the efficacy of neoadjuvant cemiplimab on measures 
of disease response, including: 
 
Major pathologic response (mPR) rate per independent 
central pathology review 
 
pCR rate and mPR rate per local pathology review  
 
Objective response rate (ORR) prior to surgery, according to 
local assessment using RECIST 1.1  
 
To evaluate the efficacy of neoadjuvant cemiplimab on event free 
survival (EFS), disease free survival (DFS), and overall survival 
(OS) 
 
To evaluate the safety profile of neoadjuvant cemiplimab  
 
To assess change in surgical plan (ablative and reconstructive 
procedures) from the screening period to definitive surgery, both 
according to investigator review and independent surgical expert 
review 
 
To assess change in post-surgical management plan (radiation, 
chemoradiation, or observation) from the screening period to 
post-surgery pathology review, both according to investigator 
review and independent surgical expert review  
 
Exploratory 
 
Objectives 
The exploratory objectives of the study are: 
 
To explore baseline tumor markers for associations with 
treatment responses, peripheral and tumor measures associated 
with cemiplimab mechanism of action and discovery of other 
potential predictive markers of efficacy or safety 
 
To describe patterns of failure (locoregional versus distant) in 
patients who experience disease recurrence 
 
To evaluate the cost implication due to changes in surgical plan 
during screening period versus actual surgical procedure 
performed  
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 
To evaluate the cost implication due to changes in post-surgical 
management plan during screening period versus actual 
post-surgical management 
 
To assess the immunogenicity of cemiplimab 
 
To assess health-related quality of life in patients with CSCC who 
receive neoadjuvant cemiplimab 
Study Design 
 
This is a single-arm, open label, multicenter phase 2 study for patients with 
stage II to IV (M0) CSCC who are candidates for surgery, but who have an 
increased risk of recurrence and/or risk of disfigurement or loss of function.  
Patients with stage III or IV (M0) CSCC of the head/neck, extremity, or trunk 
are eligible, as well as selected patients with stage II CSCC (≥3 cm longest 
diameter in an aesthetically sensitive region). 
The study consists of 2 parts: 
 
Part 1 (neoadjuvant): A screening period of up to 28 days, a 
treatment period of up to 12 weeks, and surgery after 12 weeks 
of treatment.  Part 1 of the study supports the primary endpoint 
 
Part 2 (adjuvant): Optional post-surgery cemiplimab treatment 
for up to 48 weeks (or radiation therapy, or observation only, at 
investigator discretion) 
Study Part 1 (Neoadjuvant) 
Patients with stage II to IV (M0) CSCC with planned surgery and who fulfill 
the eligibility criteria will receive cemiplimab 350 mg intravenously (IV) every 
3 weeks (Q3W) for up to 12 weeks (up to 4 doses), or until unacceptable 
toxicity, disease progression, or withdrawal of consent.  Patients will be 
evaluated in clinic prior to each dose and will undergo tumor response imaging 
assessment prior to receiving the third dose of cemiplimab (day 43±3) and prior 
to surgery (day 85).  The window for surgery is from day 75 through day 100.  
If a patient meets criteria to discontinue cemiplimab during the 12-week 
neoadjuvant period, the treating physician may divert the patient to surgery at 
an earlier time.   
Following surgical tumor resection, the primary endpoint (pCR rate) will be 
assessed by an independent central pathology review committee.  
Study Part 2 (Adjuvant) 
Patients will have the option to receive adjuvant cemiplimab treatment (350 mg 
IV Q3W) following surgery for up to 48 weeks (up to 16 doses) or until 
unacceptable toxicity, disease recurrence, or withdrawal of consent.  The first 
dose of adjuvant treatment will occur 3 weeks (±3 days) after the end of 
treatment in Part 1 (EOT1).  At the investigator’s discretion, patients may 
alternatively receive adjuvant radiation therapy (concurrent or subsequent 
cemiplimab treatment not allowed) or enter an observation-only period.  
During Part 2 of the study, patients will be evaluated in clinic every 15 weeks.  
Patients receiving adjuvant cemiplimab will undergo complete assessments as 
described in the schedule of events, while patients who do not receive adjuvant 
cemiplimab will only undergo imaging assessments following a parallel 
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Follow-Up 
Follow-up will begin after a patient has completed Part 1 and Part 2 of the study 
without disease progression (pre-surgery) or disease recurrence (post-surgery).  
Patients will be evaluated in clinic for up to 3 additional years. 
Study Duration 
Part 1:  Up to 12 weeks 
Part 2:  Up to 48 weeks 
Follow-up: Up to 3 years.  Patients will be followed until disease recurrence or 
end of study, whichever occurs first. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 76 patients will be enrolled. 
 
Target Population: 
The target population will consist of adult patients with stage III to IV (M0) 
CSCC of the head/neck, extremity, or trunk, and selected patients with stage II 
CSCC, for whom surgery would be recommended in routine clinical practice. 
Patient criteria include, but are not limited to, the following: 
 
No prior radiation therapy for CSCC 
 
At least one lesion that is measurable by RECIST 1.1  
 
For stage II patients, lesion must be ≥3 cm at the longest diameter  
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Cemiplimab 50 mg/mL supplied as a sterile liquid in single-use glass vials.  
350 mg IV infusion over 30 minutes (±10 minutes) Q3W. 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is pCR rate assessed by independent central pathology 
review. 
 
Secondary: 
The secondary endpoints are: 
 
Major pathologic response (mPR) rate assessed by independent 
central pathology review 
 
pCR rate and mPR rate assessed by local pathology review 
 
ORR prior to surgery, according to investigator assessment using 
RECIST 1.1 
 
Event free survival (EFS) 
 
Disease free survival (DFS) 
 
Overall survival (OS)  
 
Safety and tolerability as measured by the incidence of adverse events 
(AEs), serious adverse events (SAEs), deaths, and laboratory 
abnormalities  
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 
Change in surgical plan in the screening period versus actual surgery 
after neoadjuvant cemiplimab 
 
Change in post-surgical management plan in the screening period 
versus actual post-surgical management 
 
Exploratory: 
The exploratory endpoints are: 
 
Patterns of failure in patients with local, regional, or distant disease 
recurrence as measured by descriptive statistics 
 
Change in estimated costs due to change in surgical plan during 
screening period versus actual surgical procedure performed after 
neoadjuvant cemiplimab 
 
Change in estimated costs due to the change in post-surgical 
management plan during screening period versus actual post-surgical 
management 
 
Incidence of anti-drug antibody (ADA) for cemiplimab 
 
Health-related quality of life, as assessed using the European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) 
 
Procedures and Assessments 
 
Procedures Performed Only at Screening/Baseline 
Patients will undergo screening for hepatitis B virus (HBV), hepatitis C virus 
(HCV), and human immunodeficiency virus (HIV), and height measurement 
only at the screening/baseline visit for the sole purpose of determining study 
eligibility or characterizing the baseline population.  Women of childbearing 
potential will additionally undergo serum β-human chorionic gonadotropin 
(HCG) testing.  During screening, medical/oncological history is obtained. 
Efficacy Procedures 
Surgically resected tumors will be evaluated for pathologic response by an 
independent central pathology review committee. 
Changes in surgical plan and post-surgical management plan will be evaluated 
both locally and by an independent surgical committee.  Assessment 
parameters include, but are not limited to, description of planned/actual 
surgery, length of hospital stay, whether surgery was more/less extensive than 
planned, and planned/actual adjuvant radiation therapy. 
Patients will undergo radiologic imaging assessments for tumor response 
(neoadjuvant portion of the study) and for disease recurrence (adjuvant portion 
of the study and follow-up).  Imaging of externally visible lesions will be 
supplemented with digital medical photography.  Digital photography is 
mandatory at baseline and prior to surgery in Part 1 and optional for all other 
imaging visits in the study. 
Biopsy of tumors will be performed when feasible to obtain histologic or 
cytologic evidence of disease recurrence or evidence of a second primary 
tumor (SPT).  For recurrent lesions, the pattern of failure will be assessed, with 
recurrence defined as ≥1 lesion that can be categorized as local, regional, or 
distant recurrence.  
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Safety Procedures 
Safety and tolerability of cemiplimab will be evaluated via adverse event (AE) 
capturing, physical examination (complete or limited), weight, 12-lead 
electrocardiogram (ECG), vital sign assessments, and laboratory testing, 
including hematology, blood chemistry, and urinalysis.  
Statistical Plan 
Statistical Hypothesis 
The primary endpoint is pCR by independent central review.  The following 
null and alternative hypotheses will be tested for the primary efficacy endpoint: 
H0: pCR rate = 25% 
Ha: pCR rate ≠ 25% 
Justification of Sample Size 
Seventy-two (72) patients will be required to provide 90% power to reject the 
null hypothesis (pCR rate = 25%) at a 2-sided significance level of 0.05 if the 
true pCR rate is 44%.  The sample size will be further increased by 5% to 
account for patients who prematurely withdraw from the study (total sample 
size of approximately 76 patients).  
The non-clinically meaningful pCR rate of 25% will be excluded using the 
lower limit of 95% exact confidence interval (CI) if the observed pCR rate is 
36.8% or more. 
Patients who discontinue treatment early and/or withdraw will not be replaced, 
and the results will be analyzed by intention-to-treat.  To ensure meaningful 
representation of stage III/IV (M0) patients, enrollment of stage II patients will 
be capped at 25. 
Interim Analysis 
No interim analysis is planned for the primary endpoint.  After all patients have 
completed Part 1 of the study, an interim clinical study report (CSR) may be 
written to describe the analysis results for the primary endpoint.  The final CSR 
will be written to describe the final results of the study, after all patients have 
had the opportunity to complete Part 2 of the study and post-treatment follow-
up. 
Efficacy Analysis Methods 
Primary efficacy analysis: 
Pathologic complete response (pCR) rate per independent central pathology 
review, along with the 95% exact confidence interval, will be calculated using 
the Clopper-Pearson method.  
Secondary efficacy analysis: 
Pathologic complete response (pCR) rate per local pathology review, mPR rate 
per independent central pathology review, mPR rate per local pathology 
review, and ORR prior to surgery per investigator assessment, along with 95% 
exact confidence intervals, will be calculated using the Clopper-Pearson 
method. 
Event free survival (EFS), DFS, and OS will be summarized using the 
Kaplan-Meier method, and Kaplan-Meier curves will be generated.  
Descriptive statistics will be used for time-to-event endpoints.   
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Change in planned surgery will be summarized descriptively and will be listed.  
The proportion of patients for whom the surgical management plan (at time of 
screening) differed from the actual surgery after neoadjuvant therapy will be 
summarized both by investigator assessment and independent surgical expert 
committee. 
Change in planned post-surgical management will be summarized 
descriptively and will be listed.  The proportion of patients for whom radiation 
therapy (or chemoradiation) was planned during screening but not actually 
administered after neoadjuvant cemiplimab and surgery will be summarized. 
Safety Analysis Methods 
Treatment-emergent adverse events (TEAEs), SAEs, and adverse events of 
special interest (AESIs) will be summarized using descriptive statistics.  
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or 
worsened during the on-treatment period and any treatment-related AEs that 
occur during the post-treatment period but prior to patients receiving their first 
dose of cemiplimab as adjuvant therapy or another anticancer systemic therapy. 
Adverse events (AEs) during adjuvant cemiplimab will be summarized 
separately from AEs emerging in the neoadjuvant period.  AEs will be 
collected from the date of first dose of adjuvant cemiplimab up to 90 days 
following the last dose.  Additionally, any treatment-related AEs identified 
more than 90 days following the last dose will be captured. 
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1. 
INTRODUCTION 
1.1. 
Background on Cutaneous Squamous Cell Carcinoma 
Cutaneous squamous cell carcinoma (CSCC) is a malignant proliferation of epidermal 
keratinocytes with invasion of the dermis, and is distinguished from non-invasive precursor lesions 
such as actinic keratoses (Nehal, 2018).  The precise incidence of CSCC is not known because it 
is not included in most cancer registries; however, CSCC is thought to be the second most common 
non-melanoma 
skin 
cancer, 
with 
an 
increasing 
incidence 
in 
recent 
decades 
(Lomas, 2012)(Que, 2018)(Rogers, 2010).  Worldwide incidence varies widely, with the highest 
incidence in Australia and the lowest incidence in parts of Africa (Lomas, 2012).  The main risk 
factors for CSCC are advanced age, light skin, male gender, and a history of chronic sun exposure 
(Stratigos, 2015).  Most CSCCs arise in the skin of the head and neck (HN), and this is thought to 
be related to high sun exposure of skin in these regions.  Owing to chronic ultraviolet (UV) light-
induced mutagenesis, CSCC tumors are hypermutated, with a median tumor mutation burden 
(TMB) of approximately 45 mutations/Mb (Chalmers, 2017).   
Surgical resection is the centerpiece of clinical management of CSCC, achieving cure in >95% of 
patients (Kauvar, 2015).  However, some CSCC patients are at an increased risk of disease 
recurrence, risk of disfigurement, or loss of function associated with surgical resection of locally 
advanced lesions.  This phase 2 study will explore cemiplimab (350 mg intravenous [IV] every 
3 weeks [Q3W] for up to 4 doses) in the neoadjuvant (preoperative) setting in patients with stage 
II to stage IV (M0) CSCC (stage II patients must have tumors that are ≥3 cm in longest diameter).  
The primary endpoint is pathologic complete response (pCR) rate.  There is also an option for 
adjuvant (post-operative) treatment with cemiplimab. 
1.2. 
Background on Cemiplimab 
LIBTAYO® (cemiplimab) is approved in the United States, Canada, and Brazil for the treatment 
of patients with metastatic cutaneous squamous cell carcinoma or patients with locally advanced 
cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative 
radiation.   In the United States, it is approved with a suffix as cemiplimab-rwlc.   
Cemiplimab is a high-affinity, recombinant human immunoglobulin G (IgG4P) monoclonal 
antibody that binds to programmed cell death 1 (PD-1) and blocks its interaction with programmed 
death ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), countering PD-1-mediated 
inhibition of the anti-tumor immune response.  Cemiplimab is being evaluated in more than 
twenty phase 1 through phase 3 clinical studies in a variety of tumor types.  The safety profile of 
cemiplimab demonstrated in these clinical trials is consistent with the expected safety profile of 
an anti-PD-1 antibody.    
Further details on the clinical efficacy of cemiplimab for the treatment of patients with metastatic 
or locally advanced CSCC are provided in Section 1.3.  Additional information, including 
preclinical and clinical safety data, is available in the Investigator’s Brochure. 
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1.3. 
Efficacy of Cemiplimab in Advanced CSCC 
The efficacy of cemiplimab in patients with metastatic or locally advanced CSCC who were not 
candidates for curative surgery or curative radiation was evaluated in 2 open-label, multi-center, 
non-randomized, multicohort studies: a phase 1 study (NCT02383212) that included expansion 
cohorts for patients with advanced CSCC, and a pivotal phase 2 study (NCT02760498).  Across 
the 2 studies, the objective response rate (ORR) was 46.7% (95% confidence interval [CI], 35.1% 
to 58.6%) for metastatic CSCC (N = 75), 48.5% (95% CI, 30.8 to 66.5%) for locally advanced 
CSCC (N = 33), and 47.2% (95% CI, 37.5% to 57.1%) for combined CSCC (N = 108), with a 
median duration of follow-up of 8.1 months, 10.2 months, and 8.9 months, respectively.  The 
duration of response exceeded 6 months in 60% (metastatic CSCC), 63% (locally advanced 
CSCC), and 61% (combined CSCC) of patients (LIBTAYO® USPI).  
In a pilot phase 2 study of neoadjuvant cemiplimab in patients with stage III to IV HN CSCC 
(NCT03565783), preliminary results indicate a clinically meaningful rate of pCR (see 
Section 3.2.2). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of neoadjuvant cemiplimab as 
measured by pCR rate per independent central pathology review.  
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the efficacy of neoadjuvant cemiplimab on measures of disease response, 
including: 
 Major pathologic response (mPR) rate per independent central pathology review 
 pCR rate and mPR rate per local pathology review  
 ORR prior to surgery, according to local assessment using RECIST 1.1  
 To evaluate the efficacy of neoadjuvant cemiplimab on event free survival (EFS), 
disease free survival (DFS), and overall survival (OS) 
 To evaluate the safety profile of neoadjuvant cemiplimab  
 To assess change in surgical plan (ablative and reconstructive procedures) from the 
screening period to definitive surgery, both according to investigator review and 
independent surgical expert review 
 To assess change in post-surgical management plan (radiation, chemoradiation, or 
observation) from the screening period to post-surgery pathology review, both 
according to investigator review and independent surgical expert review  
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2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
 To explore baseline tumor markers for associations with treatment responses, 
peripheral and tumor measures associated with cemiplimab mechanism of action, and 
discovery of other potential predictive markers of efficacy or safety 
 To describe patterns of failure (locoregional versus distant) in patients who 
experience disease recurrence following surgery 
 To evaluate the cost implication due to changes in surgical plan during screening period 
versus actual surgical procedure performed  
 To evaluate the cost implication due to changes in post-surgical management plan 
during screening period versus actual post-surgical management 
 To assess the immunogenicity of cemiplimab 
 To assess health-related quality of life in patients with CSCC who receive neoadjuvant 
cemiplimab 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Cemiplimab administered prior to surgery will result in a clinically meaningful pCR rate in patients 
with stage II to IV (M0) CSCC.  The cutoff for clinically meaningful response is defined as 25%, 
which would provide confirmation of the efficacy signal detected in the pilot investigator-initiated 
study conducted at MD Anderson Cancer Center (NCT03565783). 
The statistical hypothesis is provided in Section 11.1. 
3.2. 
Rationale 
3.2.1. 
Rationale for Dose Selection 
The cemiplimab 350 mg IV Q3W dosing regimen was selected across the entire cemiplimab 
clinical development program.  It is now the approved regimen, both within the United States and 
in selected countries globally, to treat patients with metastatic or locally advanced CSCC who are 
not candidates for curative surgery or curative radiation.  This regimen is therefore expected to be 
effective in both the neoadjuvant and adjuvant settings.  
3.2.2. 
Rationale for Neoadjuvant Cemiplimab in Locally Advanced Patients with 
CSCC Who Are Candidates for Surgery 
This study proposes to evaluate the administration of cemiplimab earlier in the natural history of 
CSCC, in the neoadjuvant setting prior to surgery.  The clinical benefit of immune checkpoint 
blockade may be greater in this setting.  Emerging data in patients with CSCC treated with 
cemiplimab and in patients with other cancers treated with other anti-PD-1 agents in the 
neoadjuvant setting provide 2 fundamental observations: 1) neoadjuvant therapy is feasible and 
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does not result in a loss of opportunity for curative-intent surgery, and 2) preliminary clinical 
efficacy findings are encouraging.  Efficacy endpoints in the neoadjuvant setting typically include 
pCR, defined as the absence of viable cancer cells in the surgical pathology sample, and mPR, 
defined as ≤10% viable cells in the surgical pathology sample in patients who have not achieved 
pCR.  
In a pilot study of neoadjuvant nivolumab for patients with resectable non-small cell lung cancer 
(NSCLC) (NCT02259621), 22 patients were enrolled to receive 4 weeks of neoadjuvant therapy 
(3 mg/kg nivolumab every 2 weeks [Q2W] X 2 doses) (Forde, 2018).  Among 22 enrolled patients, 
20 received the 2 planned nivolumab doses and underwent surgery, 1 patient with grade 3 
pneumonia underwent surgery after 1 dose of nivolumab, and 1 patient was deemed ineligible per 
protocol.  Among the 20 patients, the median time between the second dose of nivolumab and 
surgery was 18 days (range, 11 to 29 days).  There were no treatment-related surgical delays as 
defined in the protocol.  The mPR rate was 45% (9/20) and 2 pCRs were observed.  Efficacy was 
directly associated with TMB among 11 patients who provided samples for sequencing and were 
evaluable for pathologic response: the mean number of sequence alterations was higher in 
3 patients with mPR (311 ±55 mutations/Mb) than in 8 patients without mPR 
(74 ±60 mutations/Mb) (Forde, 2018). 
The Checkmate 358 study (sponsored by Bristol-Myers Squibb) evaluated neoadjuvant nivolumab 
(240 mg Q2W X 2 doses) among 29 patients with resectable Merkel Cell Carcinoma (MCC) 
(Topalian, 2018).  Two patients either had adverse events (AEs) or withdrew consent prior to 
surgery.  Among the 27 patients who underwent surgery, the median time between the first dose 
of nivolumab and surgery was 4.3 weeks (range, 2.9 to 6.3 weeks).  Pathologic response was 
reported according to independent central review among 17 patients (47% pCR, 18% mPR) and 
local pathology review among 26 patients (27% pCR).  In some patients, this response avoided the 
need for more extensive surgery. 
Because CSCC is a paradigmatic example of an immune-responsive tumor in which surgery is the 
mainstay of treatment (Migden, 2018), it is an appropriate setting to further study neoadjuvant PD-
1 blockade.  While mechanistic data are controversial and limited to preclinical studies in other 
tumor types, there is evidence to suggest that in the neoadjuvant setting, solid tumors may be 
enriched for both lymphocytes expressing immune checkpoint targets, as well as tumor antigens 
available for cross-priming (Melero, 2016). 
In an ongoing, investigator-initiated phase 2 pilot study at MD Anderson Cancer Center 
(NCT03565783), 20 patients with stage III to IV (M0) CSCC received 2 doses of neoadjuvant 
cemiplimab (350 mg Q3W).  Clinical results indicate pCR rates were achieved in a clinically 
meaningful proportion of patients.  All 20 patients were able to undergo surgical resection, and no 
patient developed unresectable or metastatic disease during the neoadjuvant treatment period.   
To extend these encouraging preliminary results, this protocol describes a multicenter study of 
neoadjuvant cemiplimab for patients with stage II to stage IV (M0) CSCC in which the primary 
endpoint is pCR per independent central review.  Patients with stage III or IV (M0) CSCC of 
head/neck, extremity, or trunk are eligible, as well as selected patients with stage II CSCC (≥3 cm 
longest diameter lesion in an aesthetically-sensitive region). 
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In this study, patients will receive up to 4 doses of cemiplimab in the neoadjuvant setting.  The 
decision to increase the maximum number of doses of cemiplimab prior to surgery is based on 3 
considerations:  1) Among 20 patients in the pilot study (NCT03565783) , none  lost the 
opportunity for curative surgery due to delays from receiving 2 doses of neoadjuvant cemiplimab; 
2)  Some patients in the pilot study  achieved mPR, but not pCR, suggesting that an increase in the 
number of received doses may provide additional necessary time to achieve the full immunological 
efficacy of neoadjuvant cemiplimab; 3) In the current protocol, radiologic assessment after 2 doses 
will be implemented to confirm no disease progression prior to receiving the remaining doses. 
3.2.3. 
Rationale for Adjuvant Cemiplimab Following Surgery  
Adjuvant cemiplimab treatment is an appropriate option in the context of a clinical trial.  
Multidisciplinary expert guidelines from the National Comprehensive Cancer Network (NCCN) 
and European Association of Dermato Oncology (EADO)/ European Organization for Research 
and Treatment of Cancer (EORTC)/ European Dermatology Forum (EDF) recommend adjuvant 
radiation therapy in patients with positive tissue margins after surgery and in patients with 
extensive perineural invasion (Bichakjian, 2018)(Stratigos, 2015).  The European guidelines also 
recommend consideration of adjuvant radiation therapy in patients who have undergone lymph 
node dissection, if multiple lymph nodes are involved or if extracapsular involvement is observed 
(Stratigos, 2015).  Data supporting adjuvant radiation therapy recommendations for selected 
patients with CSCC are derived from retrospective studies, many of which contained heterogenous 
populations (Bichakjian, 2018).  Therefore, individualized decision making may integrate a variety 
of patient-specific factors regarding the appropriateness of adjuvant radiation therapy after CSCC 
resection. 
Expert guidelines also describe the safety profile of radiation therapy for patients with CSCC 
(Bichakjian, 2018)(Stratigos, 2015).  The frequency of these events depends on numerous 
variables, including the type, dose, and schedule of radiation therapy, and the anatomic site of the 
lesion.  Common side effects of radiation therapy include fibrosis and change in the pigmentation 
of radiated skin.  Uncommon but serious toxicities of radiation therapy include non-healing ulcers 
and necrosis of radiated tissue.  
In melanoma, prospective phase 3 studies demonstrate that adjuvant administration of other 
anti-PD-1 antibodies for approximately 1 year decreases the risk of disease recurrence after 
surgical resection of stage III or IV disease (Eggermont, 2018)(Weber, 2017).  In CSCC, a phase 3 
study sponsored by Regeneron is ongoing to determine if approximately 1 year of adjuvant 
cemiplimab treatment, compared to placebo, decreases the rate of recurrence among high-risk 
patients who have completed surgery and adjuvant radiation therapy (NCT03969004). 
In view of the high efficacy of cemiplimab against advanced CSCC and the positive phase 3 results 
among other anti-PD-1 antibodies in the adjuvant setting for melanoma patients, it is appropriate 
to evaluate cemiplimab in the post-operative setting.  Therefore, Part 2 of this protocol allows 
adjuvant cemiplimab in patients who have not experienced disease progression or unacceptable 
toxicity during Part 1 (the neoadjuvant portion) of the study.  An investigator, according to his or 
her clinical judgment, may opt to administer adjuvant radiation therapy in this study instead of 
adjuvant cemiplimab in Part 2.  Such patients will not receive cemiplimab after this therapy but 
should be followed for disease recurrence and survival during the study.  The data from Part 2 
could inform the development of a future randomized trial to define adjuvant therapy for patients 
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with CSCC.  However, the primary objective of this study is to assess neoadjuvant cemiplimab, 
not adjuvant therapy. 
3.2.4. 
Rationale for Study Population 
Among locally advanced patients with CSCC who are candidates for surgery, an ongoing 
investigator-initiated study of neoadjuvant cemiplimab has provided encouraging preliminary 
results regarding feasibility and antitumor activity (NCT03565783; see Section 3.2.2).  The current 
protocol evaluates cemiplimab in patients who are candidates for surgery and who are at an 
increased risk of disease recurrence, disfigurement, or loss of function due to CSCC. 
The American Joint Commission on Cancer (AJCC) has provided updated the tumor, node, 
metastasis (TNM) staging guidelines for HN CSCC in the 8th edition of the staging manual 
(Amin, 2017).  Patients with nodal involvement, which occurs in approximately 5% of patients 
with CSCC, are classified as stage III or IV.  Overall survival at 3 years for these patients is 
approximately 70% (Liu, 2018).  Stage III is also applied to tumors in the absence of nodal invasion 
(T3N0) if any of the following risk factors are present: deep invasion (beyond the subcutaneous 
fat or >6mm), bone erosion, or perineural involvement.  For such stage III tumors without nodal 
involvement, the risks of local recurrence and nodal metastasis at 3 years are >15% and >10%, 
respectively (Karia, 2018).  In the revised AJCC staging system, stage II is applied to tumors that 
are ≥2 to <4 cm in greatest dimension in the absence of nodal involvement (T2N0) or other risk 
factors.  Stage II tumors account for only approximately 5% of CSCC and are associated with a 
slightly lower risk of recurrence than stage III (T3N0) tumors.  However, larger stage II tumors 
(≥3cm) can be associated with risk of disfigurement or loss of function if located in aesthetically 
sensitive areas.  These patients are appropriate candidates for neoadjuvant therapy in the context 
of a clinical trial because such treatment may facilitate less extensive surgery.  Stage I tumors 
(≤2cm) account for >75% of CSCCs and have lower  risks of disease recurrence (Karia, 2018); 
such patients are not eligible for this study.  For non-HN CSCC, the 9th edition of the Union for 
International Cancer Control (UICC) staging system is applied.  The UICC uses similar stage 
groupings as those that are used for HN tumors (O'Sullivan, 2015).  Overall, the patient population 
represents a significant unmet need that could potentially be addressed with immunotherapy. 
3.3. 
Risk-Benefit 
3.3.1. 
Benefit 
As described in earlier sections, cemiplimab therapy is highly active when administered to patients 
with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or 
curative radiation.  This study will enroll patients who would be recommended for surgery in 
routine clinical practice, but who have an increased risk of recurrence due to their disease stage, 
risk of disfigurement, or loss of function due to tumor location.  The potential benefits for study 
participants include a decreased risk of disease recurrence, less-extensive surgery, and avoidance 
of postoperative radiation therapy. 
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3.3.2. 
Risk 
The fundamental risk of neoadjuvant therapy is the potential loss of opportunity for curative 
resection if the tumor progresses during neoadjuvant therapy.  To mitigate this risk, all patients 
will undergo formal radiologic response assessment after 2 doses of cemiplimab.  This will allow 
patients with early disease progression to divert the management plan to surgery (see Section 9.1). 
Adverse reactions to cemiplimab are also risks in this study.  As of 20 January 2019, for the total 
pooled population of patients treated with cemiplimab, the most common (>5%) treatment-related 
TEAEs were fatigue (18.6%), nausea (8.9%), diarrhea (8.5%), pruritus (7.7%), hypothyroidism 
(6.6%), arthralgia (6.0%), rash maculo-papular (5.8%), and rash (5.6%).   
The important identified risks from cemiplimab include:  
 Immune-related Adverse Events (irAEs): Because the therapeutic mechanism of 
cemiplimab involves increasing T cell specific effector function, cemiplimab may 
cause immune-related toxicities against normal tissues.  These events can be managed 
according to well-established guidelines for the class of anti-PD-1/PD-L1 antibodies.  
The majority of reported cases of irAEs in the cemiplimab program were mild to 
moderate, and most patients recovered following treatment discontinuation and/or use 
of systemic corticosteroid/hormone replacement.  Information concerning the early 
identification and management of irAEs is provided in 8.3.3.  
 Infusion Related Reactions (IRR): As with other therapeutic proteins, there is a 
possibility of IRRs following cemiplimab administration.  The majority of cases of 
IRRs that occurred in the cemiplimab development program were mild to moderate.  
Section 8.4.1 provides risk mitigation for acute IRRs. 
The important identified potential risks from cemiplimab include:  
 Clinical 
Consequences 
of 
Immunogenicity 
(Anti-Cemiplimab 
Antibody 
Formation): As with all monoclonal antibodies, cemiplimab has the potential to induce 
immunogenicity.  Available data from the pivotal phase 2 study of IV cemiplimab for 
advanced CSCC and other studies of IV cemiplimab indicate that the incidence of 
anti-drug antibodies (ADAs) was low and that these ADAs were not clinically 
significant.  The cemiplimab Investigator’s Brochure contains adequate risk mitigation 
for the clinical consequences of immunogenicity. 
 Embryo Fetal Toxicity: The cemiplimab Investigator’s Brochure and the study 
protocol contain adequate risk mitigation to avoid pregnancies and embryo fetal 
toxicity. 
The potential benefits of neoadjuvant and adjuvant administration of cemiplimab are justified 
when balanced against possible risks in the context of a clinical study for this patient population 
of individuals with increased risk of disease recurrence and/or risk of disfigurement or loss of 
function. 
Additional information concerning the safety profile of cemiplimab, including a risk-benefit 
statement with respect to the overall development program, can be found in the Investigator’s 
Brochure.  
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4. 
ENDPOINTS 
For endpoints measuring pCR, mPR, and ORR (Part 1 of the study), patients will be assessed at 
the time of surgery (12 weeks).  Event free survival (EFS) and OS will be assessed from the first 
dose of neoadjuvant cemiplimab until completion of follow-up.  Disease free survival (DFS) will 
be assessed from surgery until completion of follow-up.  Event free survival (EFS), DFS, and OS 
assessment will continue until all enrolled patients have completed follow-up, a total duration of 
approximately 4 years and 3 months.   
4.1. 
Primary Endpoint 
The primary endpoint is pCR rate assessed by independent central pathology review.  
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
 mPR rate assessed by independent central pathology review 
 pCR rate and mPR rate assessed by local pathology review 
 ORR prior to surgery, according to investigator assessment using RECIST 1.1 
 Event free survival (EFS) 
 Disease free survival (DFS) 
 Overall survival (OS)  
 Safety and tolerability as measured by the incidence of adverse events (AEs), serious 
adverse events (SAEs), deaths, and laboratory abnormalities 
 Change in surgical plan in the screening period versus actual surgery after 
neoadjuvant cemiplimab 
 Change in post-surgical management plan in the screening period versus actual 
post-surgical management 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are:  
 Patterns of failure in patients with local, regional, or distant disease recurrence as 
measured by descriptive statistics 
 Change in estimated costs due to change in surgical plan during screening period 
versus actual surgical procedure performed after neoadjuvant cemiplimab 
 Change in estimated costs due to the change in post-surgical management plan during 
screening period versus actual post-surgical management 
 Incidence of ADA for cemiplimab 
 Health-related quality of life, as assessed using the EORTC QLQ-C30  
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
5.2.1. 
Disease Response and Disease Recurrence 
Disease response will be assessed by surgical pathology using pCR and mPR.  Pathologic complete 
response (pCR) is defined as absence of viable cancer cells in the surgical pathology sample.  
Major pathologic response (mPR) is defined as ≤10% viable cancer cells in the surgical pathology 
sample, in patients who have not achieved pCR.  Procedures to assess pCR and mPR in the surgical 
pathology sample after neoadjuvant therapy are not described in this protocol but will be described 
in a separate charter. 
Objective response rate (ORR) will be assessed by the investigator using RECIST 1.1 
(Eisenhauer, 2009)(Appendix 4).  Procedures for assessing ORR are outlined in Section 9.2.2.3.  
Confirmation of complete or partial response is not required. 
Event free survival (EFS) is defined as time from first dose of neoadjuvant cemiplimab to any of 
the following events: progression of disease that precludes surgery, inability to undergo complete 
resection (R0 or R1), disease recurrence (local, regional, or distant) for patients who undergo 
complete resection (R0 or R1), or death due to any cause. 
Disease free survival (DFS) is defined as time from surgery to first recurrence (local, regional, or 
distant) or death due to any cause, for patients who are free of disease (R0 or R1 resection) at 
completion of surgery.  Patterns of failure in patients with local, regional, or distant disease 
recurrence will be assessed by descriptive analysis according to the procedures outlined in 
Section 9.2.2.5 and Section 9.2.2.6.  
Overall survival (OS) will be measured as time from first dose of neoadjuvant cemiplimab to death 
due to any cause. 
5.2.2. 
Changes in Planned Surgery and Post-Surgical Management (Per Investigator 
and Per Independent Review) 
Electronic case report forms (eCRFs) will capture what the management plan would be for surgery 
and post-surgical management if the patient were not enrolled in a clinical trial, as well as the 
actual surgery that was performed and the actual post-surgical management. 
5.2.2.1. 
Management Plan During the Screening Period 
The following information will be collected in the eCRF: 
 Was the overall treatment plan formulated at a multidisciplinary tumor board 
(including surgery, radiation oncology, and medical oncology)? (Yes/No) 
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 Description of planned surgical resection 
Note: eCRF pages will provide options for ablative procedures commonly performed 
in this patient population 
 Description of planned reconstruction (if applicable) 
Note: eCRF pages will provide options for ablative procedures commonly performed 
in this patient population 
 What is the expected length of inpatient hospital stay for the planned surgical 
procedures? (Days) 
 Post-surgical management plan (based on available clinical information if the patient 
were not enrolled in a clinical trial) 
 If yes, radiation or chemoradiation (including name of concurrent systemic 
therapy agent, if applicable) or observation 
5.2.2.2. 
Actual Management on the Study  
The following information will be collected in additional pages of the eCRF: 
 Was the post-surgical treatment plan formulated at a multidisciplinary tumor board 
after surgery (including surgery, radiation oncology, and medical oncology)? 
(Yes/No) 
 Description of surgical resection 
Note: eCRF pages will provide options for ablative procedures commonly performed 
in this patient population 
 Description of reconstruction (if applicable)  
Note: eCRF pages will provide options for ablative procedures commonly performed 
in this patient population 
 What was the length of inpatient hospital stay after surgery? (Days) 
 In the opinion of the investigator, was surgery after neoadjuvant cemiplimab 
unchanged, less extensive, or more extensive than what was planned during 
screening? 
Note: If more extensive or less extensive than planned during screening, additional 
details will be requested in eCRF 
 For patients who receive adjuvant radiation therapy or chemoradiation after surgery, 
the following treatment summary data will be captured in the eCRF: 
 Anatomic site of radiation therapy  
 Radiation therapy technique (eg, intensity-modulated radiotherapy)  
 Total radiation therapy dose 
 Total number of fractions 
 Fractionation schedule (eg, daily treatment at 5 days per week) 
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 Treatment interruptions (if any) 
 Start date and end date 
 If concurrent chemotherapy is administered with radiation therapy: name of 
chemotherapy drug, days and doses of administration 
For independent review, variables to assess changes in planned surgery and post-surgical 
management will be described in a separate charter.  Independent review by surgical committee 
will not be performed in real time and will not influence clinical decision making for study 
participants.  The sponsor will be blinded to results of independent review until after data cut for 
the primary endpoint. 
5.2.2.3. 
Estimated Costs of Treatment 
Planned surgery and post-surgical management as captured in the eCRF during the screening 
period, and the actual surgery and post-surgical management performed, will be mapped to 
individual procedure codes in either CPT-4 (Current Procedural Terminology, 4th Edition), 
HCPCS (Healthcare Common Procedure Coding System, Level II), or ICD-10 (the 10th revision 
of the International Statistical Classification of Diseases and Related Health Problems) format, and 
their costs will be estimated based on the latest Physician Fee Schedule published by Centers for 
Medicare & Medicaid Services (Centers for Medicare & Medicaid Services).  The difference 
between cost of planned surgery versus cost of actual surgery that is performed will then be 
calculated.  A cost of zero will be assigned to patients for whom the post-surgical management 
plan is observation.  For patients who receive adjuvant therapy, the actual cost will be estimated.   
5.3. 
Safety Variables 
Safety variables include, but are not limited to, the following:  
 Vital signs, as described in Section 9.2.3.1  
 Physical examination results, as described in Section 9.2.3.2 
 Electrocardiogram (ECG) results, as described in Section 9.2.3.3  
 Clinical laboratory results, as described in Section 9.2.3.5 
 AEs, as described in Section 8.3.4 and  Section 10.4.1   
 irAEs, as described in Section 8.3.3  
5.4. 
Pharmacokinetic Variables 
The Pharmacokinetic variable is cemiplimab concentration in serum over time (may be performed 
on ADA samples, if appropriate). 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, dose titer, and time-point/visit.  Samples in this 
study will collected at the clinic visits specified in Table 2, Table 3, and Table 4. 
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5.6. 
Exploratory Pharmacodynamic and Biomarker Variables 
There are no pharmacodynamic or biomarker endpoints in this study. 
5.7. 
Patient Reported Outcomes Variables 
Health-related quality of life (HRQoL) will be assessed using the EORTC QLQ-C30.  The EORTC 
QLQ-C30 is a 30-item generic questionnaire used to assess HRQoL in patients with cancer.  It is 
one of the most frequently used measures of HRQoL in cancer clinical trials.  The EORTC QLQ-
C30 assesses HRQoL across multiple domains, including global health status, functioning 
(physical, role, emotional, cognitive, and social), patient-reported symptom scales (fatigue, nausea 
and vomiting, pain) and single items (appetite loss, dyspnea, insomnia, constipation, diarrhea, 
financial impact).  
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a single-arm, open label, multicenter phase 2 study for patients with stage II to IV (M0) 
CSCC who are candidates for surgery, but who have an increased risk of recurrence and/or risk of 
disfigurement or loss of function.   
The study consists of 2 parts: 
 Part 1 (neoadjuvant): A screening period of up to 28 days, a treatment period of up to 
12 weeks, and surgery after up to 12 weeks of treatment.  Part 1 of the study supports 
the primary endpoint. 
 Part 2 (adjuvant): Optional post-surgery cemiplimab treatment for up to 48 weeks (or 
radiation therapy, or observation only, at investigator discretion) 
After Part 2 of the study, patients will be followed for a period of up to 3 years. 
Figure 1 provides an overview of the design for both the neoadjuvant (Part 1) and adjuvant (Part 2) 
portions of the study.  Part 2 provides an opportunity for additional cemiplimab treatment 
following surgery but does not impact the primary endpoint of pCR.   
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Figure 1: 
Study Flow Diagram 
  
 
6.1.1. 
Screening 
Screening assessments will be performed within 1 to 28 days prior to the first dose of neoadjuvant 
cemiplimab.  Patients will be eligible for treatment if all inclusion criteria are met (Section 7.2.1) 
and the patient does not meet any exclusion criteria (Section 7.2.2).  Patients are required to 
provide a tumor biopsy sample to the central lab during the screening process, unless this is 
considered to pose an unacceptable safety risk in the opinion of the investigator. 
If a patient has an ineligible test result during screening (eg, lab result), it is permissible for the 
patient to repeat the test during the screening period if the investigator considers it to be clinically 
appropriate, and to enroll in the study if all eligibility criteria are met during the screening period. 
6.1.2. 
Treatment in Part 1 (Neoadjuvant) 
Following the screening period, patients will receive cemiplimab 350 mg IV Q3W for up to 4 doses 
over 12 weeks (day 1, 22±3, 43±3, and 64±3) or until disease progression, unacceptable toxicity, 
or withdrawal of consent.  Patients will be evaluated in clinic prior to each cemiplimab treatment.  
Patients will also undergo 2 tumor response assessments (via imaging) during Part 1.  The first 
imaging assessment occurs prior to the third dose of cemiplimab on day 43.  The window for this 
imaging assessment is from day 35 through day 46 (ie, the last day that the third dose of 
cemiplimab may be given [day 43±3]).  The third dose of cemiplimab cannot be given until this 
imaging assessment is completed.  The second imaging assessment occurs prior to surgery and 
may be performed at any time during the protocol window for surgery, specified as day 75 through 
day 100.   If a patient meets criteria to discontinue cemiplimab during the 12-week neoadjuvant 
period, the treating physician may divert the patient to surgery at an earlier time.   
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6.1.3. 
Treatment in Part 2 (Adjuvant) 
Part 2 of the study will begin following surgery.  Patients will have the option to receive 
cemiplimab treatment (350 mg IV Q3W) for up to 48 weeks (16 doses) or until unacceptable 
toxicity, disease recurrence, or withdrawal of consent.  The first dose of adjuvant cemiplimab will 
occur at 3 weeks (±3 days) after end of treatment in Part 1 (EOT1).  During this part of the study, 
patients will undergo additional evaluation approximately every 15 weeks.  Patients will be 
evaluated in clinic prior to each cemiplimab treatment and will undergo clinical and imaging 
assessment during each evaluation visit.  At the discretion of the investigator, patients may 
alternatively receive adjuvant radiation therapy or enter an observation-only period.  These patients 
will be evaluated for disease recurrence by imaging, approximately every 15 weeks. 
6.1.4. 
Post-Treatment Follow-Up 
The follow-up period begins after a patient has completed Part 1 and Part 2 of the study without 
disease progression (pre-surgery) or disease recurrence (post-surgery).  During the first 2 years of 
follow-up, patients will undergo clinical assessments approximately every 4 months.  During the 
third year of follow-up, patients will undergo clinical assessments approximately every 6 months.  
Patients who experience disease recurrence will subsequently be followed for survival only.  The 
follow-up period will continue for up to 3 additional years.  
6.1.5. 
Description of Study Cohorts and Dose Escalation  
This will be a single arm study with 1 cohort.  There is no dose escalation. 
6.1.6. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
6.1.7. 
Informed Consent 
In this study, all patients will be asked to provide separate written informed consent for Part 1 and 
for Part 2 of the study, even if adjuvant cemiplimab is not administered in Part 2.  Written consent 
for Part 1 must be obtained before the first dose of neoadjuvant cemiplimab (see Table 2 for 
window).  Written consent for Part 2 must be obtained prior to any adjuvant treatment or 
assessments (see Table 3 or window).  Informed consent for Part 2 is meant to ensure that all study 
patients are informed of their treatment options (adjuvant cemiplimab, radiation-based treatment, 
or observation).  The risks and benefits regarding each option may be influenced by the outcome 
of Part 1, and therefore a separate consenting process in Part 2 is required.  
6.2. 
Interim Analysis 
No interim analysis is planned for the primary endpoint.  After all patients have completed Part 1 
of the study (Table 2), an interim clinical study report (CSR) may be written to describe the 
analysis results for the primary endpoint.  The final CSR will be written to describe the final results 
of the study, after all patients have had the opportunity to complete Part 2 of the study and post-
treatment follow-up (Table 3 and Table 4). 
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6.3. 
Study Committees 
Safety oversight for this study will be performed by Regeneron clinical sciences and 
Pharmacovigilance Risk Management, in collaboration with a contract research organization 
(CRO). 
6.3.1. 
Independent Central Pathology Review Committee 
An independent central pathology review committee will assess pathologic response rate as the 
primary endpoint for this study.  These analyses will be performed in batches, not in real time 
(clinical decision making will be based on local pathology review).  The process for these reviews 
will be described in a separate charter. 
6.3.2. 
Independent Surgical Committee 
An independent surgical committee (ISC) will retrospectively review clinical and imaging data of 
study patients obtained at the time of enrollment and at completion of neoadjuvant cemiplimab 
treatment.  The ISC will retrospectively recommend a surgical plan, both pre-cemiplimab and post-
cemiplimab, based on the available information in each situation, not in real time.  The process for 
ISC reviews will be described in a separate charter. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 76 patients will be enrolled at approximately 20 global sites. 
7.2. 
Study Population  
Patients with stage III to stage IV (M0) CSCC of the head/neck, extremity, or trunk, and selected 
patients with stage II CSCC (≥3 cm longest diameter lesion in an aesthetically-sensitive region), 
for whom surgery is planned. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. At least 18 years of age 
2. Stage II to IV (M0) CSCC, for which surgery would be recommended in routine clinical 
practice.  For stage II patients, lesion must be ≥3 cm at the longest diameter.  
Note: Staging is per AJCC 8th edition for HN tumors (Amin, 2017) and is per UICC 9th 
edition for non-HN tumors (O'Sullivan, 2015).   
3. At least 1 lesion that is measurable by RECIST 1.1 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
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5. Adequate organ and bone marrow function documented by: 
a. Hemoglobin >9.0 g/dL 
b. Absolute neutrophil count (ANC) >1.5 x 109/L 
c. Platelet count >75 x 109/L 
d. Serum creatinine <1.5 upper limit of normal (ULN) or estimated creatinine clearance 
(CrCl) >30 mL/min 
e. Adequate hepatic function:  
- 
Total bilirubin <1.5 x upper limit of normal (ULN)  
- 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both 
<3 x ULN  
- 
Alkaline phosphatase (ALP) <2.5 x ULN 
Note: For patients with Gilbert’s syndrome, total bilirubin ≤3x ULN.  Gilbert’s 
syndrome must be documented appropriately as past medical history. 
6. Willing and able to comply with clinic visits and study-related procedures 
7. Willing and able to provide informed consent signed by study patient or legally 
acceptable representative 
8. Able to understand and complete study-related questionnaires 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Solid malignancy within 5 years of the projected enrollment date, or hematologic 
malignancy (including chronic lymphocytic leukemia [CLL]) at any time 
Exception: Nonmelanoma skin cancer that has undergone potentially curative therapy, or 
in situ cervical carcinoma or in-situ prostate cancer with non-detectable prostate specific 
antigen or any other tumor that has been treated, and the patient is deemed to be in 
complete remission for at least 2 years prior to enrollment, and no additional therapy is 
required during the study period 
2. Distant metastatic disease (M1), visceral and/or distant nodal 
3. Prior radiation therapy for CSCC 
4. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or 
equivalent) within 14 days of the first dose of study drug. 
Exceptions: Physiologic replacement doses are allowed even if they are >10 mg of 
prednisone/day or equivalent, as long as they are not being administered for 
immunosuppressive intent.  Inhaled or topical steroids are permitted, provided that they 
are not for treatment of an autoimmune disorder. 
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5. Patients with active, known, or suspected autoimmune disease that has required systemic 
therapy within 5 years of the projected enrollment date. 
Exceptions: Patients with vitiligo, type I diabetes mellitus, and endocrinopathies 
(including hypothyroidism due to autoimmune thyroiditis) only requiring hormone 
replacement, childhood asthma that has resolved, or psoriasis that does not require 
systemic treatment are permitted.  
6. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing 
pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses 
of glucocorticoids to assist with management.   
7. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C virus (HBV or HCV) infection; or diagnosis of immunodeficiency 
Notes: 
 Patients will be tested for HIV, HBV, and HCV at screening. 
 Patients with known HIV infection who have controlled infection (undetectable viral 
load [HIV RNA measured via polymerase chain reaction] and CD4 count above 350 
either spontaneously or on a stable antiviral regimen) are permitted.  For patients with 
controlled HIV infection, monitoring will be performed per local standards. 
 Patients with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B 
virus DNA measured via polymerase chain reaction that is below the limit of 
detection AND receiving anti-viral therapy for hepatitis B) are permitted.  Patients 
with controlled infections must undergo periodic monitoring of HBV DNA.  Patients 
must remain on anti-viral therapy for at least 6 months beyond the last dose of 
investigational study drug. 
 Patients who are hepatitis C virus antibody positive (HCV Ab+) who have controlled 
infection (undetectable HCV RNA by polymerase chain reaction either spontaneously 
or in response to a successful prior course of anti-HCV therapy) are permitted. 
8. Active tuberculosis 
9. Myocardial infarction within 6 months of enrollment  
10. Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or 
clinical laboratory abnormality that, in the opinion of the investigator, renders the patient 
unsuitable for participation in a clinical trial due to high safety risks and/or potential to 
affect interpretation of results of the study 
11. Documented allergic or acute hypersensitivity reaction attributed to antibody treatments. 
12. Prior treatment with anti-cancer systemic therapy within the last 3 years prior to projected 
enrollment date  
13. Any prior treatment with an anti-PD1/PD-L1 agent 
14. Has participated in a study of an investigational agent or an investigational device within 
4 weeks of enrollment   
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15. Women with a positive serum chorionic gonadotropin HCG pregnancy test at the 
screening/baseline visit.  Breastfeeding women are also excluded. 
16. Women of childbearing potential* and sexually active men who are unwilling to practice 
highly effective contraception prior to the first dose of study therapy, during the study, 
and for at least 6 months after the last dose.  Highly effective contraceptive measures 
include:  
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the women of childbearing potential (WOCBP) study participant and that 
the vasectomized partner has obtained medical assessment of surgical success for the 
procedure) 
e. and/or sexual abstinence† ‡ 
* Women of childbearing potential are defined as women who are fertile following 
menarche until becoming postmenopausal, unless permanently sterile.  Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state.  The above definitions are according to Clinical Trial Facilitation 
Group (CTFG) guidance.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy or tubal ligation. 
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together.  
17. Receipt of a live vaccine within 28 days of enrollment 
18. Prior allogeneic stem cell transplantation, or autologous stem cell transplantation  
19. Recipient of a solid organ transplant (other than corneal transplants) 
20. Diagnosis of squamous cell carcinoma of unknown (or occult) primary 
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21. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities 
22. Member of the clinical site study team or his/her immediate family, unless prior approval 
granted by the sponsor 
7.3. 
Premature Withdrawal from the Study  
The investigator and sponsor have the right to discontinue a patient from study drug or withdraw 
a patient from the study at any time. 
Reasons for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to: 
 Patient withdrawal of consent at any time.  A patient has the right to withdraw from 
the study at any time, for any reason, and without repercussion. 
 Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study or continues treatment with study 
drug 
 The investigator or sponsor determines it is in the best interest of the patient 
 Patient noncompliance (eg, not complying with protocol required visits, assessments, 
and dosing instructions) 
 Pregnancy 
Every effort should be made to obtain information on patients who discontinue study drug but who 
do not withdraw consent to continue participation in the study by completing study assessments, 
as described in Table 2 and Table 3, and Table 4.  
7.4. 
Replacement of Patients  
Patients prematurely discontinued from study/study drug will not be replaced. 
8. 
STUDY TREATMENT  
8.1. 
Investigational Treatment 
Cemiplimab 350 mg IV infusion over 30 minutes (±10 minutes) Q3W for up to 4 doses prior to 
surgery in Part 1 and (optional) up to 16 doses after surgery in Part 2.  Cemiplimab 50 mg/mL will 
be supplied as a sterile liquid in single-use glass vials.   
Instructions on dose preparation are provided in the pharmacy manual.  Instructions on 
management of acute infusion reactions are provided in Section 8.4.1. 
There are no comparator treatments in this single arm study. 
8.2. 
Dose Modification 
Dose modification for an individual patient is not allowed.  The management approach described 
in this protocol includes interruption of study drug and implementation of supportive measures.   
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8.3. 
Study Drug Discontinuation  
This section provides guidance on management of AEs that are suspected to be related to study 
drug.  The general approach to missed doses of study drug (eg, due to AEs) is “time marches on.”  
Missed doses of study drug will not be made up, unless ≤3 days from the scheduled date.  
The investigator may choose to hold study drug at his/her clinical judgment regarding the safety 
of an individual patient, even if hold criteria are not formally met per protocol. 
Adverse event severity is to be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5 (Section 10.5.1). 
8.3.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Evidence of pregnancy 
 Serious or severe allergic reactions considered related to study drug 
 Liver dysfunction consistent with Hy’s law (AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN) 
 Any AE that meets criteria for permanent discontinuation described in 8.3 or 
Appendix 2 (or other unacceptable toxicity, including cemiplimab treatment delay 
≥84 days due to toxicity in Part 2 of the study) 
 Infusion reaction of ≥grade 3 severity during or directly following infusion of 
cemiplimab (Section 8.4.1) 
 Patient noncompliance (eg, not complying with protocol required visits or 
assessments)  
 Patient withdrawal of consent 
 Progression of disease (neoadjuvant portion of the study) 
 Disease recurrence (adjuvant portion of the study) 
 Administration of radiation therapy (adjuvant portion of the study) 
 The investigator or sponsor determining it is in the best interest of the patient 
8.3.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug may be temporarily stopped due to events that meet the criteria for treatment 
interruption described in Section 8.3.3 (and Appendix 2), Section 8.3.4 or Section 8.4. 
8.3.3. 
Immune-related Adverse Events and Study Drug Discontinuation 
8.3.3.1. 
Identification of Immune-Related Adverse Events 
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs, as the onset of symptoms of irAEs (eg, pneumonitis) may be subtle.  An irAE can occur 
shortly after the first dose or several months after the last dose of treatment.  All AEs of unknown 
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etiology associated with drug exposure should be evaluated to determine possible immune 
etiology.  If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes prior to labeling an AE as an irAE. 
Based on the emerging safety profile of cemiplimab and other antibodies targeting the PD-1/PD-L1 
axis, working case definitions are provided in the Investigator’s Brochure to help investigators 
distinguish irAEs from non-immune AEs commonly associated with PD-1 inhibition 
(Naidoo, 2015)(Weber, 2015).  This is not exhaustive of all possible irAEs.  Clinical presentations 
of less common irAEs, including neurologic, musculoskeletal, cardiac, renal, and ocular events 
(Hoffman, 2016)(Zimmer, 2016), should be reviewed in patients with concerning presentations. 
The case definitions in the Investigator’s Brochure have not been validated and are intended only 
as guidance for investigators to help distinguish irAEs from non-immune AEs.  These definitions 
may evolve as clinical experience increases with cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis.  Investigators’ clinical judgment may include other factors when determining 
immune-relatedness.  
Adverse events that meet the criteria for irAEs, as noted above in the Investigator’s Brochure, 
should be reported as irAEs in the eCRF.  If AEs corresponding to the common terms for irAEs 
are attributed as NOT related to cemiplimab by the investigator, additional information should be 
provided to substantiate an alternative attribution (eg, infectious diarrhea).   
If not provided at the outset, this information may be requested by immediate edit checks or in 
subsequent queries.  The sponsor may request additional information for any AE that is of a type 
known to be potentially immune-related (eg, rash, colitis, elevated transaminases, endocrine), but 
is deemed not an irAE by the investigator. 
Any grade 3 or greater irAE should be reported as an adverse event of special interest (AESI) 
(Section 10.4.3).  
8.3.3.2. 
Management of Immune-related Adverse Events 
The following general principles apply to management of irAEs: 
 
Grade 1: Continue study drug with close monitoring and provide symptomatic 
management   
 
Grade 2:  Consider withholding study drug 
 
Grade 3:  Withhold study drug 
 
Grade 4:  Discontinue study drug 
If cemiplimab is held for ≤grade 3 irAE, consider resuming when symptoms and/or laboratory 
values revert to ≤grade 1 after corticosteroid taper (typically, to ≤10 mg/day prednisone or 
equivalent).  
Permanently discontinue study drug for: 
 Recurrent grade 3 irAEs 
 Grade 2 or 3 irAEs persistent for ≥12 weeks after the last treatment with study drug  
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 Requirement for ≥10 mg per day prednisone or equivalent lasting ≥12 weeks after the 
last treatment with study drug 
Further guidance regarding management of selected irAEs is provided in Appendix 2.  Additional 
information about the safety profile of cemiplimab is in the Investigators Brochure.  Expert 
consensus guidelines regarding characterization and management of less common irAEs are also 
available (Brahmer, 2018)(Haanen, 2017)(Puzanov, 2017)(Thompson, 2018).  The management 
considerations provided here do not supersede clinical judgment in the setting of an individual 
patient.   
8.3.4. 
General Guidance for Management of Adverse Events 
This subsection and the corresponding table (Table 1) provide general guidance of treatment-
related AEs that are not specifically addressed in guidelines for management of irAEs 
(Section 8.3.3 or Appendix 2) or in management of acute infusion reactions (Section 8.4).  In the 
event of discrepancy between this section and a section that provides for detailed guidance (ie, 
Section 8.3.3, Appendix 2, or Section 8.4), the section that provides the more detailed guidance 
will supersede the general guidance in this section. 
Table 1: 
General Guidelines for Management of Treatment-Related AEs 
Toxicity 
Grade 
Hold Treatment 
Restarting Criteria 
Hematological Toxicity 
(other than grade 3 
thrombocytopenia greater 
than 7 days or associated 
with bleeding, or Grade 4 
thrombocytopenia) 
1, 2, 3 
No 
N/A 
 
4 
Yes 
Toxicity resolves to 
grade ≤1 or baseline 
Grade 3 thrombocytopenia 
greater than 7 days or 
associated with bleeding 
3 
Yes 
Toxicity resolves to 
grade ≤1 or baseline 
Grade 4 thrombocytopenia 
4 
Yes 
Discontinue permanently 
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Toxicity 
Grade 
Hold Treatment 
Restarting Criteria 
Nonhematological 
Toxicity 
1 
No 
N/A 
Note: Exceptions to be 
treated as for Grade 1 
toxicity: 
2 
Consider withholding for 
persistent symptoms 
Toxicity resolves to 
grade ≤1 
 Grade 2 alopecia 
 Grade 2 fatigue 
 Clinically insignificant 
lab abnormality not 
meeting AE criteria 
3 
Yes 
Toxicity resolves to 
grade ≤1 
4 
Yes 
Discontinue permanently  
N/A = not applicable 
Treatment after an AE may resume at the discretion of the investigator if it is in accordance with 
the toxicity management guidelines in this protocol, if resumption of treatment is thought to be in 
the best interest of the patient and if either of the following conditions are met: 
 After resolution of an AE to ≤grade 1 (or baseline)  
 The AE is considered to be manageable through supportive/medical therapy (eg, 
grade 3 hypertension that can be controlled with the addition of a second 
anti-hypertensive agent).  
8.3.5. 
Study Drug Discontinuation Due to Disease State  
During the neoadjuvant portion of the study, patients who permanently discontinue from study 
drug due to disease progression (per RECIST 1.1; Appendix 4) or toxicity will be diverted to 
surgery and must return for post-surgical follow-up visit (EOT1).  These patients must be followed 
for 90 days after last dose of cemiplimab for AE identification and reporting.  Patients who do not 
withdraw consent from the study will subsequently be followed for disease recurrence or survival, 
as outlined in Section 9.1.5.1 and Section 9.1.7. 
During the adjuvant portion of the study, patients who permanently discontinue from study drug 
due to toxicity and who not withdraw consent from study participation will be followed until 
disease recurrence (Section 9.2.2.4).  Patients who permanently discontinue from study drug due 
to disease recurrence and who do not withdraw consent from study participation will be followed 
for survival.  See Section 9.1.5.2 and Section 9.1.7 for more information. 
8.3.6. 
Resumption of Study Drug 
Patients who experience AEs requiring interruption of study drug may resume treatment if criteria 
for resumption are met, as set forth in Section 8.3.4  and Appendix 2.   
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8.3.7. 
Clinical Assessments Following Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study.  Those who agree and do not withdraw from the study will follow the visit schedules as 
outlined in Section 9.1.5.  
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete final study assessments (eg, EOT1 or EOT2).  
8.4. 
Management of Acute Infusion-Related Reactions  
8.4.1. 
Identification of Acute Infusion-Related Reactions 
Infusion-related reactions (IRRs) are known to occur with infusions of therapeutic proteins and 
have been observed in cemiplimab studies.  To assist investigators in identifying IRRs, the 
following case definition is provided: 
 Typical symptoms may include fever, chills, rigors, skin flushing, dyspnea, back pain, 
abdominal pain, and nausea 
 Infusion reactions usually occur either during the infusion or within 24 hours after the 
infusion is completed 
 Vital signs may be notable for hypotension and/or tachycardia 
 Signs and symptoms generally resolve completely within 24 hours of onset   
The investigator’s clinical judgment may include other factors when evaluating a possible IRR.  
See Investigator’s Brochure for further information about IRRs with cemiplimab.  Such reactions 
may also be referred to as systemic hypersensitivity reactions. 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use.  All infusion reactions must be reported as AEs (as defined in Section 10.4.1) and 
graded using the grading scales as instructed in Section 10.5.1. 
In the event of an infusion reaction of ≥grade 3 severity during or directly following infusion of 
cemiplimab, dosing should be stopped, and the patient must be permanently discontinued from 
study drug. 
Case report forms must capture start and stop time of the event, signs and symptoms, and 
management interventions (medications, interruption of infusion, rate reduction). 
8.4.2. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 Cough 
 Rigors/chills 
 Rash, pruritus (itching) 
 Urticaria (hives, welts, wheals) 
 Diaphoresis (sweating) 
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 Hypotension 
 Dyspnea (shortness of breath) 
 Vomiting 
 Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate.  
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate treatment 
according to typical clinical practice. 
For patients who experience infusion-related hypersensitivity reactions that are less than grade 3 
and who plan to continue treatment, premedication listed below are recommended for re-treatment. 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated), the following prophylactic medications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 1000 mg at 
least 30 minutes prior to subsequent study drug infusions. 
For grade 2 symptoms (moderate reaction that requires therapy or infusion interruption, but for 
which symptoms resolve promptly with appropriate treatment such as antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, corticosteroids, and/or IV fluids; prophylactic medications 
indicated at ≤24 hours), the following prophylactic medications are recommended for future 
infusions:  diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 
1000 mg at least 30 minutes prior to subsequent study drug  infusions.  If necessary, corticosteroids 
(up to 25 mg of hydrocortisone or equivalent) may be used. 
8.4.3. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 Anaphylaxis* 
 Laryngeal/pharyngeal edema 
 Severe bronchospasm 
 Chest pain 
 Seizure 
 Severe hypotension 
 Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc) 
 Any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
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*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST 1 OF THE FOLLOWING  
 Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
 Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
8.5. 
Method of Treatment Assignment  
Each patient who signs the informed consent form (ICF) will be assigned a patient number and 
tracked centrally as described in the Interactive Web Response System (IWRS) manual.  
8.5.1. 
Blinding 
This is an open label study; no blinding will be used. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage  
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be will be destroyed or returned to 
the sponsor or designee, according to site procedures. 
8.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
 Dispensed to each patient 
 Returned from each patient (if applicable), and 
 Disposed of at the site or returned to the sponsor or designee 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
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8.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors.  
8.7. 
Concomitant Medications and Procedures 
Any medication or procedure administered from the time of informed consent until 90 days after 
the last study dose of cemiplimab will be considered concomitant medication or procedure.  This 
includes medications that were started before the study and are ongoing during the study, as well 
as any therapies started in the follow-up period to treat treatment related AEs.  All concomitant 
treatments must be recorded in the study eCRF with the generic name, dose, dose unit, route of 
administration, frequency, indication, and start/stop date, as appropriate.  
8.7.1. 
Prohibited Medications and Procedures  
While participating in this study (not including survival follow-up), a patient may not receive any 
of the following medications from the time of informed consent to the end of the follow-up period, 
unless otherwise specified below: 
 Standard or investigational agent (other than cemiplimab) for treatment of a tumor, 
with the exception of those listed in Section 8.7.2 
 Live vaccines for at least 3 months after the last dose of study drug 
8.7.2. 
Permitted Medications and Procedures  
The following medications and procedures will be permitted, under the following conditions: 
 Any medication required to treat an AE and/or irAE, including systemic 
corticosteroids  
 Systemic corticosteroids for physiologic replacement (even if >10 mg/day prednisone 
equivalents)  
 A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune 
conditions 
 Oral contraceptives, hormone-replacement therapy, or other maintenance therapy may 
continue  
 Acetaminophen at doses ≤2 g/day 
 Surgical resection of pre-malignant lesions or basal cell carcinoma (BCC) lesions 
 Other medications and procedures may be permitted on an individual basis by the 
investigator and in consultation with the sponsor 
 Radiation therapy (with concurrent anti-cancer cytotoxic chemotherapy therapy 
and/or epidermal growth factor receptor-directed therapy) is permitted in the adjuvant 
portion of the study, at the discretion of the investigator.  Such patients will be 
followed for disease recurrence but will not receive further cemiplimab on study. 
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9. 
STUDY SCHEDULES OF EVENTS AND PROCEDURES 
9.1. 
Schedules of Events 
Study assessments and procedures are presented by study period and visit in Table 2 for the 
neoadjuvant portion of the study (Part 1) and in Table 3 for the adjuvant portion of the study 
(Part 2).  Table 4 provides the schedule of events for subsequent follow-up. 
In Part 1, patients receive up to 4 doses (12 weeks) of neoadjuvant cemiplimab (350 mg IV Q3W) 
prior to surgery.  Day 1 refers to the first dose of neoadjuvant cemiplimab administration.  Prior to 
the third dose and prior to surgery, patients will undergo imaging procedures to assess response to 
neoadjuvant treatment.  The first response assessment occurs prior to receiving the third dose of 
cemiplimab on day 43 (window: day 35 through day 46).  The third dose of cemiplimab cannot be 
given until this response assessment is completed.  The second response assessment occurs prior 
to surgery and may be performed at any time during the protocol window for surgery (day 75 
through day 100).  If a patient meets criteria to discontinue cemiplimab during the 12-week 
neoadjuvant period, the treating physician may divert the patient to surgery at an earlier time. 
In Part 2, patients receive up to 16 doses (48 weeks) of adjuvant cemiplimab (350 mg IV Q3W) 
beginning 3 weeks (±3 days) after EOT1.  Week 0 is defined as 3 weeks (±3 days) after the EOT1 
visit.  In Part 2, patients will undergo evaluation visits listed in Table 3.  Biopsy should be 
attempted for all patients in the event of suspected recurrence or suspected second primary tumor 
(SPT) as described in Section 9.2.2.7. 
Patients who complete the events in Table 2 without disease progression and complete the events 
in Table 3 without disease recurrence will be followed according to Table 4 until disease 
recurrence or the end of the study, whichever occurs first.  Patients who complete the schedule of 
events in Table 4 will enter survival follow-up. 
Notes: 
 Patients who discontinue neoadjuvant cemiplimab due to disease progression or 
toxicity but achieve complete surgical resection (R0 or R1) will follow a parallel 
imaging schedule as described in Section 9.1.5.1.  
 Any patient who fails to achieve complete surgical resection (R0 or R1) will be 
followed for survival only. 
 Patients who discontinue adjuvant cemiplimab for reasons other than disease 
recurrence will follow a parallel imaging schedule as described in Section 9.1.5.2.  
 Patients who receive adjuvant radiation therapy or enter observation only during 
Part 2 of the study will follow a parallel imaging schedule as described in 
Section 9.1.6.  
 The window for treatment visits is ±3 days.  In the event of a missed dose, patients 
will not be allowed to receive the scheduled cemiplimab dose outside of this window.  
Any missed doses will result in a reduction in the total number of allowable doses 
that may be administered.   
 
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9. Surgery will occur after posttreatment imaging response assessment and should occur 
21 days after the last dose of cemiplimab.  The window for surgery is from day 75 
through day 100.  The eCRF will capture information concerning the surgical procedure 
performed and surgical findings.  Tumor tissue from the surgical resection should be 
provided for pathologic assessment of neoadjuvant treatment response and for biomarker 
analysis.  If feasible, tissue sample should be provided as a formalin-fixed 
paraffin-embedded (FFPE) block or 25 unstained slides and should also include an 
RNAlater® sample.  Additional requirements for biomarker analysis will be described in 
the laboratory manual. 
10. See Section 9.2.2.3 for imaging requirements, which include CT/magnetic resonance 
imaging (MRI) and digital photography.  Imaging is performed at baseline, prior to the 
third dose of neoadjuvant cemiplimab, and prior to surgery.  The window for imaging 
prior to the third dose is day 35 to day 46.  Imaging taken prior to surgery may occur at 
any time during the protocol window for surgery (day 75 through day 100).  Digital 
photography is mandatory at baseline imaging assessment and at the imaging assessment 
that occurs prior to surgery; photography at imaging assessment prior to the third dose is 
optional.  Radiologic imaging is required at each imaging assessment.  At EOT1, imaging 
is optional.  
11. On-study tumor biopsy is required during screening and at the day 22 visit.  This should 
be an in-office biopsy of externally visible tumor (see Appendix 3).  If the biopsy is 
considered by the investigator to pose an unacceptable safety risk to the patient or would 
compromise tumor measurements, the biopsy requirement may be waived for an 
individual patient after notification of the medical monitor.  For patients without on-study 
screening biopsy, an archival FFPE tissue sample (block or 25 unstained slides) should be 
provided.  
12. During the screening period, the eCRF will capture the hypothetical management plan 
regarding surgery or radiation therapy in the absence of neoadjuvant cemiplimab.  During 
the presurgical period, the eCRF will capture the actual management plan after the 
completion of neoadjuvant therapy.  See Section 9.2.2.2. 
13. Mandatory blood sample for DNA extraction should be collected at screening but may be 
collected at any visit during this study.  
14. Optional blood sample for the genomic sub-study should be collected on neoadjuvant 
treatment day 1 (pre-infusion) but may be collected at any visit during this study.  
Patients who agree to participate in the genomics sub-study will be required to sign a 
separate genomics sub-study ICF before collection of the samples (see Section 9.2.7). 
15. Blood samples for ADA assessment in serum will be collected on day 1 before infusion 
and on day 85 prior to surgery (or at the early termination visit).  Pharmacokinetic (PK) 
analyses may be performed on ADA samples if appropriate as part of safety assessment 
at the individual patient level. 
16. The EORTC QLQ-C30 should be administered on day 1 of neoadjuvant treatment (prior 
to infusion) and day 85 (prior to surgery). 
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9.1.2. 
Footnotes for Table 3: Schedule of Events for Adjuvant Cemiplimab (Part 2 of the 
Study) 
1. Patients who receive radiation therapy, or observation only, will undergo their first 
imaging assessment during the same time frame as patients who receive cemiplimab 
(week 15 of Part 2).  Laboratory assessments and clinical assessments do not pertain to 
patients who receive radiation therapy or observation in Part 2, but all imaging 
assessments are required for all patients.  See Section 9.1.6. 
2. The first adjuvant cemiplimab dose should be administered at week 0 (3 weeks [±3 days] 
after the EOT1 visit).  If the initial dose does not occur within this window, adjuvant 
cemiplimab treatment may not be provided until week 3 of Part 2.  In the event of a 
missed initial dose, patients must complete all assessments outlined under “first dose” 
during their first adjuvant treatment visit. 
3. Evaluation visits should occur at week 15 of Part 2 (±10 days), week 30 (±10 days), and 
at EOT2 (21 to 37 days after the last dose) or at the early termination visit.  
4. All patients must provide written informed consent for Part 2.  This should be obtained at 
EOT1.  If not obtained at EOT1, all patients must provide written consent prior to 
initiation of any adjuvant treatment or assessments. 
5. Hematology panel is only required every 6 weeks.  On these visits, labs may be obtained 
within 3 days of a planned cemiplimab dose. 
6. Predose pregnancy tests (up to 72 hours before the dose) may be satisfied by either serum 
pregnancy test or by urine β-HCG.  Pregnancy tests are performed prior to each dose of 
cemiplimab and at EOT2.  Pregnancy tests are a requirement for WOCBP only.  
7. Imaging assessments performed in Part 2 of the study should be the same as those 
performed in Part 1 of the study, for a given patient.  Imaging requirements include 
CT/MRI and optional digital photography (see Section 9.2.2.3). 
8. Tumor biopsy should be attempted in all cases of suspected recurrence or suspected SPT 
(Section 9.2.2.4), unless there is an unacceptable safety risk associated with biopsy in a 
particular patient.  Biopsy information regarding recurrences or SPTs (or safety reason 
explaining why biopsy was not performed) will be documented in eCRF.  See 
Section 9.2.2.7 for additional information on biopsies.  
9. Blood samples for ADA assessment in serum will be collected at week 0 of Part 2 (before 
infusion), at week 15 of Part 2 (before infusion), and at any time at EOT2 or the early 
termination visit.  In Part 2, ADA assessment will only be performed for patients 
receiving adjuvant cemiplimab.  Pharmacokinetic (PK) analyses may be performed on 
ADA samples if appropriate as part of safety assessment at the individual patient level. 
10. The EORTC QLQ-C30 should be administered to during the week 15 visit only. 
 
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Table 4: 
Schedule of Events for Follow-Up After Part 2 of the Study 
Study Procedure1 
Years 1 and 2 
Year 3 
Frequency 
Every 4 months (±30 days) 
Every 6 months (±45 days)2 
Complete Physical Examination and ECOG PS 
X 
X 
Vital Signs and Weight 
X 
X 
Hematology  
X 
X 
Blood Chemistry  
X 
X 
TSH (with reflex T3, free T4) 
X 
X 
CT/MRI3 
X 
X 
Plasma ctDNA Sample 
X 
X 
ADA Sample 
X4 
 
Tumor Biopsy 
At any time that recurrence or SPT is suspected5 
Concomitant Medications 
← continuous monitoring → 
Adverse Events 
← continuous monitoring → 
ADA=anti-drug antibody; ctDNA=circulating tumor deoxyribonucleic acid; ECOG PS=Eastern Cooperative Oncology 
Group Performance Status; SPT=second primary tumor; TSH=thyroid-stimulating hormone 
9.1.3. 
Footnotes for Table 4:  Schedule of Events for Follow-Up After Part 2 of the Study 
1. The first follow-up visit will occur 4 months after the EOT2 visit.  Patients who receive 
radiation therapy or observation only in Part 2 are only required to follow the imaging 
assessments (and biopsy, if indicated) in Table 4. 
2. The last visit of year 3 will constitute the end of follow-up.  However, patients will continue 
to be followed for survival until death or until study closure. 
3. Imaging assessments performed during follow-up should be the same as those performed in 
Part 1 and Part 2 of the study, for a given patient.  Imaging requirements include CT/MRI and 
optional digital photography (see Section 9.2.2.3).   
4. Blood samples for ADA assessment in serum should be collected at the first follow-up visit 
only.  Pharmacokinetic (PK) analyses may be performed on ADA samples if appropriate as 
part of safety assessment at the individual patient level. 
5. Tumor biopsy should be attempted in all cases of suspected recurrence or suspected SPT 
(Section 9.2.2.4), unless there is an unacceptable safety risk associated with biopsy in a 
particular patient.  Biopsy information regarding recurrences or SPTs (or safety reason 
explaining why biopsy was not performed) will be documented in eCRF.  See Section 9.2.2.7 
for additional information on biopsies. 
9.1.4. 
Early Termination Visit 
Patients who withdraw consent during either part of the study will be asked to return to the clinic 
for an early termination visit.  For patients in Part 1, this will consist of the EOT1/early termination 
assessments described in Table 2.  For patients in Part 2, this will consist of the EOT2/early 
termination assessments described in Table 3.  Procedures regarding discontinuation for other 
reasons are described in Section 9.1.5. 
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9.1.5. 
Visit Schedule for Patients Who Discontinue Study Drug 
9.1.5.1. 
Visit Schedule for Patients Who Discontinue Neoadjuvant Cemiplimab 
Patients who permanently discontinue from neoadjuvant study drug due to disease progression 
(per RECIST 1.1; Appendix 4) or toxicity will undergo surgery (if clinically appropriate) and will 
return for post-surgical follow-up visit (EOT1).  These patients must be followed for 90 days after 
last dose of cemiplimab for AE identification and reporting and are ineligible to receive adjuvant 
cemiplimab.  
Patients who discontinue neoadjuvant therapy but achieve complete resection of all macroscopic 
disease (R0 or R1 resection) and who do not withdraw consent from the study will subsequently 
be followed by imaging per the schedule in Table 3 (imaging at week 15 of Part 2 (±10 days), 
week 30 (±10 days), and week 48/EOT2 followed by imaging per the schedule in Table 4 (every 4 
months for the first 2 years and every 6 months for the third year), or until disease recurrence, 
whichever occurs first.  Patients who undergo R2 surgical resection (residual gross disease) will 
be followed for survival only. 
9.1.5.2. 
Visit Schedule for Patients Who Discontinue Adjuvant Cemiplimab 
Patients who discontinue cemiplimab prior to the completion of the adjuvant dosing schedule due 
to unacceptable toxicity or reasons other than disease recurrence will be assessed by imaging only 
at week 15 of Part 2 (±10 days), week 30 (±10 days), and week 48/EOT2 or until disease 
recurrence, whichever occurs first.  Week 0 is defined as 3 weeks (±3 days) after the EOT1 visit.  
Patients who discontinue adjuvant cemiplimab due to toxicity or reasons other than disease 
recurrence but complete the week 48/EOT2 evaluation visit without disease recurrence will enter 
follow-up.  During follow-up they will undergo imaging assessments every 4 months for the first 2 
years and every 6 months for the third year. 
Patients who permanently discontinue from study drug due to disease recurrence (see 
Section 9.2.2.4) will be asked to return for an EOT2/early termination visit and will be 
subsequently followed for survival. 
9.1.6. 
Visit Schedule for Patients Who Receive Adjuvant Radiation Therapy or 
Observation Only 
After surgery, management options include adjuvant cemiplimab, adjuvant radiation therapy, or 
observation only.  A patient who receives adjuvant radiation therapy will not receive adjuvant 
cemiplimab (neither sequentially nor concurrently) during the study.   
Patients who undergo adjuvant radiation therapy or enter observation only during Part 2 of the 
study will be assessed by imaging only, at week 15 (±10 days), week 30 (±10 days), and week 48 
(±10 days) (corresponding to the equivalent EOT2 visit for patients receiving cemiplimab).  Week 
0 is defined as 3 weeks (±3 days) after the EOT1 visit.  Other assessments listed in Table 3 are not 
required for a patient who receives adjuvant radiation therapy or observation only.  However, 
biopsy should be attempted for all patients in the event of suspected recurrence or suspected SPT 
as described in Section 9.2.2.7.  
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Patients who complete the week 48 evaluation visit without disease recurrence will enter 
follow-up, in which they undergo imaging assessments every 4 months for the first 2 years and 
every 6 months for the third year. 
Details regarding the adjuvant therapy received by an individual patient will be reported in the 
eCRF (Section 12). 
9.1.7. 
Survival Follow-Up  
Survival follow-up begins after completion of the follow-up schedule of events in Table 4 
(including patients who follow an imaging schedule), or after disease recurrence.  Any patient who 
fails to achieve complete surgical resection (defined as R0 or R1) will also enter survival 
follow-up.  Patients in survival follow-up will be contacted quarterly (telephone is acceptable) for 
survival status and treatment status (subsequent anticancer systemic therapy) until the EOS.  
9.1.8. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
 Serum ß-HCG (test must be done ≤72 hours before the first dose) 
 HBV, HCV, and HIV screening 
 Height measurement 
 Recording of medical history/oncology history  
9.2.2. 
Efficacy Procedures  
The primary endpoint is pCR in the surgical pathology sample after neoadjuvant therapy, 
according to an independent central pathology review committee.   The secondary endpoint 
regarding changes to planned surgery or radiation therapy will be assessed according to an 
independent surgical review committee.  Secondary endpoints regarding response rate per RECIST 
1.1 prior to surgery and regarding disease-free survival after surgery require imaging studies. 
9.2.2.1. 
Pathologic Assessment of Tumor Response 
An independent central pathology review committee will assess pCR rate and mPR rate 
(Section 6.3.1).  A complete description of the procedures will be provided in a separate charter. 
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9.2.2.2. 
Change in Surgical Plan and Post-Surgical Management (Treatment 
Management Plan Assessment) 
During the screening period, the investigator will report what the management plan would be 
regarding surgery and post-surgery (including adjuvant radiation, if applicable) if the patient had 
not been enrolled in the clinical trial.  After completion of neoadjuvant cemiplimab, the 
investigator will report the actual surgery that was performed.  If adjuvant radiation therapy is 
administered, details will be reported.  See Section 5.2.2 for study variables regarding surgical 
plan and post-surgical management.   
9.2.2.3. 
Imaging Studies 
Imaging studies are required for secondary endpoints regarding response rate per RECIST 1.1 
(Eisenhauer, 2009) (Appendix 4) prior to surgery in Part 1 of the study and regarding disease-free 
survival after surgery in Part 2 of the study. 
Regarding baseline imaging requirements: 
 For patients with non-HN primaries, baseline imaging should be CT scan of the 
chest/abdomen/pelvis with iodinated contrast.   Magnetic resonance imaging (MRI) 
with gadolinium is acceptable for the abdomen/pelvis.  Additional CT or MRI 
imaging will be obtained for lesions of interest, as clinically indicated (ie, radiologic 
imaging of extremity for patients with CSCC of extremity).  
 For patients with HN primaries, CT neck with iodinated contrast (and/or MRI neck 
with gadolinium) is required and CT chest is required.  If patient has CSCC lesions of 
the head that are not imaged adequately by neck CT or MRI neck, additional baseline 
radiologic imaging of the head should be obtained as appropriate.  Lesions of interest 
identified in screening should be re-imaged at subsequent assessments.   
 In Part 1, digital photography is mandatory at baseline imaging assessment and at the 
imaging assessment that occurs prior to surgery; photography at imaging assessment 
prior to the third dose is optional.  Radiologic imaging is required at each imaging 
assessment in Part 1 and Part 2.  Digital photography is optional for imaging 
assessments in Part 2.  Radiologic imaging of externally visible lesions can be 
supplemented with digital medical photography and such clinical imaging may 
inform response assessments per RECIST 1.1 (Eisenhauer, 2009)(Appendix 4).  
Guidelines for digital medical photography are provided in Appendix 5.  However, 
photography will not replace radiologic imaging.  Radiologic imaging at each of the 
protocol-specified timepoints is required even if optional photography is performed.  
For each postbaseline (post-screening) imaging assessment for a given patient (from screening 
through recurrence), the investigator should, whenever possible, be consistent with the radiologic 
imaging methods that were used during screening for that patient.   
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During Part 1 of the study (neoadjuvant), imaging assessments are planned after the 2nd and 4th 
doses of cemiplimab.  During Part 2 of the study (adjuvant), imaging is performed approximately 
every 15 weeks to monitor disease recurrence during the treatment period.  There is a subsequent 
follow-up period of 3 additional years, to provide approximately 4 years total follow-up after 
surgery.  The vast majority of advanced CSCC recurrences occur within 2 years after surgery, with 
a small number of additional recurrences in year 3 after surgery (Porceddu, 2018). 
The required imaging assessments are shown in the schedules of events in Table 2, Table 3, and 
Table 4.  Additional imaging may be obtained at an earlier time point than required in the schedules 
of events if clinically indicated in the opinion of the investigator.  Unscheduled assessments would 
be reported in the eCRFs but would not substitute for the next required imaging assessment in the 
protocol schedule of events.  Positron emission tomography (PET) imaging is not required in the 
study.  However, the results of any PET imaging performed as standard of care during the study 
will be reported in eCRFs as supplemental information. 
Brain imaging is not mandatory at baseline or at subsequent assessments.  However, if the 
investigator feels that there is a clinical suspicions of brain metastases at any time, appropriate 
brain imaging should be obtained. 
At the sponsor’s discretion, de-identified imaging studies (scans and photographs) may be 
collected and reviewed by independent radiologists and/or other qualified reviewers at a later date, 
or at any time during the study. 
9.2.2.4. 
Characterization of New Skin Lesions (Disease Recurrence) or SPT Following 
Surgery 
In CSCC, the most common sites of metastases are lymph node and lung (Hillen, 2018).  New 
CSCC lesions in the skin usually are not metastatic lesions.  With rare exceptions, new CSCC 
lesions in the skin are new primary tumors due to field cancerization from chronic UV-mediated 
skin damage (Christensen, 2018).  In a previous randomized trial in advanced CSCC, recurrent 
skin disease and SPTs were recognized as distinct entities (Brewster, 2007).  In this study, SPTs 
are non-metastatic CSCC lesions in the skin that can be managed by local modality therapy as part 
of routine clinical practice.  
However, there are 2 circumstances in which a new skin lesion in a CSCC patient could represent 
metastatic disease:   
 Epidermotropic metastases (EDMs), defined as distant lesion(s) in the dermis without 
epidermal involvement (Skala, 2018)(Weidner, 1985).  Although EDM are well 
described in the melanoma literature, this would be a highly atypical pattern of 
recurrence in patients with CSCC.  However, EDM could occur in a CSCC patient 
because cutaneous metastases from squamous cancers arising in internal organs have 
been described (Bornkessel, 2006)(Plataniotis, 1999).   
NOTE:  In the event of a new rapidly growing CSCC lesion involving both dermis 
and epidermis that is not appropriate for local modality treatment and requires new 
systemic therapy, this should be designated as an EDM, not an SPT. 
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 In-transit metastases (ITMs) are defined as cutaneous nodule(s) distinct from the 
primary tumor and occurring proximal to the first lymph node basin (Xu, 2018).  Of 
note, not all CSCC lesions arising in the skin proximal to the first lymph node basin 
are ITM.  Due to chronic sun exposure, new lesions in sun-exposed skin may 
represent SPTs.  The decision about whether to call such a lesion an SPT or an ITM 
will be based on the overall clinical presentation of the lesion.  These ITMs are most 
often subcutaneous or dermal papules with occasional exophytic features 
(Carucci, 2004).  The investigator will indicate in source documents and eCRF pages 
the basis for designating a new skin CSCC lesion as ITM or SPT. 
In this study, a new CSCC lesion arising on the skin during the study period will be classified as 
an SPT unless the lesion represents ITM or EDM.  Second primary CSCC tumors are not counted 
as events for the DFS endpoint.  Patients who develop ITM or EDM will be considered to have 
experienced a DFS event.  
Second primary CSCC tumors arising during the study period should be treated with surgery or 
another permitted local modality.  Permitted non-surgical local modalities for SPTs in this study 
are: topical 5-fluorouracil, topical imiquimod, and photodynamic therapy with topical 
aminolevulinic acid or methyl aminolevulinate (Christensen, 2018). 
For any cutaneous lesion that is resected during the course of the study, the following information 
will be captured in eCRF pages: histologic diagnosis, maximum diameter, and investigator’s 
impression regarding whether lesion represents SPT or a disease recurrence (either ITM or EDM).  
The reason the investigator deems a lesion to be SPT or recurrence will be documented in eCRF. 
9.2.2.5. 
Definitions for Patterns of Disease Recurrence Following Surgery 
The pattern of treatment failure, as manifested by disease recurrence, is defined as ≥1 new CSCC 
lesion(s), either local, regional, or distant.  Definitions of locoregional and distant recurrences are 
provided in this section.   
 Locoregional recurrence:  Any of the following sites of disease recurrence: 
 For HN CSCC, nodal or soft tissue recurrence above the clavicle.   
 For non-HN CSCC, recurrence within the first draining nodal basin (or soft tissue 
associated within the first draining nodal basin) of the resected tumor. 
 In-transit metastases, defined as skin or subcutaneous metastases that are >2 cm 
from the primary lesion but are not beyond the regional nodal basin. 
 Distant recurrence:  Any of the following sites of disease recurrence:  
 For HN CSCC, nodal recurrence below the clavicle.  
 For non-HN CSCC, recurrence beyond the first draining nodal basin of the 
resected tumor bed.  Recurrence in 2 nodal basins will be considered distant 
recurrence, even if contiguous (ie, 2 mediastinal nodal basins, 2 pelvic nodal 
basins).  
 Recurrence in non-nodal tissue (including, but not limited to, lung, liver, bone, 
brain).  
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 Epidermotropic metastases, defined as distant lesion(s) in the dermis without 
epidermal involvement.   
For all recurrences, the investigator will indicate in the eCRF page whether recurrent disease for 
an individual patient at the time of first recurrence is local, regional, distant or a combination 
(concurrent locoregional + distant recurrences).  
9.2.2.6. 
Date of Disease Recurrence Following Surgery 
The date of disease recurrence is captured in the eCRF by the investigator.  Evidence of recurrence 
on imaging should be confirmed with a biopsy to obtain histologic or cytologic evidence of CSCC 
in all cases of suspected disease recurrence, unless biopsy is considered to pose an unacceptable 
safety risk in the opinion of the investigator (eg, brain lesions) (Section 9.2.2.7). 
The date of disease recurrence is the first date when recurrence is observed, as defined in the 
following clinical situations: 
 Radiologic Evidence with Confirmatory Pathology Sample: The investigator 
obtains both imaging and pathologic confirmation of recurrent disease.  If the 
pathology sample is obtained prior to the imaging, the date of the procedure to obtain 
the pathology sample will be the date of recurrence.  If the pathology sample is 
obtained after the imaging, and if the biopsy procedure date is within 21 days of the 
imaging date, the recurrence date will be the date of the imaging assessment that was 
done prior to the procedure to obtain the pathology sample.  Whenever possible, 
pathologic confirmation of the radiologic recurrence should be obtained unless 
in the judgment of the investigators, there are clinical circumstances that result 
in an unacceptable safety risk associated with biopsy for a patient. 
Note: If the procedure date that confirms pathologic recurrence is performed more 
than 21 days after the most recent imaging, the biopsy procedure date (not the 
imaging date) will be the date of recurrence.  This 21-day rule is to guard against 
retroactively declaring progression based on equivocal radiologic findings that were 
not considered to be progression at the time that the imaging was obtained, in view of 
the fact that study drug is administered every 21 days. 
 Pathologic Evidence Only:  A procedure was performed to obtain a pathology 
sample to establish disease recurrence, but there is no corresponding imaging.  
Generally, imaging should be performed in the setting of recurrent disease.  However, 
if a clinical circumstance arises in which there is only histologic (pathologic) 
confirmation of recurrence (eg, recurrent disease on the skin or palpable node for 
which imaging was not obtained due to logistical reasons) or if the imaging is more 
than 21 days prior to the procedure date (see note in bullet immediately above), the 
biopsy procedure date is the date of disease recurrence that is captured in the eCRF 
page.  
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 Radiologic Evidence Only: Only imaging was obtained (eg, a patient with radiologic 
evidence of recurrence in which the investigator feels that biopsy would pose an 
unacceptable safety risk due to location of the lesion or other clinical 
considerations).  In this case, the imaging date will be the date of disease recurrence 
that is captured in the eCRF page.  If a prior scan had equivocal findings that were not 
considered to establish recurrence (and biopsy was not obtained), and the subsequent 
scan is felt to establish evidence of recurrence (but biopsy cannot be obtained due to 
safety reasons), the date of the subsequent scan will be the date of recurrence in the 
eCRF page. 
9.2.2.7. 
Biopsies to Document Disease Recurrence or SPT Following Surgery 
Biopsy to obtain histologic or cytologic evidence of CSCC should be attempted in all cases of 
suspected recurrence or suspected SPT (defined in Section 9.2.2.4) unless biopsy is considered to 
pose an unacceptable safety risk in the opinion of the investigator (eg, brain lesions).  If biopsy of 
suspected recurrence or suspected SPT is not performed due to unacceptable safety risk associated 
with biopsy in a particular patient, the reason for not obtaining biopsy will be documented in eCRF.  
For SPTs, if biopsy is positive for CSCC, surgical removal of the lesion is recommended if possible 
(unless the biopsy was excisional).   
9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration will be collected 
pre-dose at time points according to Table 2, Table 3, and Table 4. 
Note:  Blood pressure should be measured after the patient has been resting quietly for at least 
5 minutes.  Blood pressure may be obtained from a seated or recumbent position and should be 
done consistently throughout the study.  When scheduled at the same time as other procedures, 
vital signs should be measured prior to clinical laboratory assessments, or exploratory sample 
collection. 
At day 1 of the initial (neoadjuvant) treatment period (Part 1), vital signs will be collected prior to 
infusion, and approximately 30 minutes after the completion of the infusion.  For all other 
treatment days, vital signs are collected prior to infusion, and approximately 15 minutes after the 
completion of the infusion.  The allowable window for each specified time point is ±10 minutes. 
Weight is recorded at each visit at which vital signs are recorded. 
9.2.3.2. 
Physical Examination 
A complete or limited physical examination will be performed at visits specified in Table 2, 
Table 3, and Table 4.  Care should be taken to examine and assess any abnormalities that may be 
present, as indicated by the patient’s medical history.   
Complete physical examination will include examination of head and neck, lungs, heart, abdomen, 
lymph nodes, extremities, and skin.  A brief neurologic examination also should be performed. 
Limited physical examination will include lungs, heart, abdomen, and skin. 
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9.2.3.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 2.  
The patient should be relaxed and in a recumbent or semi-recumbent position at least 5 minutes 
before recording an ECG.  The ECG strips or reports will be retained with the source.  The ECG 
will be reviewed by the investigator (paper or electronic tracing) and will be available for 
comparison with subsequent ECGs by the investigator.  The following will be recorded on the 
eCRF: 
 RR interval (sec) 
 PR interval (msec) 
 QRS interval (msec) 
 QT interval (msec) 
 Heart rate (beats per minute; recorded from the ventricular rate) 
9.2.3.4. 
ECOG Performance Status 
ECOG performance status will be performed at the time points according to Table 2, Table 3, and.  
Performance status will be assessed according to ECOG criteria in Appendix 1.   
9.2.3.5. 
Laboratory Testing 
Hematology, blood chemistry, urinalysis, and pregnancy testing samples will be collected at time 
points according to Table 2, Table 3, and Table 4. 
Detailed instructions for sample collection and shipment of samples are in the laboratory manual 
provided to study sites. 
Unless otherwise specified, all laboratory tests will be performed by local labs. 
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Blood Chemistry 
Sodium 
Total protein, serum 
 
Potassium 
Creatinine 
 
Chloride 
Blood urea nitrogen (BUN)* 
 
Carbon dioxide 
(bicarbonate)** 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose (fasting or non-
fasting) 
Alkaline phosphatase 
 
Albumin 
Total bilirubin 
 
*At ex-US centers at which a urea assays are performed instead of BUN; the urea assay will be acceptable. 
**At ex-US centers at which the bicarbonate assay is not performed as part of the routine chemistry panel, it may 
be omitted. 
Hematology 
Hemoglobin 
Differential: 
White blood cells 
 
Neutrophils 
Platelet count 
 
Lymphocytes 
 
 
Monocytes 
Urinalysis 
pH 
Glucose 
 
Specific gravity 
Blood 
 
Ketones  
Spot urine protein 
 
Other Laboratory Tests 
 HBV, HCV, HIV testing 
 Pregnancy test: Serum ß-HCG or urine ß-HCG 
 Thyroid-stimulating hormone (TSH) with reflex T3 and free T4 will be analyzed by 
the site’s local laboratory.  If TSH is abnormal, a T3 and free T4 should be measured 
by the site’s local laboratory.  Coagulation will be assessed at screening and prior to 
surgery using measurements of INR and aPTT.  
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study drug or its administration, the Medical/Study Director must be 
consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
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Criteria for reporting laboratory values as an AE are provided in Section 10.4.5.   
9.2.4. 
Survival Data Collection 
Every effort will be made to collect survival data on all patients, including patients who withdraw 
from the study for any reason but have not withdrawn consent to collect survival information.  If 
the death of a patient is not reported, the date of the last patient contact in this study will be used 
in the determination of the patient’s last known date of alive. 
9.2.5. 
Anti-Drug Antibody and Pharmacokinetic Procedures 
Blood samples will be taken to measure ADA as part of safety assessment at the individual patient 
level.  When appropriate, cemiplimab concentration may also be measured using these blood 
samples. 
9.2.5.1. 
Anti-Drug Antibody Measurements and Samples 
Anti-drug antibody samples for cemiplimab immunogenicity assessments will be collected at visits 
and time points listed in Table 2, Table 3, and Table 4.  The actual time of each blood draw must 
be recorded.  Pre-infusion is defined as before the start of subsequent cemiplimab infusions. 
Any unused samples collected for immunogenicity assessments may be used for exploratory 
biomarker research. 
9.2.5.2. 
Drug Concentration Measurements and Samples 
Cemiplimab concentrations in the serum may be measured using samples collected for ADA 
analysis, if appropriate as part of safety assessment at the individual patient level.  Concentrations 
will be measured using a validated enzyme-linked immunosorbent assay method.   
9.2.6. 
Exploratory Pharmacodynamic and Biomarker Procedures 
Samples for exploratory pharmacodynamic and biomarker analysis will be collected according to 
the time points listed in the schedules of events (Table 2, Table 3, and Table 4). 
Analysis of PD-L1 expression levels (determined by immunohistochemistry [IHC]) and TMB in 
pretreatment tumor samples will be prioritized over other exploratory tumor assessments.  These 
analyses may provide a better understanding of PD-L1 expression level and TMB as potential 
predictive biomarkers of the efficacy of cemiplimab.  These exploratory analyses will not be 
included in the CSR. 
After completion of PD-L1 expression and TMB analysis, the remaining tumor tissue and/or other 
samples sources (eg, peripheral blood) may be used to study other candidate biomarkers associated 
with efficacy of cemiplimab, including assessment of circulating tumor deoxyribonucleic acid 
(ctDNA) as a potential predictor of disease recurrence, characterization of expression of other 
immune-related or CSCC cancer-related genes (DNA, RNA and/or protein), tumor-infiltrating 
lymphocytes and other immune cell populations, HPV (human papillomavirus) status and subtype, 
human leukocyte antigen variants and antigen processing components, and T cell receptor 
repertoire.   
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Methodologies that may be employed include, but are not limited to, IHC, multiple IHC, RNA 
sequencing, RNAscope®, fluorescence in situ hybridization, flow cytometry, and whole exome 
DNA sequencing.  Candidate biomarker analysis will also be performed in pretreatment and 
posttreatment blood samples (serum, plasma, Peripheral blood mononuclear cells [PBMC], and/or 
whole blood) and, if available, samples from SPTs and recurrent disease lesions.   
9.2.6.1. 
Tumor Biopsy 
For all study patients, a pretreatment tumor sample (preferably an FFPE tissue block, or 
alternatively, 25 unstained FFPE slides) should be obtained.  The sample should be provided to 
the central lab in the screening period, but a patient’s enrollment would not be delayed if sample 
is not received in screening period.  When possible, tumor sample (FFPE block or 25 unstained 
FFPE slides) should be provided when there is histologic sampling (biopsy or surgical removal) 
of SPT or recurrent CSCC lesion (see Section 9.2.2.4 and Section 9.2.2.7).  Complete instructions 
on the collection, processing, handling, and shipment of all samples will be provided in the 
laboratory manual.   
Any available, FFPE biopsy tissue from samples collected at time points according to Table 2, 
Table 3, and Table 4, as well as archival specimens from previous treatment, in addition to clinical 
diagnostic uses, will be utilized for biomarker assays.  Specifically, these samples will be assessed 
using immunohistochemistry (to measure PD-L1 expression) and using whole exome sequencing 
(to measure tumor mutation burden).  
If sufficient sample is available, tumor tissue samples will also be subjected to multiplex 
immunohistochemistry as a measure of tumor infiltration of immune cells, gene expression 
profiling (using RNA sequencing, RNAScope®, fluorescence in situ hybridization, or other 
methods) as a measure of composite tumor microenvironmental phenotype, and targeted study of 
gene variants (tumor mutations) such as those affecting DNA repair pathways.  They may also be 
profiled using next-generation sequencing for the T cell receptor repertoire, as a measure of tumor-
associated T cell clonal proliferation. 
If biopsy is considered by the investigator to pose an unacceptable safety risk to the patient or 
would compromise tumor measurements, biopsy may be waived for an individual patient (see 
Table 2 and Section 9.2.2.7). 
9.2.6.2. 
Circulating Tumor DNA 
Tumor mutations (known oncogenic drivers, as well as indicators of overall mutational load) are 
a measure of tumor aggressiveness and growth potential, residual disease, and altered tumor 
evolution under the selective pressures of therapy.  Such analyses are exploratory methods for 
evaluating treatment response, as well as potential predictive markers of longer-term efficacy.  
Mutations will be measured in DNA isolated from plasma samples collected at time points 
indicated in the schedule of events (Table 2, Table 3, and Table 4).  Modulation of mutations 
pertaining to tumor cell function, genomic landscape, and immunogenicity all constitute 
exploratory measures.  
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9.2.6.3. 
Peripheral Blood Mononuclear Cells for Exploratory Immune Monitoring 
Proteins expressed on the surface of immune cells serve as markers of the lineage, functionality, 
and activation state of those cells, and help to characterize the cell population.  Expressed protein 
markers of lineage and activation trajectories will be measured by quantitative flow cytometry.  
Anti-tumor functionality in a T cell population is characterized by the combination of tumor 
antigen specificity (associated with the somatically recombined, clonally identifying T cell 
receptor sequence) and phenotypic properties indicative of function (measurable through both 
RNA and protein expression).  T cell activity, tumor antigen specificity, the T cell receptor (TCR) 
repertoire sequences, and other measures of the anti-tumor immune response will be measured 
through 1) functional assay of PBMC samples collected at time points indicated in the schedule of 
events (Table 2) followed by 2) molecular profiling including but not limited to high-throughput 
RNA sequencing or reverse transcriptase polymerase chain reaction (RT-PCR). 
9.2.6.4. 
Whole Blood for DNA Analysis (Mandatory Sample) 
A whole blood genomic DNA sample will be collected during screening as indicated in the 
schedule of events (Table 2).  Whole exome sequencing of germline blood DNA will be 
performed, and data will be used as a reference for tumor DNA sequencing analysis to distinguish 
germline from somatic tumor gene variants.  This sample will not be used for other research 
purposes. 
9.2.7. 
Genomics Sub-study (Optional Sample) 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF before collection of the samples.  Whole blood samples for DNA and 
RNA extraction should be collected on day 1/baseline (predose) but may be collected at any study 
visit.  DNA and RNA samples for the genomics sub-study will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15.  Sub-study samples will be stored 
for up to 15 years after the final date of the database lock and may be used for research purposes.  
If there are specific site or country requirements involving the pharmacogenomic analyses which 
the sponsor is unable to comply with, samples will not be collected at those sites.   
The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker 
response, other clinical outcome measures and possible AEs.  In addition, associations between 
genomic variants and prognosis or progression as well as related diseases may also be studied.  
These data may be used or combined with data collected from other studies to identify and validate 
genomic markers related to the study drug and related diseases.   
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing may also be performed.  The list of methods may be expanded to include novel 
methodologies that may be developed during the course of this study or sample storage period.  
Results from the genomic sub-study will not be reported in the CSR. 
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9.2.8. 
Future Biomedical Research (Optional Use of Samples) 
Patients who agree to participate in the future biomedical research sub-study will be required to 
consent to this optional sub-study before samples are banked in long-term storage.  Unused tumor 
samples for study-related research will be stored for up to 15 years after the final date of the 
database lock.  The unused samples may be utilized for future biomedical research of CSCC and 
related diseases.  No additional samples will be collected for future biomedical research.  After 
15 years, any residual samples will be destroyed.  The results of these future biomedical research 
analyses will not be presented in the CSR. 
9.2.9. 
Patient Reported Outcomes  
Patient reported outcomes will be measured at a frequency indicated in Table 2 and Table 3 using 
the self-administered EORTC QLQ-C30.  The EORTC QLQ-C30 is a validated instrument that 
assesses HRQoL across multiple domains, including global health status, functioning (physical, 
role, emotional, cognitive, and social), patient-reported symptom scales (fatigue, nausea and 
vomiting, pain) and single items (appetite loss, dyspnea, insomnia, constipation, diarrhea, financial 
impact).  Patients will be asked to complete the questionnaire prior to any study procedures being 
performed during a given study visit.  
10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
10.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients, according to local regulations.  This 
may include death from any cause and all SAEs suspected to be related to the use of the study 
drug.  It is recommended that all other SAEs be reported to the IRB/EC, according to local 
regulations. 
10.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, ECs/IRBs as appropriate, and to the 
investigators in a blinded manner.  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected.   
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and ECs/IRB as appropriate. 
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10.3. 
Definitions 
10.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
Progression of underlying malignancy will not be considered as an AE if it is clearly consistent 
with the typical progression pattern of the underlying cancer (including time course, affected 
organs, etc).  Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy or does not fit the 
expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to progression of the underlying malignancy, 
it should be reported as an AE or as an SAE as outlined in Section 10.3.2. 
10.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death.  Includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening.  In the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
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). 
Hospitalization or death due solely to manifestations consistent with typical progression of 
underlying malignancy will not be considered an SAE. 
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10.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate.  Such an event might warrant 
further investigation in order to characterize and understand it.  Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 10.4.3). 
10.3.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 24 hours 
after the infusion is completed.  All infusion reactions must be reported as AEs (defined in 
Section 10.4.1) and graded using the grading scales as instructed in Section 10.5.1. 
10.4. 
Recording and Reporting Adverse Events  
10.4.1. 
Adverse Events 
The investigator (or designee) will seek information on AEs at each patient contact and record all 
AEs that occur from the time the informed consent is signed until 90 days after the last dose of 
study drug.  Prior to initiation of study drug, only the following categories of AEs should be 
reported on the AE eCRF: 
 SAEs 
 Non-SAEs associated with a protocol-mandated intervention (eg, AEs related to an 
invasive procedure such as a biopsy) 
Other AEs that occur prior to first treatment should be reported on the medical history eCRF. 
All AEs after initiation of study drug and until 90 days after the last dose of study drug, regardless 
of relationship to study drug, will be reported on the AE eCRF.  Additionally, any SAE or other 
AE of concern that the investigator believes may be related to study drug and that occurs later than 
90 days after last study drug should be reported. 
Information on follow-up for AEs is provided in Section 10.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 10.4.5. 
10.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
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In the event the investigator is informed of an SAE that occurs 90 days after the last dose of study 
drug, only those SAEs or other AEs of concern deemed by the investigator to be related to study 
drug will be reported to the sponsor.  The investigator should make every effort to obtain follow-
up information on the outcome of an SAE until the event is considered resolved, chronic and/or 
stable. 
For the purposes of this study, planned resection procedures and associated hospitalization are not 
considered SAEs. 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient or female partner of a male study 
patient, during the study or within 180 days of the last dose of study drug.  Any 
complication of pregnancy affecting a female study patient or female partner of a 
male study patient, and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE.  Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All AESI, serious and non-serious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, 
per Section 10.4.2.  Adverse events of special interest for this study include the 
following:   
 Grade 2 or higher IRRs (Section 8.4) 
 Grade 3 or higher irAEs (Section 8.3.3) 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
10.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 The test result is associated with accompanying symptoms, and/or 
 The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
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 The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
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. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 10.5.1. 
10.4.6. 
Follow-up 
Information for any non-SAE that starts during the treatment period or within 90 days after last 
treatment will be collected from the time of the event until resolution of the event, or until the 
patient’s last study visit, whichever comes first. 
Serious adverse event information will be collected until the event is considered resolved, chronic 
and/or stable. 
10.5. 
Evaluation of Severity and Causality 
10.5.1. 
Evaluation of Severity 
The severity of AEs (including test findings classified as AEs) will be graded using the NCI-
CTCAE v5.  Adverse events not listed in the NCI-CTCAE v5 will be graded according to the 
following scale (Table 5): 
Table 5: 
Grading System for Adverse Events Not Listed in NCI-CTCAE  
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.   
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*.   
3  
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
4  
Life–threatening 
Life-threatening consequences; urgent intervention indicated. 
5  
Death 
Death related to AE 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
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10.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
 Not Related: 
There is no reasonable possibility that the event may have been 
caused by the study drug 
 Related: There is a reasonable possibility that the event may have been caused by 
the study drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
 resolve or improve after interruption or discontinuation of study drug  
 reappear or worsen when dosing with study drug is resumed 
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
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Causality to adjuvant surgery: 
 Related: 
 The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
 Not Related: 
 The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on 
a periodic cumulative aggregate basis. 
10.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the IB and has a reasonable suspected causal relationship to the study drug). 
11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the first database lock. 
The primary analysis will be performed when all patients have completed surgery or deemed no 
longer a candidate for surgery after treatment with neoadjuvant cemiplimab.  An updated analysis 
will be provided after all patients have completed post-treatment follow-up or end of study. 
Endpoints are listed in Section 4.  Analysis variables are listed in Section 5. 
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11.1. 
Statistical Hypothesis 
The primary endpoint is pCR by independent central review.  The following null and alternative 
hypotheses will be tested for the primary efficacy endpoint: 
 H0: pCR rate = 25% 
 Ha: pCR rate ≠ 25% 
11.2. 
Justification of Sample Size 
Seventy-two (72) patients will be required to provide 90% power to reject a null hypothesis of a 
pCR rate of 25% at a 2-sided significance level of 0.05 if the true pCR rate is 44%.  
The sample size will be further increased by 5% to account for patients who prematurely withdraw 
from the study.  Hence, the total sample size will be approximately 76 patients.  Patients who 
discontinue treatment early and/or withdraw from the study will not be replaced.  Results will be 
analyzed according to intention-to-treat.  The 95% binomial exact confidences intervals for 
observed pCR with 76 patients is provided in Table 6. 
The non-clinically meaningful pCR rate of 25% will be excluded using the lower limit of 95% 
exact CI if the observed pCR rate is 36.8% or more.  
Table 6: 
The 95% Binomial Exact Confidence Intervals for Observed pCR with a 
Sample Size of 76 Patients  
Number of pCR 
patients 
Observed pCR rate 
95%CI – lower 
95% CI – upper 
23 
0.303 
0.202 
0.419 
24 
0.316 
0.214 
0.433 
25 
0.329 
0.225 
0.446 
26 
0.342 
0.237 
0.460 
27 
0.355 
0.249 
0.473 
28 
0.368 
0.261 
0.487 
29 
0.382 
0.272 
0.500 
30 
0.395 
0.284 
0.514 
31 
0.408 
0.296 
0.527 
32 
0.421 
0.309 
0.540 
33 
0.434 
0.321 
0.553 
To ensure meaningful representation of stage III/IV (M0) patients, enrollment of stage II patients 
will be capped at 25 patients. 
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11.3. 
Subgroup Analyses 
Subgroup analyses will be performed to determine the consistency of treatment effect across 
various demographics and baseline characteristics.  Between-group treatment effect, along with its 
nominal 95% CI, for the primary endpoint will be estimated within each category for the following 
subgroups:  
 Age (<65 years, ≥65 years) 
 Gender (Male, Female) 
 Race (White, Non-white) 
 Anatomic region of resected tumor (HN, Non-HN) 
 Tumor stage (II, III/IV) 
 ECOG status (0, 1) 
As regards the DFS endpoint, a descriptive comparison will be performed between subgroups of 
patients who receive adjuvant cemiplimab versus adjuvant radiation therapy versus observation 
after surgery. 
11.4. 
Analysis Sets 
11.4.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) will include all enrolled patients.  Efficacy endpoints will be analyzed 
using the FAS. 
11.4.2. 
Safety Analysis Set 
The safety analysis set (SAF) will include all enrolled patients who received at least one dose of 
cemiplimab.  Treatment compliance/administration and all clinical safety variables will be 
analyzed using the SAF. 
11.4.3. 
PK Analysis set 
The PK analysis set includes all patients who received at least 1 dose of cemiplimab (SAF) and 
who had at least 1 non-missing cemiplimab concentration following the first dose of cemiplimab.  
11.4.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all subjects/patients who received study drug and had at least 1 
non-missing ADA result following the first study dose. 
The neutralizing antibody (Nab) analysis set includes all patients who received any study drug and 
who are negative in the ADA assay or with at least 1 non-missing result in the NAb assay (patients 
who are ADA negative are set to negative in the NAb analysis set). 
11.4.5. 
Exploratory Pharmacodynamic and Biomarker Analysis Set 
The biomarker analysis set for each analysis includes all patients who received cemiplimab and 
who have data available from baseline.  
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11.5. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.5.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients 
 The total number of enrolled patients 
 The total number of patients in each analysis set (eg, FAS, provided in Section 11.4) 
 The total number of patients who discontinued from study drug, and the reasons for 
discontinuation 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.5.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively.   
11.5.3. 
Efficacy Analyses 
11.5.3.1. Primary Efficacy Analysis 
The pCR rate per independent central pathology review along with 95% exact confidence interval 
will be calculated using Clopper-Pearson method (Clopper, 1934).  
11.5.3.2. Secondary Efficacy Analysis 
The pCR rate per local pathology review, mPR rate per independent central pathology review, 
mPR rate per local pathology review, and ORR prior to surgery per investigator assessment, along 
with 95% exact confidence intervals, will be calculated using Clopper-Pearson method (Clopper, 
1934). 
Event free survival (EFS), DFS and OS will be summarized using Kaplan-Meier method.  
Kaplan-Meier curves will be presented.  Descriptive statistics will be used for time to event 
endpoints.   
Change in planned surgery will be summarized descriptively and will be listed.  The proportion of 
patients for whom the surgical management plan (at time of screening) differed from the actual 
surgery after neoadjuvant therapy will be summarized both by investigator assessment and 
independent surgical expert committee. 
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Change in planned post-surgical management will be summarized descriptively and will be listed.  
The proportion of patients for whom radiation therapy (or chemoradiation) was planned during 
screening but not actually administered after neoadjuvant cemiplimab and surgery will be 
summarized. 
11.5.4. 
Control of Multiplicity 
Not applicable. 
11.5.5. 
Safety Analysis 
Treatment-emergent AEs/AESIs/SAEs and lab abnormalities will be summarized using 
descriptive statistics.  
11.5.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The treatment period is defined as the time from the day of first dose of neoadjuvant 
cemiplimab to the day of the last dose of neoadjuvant cemiplimab plus 90 days or to 1 
day before patients receive their first dose of adjuvant cemiplimab or another 
anticancer systemic therapy, whichever is earlier.  
 The post-treatment period is defined as the time starting one day after the end of 
on-treatment period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
on-treatment period and any treatment-related AEs that occur during the post-treatment period but 
prior to patients receiving their first dose of cemiplimab as adjuvant therapy or another anticancer 
systemic therapy.  
Adverse events (AEs) during adjuvant cemiplimab will be summarized separately from AEs 
emerging in the neoadjuvant period.  AEs will be collected from the date of first dose of adjuvant 
cemiplimab up to 90 days following the last dose.  Additionally, any treatment-related AEs 
identified more than 90 days following the last dose will be captured. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term, and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and 
preferred term 
 TEAEs by severity (according to the grading scale outlined in Section 10.5.1), 
presented by SOC and preferred term 
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 TEAEs related to treatment, presented by SOC and preferred term 
 Treatment-emergent AESIs (defined with a preferred term or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
11.5.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Summary tables for worst laboratory values during on-treatment period with NCI CTCAE all grade 
and grade ≥3 will be generated.  Summary of Shift tables from baseline to worst post-treatment 
NCI CTCAE grade during on-treatment period will be generated.  
Listings will be provided with flags indicating the out of laboratory range values. 
11.5.5.3. Treatment Exposure 
Number of doses and treatment duration will be summarized using descriptive statistics based on 
SAF. 
11.5.5.4. Treatment Compliance 
Treatment compliance, defined as: 
(Number of doses of study drug administered during treatment period)
(Number of doses of study drug planned to be administered during treatment period) ×100% 
where temporary dose interruption is not excluded from treatment period, will be summarized. 
11.5.6. 
 Analysis of Anti-Drug Antibody Data 
Immunogenicity will be characterized by the ADA and NAb response observed: 
 Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels. 
 Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative. 
 Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate. 
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 Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay. 
 Maximum ADA Titer values 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
 NAb status for samples that are positive in the ADA assay. 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by patient/subject, time point, and dose cohort/group will be 
provided.  Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence 
(N) and percent of patients (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated.  Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.5.7. 
Analysis of Drug Concentration Data 
Cemiplimab concentrations in serum may be measured from ADA samples in individual patients 
if appropriate (ie, as part of safety assessment at individual patient level).  
11.5.8. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data 
Biomarker data will be analyzed using standard scientific methods and summarized by descriptive 
statistics and plot.  Correlative analysis with clinical response may be performed using correlation 
coefficient, box plot and scatter plot, and basic regression models.  Both comparative analysis and 
correlative analysis will be exploratory in nature and will be described in a separate report.   
11.5.9. 
Analysis of Patient-Reported Outcomes Data 
The EORTC QLQ-C30 domain scores at each time point as well as change from baseline over 
time in these scores will be described. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – study drug supply 
 EDC system – data capture – Medidata Rave 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study.  This study will use the principles of risk-based 
monitoring (ICH).  This means that the number of visits for any given site may vary based on site 
risk indicators.  The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and eCRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the eCRF.  Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
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12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel.  All required eCRFs must be completed for each and every patient 
enrolled in the study.  The investigator must ensure the accuracy, completeness, and timeliness of 
the data reported to the sponsor in the eCRFs.  After review of the clinical data for each patient, 
the investigator must provide an electronic signature.  A copy of each patient eCRF casebook is to 
be retained by the investigator as part of the study record and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to inspection.  
In addition, representatives of the sponsor may observe the conduct of any aspect of the clinical 
study or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
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12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation.  Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP.  See Section 6.1.7 
for informed consent procedures in this study. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
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If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately.  All study patients must be informed of the new information and provide their 
written consent if they wish to continue in the study.  The original signed revised ICF must be 
maintained in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by a patient identification number only, 
on eCRFs or other documents submitted to the sponsor.  Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter.   
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
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17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A Phase 2 Study of Neoadjuvant Cemiplimab for Stage II to 
IV (M0) Cutaneous Squamous Cell Carcinoma (CSCC)” and agree to abide by all provisions set 
forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, 
Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Phase 2 Study of Neoadjuvant Cemiplimab for Stage II to IV (M0) Cutaneous 
Squamous Cell Carcinoma (CSCC) 
Protocol Number: 
R2810-ONC-1901 
Protocol Version:   
R2810-ONC-1901 Original 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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APPENDIX 1. EASTERN 
COOPERATIVE 
ONCOLOGY 
GROUP 
CRITERIA 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair 
5 
Dead 
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APPENDIX 3. GUIDELINES FOR EXPLORATORY BIOPSIES  
This appendix provides timepoints and research exploratory biopsies of externally visible lesions 
in the office setting.  These biopsies are performed during the screening period and on day 22 (±3 
days).  
Research Procedures for ALL Biopsies: 
Where and How: 
The technique and sites of biopsies will be selected by the investigator based on the sizes and 
locations of lesions.  Generally, biopsies will be punches of approximately 3mm diameter.  In 
patients with nodal metastases and no residual primary, core needle biopsy may be performed.  
Biopsies should not be taken at the perimeter of a lesion because this could interfere with 
measurement of longest diameters for response assessments.  Whenever possible, biopsy sites 
should be ≥5 mm from the edge of baseline lesional area if appropriate.  
How many: 
2 to 3 biopsies will be obtained at baseline and again at neoadjuvant treatment day 22 
(±3 business days).  The first biopsy will be processed for FFPE, the second biopsy will be 
processed in RNAlater®, and the third biopsy (if obtained) will processed for FFPE. 
11. Disposition of Samples 
Biopsy samples required for exploratory assessments (baseline, neoadjuvant treatment day 22) 
will be provided to the sponsor.  Further information is available in the laboratory manual. 
 
 
 
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APPENDIX 4. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS: RECIST GUIDELINE (VERSION 1.1) 
This appendix has been excerpted from the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline version 1.1 (Eisenhauer, 2009).  For full details pertaining to the RECIST 1.1 
criteria, please refer to the publication. 
1. 
Assessment of Tumor Burden Measurable Disease at Baseline 
Overall tumor burden must be assessed at baseline and will be used as comparator for subsequent 
measurements.  Tumor lesions will be characterized as measurable or non-measurable as follows: 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1; 
Eisenhauer, 2009).  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
1.1. 
Measurable disease  
Tumor lesions 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 computed tomography (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) 
 20 mm by chest x-ray 
 Malignant lymph nodes:  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
1.2. 
Non-measurable disease   
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT, MRI, or PET) are 
considered as non-measurable. 
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1.2.1. Special Considerations 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  “Cystic lesions” thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above.  However, if 
noncystic lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
1.3. 
Methods of Assessment 
All measurements must be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 CT and MRI.  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g., for body scans). 
1.4. 
Baseline Documentation of Target and Non-Target Lesions 
Target lesions:  When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline.  Target lesions should be selected on the basis of their size (lesions with the longest 
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diameter), be representative of all involved organs, and should lend themselves to reproducible 
repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered 
non-target lesions.  Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions:  All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline.  Measurements 
of these lesions are not required, but the presence, absence, or, in rare cases, unequivocal 
progression of each should be noted throughout follow-up.  In addition, it is possible to record 
multiple non-target lesions involving the same organ as a single item on the case record form (e.g., 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
1.5. 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response for 
target and non-target lesions. 
1.5.1. Evaluation of Target Lesions 
 Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm (<1 cm). 
 Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the 
appearance of one or more new lesions is also considered progressions). 
 Stable Disease:  Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum diameters 
while on study. 
Special notes on the assessment of target lesions: 
 Lymph nodes:  Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded and should be measured in the same 
anatomical plane as the baseline examination, even if the nodes regress to below 
10 mm on study.  This means that when lymph nodes are included as target lesions, 
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the ‘sum’ of lesions may not be zero even if complete response criteria are met, since 
a normal lymph node is defined as having a short axis of <10 mm. 
 Target lesions that become ‘too small to measure’:  All lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  If the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm.  
However, when such a lesion becomes difficult to assign an exact measure to then: (i) 
if it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  (ii) if the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (note:  in case of a lymph node believed to be present and faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well).  This default value is derived from the 5 mm CT slice thickness (but should 
not be changed with varying CT slice thickness). 
 Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have coalesced such that they are no longer separable, 
the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
1.5.2. Evaluation of Non-Target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
 Complete Response:  Disappearance of all nontarget lesions and normalization of 
tumor marker level.  All lymph nodes must be nonpathological in size (<10 mm short 
axis). 
 Non-CR/Non-PD:  Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 Progressive Disease:  Appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
Although a clear progression of “nontarget” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or investigator). 
1.6. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important.  There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal:  ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
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to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions).  This is particularly important when the patient’s baseline 
lesions show partial or complete response.  For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression.  An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The patient’s brain metastases are considered to be evidence of progressive 
disease even if he/she did not have brain imaging at baseline.  If a new lesion is equivocal, for 
example because of its small size, continued therapy and follow-up evaluation will clarify if it 
represents truly new disease.    
1.7. 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment until the end 
of treatment.   The patient's best response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions.  
Revised Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Eisenhauer, 2009) 
is summarized in the table below.  
Response According to Revised Response Evaluation Criteria in Solid Tumors 
(Version 1.1) in Patients with Target (and Non-Target) Lesions 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response* 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/non-PD/not all evaluated 
No 
PR 
SD 
Non-CR/non-PD/not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD* 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Abbreviations:  CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease; 
NE=inevaluable. 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
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.  
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APPENDIX 5. DIGITAL PHOTOGRAPHIC PROCEDURES 
In this study, radiology studies will be the primary method of tumor assessment.  For patients with 
externally visible lesions, the investigator may wish to supplement response assessments with 
digital medical photography.  This Appendix provides guidelines for optional digital medical 
photography. 
Image Capture 
 Close-up view with millimeter scale of the target area of the CSCC 
 Global view of the target CSCC area 
Equipment 
 Camera: Canon SL1 with Ranging Lights  
 Lens: 60 mm Canon Lens 
 Flash: Canfield TwinFlash RL 
 Millimeter scale attachment  
 Dedicated laptop with Canfield Capture Application (software includes capturing, 
viewing and transferring images) 
 Canfield Tracing and Analysis application 
 Standardized background material 
The supplied equipment is to be used exclusively for this study.  No modification, adjustments, or 
repairs of the camera equipment are to be undertaken without the expressed instruction of Canfield 
Scientific, Inc. 
Canfield will provide each study site with the necessary hardware as well as technical support as 
needed.  All supplied photographic equipment remains the property of the Sponsor.  
Proper Patient Preparation and Positioning: 
In these clinical photographs for the duration of the study, the only variable allowed to change is 
the skin condition itself.  Therefore, anything extraneous to the condition (furniture, etc) is to be 
eliminated from the photographic field, starting at the entry visit through the final visit.  The 
necessity of good end-of-study photographs should be stressed to patients to ensure their 
cooperation.  Lighting, framing, exposure, and reproduction ratios must be held constant.  In the 
end, the images should read like a time-lapse movie.  
In the close-up view, the area of interest is the individual target lesion itself.  In the global view, 
the area of interest includes the target lesion as well as relevant anatomical landmarks, eg, side of 
face, side of neck, upper torso, full view of shoulder, etc.  Photographs should be taken with the 
camera positioned at the same vertical height as the center of area of interest.  Further, all shots 
should be made with the axis of the camera lens perpendicular to the surface of area of interest 
when possible.  Glancing shots where the camera lens is not perpendicular to the patient’s area of 
interest are to be avoided as these photographic angles may distort the image perspective yielding 
inaccuracies when measurement of lesions is performed on photos by central review. 
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The supplied standardized background material is to be used.  Do not use wrinkled or crimped 
material. 
The Canfield Capture software controls the setting of the camera specific to the protocol.  The lens 
is set for auto focusing.  The close-up view is accomplished using the attached standardized mm 
scale.  The global view is accomplished when the ranging lights converge on the target area.  Any 
doubt as to the correctness of the photographic technique should result in an immediate re-shoot.  
At the baseline visit, a profile view (perpendicular to the skin’s plane) will also be obtained of 
each lesion to capture any projection above the skin.  For all lesions in which the baseline profile 
view demonstrates significant projection above the skin, defined as ≥15 mm, the profile view will 
also be obtained at subsequent scheduled clinical assessments of response.  
For each global view and each close-up view, an unannotated photograph must be taken 
followed by a manually annotated photograph. 
For response assessments, Canfield imaging software should be used to assure that the photograph 
is taken at the same position and angle as the Baseline photograph.  The annotated image from the 
prior visit should be referenced on the laptop screen prior to making annotations on the new image. 
Photographic Procedures: 
1. Prior to capturing the patient images using the camera system, the photographer launches 
the Canfield Scientific Canfield Capture Application by selecting the icon from the 
desktop.  
2. The photographer either creates a New Patient for an initial visit or, for a return subject, 
highlights the appropriate existing Patient ID listed in the Canfield Capture database.  The 
visit name (as per study schedule) is selected by the photographer and the image date is 
captured by the software. 
3. With the patient’s target area positioned correctly in front of the camera system, the 
Photographer adjusts the camera distance for accurate system focus.  The first capture is a 
Close-up view of patient’s target CSCC area(s) using the attached mm scale, consisting of 
one individual CSCC lesion.  The second capture is Global view of patient’s target CSCC 
area(s), consisting of up to two individual CSCC lesions.  For the global view the camera 
is moved closer to or further away from the target until the two green ranging lights 
converge to become one dot. 
4. The Photographer captures the image and is then prompted to review image acceptability.  
The Photographer either accepts the image and moves on to the next capture or does not 
accept and recaptures the image.  
5. After capturing the series of non-annotated lesion(s), the Investigator will annotate the 
circumference and axes delimiters of lesion with supplied skin pen.  Following the same 
procedure as the non-annotated image capture the site will capture the series of annotated 
lesion(s) images. 
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6. Following the session, the Photographer submits the images to Canfield.  Upon exiting, the 
software automatically reads, checksums, encrypts, packages, and duplicates the data to 
submit to Canfield via internet or removable media submission.  
a. Internet: A secure, validated, compliant web server set up at Canfield is used for secure 
transfer of study images by study sites.  Images are to be transferred the day they are 
recorded.  Only approved individuals by the Sponsor have access to the website.  
The application logs a record of this action to a local database and prompts the Photographer when 
completed.  
7. Upon completion of photography session, the Investigator will log in to the Canfield 
tracing application may (optional) annotate the lesion and the software will provide 
measurements (surface area, longest diameter, perpendicular diameter) of the lesion. 
8. Trained Canfield staff review the data files for technical quality and acceptability and 
communicate any comments to the site. 
9. At the end of the study, a copy of site specific patient images will be provided to each site.  
This is in addition to the Photography Result Reports available for printing from the 
Clinical Services Website after each session.  Remote access to all images by the Sponsor 
is also provided.  
Any questions or problems regarding the photographic portion of this study are to be forwarded to 
the assigned Project Manager at Canfield Scientific. 
Canfield Scientific, Inc. 
253 Passaic Avenue 
Fairfield, NJ 07004 United States 
 
 
 
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