Clinical trial NCT04646005
Conditions: Cervical Cancer
Keywords: HPV16 positive Squamous histology Recurrent Metastatic Adenocarcinoma/adenosquamous histology
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-06-28; Completion date: 2024-05-29
Enrollment: 113 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b after progression on first line chemotherapy, as assessed by objective response rate (ORR).

The secondary objectives of the study are:

* To characterize the safety profile of cemiplimab + ISA101b
* To assess preliminary efficacy of cemiplimab + ISA101b as measured by duration of response (DOR), progression-free survival (PFS), and overall survival (OS)

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Cemiplimab intervention 2: ISA101b
Intervention descriptions: intervention 1: Administered intravenously (IV) every three weeks (Q3W) intervention 2: Administered by subcutaneous (SC) injection on day 1, day 29, and day 50

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R2810-ONC-ISA-1981 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 1 
CONFIDENTIAL 
EudraCT Number: 2020-001239-29 
IND Number: 19715 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2 STUDY OF CEMIPLIMAB, AN ANTI-PD-1 MONOCLONAL 
ANTIBODY, AND ISA101B VACCINE IN PATIENTS WITH 
RECURRENT/METASTATIC HPV16 CERVICAL CANCER WHO 
HAVE EXPERIENCED DISEASE PROGRESSION AFTER FIRST LINE 
CHEMOTHERAPY 
Compound: 
Cemiplimab (REGN2810 [anti-PD-1 mAb]) 
Clinical Phase: 
2 
Protocol Number: 
R2810-ONC-ISA-1981 
Protocol Version: 
R2810-ONC-ISA-1981 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
14 Sep 2020 
Original Date of Issue: 
07 Apr 2020 
Medical/Study Director: 
  
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential:  This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
VV-RIM-00164906-1.0 Approved - 31 Aug 2021 GMT-5:00
NCT04646005


Clinical Study Protocol 
 
R2810-ONC-ISA-1981 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The main reasons for this amendment are to allow: 
1. The enrollment of patients with adenocarcinoma/adenosquamous as well as squamous 
cell histologies of cervical cancer. Patients with adenocarcinoma/adenosquamous 
histology will account for up to approximately 20% of the patient population, and this is 
not expected to impact the primary endpoint of ORR estimation. 
2. A change in the primary endpoint of this single arm study from statistical hypothesis 
testing to estimation of the ORR with associated confidence intervals, and to permit an 
administrative assessment after the first 53 patients have had the opportunity for at least 4 
tumor assessments.  
The following table outlines the changes made to the protocol and the affected sections. 
Description of Change 
Brief Rationale 
Section # and Name 
Added patients with 
adenocarcinoma/adenosquamous 
histology and increased the sample 
size to 105 patients. 
Based on clinical experience 
with cemiplimab, patients with 
adenocarcinoma/adenosquamous 
histologies may potentially 
benefit from treatment with 
cemiplimab and ISA101b. 
List of Abbreviations and Definitions 
of Terms 
Clinical Study Protocol Synopsis 
(Study Design, Population, Statistical 
Plan) 
Section 1.1 Background of Cervical 
Cancer 
Section 3.1 Hypothesis 
Section 6.1 Study Description and 
Duration 
Section 7.1 Number of Patients 
Planned  
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria, 
criterion #2  
Section 11.2 Justification of Sample 
Size 
Section 11.3.1 Full Analysis Set 
Section 11.3.2 Safety Analysis Set 
(removed) 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.4 Control of Multiplicity 
Removed statistical hypothesis 
testing and added the option for an 
administrative efficacy review 
when at least 4 tumor assessments 
are collected for the first 53 
patients. 
To analyze data without a 
formal hypothesis. 
Clinical Study Protocol Synopsis 
(Statistical Plan) 
Section 3.1 Hypothesis 
Section 6.2 Planned Interim Analysis 
Section 11.1 Statistical Hypothesis 
Section 11.4.3 Efficacy Analysis 
Section 11.5 Interim Analysis 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Added approved indications for 
cemiplimab and updated clinical 
trial data. 
To reflect recent approvals in 
basal cell carcinoma (BCC) and 
non-small cell lung cancer 
(NSCLC) 
Section 1.2 Background on 
Cemiplimab 
Section 3.3.2.1 Benefit for 
Cemiplimab 
Section 8.1 Investigational and 
Reference Treatments 
The risk-benefit and permitted 
concomitant medication sections 
have been updated to provide 
guidance about when patients may 
receive a COVID-19 vaccine prior 
to and while enrolled in this study. 
Guidance has been added about 
when patients may be vaccinated 
prior to and while enrolled in 
this study to support global 
vaccination activities during the 
COVID-19 pandemic. 
Section 3.3.1.1 COVID-19 
Vaccination During the Study 
Section 8.7.2 Permitted Medications 
Section 11 Statistical Plan 
Added language regarding the 
formulation of ISA101b 
To clarify that ISA101b 
constitutes 2 separate injections. 
Section 8.1.2 ISA101b 
Added language for study drug 
discontinuation due to 
myocarditis/pericarditis 
To better monitor the safety of 
study patients. 
Section 8.2.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
Clarified safety guidelines guidance 
for management of immune-
mediated adverse events (imAEs). 
To align with most current 
safety guidance. 
Section 8.2.2.2 Reasons for Temporary 
Discontinuation of Study Drug (new) 
Section 8.2.3 Immune-Mediated 
Adverse Events 
Section 8.2.3.1 Identification of 
Immune-mediated Adverse Events 
Section 8.2.3.2 Management of 
Immune-Mediated Adverse Events 
Section 8.2.4 General Guidance for 
Management of Adverse Events (new) 
Table 1 General Guidelines for 
Management of Treatment-Related 
Adverse Events (new) 
Section 8.3 Management of Acute 
Reactions 
Section 8.3.1 Acute Intravenous 
Infusion Reactions 
Section 8.3.1.1 Interruption of 
Intravenous Infusion 
Section 10.1.1 Adverse Events 
Section 10.1.2 Serious Adverse Events 
Section 10.1.3 Other Events that 
Require Accelerated Reporting to 
Sponsor 
Section 10.1.3.1 Immune-Mediated 
Adverse Events 
Section 10.1.4 Reporting Adverse 
Events Leading to Withdrawal from 
the Study 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Section 10.1.5 Abnormal Laboratory, 
Vital Signs, or Electrocardiogram 
Results 
Appendix 2 Guidelines for 
Management of Immune-Mediated 
Adverse Events 
Schedule of events updates: 
- 
Changed imaging window 
from 3 days to 7 days 
- 
Added footnote 6 to tumor 
tissue sample 
To provide clarity on timing of 
assessments 
Section 9.1 Schedule of Events 
Table 2 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, footnote #6, 
#10  
Section 9.2.2.1 Computed 
Tomography and/or Magnetic 
Resonance Imaging 
Information was added regarding 
immunogenicity characterization by 
status and level of observed 
response of antidrug antibody 
(ADA) analysis. 
This update clarifies that ADA 
analysis also includes an ADA 
Negative category 
Section 11.4.8 Analysis of 
Immunogenicity Data 
Administrative updates 
To correct administrative 
language 
Title Page 
Minor editorial changes 
To correct typographical, 
grammatical, and formatting 
errors. 
Throughout the document 
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CONFIDENTIAL 
Amendment 1 
The main reasons for this amendment are as follows: 
• To provide total study duration including time for enrollment, time to primary 
analysis, and time for survival follow up. 
• To provide clarification that the order of ISA101b and cemiplimab administration is 
as follows: cemiplimab first, then ISA101b one hour later. Additionally, patients need 
to be observed for 4 hours after each administration of ISA101b.  
• To allow archival tissue to be sent during the time between signing of the informed 
consent form and the start of the screening period. 
• To provide language regarding study-conduct during the Coronavirus Disease 2019 
(COVID-19) pandemic. 
Description of Change  
Brief Rationale  
Section # and Name  
The study duration was edited to 
include values for time for 
enrollment, time to primary analysis, 
and time for survival follow up. 
Text updated based on health 
authority feedback. 
Clinical Study Protocol Synopsis: 
Study Duration 
Section 6.1 Study Description and 
Duration 
Edited inclusion criteria to specify 
that the legal age of consent depends 
on the country of enrollment. 
Text updated to conform to country-
specific legal age of consent globally. 
Section 7.2.1Inclusion Criteria, #1 
Clarification added that ISA101b 
needs to be given 1 hour after 
cemiplimab administration on days 
29 and 50, and that patients need to 
be observed for 4 hours after each 
ISA101b administration. 
Text updated for consistency with 
other ISA + cemiplimab programs 
and to help distinguish between 
immune-mediated adverse events and 
injection site reactions. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description 
Duration 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, footnote 
#8 and #9 
Edited text to allow archival tissue to 
be sent during the time between 
signing of the informed consent form 
and the start of the screening period. 
To clarify that samples may be sent 
as soon as informed consent is 
obtained. 
Section 9.2.1.1 HPV16 Diagnostic 
Test 
Added language regarding site 
enrollment and initiation in light of 
COVID-19. 
To describe the plan, during the 
public health emergency due to 
COVID-19, for trial sites that have 
not already begun patient screening 
or enrollment in the study. 
Section 3.3.1 Patient Screening and 
Site Initiation in Response to 
COVID-19 
Added language regarding the 
continuity of clinical study conduct 
and oversight related to COVID-19. 
To describe the continuity plan for 
conducting clinical study activities 
and study oversight activities during 
the public health emergency due to 
COVID-19 
Section 9.1 Schedule of Events 
Removed concentration of 
cemiplimab in vials. 
To not specify concentration of 
cemiplimab provided to study sites in 
the event that concentrations change 
during the study.  
Section 8.1.1 Cemiplimab 
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Description of Change  
Brief Rationale  
Section # and Name  
Added language to allow the 
continuation of treatment with 
cemiplimab after toxicity due to 
ISA101b. 
Text added to mirror the present 
language regarding the continuation 
of treatment with ISA101b after 
toxicity due to cemiplimab. 
Section 8.2.1 Dose Modification 
Added ±3-day window to timing of 
dose administration if a dose of 
ISA101b is missed. 
To provide flexibility in the 
administration of dosing due to 
ISA101b-specific adverse events. 
Section 8.3.3.3.1 Management of 
ISA101b-Specific Adverse Events 
The schedule of events footnote 
regarding pregnancy testing was 
edited to allow either serum or urine 
testing at all time points. 
The text was changed for clarification 
purposes. 
Section 7.2.2 Exclusion Criteria, #21 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, footnote 
#17 
Section 9.2.1 Procedures Performed 
Only at the Screening Visit 
Section 9.2.3.6 Laboratory Testing 
Updated schedule of events as 
follows: 
Added assessment of concomitant 
medications at the screening visit 
Added anti-drug antibody (ADA) 
assessments at C1D1, C3D1, and 
C5D1 
To provide consistency across the 
study. 
To match the ADA footnote 
Table 1 Schedule of Events 
Added hourly vital sign 
measurements during the 4-hour 
observation period after 
administration of ISA101b.  
To confirm patient safety 
immediately following administration 
of ISA101b. 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, footnote 
#14 
Section 9.2.3.4 Vital Signs 
Clarified that peripheral blood 
mononuclear cells (PBMC) collection 
is also performed on day 1 of cycles 2 
through 4 and 5+. 
To be consistent with the schedule of 
events table 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, footnote 
#20 
Edited details regarding CT/MRI 
scans and confirmation of complete 
response or partial response. 
To clarify which tests, modalities, 
and techniques are acceptable for 
efficacy measurements. 
Section 5.2 Efficacy Variables 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #10 
Section 9.2.2.1 Computed 
Tomography and/or Magnetic 
Resonance Imaging 
Appendix 3 Response Evaluation 
Criteria in Solid Tumors: RECIST 
Guideline (Version 1.1) 
Response According to Revised 
Response Evaluation Criteria in Solid 
Tumors (Version 1.1) in Patients with 
Target (and Non-Target Lesions 
When Confirmation is Required 
(table revised) 
Best Overall Response When 
Confirmation of CR and PR are 
Required (new table) 
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Description of Change  
Brief Rationale  
Section # and Name  
Added language to allow total T3 and 
total T4 samples to be measured at 
the site’s local laboratory if free T3 
and free T4 cannot be collected. 
Text updated to provide leniency in 
the event that free T3 and free T4 
cannot be measured at the site’s local 
laboratory. 
Section 9.2.3.6 Laboratory Testing 
Edited text regarding tumor 
assessments to clarify that 
assessments are performed after every 
2 doses of cemiplimab for the first 
4 cycles, and subsequent cycles will 
have assessments after every 3 doses 
of cemiplimab. 
For clarification. 
Section 3.3.2.2 Risk for Cemiplimab 
Replaced immune-related adverse 
events (irAEs) with immune-
mediated adverse events (imAEs). 
To be consistent with company-wide 
language. 
Throughout the protocol 
Minor typographical edits. 
For correction and clarity 
Throughout the protocol 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AC 
Adenocarcinoma/adenosquamous 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APC 
Antigen presenting cell 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CNS 
Central nervous system 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete response 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSR 
Clinical Study Report 
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
DOR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
HBsAg +  
Hepatitis B virus surface antigen positive 
HBV 
Hepatitis B virus 
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CONFIDENTIAL 
HCV 
Hepatitis C virus 
HCV Ab + 
Hepatitis C virus antibody positive  
HDR 
Homologous DNA repair gene 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HPV 
Human papillomavirus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG4P 
Immunoglobulin G subclass 4 
IHC 
Immunohistochemistry 
imAE 
Immune-mediated adverse event 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ISA 
ISA Pharmaceuticals B.V. 
ISR 
Injection site reaction 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NOAEL 
No-observed-adverse-effect-level 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PCSV 
Potentially clinically significant value 
PD-1 
Programmed death-1 (receptor) 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
Q3W 
Every 3 weeks 
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Clinical Study Protocol 
 
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RBC 
Red blood cell 
rDOR 
Duration of Response based upon radiographic response  
RECIST 
Response Evaluation Criteria in Solid Tumors 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Stable disease 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor-infiltrating lymphocytes 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................18 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background on Cervical Cancer .................................................................................22 
1.2. 
Background on Cemiplimab .......................................................................................23 
1.3. 
Background on ISA101b ............................................................................................24 
1.3.1. 
Nonclinical Data .........................................................................................................25 
1.3.2. 
Clinical Experience .....................................................................................................25 
1.3.3. 
Safety Profile ..............................................................................................................27 
1.3.4. 
Pharmacokinetics ........................................................................................................28 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
2.3. 
Exploratory Objectives ...............................................................................................29 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................30 
3.1. 
Hypothesis ..................................................................................................................30 
3.2. 
Rationale .....................................................................................................................30 
3.2.1. 
Rationale for Study Design .........................................................................................30 
3.2.2. 
Rationale for Dose Selection ......................................................................................31 
3.3. 
Risk-Benefit ................................................................................................................31 
3.3.1. 
Patient Screening and Site Initiation in Response to COVID-19 ...............................31 
3.3.1.1. 
COVID-19 Vaccination During the Study .................................................................32 
3.3.2. 
Risk-Benefit for Cemiplimab .....................................................................................32 
3.3.2.1. 
Benefit for Cemiplimab ..............................................................................................32 
3.3.2.2. 
Risk for Cemiplimab ...................................................................................................32 
3.3.2.3. 
Benefit:Risk for Cemiplimab ......................................................................................32 
3.3.3. 
Risk-Benefit for ISA101b ...........................................................................................33 
3.3.3.1. 
Benefit of ISA101b .....................................................................................................33 
3.3.3.2. 
Risk of ISA101b .........................................................................................................33 
3.3.3.3. 
Benefit:Risk for Cemiplimab/ISA101b Combination ................................................33 
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4. 
ENDPOINTS ..............................................................................................................35 
4.1. 
Primary Endpoint ........................................................................................................35 
4.2. 
Secondary Endpoints ..................................................................................................35 
4.3. 
Exploratory Endpoints ................................................................................................35 
5. 
STUDY VARIABLES................................................................................................36 
5.1. 
Demographic and Baseline Characteristics ................................................................36 
5.2. 
Efficacy Variables ......................................................................................................36 
5.3. 
Safety Variables ..........................................................................................................36 
5.4. 
Immunogenicity Variables ..........................................................................................36 
5.5. 
Pharmacodynamic and Other Biomarker Variables ...................................................36 
6. 
STUDY DESIGN .......................................................................................................38 
6.1. 
Study Description and Duration .................................................................................38 
6.1.1. 
End of Study Definition ..............................................................................................39 
6.2. 
Planned Interim Analysis ............................................................................................39 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............40 
7.1. 
Number of Patients Planned .......................................................................................40 
7.2. 
Study Population .........................................................................................................40 
7.2.1. 
Inclusion Criteria ........................................................................................................40 
7.2.2. 
Exclusion Criteria .......................................................................................................41 
7.3. 
Premature Withdrawal from the Study .......................................................................45 
7.4. 
Replacement of Patients .............................................................................................45 
8. 
STUDY TREATMENTS............................................................................................46 
8.1. 
Investigational and Reference Treatments ..................................................................46 
8.1.1. 
Cemiplimab .................................................................................................................46 
8.1.2. 
ISA101b ......................................................................................................................46 
8.2. 
Dose Modification and Study Treatment Discontinuation Rules ...............................46 
8.2.1. 
Dose Modification ......................................................................................................46 
8.2.2. 
Study Drug Discontinuation .......................................................................................46 
8.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................47 
8.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................47 
8.2.3. 
Immune-Mediated Adverse Events ............................................................................47 
8.2.3.1. 
Identification of Immune-mediated Adverse Events ..................................................47 
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8.2.3.2. 
Management of Immune-Mediated Adverse Events ..................................................48 
8.2.4. 
General Guidance for Management of Adverse Events .............................................49 
8.3. 
Management of Acute Reactions ................................................................................50 
8.3.1. 
Acute Intravenous Infusion Reactions ........................................................................50 
8.3.1.1. 
Interruption of the Intravenous Infusion .....................................................................51 
8.3.1.2. 
Termination of the Intravenous Infusion ....................................................................52 
8.3.1.3. 
Local Injection Site Reactions ....................................................................................52 
8.4. 
Method of Treatment Assignment ..............................................................................53 
8.5. 
Blinding ......................................................................................................................53 
8.6. 
Treatment Logistics and Accountability .....................................................................53 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................53 
8.6.1.1. 
Cemiplimab .................................................................................................................53 
8.6.1.2. 
ISA101b ......................................................................................................................53 
8.6.2. 
Supply and Disposition of Treatments .......................................................................54 
8.6.2.1. 
Cemiplimab .................................................................................................................54 
8.6.2.2. 
ISA101b ......................................................................................................................54 
8.6.3. 
Treatment Accountability ...........................................................................................54 
8.6.4. 
Treatment Compliance ................................................................................................54 
8.7. 
Concomitant Medications ...........................................................................................54 
8.7.1. 
Prohibited Medications ...............................................................................................55 
8.7.2. 
Permitted Medications ................................................................................................55 
8.8. 
Treatment with Cemiplimab Beyond Disease Progression ........................................56 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................58 
9.1. 
Schedule of Events .....................................................................................................58 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................62 
9.1.2. 
End of Treatment Visit ...............................................................................................63 
9.1.3. 
Unscheduled Visits .....................................................................................................63 
9.1.4. 
Follow-Up ...................................................................................................................63 
9.2. 
Study Procedures ........................................................................................................64 
9.2.1. 
Procedures Performed Only at the Screening Visit ....................................................64 
9.2.1.1. 
HPV16 Diagnostic Test ..............................................................................................64 
9.2.2. 
Efficacy Procedures ....................................................................................................64 
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9.2.2.1. 
Computed Tomography and/or Magnetic Resonance Imaging ..................................64 
9.2.3. 
Safety Procedures .......................................................................................................65 
9.2.3.1. 
Electrocardiogram .......................................................................................................65 
9.2.3.2. 
Performance Status .....................................................................................................65 
9.2.3.3. 
Body Weight and Height ............................................................................................65 
9.2.3.4. 
Vital Signs ..................................................................................................................66 
9.2.3.5. 
Physical Examination .................................................................................................66 
9.2.3.6. 
Laboratory Testing ......................................................................................................66 
9.2.3.7. 
Additional Samples .....................................................................................................67 
9.2.4. 
Drug Concentration and Pharmacokinetic Measurements .........................................67 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................68 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................68 
9.2.7. 
Peripheral Blood Biomarkers .....................................................................................68 
9.2.8. 
Survival Data Collection .............................................................................................68 
9.2.9. 
Future Biomedical Research (Optional) .....................................................................68 
9.2.10. 
Pharmacogenomic Analysis (Optional) ......................................................................69 
10. 
SAFETY EVALUATION AND REPORTING .........................................................70 
10.1. 
Recording and Reporting Adverse Events ..................................................................70 
10.1.1. 
Adverse Events ...........................................................................................................70 
10.1.2. 
Serious Adverse Events ..............................................................................................70 
10.1.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................70 
10.1.3.1. 
Immune-Mediated Adverse Events ............................................................................71 
10.1.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................71 
10.1.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................71 
10.2. 
Definitions ..................................................................................................................72 
10.2.1. 
Adverse Event .............................................................................................................72 
10.2.2. 
Serious Adverse Event ................................................................................................72 
10.2.3. 
Adverse Events of Special Interest .............................................................................73 
10.2.4. 
Infusion Reactions ......................................................................................................73 
10.2.5. 
Severity .......................................................................................................................73 
10.2.6. 
Causality .....................................................................................................................73 
10.3. 
Safety Monitoring .......................................................................................................75 
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10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................75 
11. 
STATISTICAL PLAN................................................................................................76 
11.1. 
Statistical Hypothesis ..................................................................................................76 
11.2. 
Justification of Sample Size........................................................................................76 
11.3. 
Analysis Sets ...............................................................................................................76 
11.3.1. 
Full Analysis Set .........................................................................................................76 
11.3.2. 
Pharmacokinetic Analysis Sets ...................................................................................77 
11.3.3. 
Immunogenicity Analysis Sets ...................................................................................77 
11.4. 
Statistical Methods ......................................................................................................77 
11.4.1. 
Patient Disposition ......................................................................................................77 
11.4.2. 
Demography and Baseline Characteristics .................................................................77 
11.4.3. 
Efficacy Analyses .......................................................................................................77 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................77 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................78 
11.4.4. 
Control of Multiplicity ................................................................................................78 
11.4.5. 
Safety Analysis ...........................................................................................................78 
11.4.5.1. 
Adverse Events ...........................................................................................................78 
11.4.5.2. 
Deaths, other SAEs, and TEAEs leading to permanent treatment 
discontinuation will be summarized.Other Safety ......................................................79 
11.4.5.3. 
Treatment Exposure ....................................................................................................79 
11.4.5.4. 
Treatment Compliance ................................................................................................79 
11.4.6. 
Pharmacokinetics ........................................................................................................79 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................79 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................79 
11.4.8. 
Analysis of Immunogenicity Data ..............................................................................80 
11.5. 
Interim Analysis ..........................................................................................................80 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........80 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................81 
12.1. 
Data Management and Electronic Systems ................................................................81 
12.1.1. 
Data Management .......................................................................................................81 
12.1.2. 
Electronic Systems ......................................................................................................81 
12.2. 
Study Monitoring ........................................................................................................81 
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12.2.1. 
Monitoring of Study Sites ...........................................................................................81 
12.2.2. 
Source Document Requirements ................................................................................82 
12.2.3. 
Case Report Form Requirements ................................................................................82 
12.3. 
Audits and Inspections ................................................................................................82 
12.4. 
Study Documentation .................................................................................................83 
12.4.1. 
Certification of Accuracy of Data ...............................................................................83 
12.4.2. 
Retention of Records ..................................................................................................83 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................83 
13.1. 
Good Clinical Practice Statement ...............................................................................83 
13.2. 
Informed Consent .......................................................................................................83 
13.3. 
Patients Confidentiality and Data Protection ..............................................................84 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................84 
13.5. 
Clinical Study Data Transparency ..............................................................................84 
14. 
PROTOCOL AMENDMENTS ..................................................................................85 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................85 
15.1. 
Premature Termination of the Study ...........................................................................85 
15.2. 
Close-out of a Site ......................................................................................................85 
16. 
CONFIDENTIALITY ................................................................................................85 
17. 
FINANCING AND INSURANCE .............................................................................86 
18. 
PUBLICATION POLICY ..........................................................................................86 
19. 
REFERENCES ...........................................................................................................87 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................91 
 
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LIST OF TABLES 
Table 1: 
General Guidelines for Management of Treatment-Related Adverse Events ............49 
Table 2: 
Schedule of Events .....................................................................................................59 
Table 3: 
The 2-sided 95% Confidence Intervals for Observed ORR Based on a 
Sample Size of 105 Patients .......................................................................................76 
 
LIST OF FIGURES 
Figure 1: 
Composition of ISA101b (HPV-DP-5P and HPV-DP-7P) Vaccine Containing 
Peptides Covering HPV16 E6 and E7 Oncoprotein Sequences ...................................24 
Figure 2: 
Study Flow Diagram ...................................................................................................39 
 
LIST OF APPENDICES 
APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .............................................................................................................92 
APPENDIX 2. GUIDELINES FOR MANAGEMENT OF IMMUNE-MEDIATED 
ADVERSE EVENTS ..........................................................................................93 
APPENDIX 3. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: 
RECIST GUIDELINE (VERSION 1.1) ...........................................................110 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2 Study of Cemiplimab, an Anti-PD-1 Monoclonal Antibody, and 
ISA101b Vaccine in Patients with Recurrent/Metastatic HPV16 Cervical 
Cancer Who Have Experienced Disease Progression after First Line 
Chemotherapy 
Site Location(s) 
Multiple sites globally. 
Objective(s) 
The primary objective of the study is to estimate the clinical benefit of 
cemiplimab + ISA101b after progression on first line chemotherapy, as 
assessed by objective response rate (ORR). 
The secondary objectives of the study are: 
• 
To characterize the safety profile of cemiplimab + ISA101b 
• 
To assess preliminary efficacy of cemiplimab + ISA101b as 
measured by duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS) 
Study Design 
This will be a single-arm, phase 2, global study of treatment with 
cemiplimab + ISA101b in HPV16-positive cervical cancer patients with 
disease progression on first line chemotherapy in the recurrent or metastatic 
setting. Study treatment and duration include cemiplimab every 3 weeks 
(Q3W) (with 3 doses of ISA101b on days 1, 29, and 50) until progression 
or any reason for early discontinuation. The primary endpoint is ORR. 
Patients will undergo screening evaluations to determine eligibility within 
28 days prior to first treatment. All patients will receive the following 
regimen:  
• 
ISA101b 100 μg/peptide by subcutaneous (SC) injection on day 1, 
day 29, and day 50 (total of 3 doses). 
• 
Cemiplimab 350 mg given by intravenous (IV) infusion over 30 
minutes Q3W on days 8 and 29 in cycle 1, on days 1 and 22 in 
cycle 2 through 4, and on days 1, 22, and 43 in all subsequent cycles 
or until disease progression or discontinuation of study drug for any 
other reason. 
Note: On days 29 and 50, cemiplimab will be administered first, 
and ISA101b will be administered approximately 1 hour after the 
end of the cemiplimab infusion. Patients must be observed for 4 
hours after each ISA101b administration. 
There will be a 90-day safety follow-up after the last dose of cemiplimab. 
Patients who discontinue study drug for reasons other than progression will 
be followed approximately every 4 months by scans (eg, CT scan and/or 
MRI) until disease progression or until the patient commences another 
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anticancer systemic therapy, whichever comes first. After progression, 
survival follow-up should occur approximately every 4 months.  
Study Duration 
Study duration includes a 28-day screening period. During the treatment 
period, cycle 1 will be 7 weeks long, cycles 2 through 4 will be 6 weeks 
long, and all subsequent cycles will be 9 weeks long. Additionally, there 
will be a 90-day safety follow-up after the last dose. 
Patients will be assessed for response at cycle 1 day 50 (week 7), then once 
per cycle (every 6 weeks for 3 cycles, then every 9 weeks in all subsequent 
cycles or until disease progression or discontinuation of study drug for any 
other reason). Patients with confirmed complete response (CR) after a 
minimum of 48 weeks of treatment may elect to discontinue treatment and 
continue with all relevant study assessments (eg, efficacy assessments). 
The total duration of study from start of screening to final analysis of OS is 
expected to be approximately 36 months (approximately 12 months of 
accrual, approximately 12 months of treatment, and approximately 12 
months of follow up). 
End of Study Definition 
The end of the study is defined as the date of the last contact of the last 
patient in the study. 
Population 
 
 
Sample Size: 
Approximately 105 patients are planned to be enrolled in the study. 
 
Target Population: 
The study population is patients with HPV16 positive cervical cancer with 
squamous histology or adenocarcinoma/adenosquamous histology who 
have progressed on first line chemotherapy in the recurrent or metastatic 
setting. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Cemiplimab 
Cemiplimab will be administered IV at a dose of 350 mg over 30 minutes 
(±10 minutes) Q3W. 
 
Study Drug 
 
Dose/Route/Schedule: 
ISA101b 
ISA101b 100 μg/peptide will be administered by 2 separate SC injections 
per dose on day 1, day 29, and day 50 (total of 3 doses). 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is ORR based on radiographic response, measured by 
RECIST version 1.1. 
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Secondary: 
The secondary endpoints are: 
• 
Incidence and severity of treatment-emergent adverse events 
(TEAEs)/adverse events of special interest (AESIs)/serious 
adverse events (SAEs) and ≥ grade 3 laboratory abnormalities 
during the treatment period and up to 90 days after the last dose of 
study treatment  
• 
DOR  
• 
PFS 
• 
OS 
Procedures and Assessments 
Tumor imaging (computed tomography [CT] or magnetic resonance 
imaging [MRI]) will be performed to measure tumor burden and to 
characterize the efficacy profile of study treatments using response criteria.  
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.   
Physical examination, laboratory tests, vital signs, electrocardiogram 
(ECG), pregnancy test for women of childbearing potential, and recording 
of adverse events (AEs) and concomitant medications will be performed to 
ensure patient safety and to characterize the safety profiles of study 
treatments. 
Other assessments will include: 
• 
Blood samples for pharmacokinetics (PK) 
• 
Blood samples to assess anti-cemiplimab antibodies 
• 
Baseline tumor tissue analysis of PD-L1 expression, tumor DNA 
and RNA sequence profiling and in situ tumor infiltrating immune 
cell subsets and density by IHC/RNAscope 
• 
Peripheral blood mononuclear cell sample analysis of HPV16 
antigen specific T-cell responses 
Statistical Plan 
Primary efficacy analysis will be performed when the last patient enrolled 
has had the opportunity for at least 4 tumor assessments. 
The planned total sample size for this study is 105 patients. 
The primary objective of the study is to estimate the clinical benefit of 
cemiplimab + ISA101b after progression on first line chemotherapy, as 
assessed by objective response rate (ORR). With 105 patients, the table 
below presents various response rates and associated 2-sided 95% CIs using 
a normal approximation of the binomial distribution, and precision of 
estimation defined as distance from the boundary to the center. If observed 
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ORR ranges from 20.0% to 34.3%, the precision estimation using 105 
patients ranges from 7.7% to 9.1%. 
The 2-sided 95% Confidence Intervals for Observed ORR Based on a 
Sample Size of 105 Patients 
Number of 
Responders 
Observed 
ORR 
95% CI 
Precision 
21 
20.0% 
(12.4, 27.7) 
7.7% 
24 
22.9% 
(14.8, 30.9) 
8.0% 
27 
25.7% 
(17.4, 34.1) 
8.4% 
31 
29.5% 
(20.8, 38.3) 
8.8% 
36 
34.3% 
(25.2, 43.4) 
9.1% 
The primary endpoint for efficacy analyses is the investigator-assessed ORR 
as determined by RECIST version 1.1. The ORR along with the 2-sided 95% 
confidence interval using a normal approximation of the binomial 
distribution will be summarized.  
The secondary efficacy endpoints as measured by DOR, PFS, and OS will 
be summarized by median and its 95% confidence interval using the Kaplan-
Meier method. 
Treatment-emergent AEs/AESIs/SAEs and grade 3 or greater laboratory 
abnormalities will be summarized using descriptive statistics. 
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1. 
INTRODUCTION 
1.1. 
Background on Cervical Cancer 
The global annual incidence of cervical cancer is approximately 527,000 cases per year, and there 
are approximately 265,000 deaths (Torre, 2015). The highest incidence rates are in the Caribbean, 
Africa, Eastern Europe, and South America (Forman, 2012). In the United States (US), there are 
approximately 13,170 new cases and 4,250 deaths annually (Siegel, 2019). In most cases, 
causation is due to infection with human papillomavirus (HPV). Although vaccination against high 
risk strains of HPV is projected to gradually decrease the global incidence of cervical cancer in the 
next 15 years, the burden of this disease remains profound (Bray, 2012). 
Internationally, the etiologic fraction of HPV-associated malignancy, based on HPV detection, 
varies by geography and anatomic site, but overall suggests that 70% of cervical cancers are caused 
by HPV16/18, and HPV16 is the primary oncogenic virus in other anogenital and oropharyngeal 
cancers. In a study of 777 cervical cancer tissue samples, the HPV16 genotype was detected in 
50.1% while the HPV18 genotype was detected in 16.1%, comprising 66.2% of HPV-associated 
cervical cancers. Widespread uptake of HPV16/18 vaccines has already been shown to decrease 
high-grade cervical lesions and is anticipated to substantially reduce the burden of HPV-associated 
cancers (Saraiya, 2015). 
For patients with locally advanced disease, the curative intent therapy is definitive radiation with 
concurrent cisplatin. However, recurrent or metastatic disease occurs in approximately one third 
of cervical cancer patients in the US. For women with recurrent or metastatic disease, the GOG240 
study established that standard first line therapy is platinum plus taxane doublet with the addition 
of bevacizumab, if clinically appropriate. Median survival with the triplet regimen is 17 months 
(Tewari, 2014). 
After progression on first line platinum-taxane based chemotherapy for recurrent or metastatic 
disease, conventional cytotoxic chemotherapy has limited efficacy. Non-randomized phase 2 trials 
have demonstrated survival times of 7.4 to 8.1 months (N = 29 and N = 43 patients, respectively) 
with single agent pemetrexed, gemcitabine, topotecan, vinorelbine, or irinotecan monotherapy 
(Lorusso, 2010), (Miller, 2008), (Schilder, 2005), (Bookman, 2000), (Muggia, 2004), 
(Muggia, 2005), (Look, 1998), (Takeuchi, 1991).  
Immunotherapy for advanced cervical cancer is a burgeoning field. Almost all cervical cancer is 
associated with high risk strains of HPV (Cancer Genome Atlas Research, 2017), and the presence 
of viral antigen may support anti-tumor immune responses. An example of a virally-associated 
tumor for which immunotherapy has demonstrated efficacy is Merkel Cell carcinoma 
(Gillison, 2016), (Nghiem, 2016). Cervical squamous cell carcinoma (SCC) may evade immune 
response by expression of PD-L1 (programmed-death ligand 1), the ligand for the immune-
checkpoint receptor PD-1 (programmed death-1) on T cells (Heeren, 2016).  
A non-randomized phase 2 trial of the anti-PD1 antibody pembrolizumab showed a durable 
response rate for patients with PD-L1 positive metastatic or recurrent cervical cancer treated with 
pembrolizumab monotherapy. Response rate for these patients was 14.6% (12/82 patients) with a 
median follow up time of 10.2 months (0.6 to 22.7 months) (Chung, 2019). These data led to an 
accelerated approval by the US FDA for patients with PD-L1 positive tumors in the United States. 
A non-randomized phase 1/2 trial showed a durable response rate for patients with metastatic or 
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recurrent cervical cancer treated with nivolumab monotherapy. Response rate for these patients 
was 26.3% (5/19 patients) with a median follow up of 19.2 months (1.4 to 31.4 months) 
(Naumann, 2019). An ongoing multicohort phase 1/2 trial showed early signals of durable 
responses in both first and second line metastatic cervical cancer with combination therapy with 
nivolumab and ipilimumab, an antibody directed against the CTLA-4 immune checkpoint. 
Responses ranged from 23.1% (6/26 patients) to 45.8% (11/24 patients) in varying dose levels. 
Median follow-up time ranged from 10.7 to 13.9 months (Naumann, 2019). The anti-PD1 
monoclonal antibody cemiplimab (also known as REGN2810) has also demonstrated preliminary 
efficacy against cervical cancer, as described in Section 1.2. 
These data are reassuring that immunotherapy has a role in recurrent/metastatic cervical cancer. 
While PD-1/PD-L1 blockade alone has a modest response rate, the consistent durability of these 
responses make it into a reasonable backbone for future combination therapies.  
Taken together, these data support a single arm study of the anti-PD1 antibody cemiplimab in 
combination with other agents such that may enhance anti-tumor immune responses, such as 
ISA101b in patients with recurrent or metastatic HPV16+ cervical cancer with SCC and AC 
histology who have experienced disease progression after first line chemotherapy (Section 1.3). 
1.2. 
Background on Cemiplimab 
LIBTAYO® (cemiplimab) is approved 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. It is also approved for the 
treatment of patients with locally advanced basal cell carcinoma, and as a first-line treatment 
option in advanced non-small cell lung cancer. 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 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 20 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. 
In the cemiplimab phase 1 study (R2810-ONC-1423), patients with cervical cancer were enrolled 
in the dose escalation phase and in 2 expansion cohorts. Cumulatively, there were 4/23 (17%) 
responses. All responses were in SCC patients. Duration of response ranged from 6.4 to 
14.7 months (NCT03257267). 
Cemiplimab is currently under investigation in R2810-ONC-1676, an open-label, randomized, 
multi-center, phase 3 trial comparing cemiplimab versus investigator’s choice (IC) chemotherapy 
in patients with recurrent or metastatic cervical cancer after platinum-based therapy. The primary 
objective is to compare overall survival (OS) between the arms. The trial showed a clinically and 
statistically significant survival benefit in patients with squamous cell carcinoma (SCC) and 
adenosquamous/adenocarcinoma (AC) histology. A total of 608 patients, including 477 patients 
with SCC histology and 131 patients with AC histology, were randomized in a 1:1 ratio to receive 
either monotherapy with cemiplimab or IC chemotherapy. Patients on the cemiplimab arm had a 
median survival of 12.0 months (95% CI 10.3 months to 13.5 months). Patients on the 
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chemotherapy arm had a median survival of 8.5 months (95% CI 7.5 months to 9.6 months). In 
addition to a survival benefit, patients had a clinically and statistically significant improvement in 
progression free survival (PFS) and overall response rate (ORR) (Tewari, 2021). Patients on the 
cemiplimab arm had an ORR of 16.4% (95% CI 12.5% to 21.1%). Patients on the chemotherapy 
arm had an ORR of 6.3% (95% CI 3.8 to 9.6%) (Press Release: Phase 3 Trial of Libtayo® 
(cemiplimab) Monotherapy in Advanced Cervical Cancer Stopped Early for Positive Result on 
Overall Survival, 2021). 
Additional information, including preclinical and clinical safety data, is available in the 
Investigator’s Brochure. 
1.3. 
Background on ISA101b 
ISA101/ISA101b1 is a therapeutic vaccine targeting the HPV type 16 E6/E7 proteins. The HPV16 
long peptides in ISA101b act as a therapeutic vaccine that stimulates the actions of both CD4+ T-
helper cells and CD8+ cytotoxic T cells against the known oncogenic sequences of the HPV16 
virus. These long peptides, containing multiple cytotoxic T-lymphocyte (CTL) and T-helper 
epitopes, are predominantly processed by professional antigen presenting cells (APCs), the 
dendritic cells (Bijker, 2007), (Bijker, 2008), (Rosalia, 2013). This leads to presentation of the 
exact amino acid sequences (epitopes) by human leukocyte antigen (HLA) class I and II molecules 
on dendritic cells. 
ISA101b consists of 9 overlapping long E6 peptides (five 32-mer and four 25-mer E6 peptides) 
and three 35-mer E7 peptides as shown in Figure 1. These peptides overlap by 10 to 18 residues 
and cover the complete sequence of HPV16 E6. The E7 oncoprotein sequence is almost completely 
represented by the peptide sequences (only amino acids 57 to 63 are not covered), due to the 
omission of 1 poorly manufacturable peptide (G-3980-R).  
Figure 1: 
Composition of ISA101b (HPV-DP-5P and HPV-DP-7P) Vaccine Containing 
Peptides Covering HPV16 E6 and E7 Oncoprotein Sequences  
 
The peptide sequences are synthetically produced and individually released and stored as bulk 
drug substances according to current good manufacturing processes. 
                                                 
1 The formerly developed product is called ISA101. ISA101b is a refined and reformulated version of ISA101 
designed to improve the ability to manufacture the vaccine at large scale and to increase the stability of the 
product. 
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A dose of 100 μg/peptide has been selected for further study based on both the strength of the 
induced HPV16 immune response and safety data in clinical trials. Additional details are provided 
in the ISA101b Investigator’s Brochure. 
1.3.1. 
Nonclinical Data 
ISA101b is designed as a therapeutic vaccine, which targets distinct human pathogenic viral 
antigens 
and 
triggers 
a 
highly 
human-specific 
immune 
response. 
The 
involved 
immunostimulatory/ immunomodulatory effects (eg, cascades of involved chemokines/cytokines 
and cells of the immune system but also organ and target antigen structures), as well as the HPV 
induced effects/target structures are highly human specific. Consequently, there are no known 
suitable animal species for the non-clinical safety testing of peptide vaccines. The HLA structure 
differs significantly between animal species; therefore, no other animal species shares an identical 
HLA structure with humans.  
The synthetic long peptides (SLP) used in ISA101b are not able to directly bind to the major 
histocompatibility complex (MHC), but act by being processed by Dendritic cells (DC) of 
experimental animals or human beings, followed by loading into the available MHC class I or II 
molecules of the individual animal or person. A selected long peptide of HPV16 E7, when 
formulated with one of several adjuvants, including Montanide ISA 51 VG (Montanide), has 
shown substantial beneficial activity by inducing murine-specific T-cell responses against 
established tumors in mice induced by HPV16 E6/E7, particularly when combined with 
chemotherapeutics such as cisplatin or a combination of carboplatin and paclitaxel. In rabbits a set 
of overlapping SLP of the 2 tumorigenic proteins E6 and E7 of cottontail rabbit papilloma virus 
(CRPV) formulated in Montanide induced rabbit-specific immune responses and cured rabbits of 
CRPV-induced papillomas. In summary, efficacy/induction of the targeted immune response was 
demonstrated in mouse and rabbit disease models. Toxicology studies in rats (HPV-16-SLP) and 
rabbits (ISA101) showed high vaccine-induced antibody levels against the immunogen. The 
therapeutic vaccine was well tolerated systemically after SC administration at high doses. In these 
studies, the vaccine was given together with the adjuvant Montanide to mimic clinical studies. 
Doses in the rat were up to 120 μg/peptide per injection, while in the rabbit study the animal dose 
(300 μg/peptide per injection) was the same absolute dose as used in earlier clinical trials, not 
adjusted for body weight or surface area. The only findings consisted of injection site findings 
related to the local, immunostimulatory effects of the vaccination.  
Nonclinical data including immunogenicity and toxicology are described in the ISA101b 
Investigator’s Brochure.  
1.3.2. 
Clinical Experience 
Previous Experience with HPV-16-SLP 
HPV-16-SLP (a prototype vaccine predecessor of ISA101b produced at the Leiden University 
Medical Center) was tested in several investigator-sponsored studies in patients with HPV16 
positive gynaecological premalignant and malignant diseases. The combined studies of the Leiden 
University Medical Center research group have shown that in the majority of patients with 
premalignant cervical intraepithelial neoplasia or vulvar intraepithelial neoplasia lesions, and in 
slightly more than half of the patients with recurrent or metastatic cervical cancer, a positive T-cell 
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response can be induced by vaccination with HPV-16-SLP in Montanide adjuvant compared with 
a weak or nondemonstrable T-cell response in patients who were not vaccinated. These results 
were recently confirmed in an independent study with vulvar intraepithelial neoplasia patients 
(van Poelgeest, 2016). 
In a pilot study in patients with late stage cervical cancer, the T-cell immune responses induced by 
a single dose of HPV-16-SLP were considerably augmented by timing the vaccination 15 days 
after the second cycle of carboplatin/paclitaxel chemotherapy, due to the much lower levels of 
myeloid-derived suppressor cells, but intact T cell numbers and function at this time point 
(Welters, 2018). 
CervISA Study of ISA101/101b in Patients with Advanced, Metastatic, or Recurrent HPV16 
Positive Cervical Cancer 
Encouraging results using ISA101/ISA101b have been observed in a single arm study (CervISA) 
in women with advanced HPV16 positive cervical cancer. This study evaluated the safety, 
tolerability, immune responses, and clinical outcomes of ISA101/101b given in sequence with 
carboplatin and paclitaxel in women with HPV16 positive advanced cervical cancer. The 
maximum treatment duration was six 21-day cycles of carboplatin and paclitaxel (total 18 weeks) 
if there were no dose interruptions or delays. On day 15 (± 3 days) of cycles 2, 3, and 4, patients 
were vaccinated with ISA101 without or with pegylated IFNα (depending on cohort assignment). 
The patients were vaccinated with a fixed dose of ISA101/101b every 3 weeks (Q3W) for a total 
of 3 vaccinations. The enrollment in the CervISA study has been completed, including 72 patients 
that received ISA101 vaccination at a dose level of up to 300 μg/peptide. In addition, in a bridging 
cohort, 12 patients received ISA101b vaccination at the recommended phase 2 dose (RP2D) of 
100 μg/peptide without or with bevacizumab.  
Administration of ISA101/101b induced potent, specific, and durable immune responses to 
HPV16 epitopes. The HPV16 immune response was minimal at baseline and after the first cycle 
of chemotherapy, before the first dose of ISA101. After 2 or 3 doses of vaccination with ISA101, 
the HPV16-specific immune response was substantially increased, particularly at the 40 and 
100 μg/peptide dose levels. A further increase in the HPV16-specific T-cell immune response was 
not observed at the 300 μg/peptide dose level. Though only measured in 9 patients in each of the 
expansion cohorts vaccinated with the 40 and 100 μg/ peptide doses, the HPV-specific response 
appeared to be durable and was sustained for several months after the first vaccination.   
The T-cell response against common microbial recall antigens (memory mix, MRM) not present 
in the vaccine showed that these immune responses increased following the first 2 cycles of 
chemotherapy but was unaffected by administration of ISA101. 
An increase in OS was associated with the strength of the vaccine-induced HPV16 T-cell response 
to ISA101. ISA101/101b was generally well tolerated. The most common associated adverse 
events (AEs) were grade 1 or 2 local injection site reactions (ISRs). The ISRs were dose related 
and observed in approximately 85 to 90% of the patients who received the RP2D of 
100 μg/peptide. In addition, systemic allergic reactions were observed, particularly in patients 
receiving ISA101 at the 300 μg/peptide dose level. No clinically important overlapping toxicities 
of ISA101/ISA101b were identified with chemotherapy (paclitaxel and carboplatin).  
Additional information on this study is provided in the ISA101b Investigator’s Brochure. 
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Study ISA101-MDACC in Patients with HPV16 Positive Tumors 
Study ISA101-MDACC was an investigator-sponsored study at the MD Anderson Cancer Center 
(MDACC), designed to evaluate the overall response rate of patients with recurrent/metastatic 
incurable HPV16 positive malignancies after ISA101 vaccination in combination with the PD-1 
inhibitor nivolumab. Patients in this study had tumors with a confirmed HPV16 genotype as judged 
by Cervista HPV16/18. Patients had an Eastern Cooperative Oncology Group (ECOG) 
performance status 0 to 1 and could have had up to 1 prior regimen for recurrence. ISA101 100 
μg/peptide was given SC on days 1, 22, and 50. Nivolumab 3 mg/kg was given intravenously (IV) 
every 2 weeks beginning on day 8 for up to 1 year. 
The trial was completed in January 2017 after accruing 24 patients in 1 year; 22 with oropharyngeal 
carcinoma (OPC) and 1 patient each with anal and cervical cancer. Eighteen patients (75%) had 
progression within 6 months of prior platinum therapy and 1 was platinum-naïve. Twelve patients 
(50%) had prior cetuximab treatment. Study treatment was frontline for recurrence in 10/24 and 
second-line in 14/24. The patients with anal or cervical cancer did not show objective tumor 
regression, but 1 had stable disease (SD).   
The overall response rate in the 24 patients overall was 8/24 (33%), and in the subset with OPC 
8/22 (36%). There were 2 (9%) complete responders (CR), 6 (27%) partial responders (PR), 2 
(9%) patients with SD, and 12 (55%) patients with progressive disease (PD). As of 01 Sep 2017, 
5 of 8 patients with response remained without progression with median duration of response 
(DOR) 10.3 months (95% CI: 10.3 – inestimable). Of these 8 patients, all had OPC, 6 had 
progressed within 6 months of prior platinum therapy, 1 was platinum-naïve, 6 had prior 
cetuximab, 5 had progressed within 6 months of cetuximab, and 4 were treated in second-line. 
Toxicity included grade 3 transaminase and grade 4 lipase elevation in 1 patient each. Grade 1 to 
2 toxicity included fever (5 patients); injection site reaction (6 patients); and transaminase 
elevation, fatigue, nausea (3 patients each) (Massarelli, 2019). 
ISA101 was generally well tolerated in patients with HPV16 positive cancers, including OPC, and 
there did not appear to be overlapping toxicities with nivolumab. Based on its composition and 
clinical data, the safety, tolerability, and immune responses of ISA101b are comparable to ISA101. 
Additional details are provided in the ISA101b Investigator’s Brochure. 
1.3.3. 
Safety Profile 
Clinical experience in approximately 100 patients who have received ISA101 indicates that the 
most common AEs associated with ISA101 are local ISRs. The ISRs were dose related and 
observed in approximately 90% of the patients who received the RP2D of 100 μg/peptide. In 
addition, systemic allergic reactions have been observed, particularly in patients receiving higher 
doses of 300 μg/peptide (33%) compared to <5% at the 100 μg/peptide dose.  
Based on its composition and initial clinical data, ISA101b appears to have a comparable safety 
profile to ISA101. The available safety data with ISA101b indicate that it has an acceptable safety 
profile for use at 100 μg/peptide. The most frequent toxicities are local ISRs (predominantly 
grade 1 to 2). Systemic allergic reactions are potentially the most serious adverse reactions to 
ISA101/ISA101b.  
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No overlapping toxicities of ISA101/ISA101b with either chemotherapy (paclitaxel and 
carboplatin) or anti-PD-1 therapy (nivolumab) have been detected. No autoimmune AEs have been 
reported in relationship to HPV-16-SLP, ISA101 or ISA101b. Immune-mediated treatment-
emergent adverse events (TEAEs) have been reported with anti-PD-1 antibodies. For further 
information on ISA101b regarding appropriate recommendations and precautions, refer to the 
ISA101b Investigator’s Brochure. 
1.3.4. 
Pharmacokinetics 
The pharmacokinetic (PK) characteristics of ISA101/ISA101b have not been studied since the PK 
of a vaccine is not considered clinically relevant and does not correlate with its pharmacodynamic 
or immunologic actions. Pharmacodynamic effects are best assessed by the immunogenicity 
studies that have been incorporated in the clinical studies. 
Furthermore, ISA101/ISA101b is not metabolized in the conventional sense: the long peptides are 
taken up by antigen presenting cells (APCs), which process them to smaller peptides, called T-cell 
epitopes, which are then presented in HLA molecules on the surface of the APC. In the meantime, 
the APC traffics to a draining lymph node, where naive T cells recognize the presented T-cell 
epitopes and are activated by these epitopes. The peptides are processed within APCs through the 
standard HLA class I and II processing pathways. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b 
after progression on first line chemotherapy, as assessed by objective response rate (ORR). 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To characterize the safety profile of cemiplimab + ISA101b 
• To assess preliminary efficacy of cemiplimab + ISA101b as measured by DOR, 
progression-free survival (PFS), and OS 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To correlate clinical efficacy with baseline tumor tissue immune biomarkers including 
PD-L1, immune cell subsets, MHC class I/II, gene expression profile and tumor 
mutational burden. 
• To correlate clinical efficacy with on-treatment changes in HPV antigen specific T-cell 
responses, immune cell subsets and serum cytokine biomarkers  
• Explore novel molecular and cellular predictive and pharmacodynamic biomarkers 
associated with clinical efficacy, including cellular and molecular parameters in tumor 
tissue and peripheral blood.  
• To assess the immunogenicity of cemiplimab when combined with ISA101b 
• To explore other HPV serotypes present in HPV16+ tumors 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
In recurrent/metastatic HPV16 cervical cancer patients who have progressed on or after first line 
chemotherapy in the recurrent or metastatic setting, cemiplimab + ISA101b will lead to durable 
objective responses in a clinically meaningful proportion of patients, and these will be associated 
with the production of increased anti-HPV16 E6/E7 effector T-cell responses. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Unmet medical need in cervical cancer after progression on first line chemotherapy 
For women with recurrent or metastatic cervical cancer, the GOG240 study established that 
standard first line therapy is platinum plus taxane doublet with the addition of bevacizumab if 
clinically appropriate. Median survival with the triplet regimen is 17 months (Tewari, 2017). After 
progression on first line platinum-taxane based chemotherapy for recurrent or metastatic disease, 
the efficacy of cytotoxic chemotherapy is low with an approximate median survival of 7 months.   
Study of immunotherapeutic approaches in cervical cancer is of interest due to the presence of 
HPV viral antigen in virtually all tumors. Blockade of the PD-1 immune checkpoint with 
pembrolizumab achieved objective responses in 12% (12/98) of patients with recurrent/metastatic 
cervical cancer (Chung, 2019). In the subset of patients with PD-L1 positive tumors (CPS ≥1%), 
ORR was 14.6% (12/82). These observations led the US Food and Drug Administration (FDA) to 
grant accelerated approval for pembrolizumab for the treatment of this subgroup of patients. A 
randomized phase 3 trial of cemiplimab versus chemotherapy will determine if PD-1 blockade 
improves overall survival in second line (or greater) cervical cancer patients (NCT03257267). 
Cemiplimab is also being explored in monotherapy and combination therapy in a variety of solid 
and liquid tumor types. Cemiplimab received regulatory approval for advanced cutaneous 
squamous cell carcinoma with an overall ORR of 47.2% (Cemiplimab Investigator’s Brochure). 
Generating HPV-specific T cells with ISA101b synthetic long peptide vaccine is a research 
strategy to achieve anti-tumor immune responses. However, vaccination alone of advanced stage 
cervical cancer patients did not achieve clinical benefit (Welters, 2018), possibly due to 
intratumoral expression of inhibitory immune molecules such as PD-L1. This possibility is 
supported by the results of a phase 2 study of nivolumab + ISA101 in 22 patients with OPC (and 2 
others, of which, 1 had cervical cancer), in which the observed ORR of 33% is greater than that 
which would be expected with PD-1 blockade alone (Massarelli, 2019). 
Combinatorial approaches to stimulate convergent aspects of host immunity by employing 
complementary immunomodulators, as well as, immune-stimulatory aspects of conventional 
modalities, may result in the development of more effective cancer therapies. Treatment with the 
PD-1 inhibitor pembrolizumab has shown initial efficacy as monotherapy in recurrent or metastatic 
cervical cancer after disease progression on or after chemotherapy (FDA, 2018). In order to 
achieve higher and longer duration of responses and survival, however, combining anti-PD-1 mAb 
treatment with novel immunotherapy approaches will be required. In addition, while initial data 
obtained with ISA101 indicated that a robust and clinically active immune responses against 
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HPV16 E6/E7 could be obtained in HPV16 positive patients with pre-malignant lesions, such as 
vulvar intraepithelial neoplasia (VIN) (Kenter, 2009), patients with advanced malignancies are 
known to have a variety of mechanisms that limit the immune response, including changes in the 
local tumor microenvironment. In order to observe robust and clinically active immune responses 
in patients with advanced cervical cancer, the HPV16 vaccine will need to be combined with one 
or more immune-modulatory strategies to overcome the tumor-induced local and generalized 
immunosuppression. Encouraging results using ISA101/ISA101b have been observed in a single 
arm study (CervISA) in women with advanced HPV16 positive cervical cancer. 
Study ISA101-MDACC was an investigator-initiated study at the MD Anderson Cancer Center 
(MDACC), which was designed to evaluate the ORR of ISA101 vaccination in combination with 
the PD-1 inhibitor, nivolumab, in patients with recurrent/ metastatic incurable HPV16 positive 
malignancies. The primary objective was assessment of overall clinical response rate targeting 
30% using a Simon 2-stage MiniMax design. This was based on an estimated overall clinical 
response rate of approximately 20% with nivolumab alone in patients with recurrent p16+ 
oropharynx cancer. Secondary objectives included tolerability, PFS, OS, and HPV-specific 
immune response.  
This study showed that ISA101 increases the overall clinical response rate in metastatic HPV16 
positive OPC patients when administered in combination with nivolumab (33%) 
(Massarelli, 2019) compared to historical controls (Ferris, 2016), which was coupled to an 
approximate doubling of the expected median OS of these patients. This suggests that the efficacy 
of anti-PD-1 therapy may be enhanced by the addition of an HPV16 specific therapeutic cancer 
vaccine such as ISA101(b). The combination of stimulating the HPV16 specific immune response, 
while mitigating the impact of the immunosuppressive microenvironment, appears to be a 
promising strategy that warrants further evaluation. 
To confirm and extend these results, a randomized phase 2 study is ongoing to compare 
cemiplimab + ISA101b versus cemiplimab in patients with recurrent/metastatic HPV16 
Oropharyngeal Cancer (OPC) (ISA101b-HN-01-17). Approximately 194 patients will be enrolled, 
and the primary endpoint is ORR.  
The current study seeks to address the unmet need in recurrent or metastatic cervical cancer 
patients who have progressed on first line chemotherapy. 
3.2.2. 
Rationale for Dose Selection 
The dose and schedule for both ISA101b and cemiplimab are the same as in the phase 2 study 
ISA101b-HN-01-17. The dose of cemiplimab 350 mg Q3W is consistent with cemiplimab dosing 
in solid tumor development. 
3.3. 
Risk-Benefit 
3.3.1. 
Patient Screening and Site Initiation in Response to COVID-19 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the Sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, the 
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Sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable initiation 
of study sites for this study, as allowed by local laws and regulations. 
3.3.1.1. 
COVID-19 Vaccination During the Study  
It is recommended for patients to complete COVID-19 vaccination at least 14 days prior to 
receiving the first dose of ISA101b or to delay COVID-19 vaccination until at least 14 days after 
the final dose of ISA101b. 
For more information regarding the permitted timing of COVID-19 vaccinations, see 
Section 8.7.2. 
3.3.2. 
Risk-Benefit for Cemiplimab 
3.3.2.1. 
Benefit for Cemiplimab 
Cemiplimab is a fully human monoclonal antibody against PD-1 and is currently being evaluated 
in patients with advanced solid malignancies and B-cell lymphomas whose cancers are incurable 
and/or have failed to respond to or showed tumor progression despite standard therapy, or patients 
who are not candidates for standard therapy, or for whom no available therapy is expected to 
convey clinical benefit. Cemiplimab has demonstrated efficacy (based on ORR and DOR) and is 
approved in the US for patients with advanced cutaneous squamous cell carcinoma (CSCC), 
locally advanced basal cell carcinoma, and as a first-line treatment option in advanced non-small 
cell lung cancer. 
As described in earlier sections, antibodies to PD-1/PDL-1 have been shown to be effective 
therapeutic options for metastatic cervical cancer. Cemiplimab is currently being evaluated in a 
phase 3 randomized study for survival benefit over chemotherapy. The potential benefit for 
patients includes increased response rate, longer duration of response, avoidance of risks 
associated with chemotherapy and increased survival. 
3.3.2.2. 
Risk for Cemiplimab 
To mitigate this risk, tumor assessments are performed after every 2 doses of cemiplimab for the 
first 4 cycles. Subsequent cycles will have tumor assessments after every 3 doses of cemiplimab. 
Tumor assessments are designed to allow patients to pursue other treatment plans if clinically 
indicated. 
The safety profile of cemiplimab is similar to the safety profile of other anti-PD-1/PD-L1. The 
important identified risks are immune-mediated adverse events (imAEs) and infusion-related 
reactions (IRRs). The mitigation strategies for these risks are described in Section 8.2.3.1 through 
Section 8.3.1. 
More detailed information about the known and expected risks and reasonably expected AEs of 
cemiplimab may be found in the most recent approved version of the Investigator’s Brochures. 
3.3.2.3. 
Benefit:Risk for Cemiplimab 
Based on the currently available safety information for cemiplimab, safety information from other 
anti-PD-1 antibodies, the adequate risk identification and minimization described in the 
Investigator’s Brochure/protocols/informed consent forms (ICFs), the emerging preliminary 
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activity of cemiplimab on solid malignancies (including CSCC, non-small cell lung cancer 
[NSCLC] and cervical), the benefit-risk is considered favorable for continued clinical studies in 
these and other indications. 
3.3.3. 
Risk-Benefit for ISA101b 
3.3.3.1. 
Benefit of ISA101b 
ISA101b is designed as a therapeutic vaccine, which targets distinct human pathogenic viral 
antigens 
and 
triggers 
a 
highly 
human-specific 
immune 
response. 
The 
involved 
immunostimulatory/ immunomodulatory effects (eg, cascades of involved chemokines/cytokines 
and cells of the immune system but also organ and target antigen structures), but also the HPV 
induced effects/target structures are highly human specific.  
As described in earlier sections, ISA101b and its precursor have been shown to initiate and/or 
stimulate an HPV16 specific immune response in patients with HPV16 induced lesions. This was 
specifically evident in patients with HPV16 metastatic cervical cancer. A pilot study with 
combination of ISA101b showed an increased response rate and overall survival. Therefore, the 
potential benefits for patients receiving ISA101b include increased response rate, longer duration 
of response, avoidance of risks associated with chemotherapy and increased survival. 
3.3.3.2. 
Risk of ISA101b 
The fundamental risk is a lack of response. To mitigate this risk, patients will undergo frequent 
tumor assessments. This will allow patients to pursue other treatment plans. 
As with all immunomodulation agents, the TEAEs of interest are local and systemic immune-
mediated AEs. Local ISRs are detailed in Section 8.3.1.3. ImAEs and IRRs are detailed in 
Section 8.2.3 and Section 8.3.1. 
More detailed information about the known and expected risks and reasonably expected AEs of 
ISA101b may be found in the most recent approved version of the Investigator’s Brochures. 
3.3.3.3. 
Benefit:Risk for Cemiplimab/ISA101b Combination 
The combination of ISA101b and cemiplimab in this study is expected to have a positive 
benefit-risk profile for the treatment of patients with HPV16 positive cervical cancer. Anti-PD1 
inhibitors given as monotherapy have shown activity and a well-established acceptable toxicity 
profile in recurrent/metastatic cervical cancer patients. ISA101b has been demonstrated to induce 
a robust and persistent T-cell response in patients with HPV16 driven malignancies, including 
cervical cancer and OPC. The combination of ISA101b with the anti-PD1 nivolumab achieved 
higher response rates compared to a historical control of nivolumab alone in the treatment of 
HPV16 positive OPC, albeit in a small number of patients with heterogeneous prior therapy. 
Finally, the combination of ISA101 with nivolumab has shown no unexpected toxicities in patients 
with OPC (Massarelli, 2019). 
Since HPV-positive OPC patients with recurrent cancer routinely receive checkpoint inhibitors in 
first or second-line treatment, the use of cemiplimab as the treatment backbone is acceptable in 
order to objectively test the hypothesis of improved efficacy with the addition of ISA101b to an 
anti-PD-1 inhibitor in HPV-driven malignancies.  
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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of cemiplimab and ISA101b may be found in the most recent approved versions of 
the respective Investigator’s Brochures. 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is ORR based on radiographic response, measured by RECIST version 1.1.  
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Incidence and severity of TEAEs/adverse events of special interest (AESIs)/serious 
adverse events (SAEs) and ≥ grade 3 laboratory abnormalities during the treatment 
period and up to 90 days after the last dose of study treatment  
• DOR  
• PFS 
• OS 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Association of clinical efficacy endpoints with baseline tumor biomarker parameters 
(PD-L1, immune cell subsets, MHC class I/II, gene expression profile and tumor 
mutational burden) 
• In a subset of study sites: Association of clinical efficacy endpoints with post-treatment 
changes in frequency and clonal repertoire of HPV antigen specific T cells, peripheral 
blood immune cell subsets (Teff, Treg, myeloid, dendritic and NK cells) and serum 
cytokine levels 
• Cemiplimab immunogenicity as measured by anti-drug antibodies (ADA) to 
cemiplimab 
• HPV serotyping of archival tumor 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables include, but are not limited to, the following: 
• Tumor Assessments for Response: CT and/or MRI scan 
• ORR with confirmed CR or PR per RECIST 1.1 when evaluating best overall response 
(BOR) 
• DOR 
• PFS 
• OS 
Variables are further defined in Section 11.4. 
5.3. 
Safety Variables 
Safety variables include, but are not limited to, the incidence and severity of the following: 
• TEAEs (Section 10.2.1) 
• SAEs (see Section 10.2.2) 
• AESIs (see Section 10.2.3) 
• ≥3 grade laboratory abnormalities (see Section 10.1.3) 
Variables are further defined in Section 11.4. 
5.4. 
Immunogenicity Variables 
The immunogenicity variables for cemiplimab are ADA status, titer, and time-point/visit. Samples 
in this study will be collected at the clinic visits specified in Table 2. 
5.5. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and biomarker variables are:  
• Baseline tumor tissue PD-L1 expression by immunohistochemistry (IHC) 
• Baseline tumor tissue density of immune cell subsets (Teff, Treg, myeloid cell, 
others) 
• Changes in peripheral HPV16 E6/E7 specific T cell frequency, clonal repertoire and 
functional phenotype (cytokine secretion profile, surface marker expression) 
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• Changes in peripheral blood immune cell subsets (Teff, Treg, myeloid, dendritic and 
NK cells) 
• Changes in systemic inflammatory markers (IFNγ, TNF-alpha, others) 
• HPV serotyping of archival tumor 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This will be a single-arm, phase 2, global study of treatment with cemiplimab + ISA101b in 
HPV16-positive cervical cancer patients with disease progression on first line chemotherapy in the 
recurrent or metastatic setting. Study treatment and duration include cemiplimab every 3 weeks 
(with 3 doses of ISA101b on days 1, 29, and 50) until progression or any reason for early 
discontinuation as outlined in Section 7.3 and Section 8.2.2. 
Patients will undergo screening evaluations to determine eligibility within 28 days prior to first 
treatment. All patients will receive the following regimen:  
• ISA101b 100 μg/peptide by SC injection on day 1, day 29, and day 50 (total of 3 doses). 
• Cemiplimab 350 mg given by IV infusion over 30 minutes Q3W on days 8 and 29 in 
cycle 1, on days 1 and 22 in cycles 2 through 4, and on days 1, 22, and 43 in all 
subsequent cycles or until disease progression or discontinuation of study drug for any 
other reason.  
Note: On days 29 and 50, cemiplimab will be administered first, and ISA101b will be 
administered approximately 1 hour after the end of the cemiplimab infusion. Patients 
must be observed for 4 hours after each ISA101b administration. 
The timing of doses is summarized in Figure 2. Cycle 1 will be 7 weeks long, cycles 2 through 4 
will be 6 weeks long, and all subsequent cycles will be 9 weeks long. 
Patients will be assessed for response at cycle 1 day 50 (week 7), then once per cycle (every 
6 weeks for 3 cycles, then every 9 weeks in all subsequent cycles or until disease progression or 
discontinuation of study drug for any other reason; Section 8.8, Section 8.2.2, and Section 7.3, 
respectively). Patients with confirmed CR after a minimum of 48 weeks of treatment may elect to 
discontinue treatment and continue with all relevant study assessments (eg, efficacy assessments).  
There will be a 90-day safety follow-up after the last dose of cemiplimab. Patients who discontinue 
study drug for reasons other than progression will be followed approximately every 4 months by 
scans until disease progression or until the patient commences another anticancer systemic therapy, 
whichever comes first. After progression, survival follow-up should occur approximately every 
4 months. 
The total duration of study from start of screening to final analysis of OS is expected to be 
approximately 36 months (approximately 12 months of accrual, approximately 12 months of 
treatment, and approximately 12 months of follow up). 
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Figure 2: 
Study Flow Diagram 
 
1 Withdrawal due to reasons as listed in Section 7.3 and Section 8.2.2. 
End of treatment is defined as the end of study drug. Patients may discontinue study drug for 
progression of disease or for any reason listed in Section 7.3 and Section 8.2.2. Thirty days after 
the last dose of study drug, patients will have EOT visit. Ninety days after the last dose of study 
drug, patients will have the safety follow-up visit (Table 2). 
A patient who progresses on treatment will have EOT visit and safety follow-up visit. End of study 
(EOS) disposition will be on or after the safety follow-up visit. They will then enter survival 
follow-up.  
A patient who discontinues treatment for reasons other than progression, as listed in Section 7.3 
and Section 8.2.2, will have EOT and safety follow-up visit. They will then have tumor 
assessments until progression or the start of another anticancer therapy. At progression or start of 
another anticancer therapy, patients will have EOS disposition and then enter survival follow-up. 
6.1.1. 
End of Study Definition 
The end of the study is defined as the date of the last contact of the last patient of the last 
investigational site in the study. 
6.2. 
Planned Interim Analysis 
There will be no formal interim analysis in this study. Administrative efficacy review may be 
performed when at least 4 tumor assessments are collected for the first 53 patients. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 105 patients are planned to be enrolled in the study. 
7.2. 
Study Population 
The study population is patients with HPV16 positive cervical cancer with squamous histology 
(SCC) or adenocarcinoma/adenosquamous (AC) histology who have progressed on first line 
chemotherapy in the recurrent or metastatic setting. Patients with AC histology will be capped at 
approximately 20% of total enrollment.  
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Adult patients ≥18 years of age (or the legal age of adults to consent to participate in a 
clinical study per country specific regulations). 
2. Has histologically confirmed recurrent or metastatic HPV16 positive  cervical cancer as 
determined by an investigational HPV16 PCR assay by Qiagen, who have experienced 
disease progression after treatment with platinum containing therapy (must have been used 
to treat metastatic, persistent, or recurrent cervical cancer). NOTE: Platinum-therapy given 
in other settings (eg, concurrent with radiation therapy as part of curative-intent therapy, 
after radiation [or chemoradiation] as adjuvant treatment in a patient with no evidence of 
disease) does not satisfy the eligibility requirement regarding prior platinum therapy.   
Acceptable histology is squamous carcinoma and adenocarcinoma/adenosquamous 
carcinomas. Sarcomas and neuro-endocrine carcinomas are not eligible histologies. 
3. Patient must be determined to be positive for HPV16 genotype, as determined by a 
specified central reference laboratory.  
4. Patient must have measurable disease as defined by RECIST 1.1. Measurable disease is 
defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest 
dimension to be recorded). Each lesion must be ≥10 mm when measured by computed 
tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical 
exam or must be ≥20 mm when measured by chest x-ray. Lymph nodes must be ≥15 mm 
in short axis when measured by CT or MRI. Tumors within a previously irradiated field 
will be designated as non-measurable lesions unless progression is documented or a biopsy 
is obtained to confirm persistence at least 90 days following completion of radiation 
therapy. 
5. Patients must meet at least 1 of the following criteria regarding prior bevacizumab therapy: 
a. Received prior bevacizumab-containing therapy and experienced subsequent 
progression of disease 
b. Received prior bevacizumab-containing therapy which was discontinued due to 
toxicity 
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c. Was unsuitable for bevacizumab due to i) unacceptable risk of fistula formation, ii) 
poorly controlled hypertension, iii) low risk disease according to Moore criteria  
d. Refused prior bevacizumab 
e. Did not have access to bevacizumab 
6. Patients must meet at least 1 of the following criteria regarding prior taxol therapy 
a. Received prior taxol-containing therapy and experienced subsequent progression of 
disease 
b. Received prior taxol-containing therapy which was discontinued due to toxicity 
c. Was unsuitable for taxol therapy due to i) neuropathy, ii) allergy or intolerance to taxol 
or one of its components  
d. Refused prior taxol 
7. ECOG performance status of 0 or 1.  
8. Has adequate organ and bone marrow function documented by: 
a. Hemoglobin ≥8 g/dL  
b. Absolute neutrophil count ≥1.0 x 109/L  
c. Platelet count ≥75 x 109/L 
d. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated glomerular filtration 
rate >30 mL/min/1.73m2. A 24-hour urine creatinine collection may substitute for the 
calculated creatinine clearance to meet eligibility criteria.  
e. Adequate hepatic function:  
(i) Total bilirubin ≤1.5 x ULN (≤3 x ULN if tumor liver involvement)  
(ii) Aspartate Aminotransferase (AST) ≤2.5 x ULN (≤3 x ULN if tumor liver involvement)  
(iii)Alanine Aminotransferase (ALT) ≤2.5 x ULN (≤3 x ULN if tumor liver involvement) 
(iv) Alkaline Phosphatase (ALP) ≤2.5 x ULN (≤3 x ULN if tumor liver or bone 
involvement)  
NOTES: 
− In patients with tumor liver involvement if levels of AST ≥3 x ULN or ALT ≥3 x 
ULN, and bilirubin levels ≥2 x ULN will be excluded regardless of the above 
criteria  
− Patients with Gilbert’s syndrome do not need to meet total bilirubin requirements 
provided their total bilirubin is not greater from their historical level. Gilbert’s 
syndrome must be documented appropriately as past medical history 
9. Anticipated life expectancy ≥20 weeks. 
10. Is willing and able to comply with clinic visits and study-related procedures and 
requirements 
11. Able to understand and complete study-related questionnaires 
12. Provide informed consent signed by study patient or legally acceptable representative 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
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1. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway. 
2. Prior treatment with other systemic immune-modulating agents that was  
a. less than 4 weeks (28 days) of the enrollment date, or  
b. associated with imAEs of any grade within 90 days prior to enrollment, or  
c. associated with toxicity that resulted in discontinuation of the immune-modulating 
agent.  
Examples of immune-modulating include therapeutic vaccines, cytokine treatments 
(other than granulocyte colony stimulating factor, thrombopoietin analogues, or 
erythropoietin), or agents that target cytotoxic T lymphocyte antigen 4 (CTLA-4), 4-
1BB (CD137), PI 3-K-delta, LAG3, or OX-40. 
3. Major surgery or radiation therapy within 14 days of first administration of study drug  
4. Has received treatment with an approved systemic therapy within 4 weeks of first dose of 
study drug, or has not yet recovered (ie, grade ≤1 or baseline) from any acute toxicities 
except for laboratory changes as described in inclusion criteria and as below:  
a. Neuropathy of grade ≤2 
b. Alopecia of any grade 
5. Has another malignancy that is progressing or requires active treatment and/or history of 
malignancy other than cervical cancer within 3 years of date of first planned dose of study 
drug, except: 
a. Non-melanoma skin cancer that has undergone potentially curative therapy  
b. Ductal carcinoma in situ of the breast 
c. Any tumor that has been deemed to be effectively treated with definitive local control 
(with or without continued adjuvant hormonal therapy), and the patient is deemed to 
be in complete remission for at least 2 years prior to first dose of study drug, and no 
additional therapy is required during the study period.  
Note: Patients with hematologic malignancies (eg, chronic lymphocytic leukemia) are 
excluded. 
6. Has any condition that requires ongoing/continuous corticosteroid therapy (>10 mg 
prednisone/day or anti-inflammatory equivalent) within 4 weeks prior to the first dose of 
study drug. Patients who require a brief course of steroids (up to 2 days in the week before 
enrollment) or physiologic replacement are not excluded. 
7. Has ongoing or recent (within 5 years) evidence of significant autoimmune disease that 
required treatment with systemic immunosuppressive treatments.  The following are not 
exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as 
hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis 
that does not require systemic treatment.  
8. Has untreated or active primary brain tumor, CNS metastases, leptomeningeal disease or 
spinal cord compression.  
Exception: Patients with previously treated brain metastases may participate provided that 
the lesions are stable (without evidence of progression between 2 consecutive scans 
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(eg, CT scan and/or MRI) at least 6 weeks prior to imaging obtained during the screening 
period), there is no evidence of new or enlarging brain metastases, and the patient does not 
require any immunosuppressive doses of systemic corticosteroids for management of brain 
metastases within 4 weeks of the first dose of study drug. 
9. Has encephalitis, meningitis, organic brain disease (eg, Parkinson’s disease) or 
uncontrolled seizures in the year prior to first dose of study drug. 
10. Has a known history of, or any evidence of interstitial lung disease, or active, non-
infectious pneumonitis within 5 years prior to the first dose of study drug. A history of 
radiation pneumonitis in the radiation field is permitted. 
11. Has participated in a study of an investigational agent or an investigational device within 
4 weeks of first dose of study drug. 
12. Has uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C infection; or diagnosis of immunodeficiency. 
NOTES: 
• Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at 
screening. 
• Patients with known HIV infection who have controlled infection (undetectable viral 
load (HIV RNA PCR) 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 (HepBsAg+) who have controlled infection (serum hepatitis 
B virus DNA PCR 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 antibody positive (HCV Ab+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted. 
13. Has any infection requiring hospitalization or treatment with IV anti-infectives within 
2 weeks of first dose of study drug. 
14. Has received a live vaccine within 4 weeks of planned start of study medication. 
15. Has had prior allogeneic stem cell transplantation, or autologous stem cell transplantation 
within 12 weeks of the start of study drug, unless discussed with and approved by the 
sponsor.  
16. Recipients of organ transplants at any time unless discussed with and approved by the 
medical monitor. 
17. Has known allergy or hypersensitivity to components of study drug 
18. Has known psychiatric or substance abuse disorders that would interfere with participation 
with the requirements of the study. 
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19. Has any medical condition, 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 
20. Member of the clinical site study team or his/her immediate family, unless prior approval 
granted by the sponsor. 
21. Patients with a positive serum/urine hCG pregnancy test must have pregnancy medically 
ruled out to be eligible for study. Breastfeeding women are also excluded. 
22. Continued sexual activity in women of childbearing potential (WOCBP)*, or sexually 
active men, who are unwilling to practice highly effective contraception prior to the initial 
dose/start of the first treatment, 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 WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure)  
e. and/or sexual abstinence†,‡.  
* 
WOCBP 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 amenorrhoea method 
(LAM) are not acceptable methods of contraception. Female condom and male condom 
should not be used together. 
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7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and sponsor have the right to discontinue a patient from study treatment or 
withdraw a patient from the study at any time. 
Reasons for discontinuation of study treatment or withdrawal from the study may include, but are 
not limited to: 
• Patient withdrawal of consent at any time 
• 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 treatment 
but who do not withdraw consent to continue participation in the study by completing study 
assessments, as described in Section 9.1.4.  
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.2.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from the study who had received at least 1 treatment with 
cemiplimab and/or ISA101b will not be replaced (Section 7.3). 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
ISA101b is an investigational treatment. Cemiplimab is being used as an investigational treatment 
for cervical cancer and is approved for the treatment for advanced cutaneous squamous cell cancer 
(CSCC), locally advanced basal cell carcinoma, and as a first-line treatment option in advanced 
non-small cell lung cancer.  
Additional information regarding cemiplimab and ISA101b is provided in the respective 
Investigator’s Brochures. 
8.1.1. 
Cemiplimab 
Cemiplimab (REGN2810) is supplied as a liquid in sterile, single use vials. Cemiplimab will be 
administered IV at a dose of 350 mg over 30 minutes (±10 minutes) Q3W. 
8.1.2. 
ISA101b 
The study drug product ISA101b is provided in 2 vials, HPV-DP-5P containing 5 peptides and 
HPV-DP-7P containing 7 peptides. Bulk preparation, sterile filtration, filling, and lyophilization 
have been developed for each drug product. ISA101b 100 µg/peptide will be administered by SC 
injections.  ISA101b is not provided or prepared as an individual product.  Two discrete injections, 
one of HPV-DP-5P and one of HPV-DP-7P, together in vivo constitute ISA101b. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Dose Modification and Study Treatment Discontinuation Rules 
8.2.1. 
Dose Modification 
Dose modification of cemiplimab for an individual patient is not allowed.  
If cemiplimab is delayed, interrupted, or discontinued due to toxicity clearly related to cemiplimab 
as described in the cemiplimab Investigator’s Brochure, and this toxicity is not considered related 
to ISA101b, the remaining doses of ISA101b may be administered. It is recommended to discuss 
such cases with the Medical Monitor. 
If ISA101b is delayed, interrupted, or discontinued due to toxicity clearly related to ISA101b as 
described in the ISA101b Investigator’s Brochure, and this toxicity is not considered related to 
cemiplimab, the remaining doses of cemiplimab may be administered. It is recommended to 
discuss such cases with the Medical Monitor. 
There will be no dose reduction for ISA101b in this study. 
8.2.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug due to disease progression, toxicity, or 
another reason who do not withdraw consent from study participation will be asked to return to 
the clinic for all remaining study visits per the visit schedule (Table 2) and will be expected to 
continue with safety follow-up assessments.  
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8.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug (cemiplimab and/or ISA101b) will be permanently stopped in the event of: 
• Serious or severe allergic reactions considered related to study drug 
• Grade 3 infusion related reaction 
• Grade 3 uveitis  
• Grade 3 or 4 neurologic toxicity  
• Grade 3 or 4 myocarditis/pericarditis 
• Any grade 4 non-hematologic toxicity except for clinically insignificant laboratory 
abnormalities 
• Any non-hematologic toxicity that led to temporary withholding of study treatment 
which does not resolve to grade 1 or baseline within 12 weeks of last study drug 
infusion except for immune-mediated endocrinopathies controlled with hormonal 
therapy 
• Grade 4 hematologic toxicity that does not resolve to less than grade 4 within 2 weeks 
of last infusion or to grade 2 (neutropenia) or grade 1 or baseline (others) within 
12 weeks of last study drug infusion. 
• Physician/patient decision 
• Treatment delay of ≥84 consecutive days from last dose of study drug 
8.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study treatment may be temporarily stopped due to events that meet the criteria for treatment 
interruption described in Section 8.2.3 (and Appendix 2) or Section 8.3. 
8.2.3. 
Immune-Mediated Adverse Events 
8.2.3.1. 
Identification of Immune-mediated Adverse Events 
Investigators must be extremely vigilant and be ready to intervene early in the management of 
imAEs, as the onset of symptoms of imAEs (eg, pneumonitis) may be subtle. An imAE can occur 
at any time during treatment or several months after the last dose of treatment. All AEs of unknown 
etiology associated with study drug exposure should be evaluated to determine possible immune 
etiology. If an imAE is suspected, efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an AE as an imAE. 
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 imAEs from non-immune AEs commonly associated with PD-1 inhibition 
(Naidoo, 2015), (Weber, 2015). This is not exhaustive of all possible imAEs. Clinical 
presentations of less common imAEs, including neurologic, musculoskeletal, cardiac, renal, and 
ocular events (Hofmann, 2016), (Zimmer, 2016), should be reviewed in patients with concerning 
presentations. 
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The case definitions in the Investigator’s Brochure have not been validated and are intended only 
as guidance for investigators to help distinguish imAEs 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 if 
an AE is immune-mediated.  
8.2.3.2. 
Management of Immune-Mediated Adverse Events 
Adverse events that meet the criteria for imAEs, as noted above in the Investigator’s Brochure, 
should be reported as imAEs in the eCRF. If AEs corresponding to the common terms for imAEs 
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-mediated (eg, rash, colitis, elevated transaminases, endocrine 
events), but is deemed not an imAE by the investigator. 
Any grade 3 or greater imAE should be reported as an AESI (Section 10.2.3). 
The following general principles apply to management of imAEs, unless otherwise specified in 
Appendix 2: 
Grade 1:  Continue study treatment with close monitoring and provide symptomatic management 
Grade 2:  Consider withholding study treatment 
Grade 3:  Withhold study treatment 
Grade 4:  Discontinue study treatment 
If cemiplimab is held for ≤ grade 3 imAE, consider resuming when symptoms and/or laboratory 
values revert to baseline or ≤ grade 1 after corticosteroid taper (typically, to ≤10 mg/day 
prednisone or equivalent).  
Permanently discontinue study treatment for: 
• Recurrent grade 3 imAEs  
• Grade ≥3 or recurrent grade 2 Pneumonitis  
• Grade ≥3 Hepatitis with AST/ALT >5×ULN or total bilirubin >3×ULN  
• Grade ≥3 Nephritis with renal dysfunction 
• Grade ≥3 Uveitis 
• Grade ≥3 Neurologic toxicity 
• Grade ≥3 Myocarditis or pericarditis 
• Grade ≥3 Infusion related reaction 
• Confirmed Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or 
drug reaction with eosinophilia and systemic symptoms (DRESS) 
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• Grade ≥3 or recurrent grade 2 imAEs in patients previously treated with idelalisib 
• Grade ≥3 infusion-related reaction 
• Grade 2 or 3 imAEs persistent for ≥12 weeks after the last study treatment (excluding 
endocrinopathies 
• Requirement for ≥10 mg per day prednisone or equivalent lasting ≥12 weeks after the 
last study treatment 
Further guidance regarding management of selected imAEs is provided in Appendix 2. Additional 
information about the safety profile of cemiplimab is in the Investigators Brochure. Expert 
consensus guidelines that provide guidance managing less common imAEs are available and may 
be updated periodically (Brahmer, 2018) (Haanen, 2017) (Puzanov, 2017) (Thompson, 2018).  
The management considerations provided here should not supersede clinical judgment in the 
setting of an individual patient.  The investigator may choose to hold study treatment at his/her 
clinical judgment regarding the safety of an individual patient, even if hold criteria are not formally 
met per protocol.  
Any patient currently receiving cemiplimab who was previously treated with a 
phosphatidylinositol 3-kinase (PI3K) inhibitor and who develops stomatitis or mucositis should 
temporarily suspend study treatment. If this or any other imAE occurs among these patients, the 
sponsor should be informed as soon as possible to discuss further management of the patient. An 
imAE of any grade in a patient previously treated with a PI3K inhibitor should be reported as an 
AESI. 
8.2.4. 
General Guidance for Management of Adverse Events 
This subsection provides general guidance of treatment-related AEs (Table 1) that are not 
specifically addressed in guidelines for management of imAEs (Section 8.2.3.2 or Appendix 2) or 
in management of acute infusion reactions (Section 8.3). In the event of discrepancy between this 
section and a section that provides for detailed guidance (ie, Section 8.2.3.2, Appendix 2 or 
Section 8.3), 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 Adverse Events 
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 
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Toxicity 
Grade 
Hold Treatment 
Restarting Criteria 
Grade 4 thrombocytopenia 
4 
Yes 
Discontinue 
permanently 
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 
Discontinue permanently 
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. 
Management of Acute Reactions 
8.3.1. 
Acute Intravenous Infusion 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.  
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See the 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 10.2.4) and 
graded using the grading scales as instructed in Section 10.2.5. 
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 treatment. 
Case report forms must capture start and stop time of the event, signs and symptoms, and 
management interventions (medications, interruption of infusion, rate reduction). 
8.3.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• 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 once symptoms resolve. 
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 response 
according to typical clinical practice. 
For patients who experience infusion-related hypersensitivity reactions that are ≤grade 2 during 
infusion, infusion should be interrupted or infusion rate reduced. For those 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 treatment 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 
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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 treatment infusions.  If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
8.3.1.2. 
Termination of the Intravenous 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 
*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 ONE OF THE 
FOLLOWING  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
8.3.1.3. 
Local Injection Site Reactions 
Local ISRs must be reported as AEs and graded according to Section 10.2.5. 
8.3.1.3.1. Management of ISA101b-Specific Adverse Events 
ISA101b will be discontinued for any severe (≥ grade 3) ISR. Severity will be graded according 
to Section 10.2.5. 
ISA101b administration should be delayed for the following: 
• Any ≥ grade 3 ISA101b-related AE. 
• Temperature >38°C over the last 24 hours prior to administration. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of ISA101b. 
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The occurrence of an ISA101b -associated systemic allergic reaction will be managed according 
to standard practice, including close observation, antihistamines, and fluids, as well as steroids or 
epinephrine if clinically indicated. ISA101b should not be administered again following resolution 
of a grade 4 systemic allergic reaction. Refer to the ISA101b Investigator’s Brochure for details. 
Local ISR at site(s) of previous administration of ISA101b of > grade 3 should be treated 
symptomatically and followed until resolution to grade 1 is observed. 
Patients may resume treatment with the next dose of ISA101b when study drug-related AEs 
resolve to grade ≤1 or baseline value, with the following exception: patients may resume treatment 
in the presence of grade 2 fatigue.  
If day 29 of ISA101b is missed, the second dose of ISA101b will be given on day 45 (±3 days) 
and the third dose will be given on day 66 (±3 days). If day 29 was missed due to an AE or lab 
abnormality, this must have resolved prior to resumption of dosing. 
If day 50 of ISA101b is missed, the third dose of ISA101b will be given on day 66 (±3 days). If 
day 50 was missed due to an AE or lab abnormality, this must have resolved prior to resumption 
of dosing. 
8.4. 
Method of Treatment Assignment 
Each patient who signs the ICF will be assigned a patient number and tracked centrally. 
Eligible patients will be enrolled sequentially as confirmed and tracked by the sponsor.  
Details on treatment assignment can be found in the Interactive Web Response System (IWRS) 
manual. 
8.5. 
Blinding 
This is a single arm study. Blinding is not applicable. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage 
8.6.1.1. 
Cemiplimab 
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. 
8.6.1.2. 
ISA101b 
ISA101b is provided in 2 vials, HPV-DP-5P containing 5 peptides and HPV-DP-7P containing 7 
peptides. Bulk preparation, sterile filtration, filling, and lyophilization have been developed for 
each product.  
Lyophilized powder of the 2 drug products is stored in glass vials in the dark at -20°C. 
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Before SC injection, the peptide compositions of each of the 2 drug products will be reconstituted 
in Reconstitution Solution (containing Water For Injection, Ethanol, Propylene Glycol, Citric acid 
and Macrogolglycerol Ricinoleate) and mixed with Montanide. 
8.6.2. 
Supply and Disposition of Treatments 
8.6.2.1. 
Cemiplimab 
Cemiplimab 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 destroyed at the site or returned 
to the sponsor or designee.  
8.6.2.2. 
ISA101b 
The Sponsor will provide ISA101b to the study sites.  
The maximum recommended hold time between ISA101b vaccine preparation and administration 
is 2 hours. Instructions for vaccine preparation and administration are given in the Pharmacy 
Manual. The ISA101b vaccine consists of 2 separate injections and is administered in 2 different 
limbs. It is recommended to administer the vaccine in 2 different limbs and rotate injection sites 
between administrations, eg, first ISA101b vaccination in the upper-legs, second ISA101b 
vaccination in the upper-arms and third ISA101b vaccination in the upper-legs. 
Additional information regarding ISA101b is provided in the ISA101b Investigator’s Brochure. 
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. 
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 
Any procedure performed or treatment administered (prescription medications and over-the-
counter preparations) from the time of informed consent until 90 days after the last study treatment 
or start of another systemic anticancer therapy, whichever comes first, will be considered 
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concomitant treatment. This includes medications and other therapies for which administration 
started 30 days before the first dose of the study drug and will continue during the study, as well 
as any therapies started in the follow-up period to treat a study-drug-related AE. All concomitant 
treatments must be recorded in the study eCRF with the generic name, dose, dose unit, frequency, 
indication, and start/stop date, as appropriate. 
8.7.1. 
Prohibited Medications  
While participating in this study, a patient may not receive any standard or investigational agent 
for treatment of a tumor other than cemiplimab as monotherapy or in combination with ISA101b, 
per the study’s specified dosing regimens. 
• After communication with the sponsor, focal palliative treatment (eg, radiation) is 
allowed under the following circumstances: 
− For local control of a tumor once a patient has completed 24 weeks of study 
treatment.  
− For pain management at sites of bone disease or lesions in the brain (as long as the 
lesions are not followed for treatment response evaluation).  
• Patients using immunosuppressive doses (>10 mg per day of prednisone or equivalent) 
of systemic corticosteroids other than for corticosteroid replacement will not be eligible 
for the study. It is recommended that patients do not receive systemic corticosteroids 
such as hydrocortisone, prednisone, prednisolone (Solu-Medrol®), or dexamethasone 
(Decadron®) at any time throughout the study except in the case of a life-threatening 
illness and/or to treat an imAE. 
• It is recommended that patients do not receive other immunosuppressive medications 
at any time throughout the study except in the case of a life-threatening emergency 
and/or to treat and imAE or IRR. Examples of immunosuppressives that may be used 
for treatment of imAEs are mentioned in Appendix 2. Investigators are allowed to treat 
adverse events requiring immunosuppressive medication using their institutional 
standard, which may involve medications not specifically mentioned in the protocol. 
• Prophylactic or therapeutic anticoagulation therapy is allowed after discussion with 
study sponsor as gastrointestinal adverse events are common with immune checkpoint 
inhibitors. Patients on anticoagulants have to be monitored closely.  
• Patients are not allowed to undergo surgical resection of the primary tumor site. 
8.7.2. 
Permitted Medications  
While participating in this study, a patient may receive medications or therapies other than study 
drug under the following conditions:  
• Physiologic replacement doses of systemic corticosteroids are permitted, even if 
>10 mg/day prednisone equivalents. 
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• A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
• Gonadotropin-releasing hormone agonist therapy (eg, for prostate cancer) may be 
continued and is not prohibited. 
• Hormone-replacement therapy is allowed. 
• Inhaled, topical, ophthalmologic, or intranasal steroids are allowed. 
• Treatments for bone metastases (bisphosphonates, denosumab) are allowed. 
• Any other medication which is considered necessary for the patient’s welfare, and 
which is not expected to interfere with the evaluation of the study drug, may be given 
at the discretion of the investigator. 
COVID-19 Vaccination During the Study 
COVID-19 vaccination may be administered to patients enrolled in R2810-ONC-ISA-1981 in 
accordance with local regulatory guidance.  Currently, there is limited data on safety and efficacy 
interactions between approved COVID-19 vaccines and cemiplimab and/or ISA101b.  
It is recommended for patients to complete COVID-19 vaccination at least 14 days prior to 
receiving the first dose of ISA101b or to delay COVID-19 vaccination until at least 14 days after 
the final dose of ISA101b. 
It is recommended to use different limbs for the administration of a COVID-19 vaccine and 
contiguous ISA101b vaccine. It is recommended not to receive a COVID-19 vaccine if the patient 
has a known allergy to the COVID-19 vaccine or one of its components.  
There should be an individual risk/benefit analysis for each patient when receiving COVID-19 
vaccination while enrolled in R2810-ONC-ISA-1981. 
8.8. 
Treatment with Cemiplimab Beyond Disease Progression  
It is recognized that a minority of patients treated with immunotherapy may derive clinical benefit 
despite initial evidence of progressive disease.  
Patients who experience RECIST 1.1-defined progressive disease will be permitted to continue 
treatment until further progression is observed, provided the following criteria are met:  
• Investigator assesses continued use of a PD-1 therapy is appropriate 
• Patient continues to meet all other study eligibility criteria, as defined in the 
inclusion/exclusion criteria (Section 7.2) 
• Patient is tolerant of cemiplimab and has a stable performance status.  
• Patient provides written informed consent prior to resuming treatment by signing the 
current version of the ICF (eg, the patient repeats the written informed consent that was 
done prior to initial study enrollment). 
• Patients do not have evidence of rapidly progressing disease 
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It is understood that, if there is further progression after resumption of treatment (≥30% increase 
in tumor burden from the time of initial progressive disease by RECIST criteria; this includes an 
increase in the sum of all target lesions and/or the development of new lesions), that cemiplimab 
will be discontinued. 
Patients should continue with assessments according to Table 2. 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 2. 
The allowable window for all visit days and assessments is ±3 business days (excluding weekends 
and holidays), unless otherwise stated. All other "days" in the protocol refer to calendar days. For 
tumor assessments (CT or MRI), the window is ±7 days from planned scan dates, unless otherwise 
stated.  
Missed doses of cemiplimab or visits will not be made up. In the case of missed doses of 
cemiplimab, tumor assessments should still follow original schedule. If a patient is unable to 
undergo scans within the window due to logistical or medical reasons, tumor assessment will be 
obtained at the next available date. 
Missed doses of ISA101b are detailed in Section 8.3.1.3.1. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
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Table 2: 
Schedule of Events 
Study Procedure 
Screening 
Visit1 
Cycle 12, 3 
Cycle 2 to 42, 3 
Cycles 5+2, 3 
EOT 
Visit4,5 
Safety 
Follow-up4,5 
Tumor 
Assessment5 
Survival 
Follow-up4,5 
Day -28 to 
Day -1 
Day 
1 
Day 
8 
±3 
Day 
29 
±3 
Day 
50 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
64 
±3 
30 days 
after last 
dose 
±7 days 
90 days 
after last 
dose 
±10 days 
Every 4 months 
(±10 days) 
Every 4 
months (±10 
days) 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics substudy informed 
consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future biomedical research 
consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram7 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Tumor tissue sample 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Cemiplimab (experimental)8 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
ISA101b (experimental)8, 9 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy (Radiologic): 
CT scan and/or MRI10 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X11 
X 
X 
 
Safety: 
Weight and height (height at 
screening only) 
X 
X12 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Complete physical 
examination13 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
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Study Procedure 
Screening 
Visit1 
Cycle 12, 3 
Cycle 2 to 42, 3 
Cycles 5+2, 3 
EOT 
Visit4,5 
Safety 
Follow-up4,5 
Tumor 
Assessment5 
Survival 
Follow-up4,5 
Day -28 to 
Day -1 
Day 
1 
Day 
8 
±3 
Day 
29 
±3 
Day 
50 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
64 
±3 
30 days 
after last 
dose 
±7 days 
90 days 
after last 
dose 
±10 days 
Every 4 months 
(±10 days) 
Every 4 
months (±10 
days) 
Limited physical 
examination14 
 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
 
Continuous Monitoring for Adverse Events   
X 
 
 
Phone contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: 
Hematology16 
X 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistry16 
X 
X12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prothrombin time Activated 
partial thromboplastin time 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
TSH (with reflex T3, free T4) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBP17 
X 
X12 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
PK, ADA, Biomarkers: 
PK sample (cemiplimab)18 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
ADA sample (cemiplimab)19 
 
X  
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Soluble biomarkers (serum) 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
ctDNA plasma sample 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
T cell immune monitoring 
PBMC sample20 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
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Study Procedure 
Screening 
Visit1 
Cycle 12, 3 
Cycle 2 to 42, 3 
Cycles 5+2, 3 
EOT 
Visit4,5 
Safety 
Follow-up4,5 
Tumor 
Assessment5 
Survival 
Follow-up4,5 
Day -28 to 
Day -1 
Day 
1 
Day 
8 
±3 
Day 
29 
±3 
Day 
50 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
1 
±3 
Day 
22 
±3 
Day 
43 
±3 
Day 
64 
±3 
30 days 
after last 
dose 
±7 days 
90 days 
after last 
dose 
±10 days 
Every 4 months 
(±10 days) 
Every 4 
months (±10 
days) 
Pharmacogenomics (optional 
sub-study)21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Patients who fail screening may be screened 1 additional time and an ICF will need to be 
signed at the re-screen. Some procedures may not need to be repeated if they were 
previously completed within 28 days prior to cycle 1 day 1. 
2. Cycle 1 is 7 weeks long, cycles 2 through 4 are 6 weeks long, and all subsequent cycles 
are 9 weeks long. 
3. Due to ±3-day windows of visits, the last day of a cycle may coincide with the first day 
of the next cycle (eg, C1D50 may be the same visit as C2D1, etc). 
4. Patients who discontinue study drug due to progression of disease should proceed to the 
EOT visit, safety follow-up, and survival follow-up. 
5. Patients who discontinue study drug for reasons other than progression of disease (as 
detailed in Section 7.3 and Section 8.2.2) should proceed to the EOT visit, safety follow-
up, and tumor assessments. If these patients experience progression during tumor 
assessments, they should proceed to survival follow-up. 
6. Informed consent must be provided before the initiation of screening procedures and must 
be obtained within 45 days prior to cycle1 day 1. All screening assessments must be 
performed within 28 days prior to cycle 1 day 1 (for tumor tissue sample, see 
Section 9.2.1.1). Assessments performed as part of standard of care that fall within the 
screening window, but before informed consent is obtained, may be used for screening and 
need not be repeated for enrollment eligibility. 
7. Local electrocardiograms (ECG) should be performed before blood is drawn during visits 
requiring blood draws. 
8. On days when cemiplimab and ISA101b are administered together, cemiplimab will be 
administered first, and ISA101b will be administered approximately 1 hour after the end 
of the cemiplimab infusion. 
9. Patients must be observed for 4 hours after each ISA101b administration. 
10. During the treatment period, imaging should be acquired in the window of the scheduled 
imaging day (scheduled imaging day ±7 days). Brain imaging is optional as clinically 
indicated.  
11. If the EOT visit falls within 30 days of the last cycle tumor assessment, the CT scan and/or 
MRI does not need to be repeated. 
12. If cycle 1 day 1 is within 72 hours of screening, this assessment does not need to be repeated 
at cycle 1 day 1. 
13. Complete physical examination includes head and neck, lungs, heart, abdomen, lymph 
nodes, extremities, and skin. A brief neurologic examination should also be performed.   
14. Limited physical exam includes lungs, heart, abdomen, and skin.  
15. Vital signs are collected within 10 minutes prior to infusion, and approximately 15 minutes 
(±10 minutes) after the completion of the infusion. Vital signs will also be taken every hour 
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during the 4-hour observation after administration of ISA101b. 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, PK, or exploratory 
sample collection. 
16. Hematology and chemistry samples may be obtained ≤72 hours prior to cemiplimab 
treatment. 
17. Pre-dose serum or urine β-human chorionic gonadotropin (HCG) up to 72 hours prior to 
study drug administration. Serum/urine pregnancy tests are requirements for women of 
child bearing potential only.  
18. Serum samples for cemiplimab concentration will be collected from all patients pre-dose 
(Ctrough) on cycle 1 day 1 and every other cycle for the first 2 years of treatment. After 
2 years, samples for cemiplimab concentration will be collected pre-dose every 6 months 
(24 weeks) during therapy and at EOT. 
19. ADA serum samples for cemiplimab will be collected pre-dose of cemiplimab 
administration on day 1 of cycle 1, and pre-dose of cemiplimab on day 1 of cycles 3 and 
5 for the first year of treatment, then pre-dose every 4 cycles for the subsequent years of 
treatment (eg, C9, C13 and so on) and at EOT. In the event of AESI, additional samples 
may be collected for ADA analysis at or near the event when possible. 
20. Peripheral blood mononuclear cell (PBMC) collection is optional. PBMC samples will be 
collected pre-dose on day 1, 8, and 29 of cycle 1, pre-dose on day 1 of cycles 2 through 4, 
day 1 of cycles 5+, and at end of treatment. 
21. Pharmacogenomics (optional sub-study): See Section 9.2.10. 
9.1.2. 
End of Treatment Visit 
All patients will attend an end of treatment visit 30 days after their last dose of study drug. 
Patients who are withdrawn from the study before the primary endpoint visit (cycle 4 day 43) will 
be asked to return to the clinic once for an end of treatment visit consisting of the assessments 
described in Table 2. 
9.1.3. 
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. 
9.1.4. 
Follow-Up  
After progression, patients will complete end of treatment visit, safety follow-up visit, and have 
survival follow-up approximately every 4 months (Table 2). 
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Patients who discontinue study drug for reasons other than progression will be followed 
approximately every 4 months by scans until disease progression or until patient commences 
another anticancer systemic therapy, whichever comes first. 
After progression, survival follow-up should occur approximately every 4 months. This may be 
done by phone contact. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: 
• Inclusion/exclusion criteria 
• Informed consent 
• Medical history and demographics 
• Tumor tissue sample for documentation of pathologic confirmation of cervical cancer 
and HPV16 diagnostic testing 
• HBV, HCV, and HIV testing 
Patients who fail screening may be screened 1 additional time. Some procedures may not need to 
be repeated if they were previously completed within 28 days prior to cycle 1 day 1, and an ICF 
will need to be re-signed if prior ICF signing is beyond 45 days of cycle 1 day 1. 
9.2.1.1. 
HPV16 Diagnostic Test 
For HPV16 determination, a formalin-fixed, paraffin-embedded tissue block or unstained slides of 
tumor samples must be provided after the ICF is signed. Tumor biopsies should be of sufficient 
size or quantity to ensure an adequate amount of tissue for analysis. Complete instructions on the 
collection, processing, handling and shipment of all samples will be provided in the laboratory 
manual. A validated assay at a central laboratory will be used for determination of HPV16 
genotyping in patient samples and to determine eligibility based on HPV16 positivity. Samples 
should be sent to the central laboratory at any point during the period between ICF signing and 
cycle 1 day 1 (including prior to the screening period; effort should be made to ship the sample 
just after the ICF is signed to ensure the result is received on time to confirm eligibility). The use 
of HPV16 for decisions regarding treatment with ISA101/ISA101b is considered investigational. 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Computed Tomography and/or Magnetic Resonance Imaging 
Diagnostic quality contrast-enhanced CT and contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. In patients whom contrast is strictly 
contraindicated, non-contrast MRI scans and CT chest scans are acceptable. The chest, abdomen, 
and pelvis must be imaged along with any other known or suspected sites of disease. If more than 
one imaging modality is used at screening for the same anatomies, the most accurate imaging 
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modality according to RECIST 1.1 should be used when recording data. The same imaging 
modality and techniques used at screening should be used for all subsequent assessments. At 
screening, MRI of the brain with contrast or without contrast if contrast is contraindicated, or CT 
with contrast when MRI is contraindicated, should be performed in patients with a known history 
of treated brain metastasis. Additional sites of known disease (including CNS) should be imaged 
at screening. Refer to the Site Imaging Manual for details of imaging requirements. 
After the baseline tumor assessment, radiographic tumor assessments will be obtained in all 
patients at the time points indicated in Table 2 (with a window of ±7 days). During safety follow-
up, radiographic evaluation will be performed every 4 months until RECIST 1.1-defined 
progressive disease, withdrawal of consent, death, or initiation of another anticancer treatment.  
Tumor assessments should be performed even if dosing is interrupted. Weeks and months are in 
reference to the calendar week and month and should not be adjusted due to dosing 
delays/interruptions. Cycle 1 day 1 date is the reference for all visits including tumor assessments 
visits. 
De-identified scans will be collected and, at the Sponsor’s discretion, reviewed by independent 
radiologists using RECIST criteria at a later date, or at any time during the study.  
9.2.2.1.1. Tumor Burden Assessments 
Tumor measurements will be performed in accordance with RECIST 1.1. Criteria 
(Eisenhauer, 2009) (Appendix 3) and should be done by the same investigator or radiologist for 
each assessment of a patient, to the extent feasible.   
Investigators will assess response to therapy using RECIST 1.1 criteria. RECIST 1.1-defined 
progressive disease determined by the investigator will be used for clinical management of the 
patient. RECIST 1.1-based tumor burden assessments will be used for evaluation of efficacy 
endpoints. 
9.2.3. 
Safety Procedures 
9.2.3.1. 
Electrocardiogram 
Local ECGs should be performed before blood is drawn during visits requiring blood draws. A 
standard 12-lead ECG will be performed at time points according to Table 2. Heart rate will be 
recorded from the ventricular rate, and the PR, QRS, RR and QT (identify QTcB or QTcF) 
intervals will be recorded. The ECG strips or reports will be retained with the source. 
9.2.3.2. 
Performance Status 
Eastern Cooperative Oncology Group performance status will be performed at the time points 
according to Table 2. Performance status will be assessed according to ECOG criteria in 
Appendix 1. 
9.2.3.3. 
Body Weight and Height 
Body weight will be assessed using calibrated scales. Patients should void (empty bladder) prior 
to weight assessment. Patients should be wearing undergarments only and no shoes during weight 
assessments. Body weight will be recorded to the nearest 0.1 kg. 
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Height will be assessed at screening only. 
9.2.3.4. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration will be collected 
pre-dose and post-dose at time points according to Table 2. Vital signs will also be taken every 
hour during the 4-hour observation period following ISA101b administration. 
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, PK, or exploratory sample 
collection. 
9.2.3.5. 
Physical Examination 
A thorough and complete physical examination will be performed at visits specified in Table 2. 
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 
(including liver and spleen), lymph nodes, extremities, and skin, as well as a brief neurologic 
examination.  
Limited physical examination will include examination of lungs, heart, abdomen, skin, and other 
organ systems at visits specified in Table 2. 
9.2.3.6. 
Laboratory Testing 
Hematology, blood chemistry, coagulation, TSH (with reflex T3, free T4), urinalysis, and 
pregnancy testing samples will be analyzed by the site’s local laboratory. 
Samples for laboratory testing will be collected at visits according to Table 2. Tests will include: 
Blood Chemistry 
Sodium 
Glucose 
Aspartate aminotransferase (AST) 
Potassium 
Albumin 
Alanine aminotransferase (ALT) 
Chloride 
Total protein, serum 
Alkaline phosphatase 
Carbon dioxide 
(bicarbonate)* 
Creatinine 
Bilirubin (total/direct)*** 
Calcium 
Blood urea nitrogen (BUN)** 
Uric acid 
*At sites at which the bicarbonate assay is not performed as part of the routine chemistry panel, it may be omitted 
**At sites at which a urea assay is performed instead of BUN, the urea assay will be acceptable. 
***Total or direct bilirubin may be measured, whichever is standard per site. 
Hematology 
Hemoglobin 
Differential: 
White blood cells (WBCs) 
 
Neutrophils 
Platelet count 
 
Lymphocytes 
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Monocytes 
Urinalysis 
pH 
Ketones 
Glucose 
Specific gravity 
Protein 
Blood 
Other Laboratory Tests 
Thyroid Function Tests: Thyroid-stimulating hormone (with reflex T3, free T4) will be tested at 
visits specified in Table 2 while the patient is on treatment. If TSH is abnormal, T3 and free T4 
should be measured at the investigative site’s local laboratory. If an investigative site routinely 
performs total T3 and/or total T4 tests, these measurements will be acceptable in lieu of free T3 or 
free T4. 
Coagulation Tests: Prothrombin time and activated partial thromboplastin time testing will be 
performed at visits specified in Table 2 while the patient is on treatment. Sites may report INR and 
activated PTT if it is the standard of care at that site. 
Viral Serology Tests: HBV, HCV, and HIV serum antibodies will be tested at visits specified in 
Table 2. 
Pregnancy Tests: Serum β-HCG or urine β-HCG will be measured ≤72 hours prior to study drug 
administration) and serum/urine β-HCG will be measure at all other time points as specified in 
Table 2. 
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 medication 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. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.3.7. 
Additional Samples 
Any additional samples (eg, pulmonary effusion fluid, ascites fluid, etc) collected as a part of 
standard-of-care or symptomatic management while on study may be sent for analysis.  These 
collections are optional but encouraged for further understanding of interactions between patients, 
disease, and study drugs. 
9.2.4. 
Drug Concentration and Pharmacokinetic Measurements 
Samples for cemiplimab concentration will be collected at visits listed in Table 2.  
Any unused samples may be used for exploratory biomarker research or to investigate AEs as 
appropriate. 
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9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment of cemiplimab will be collected at time points listed in Table 2. In 
response to AESI like anaphylaxis or hypersensitivity, additional ADA samples closer to the event 
may be collected and analyzed when possible, based on the judgement of the medical investigator 
and/or medical monitor (in treatment, follow-up, or resumption of treatment). The exact date and 
time of sample collection must be recorded and entered into the electronic data capture (EDC). 
Any unused samples may be used for exploratory biomarker research or to investigate AEs as 
appropriate. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to better understand the baseline predictive 
biomarkers of cemiplimab + ISA101b response that may include but are not limited to tumor tissue 
analysis of PD-L1 expression and immune cell subsets by IHC or RNAScope, tumor DNA and 
RNA sequencing. Pharmacodynamic and tumor biomarker samples will be collected at time points 
according to Table 2, and measurements will be performed to determine treatment effect on the 
disease and relevant physiological processes. The biomarkers studied are believed to be relevant 
to the pathophysiology of indication target engagement, mechanism of action of cemiplimab and 
possible toxicities.  
Biomarker assays may include, but will not be limited to, the following: 
• Tumor specific and HPV gene panel (circulating tumor DNA sequence profile) 
• T cell effector and innate immune cytokine panel (serum cytokines) 
• T cell, myeloid cell subset analysis, functional HPV E6/E7 specific T cell assays 
9.2.7. 
Peripheral Blood Biomarkers 
Samples for peripheral blood (plasma, serum, and PBMC samples) biomarker assessments will be 
collected at time points listed in Table 2. 
PBMC collection is optional. PBMCs from patients receiving cemiplimab may be used for 
characterization of immune cell subsets including T cells, B cells, natural killer cells, monocytes, 
dendritic cells, and subsets of these cell types.  Peripheral blood mononuclear cell samples may 
also be used to assess immune cell function, including T cell activation and proliferation. 
9.2.8. 
Survival Data Collection 
Every effort will be made to collect survival data on all patients, including patients who 
discontinued 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. Use of publicly 
available information should only be in accordance with local law. 
9.2.9. 
Future Biomedical Research (Optional) 
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.  The unused 
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biomarker samples for study-related research, as well as unused PK and ADA samples, 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. Future biomedical research may include assay 
development and/or validation, and the samples may be used as references or controls in unrelated 
experiments After 15 years, any residual samples will be destroyed. The results of these future 
biomedical research analyses will not be presented in the CSR. 
9.2.10. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of a pharmacogenomics-specific whole blood sample. This 
sample may be collected during screening or any other time point for study-related research 
(Table 2), and genomic DNA will be extracted for analysis as described below. 
The DNA samples for pharmacogenomics analyses will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15 samples. Samples will be stored for 
up to 15 years after the final date of the database lock. If there are specific site or country 
requirements involving the pharmacogenomic analyses with which the sponsor is unable to 
comply, samples will not be collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical 
(safety or efficacy) or biomarker response to cemiplimab, clinical outcome measures, and possible 
AEs. In addition, associations between genomic variants and prognosis or progression of cervical 
cancer or 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, 
target pathway, or cervical cancer 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, methods for quantifying 
epigenetic modifications, and sequencing of the somatically recombined adaptive immune receptor 
loci may also be performed, including comparison to DNA extracted from tumor tissue biopsies. 
The list of methods may be expanded to include novel methodology that may be developed during 
the course of this study or sample storage period. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
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 study 
treatment, or until the patient commences another anticancer systemic therapy, whichever comes 
first.  After informed consent has been obtained but prior to initiation of study drug, only the 
following AEs should be reported: 
• SAEs 
• Non-SAEs caused by a protocol-mandated intervention (eg, non-SAEs related to 
invasive procedures such as biopsies) 
Other AEs that occur prior to the first treatment should be reported on the medical history CRF. 
All AEs after initiation of study treatment and until 90 days after the last study treatment, 
regardless of relationship to study treatment, will be reported on the AE CRF.  Additionally, any 
SAE or other AE of concern that the investigator believes may be related to study treatment and 
that occurs later than 90 days after last study treatment, or after the patient has commenced another 
anticancer systemic therapy (whichever comes first) should be reported. 
Study treatment includes cemiplimab and ISA101b. 
Information on follow-up for AEs is provided in Section 10.1.2.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 10.1.5. 
10.1.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study treatment must be reported to 
the sponsor (or designee) within 24 hours.  Refer to the study reference manuals for the procedure 
to be followed. 
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. 
In the event the investigator is informed of an SAE that occurs after 90 days after the last dose of 
study treatment, or after the patient commences another anticancer systemic therapy (whichever 
comes first), only those SAEs or other AEs of concern deemed by the investigator to be related to 
study treatment will be reported to the sponsor.  The investigator should make every effort to 
obtain follow-up information on the outcome of a treatment-related SAE until the event is 
considered chronic and/or stable. 
10.1.3. 
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: 
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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 during the study or within 6 months of the last 
dose of study drug.  Any complication of pregnancy affecting a female 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 (applicable to cemiplimab only): 
All AESI, serious and 
nonserious, must be reported within 24 hours of identification using the same 
reporting process as for SAE reporting, per Section 10.1.2.  Adverse events of 
special interest for this study include the following:   
The following will be considered AESI for this study: 
• Grade ≥2 infusion related reactions  
• Grade ≥2 allergic/hypersensitivity reactions 
• Grade ≥3 imAEs (see Section 10.1.3.1) 
• An imAE of any grade in a patient previously treated with a PI 3-K inhibitor 
NOTE (Applicable to cemiplimab only):  An imAE can occur shortly after the 
first dose or several months after the last dose of treatment.  All AEs of unknown 
etiology associated with drug exposure should be evaluated to determine possible 
immune etiology.  If an imAE is suspected, efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling 
an AE as an imAE. 
10.1.3.1. Immune-Mediated Adverse Events 
Detailed guidance of management of imAEs is provided in Section 8.2.3 and Appendix 2. 
NOTE: Regarding imAEs, for any AE that is of a type known to be potentially immune-related 
(eg rash, colitis, elevated transaminases, or endocrine) but is deemed not to be an imAE by the 
investigator, the sponsor may request additional information. 
10.1.4. 
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 monitor within 30 days. 
10.1.5. 
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 
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• The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• 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 monitor 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 10.2.5. 
10.2. 
Definitions 
10.2.1. 
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 
(ICH, Oct 1994). 
10.2.2. 
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 a hospital admission (any duration) or an 
emergency room visit 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 
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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.  
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest 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.   
10.2.4. 
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 10.2.1) and graded using the 
grading scales as instructed in Section 10.2.5. 
10.2.5. 
Severity 
The severity of AEs, infusion reactions, and injection site reactions will be graded using the NCI-
CTCAE v5.0 grading system. Adverse events not listed in the NCI-CTCAE v5.0, will be graded 
according to the following scale: 
• 1 (Mild): Mild AE (minor; no specific medical intervention; asymptomatic laboratory 
findings only, radiographic findings only; marginal clinical relevance) 
• 2 (Moderate): Moderate AE (minimal intervention; local intervention; noninvasive 
intervention [packing, cautery]) 
• 3 (Severe): Severe and undesirable AE (significant symptoms requiring hospitalization 
or invasive intervention; transfusion; elective interventional radiological procedure; 
therapeutic endoscopy or operation) 
• 4 (Life–threatening): Life-threatening or disabling AE (complicated by acute, life 
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis. Life-threatening physiologic consequences; need for intensive care 
or emergent invasive procedure; emergent interventional radiological procedure, 
therapeutic endoscopy or operation) 
• 5 (Death): Death associated with an AE. 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
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judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
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. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, 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. 
Causality to the study conduct (protocol specified procedure): 
• 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. 
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• 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. 
10.3. 
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; 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. 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug (cemiplimab), as 
appropriate per local reporting requirements. In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements. All notifications to investigators will 
contain only masked information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (cemiplimab) is assessed against the Reference Safety 
Information section of the most recently approved version of the Investigator’s Brochure that is 
effective for expedited safety reporting.  
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 IECs/IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study. The SAP will 
be revised prior to the database lock 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.  
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
Data collected regarding the impact of the COVID-19 pandemic on the patients will be 
summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 on the efficacy (eg, missing data due to COVID-
19) and safety evaluation will be specified in the SAP. 
11.1. 
Statistical Hypothesis 
This is a single arm, open label study and there is no formal statistical hypothesis in this study. 
11.2. 
Justification of Sample Size 
The planned total sample size for this study is 105 patients. 
The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b 
after progression on first line chemotherapy, as assessed by objective response rate (ORR). With 
105 patients, Table 3 below presents various response rates and associated 2-sided 95% CIs using 
a normal approximation of the binomial distribution, and precision of estimation defined as 
distance from the boundary to the center. If observed ORR ranges from 20.0% to 34.3%, the 
precision estimation using 105 patients ranges from 7.7% to 9.1%. 
Table 3: 
The 2-sided 95% Confidence Intervals for Observed ORR Based on a 
Sample Size of 105 Patients 
Number of Responders 
Observed ORR 
95% CI 
Precision 
21 
20.0% 
(12.4, 27.7) 
7.7% 
24 
22.9% 
(14.8, 30.9) 
8.0% 
27 
25.7% 
(17.4, 34.1) 
8.4% 
31 
29.5% 
(20.8, 38.3) 
8.8% 
36 
34.3% 
(25.2, 43.4) 
9.1% 
11.3. 
Analysis Sets 
11.3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all enrolled patients who received any study drug. Efficacy, 
safety, and baseline variables will be analyzed or summarized using the FAS. 
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11.3.2. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had a at 
least 1 non-missing result following the first dose of study drug. 
11.3.3. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received cemiplimab and had at least 1 non-
missing ADA result following the first study dose.  
11.4. 
Statistical Methods 
In general, the descriptive summary for continuous variables will include the number of 
observation(n), mean, standard deviation (SD), Q1, median, Q3, minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
For time to event data, the descriptive summary will include the median time-to event and its 95% 
confidence interval using the Kaplan-Meier method. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The number of screened patients 
• The number of patients in each analysis set 
• The number of patients who discontinued the study, and the reasons for 
discontinuation 
• The number of patients who discontinued from study treatment, and the reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
11.4.3. 
Efficacy Analyses 
In order to describe ORR, the interim data cutoff for efficacy analysis will be after the 53rd patient 
enrolled has had an opportunity for 4 tumor assessments.  
The final data cutoff for efficacy analysis will be when the last patient enrolled has had the 
opportunity for 4 tumor assessments. 
11.4.3.1. Primary Efficacy Analysis 
Primary efficacy analysis will be performed when the last patient enrolled has had the opportunity 
for at least 4 tumor assessments. 
The primary endpoint for efficacy analyses is the investigator-assessed ORR as determined by 
RECIST version 1.1 (Eisenhauer, 2009). The ORR is defined as the proportion of patients who 
achieve a best overall response (BOR) of CR or PR. Patients who are not evaluable for BOR will 
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be considered as non-responders. The ORR along with the 2-sided 95% confidence interval using 
a normal approximation of the binomial distribution will be summarized.  
11.4.3.2. Secondary Efficacy Analysis 
The secondary efficacy endpoints as measured by DOR, PFS, and OS will be summarized by 
median and its 95% confidence interval using the Kaplan-Meier method.   
11.4.4. 
Control of Multiplicity 
This a single arm, open label, and observational study. Multiplicity control is not applicable. 
11.4.5. 
Safety Analysis 
Treatment-emergent AEs/AESIs/SAEs and grade 3 or greater laboratory abnormalities will be 
summarized using descriptive statistics. 
11.4.5.1. 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 on-treatment period is defined as the day from first dose of study drug to the last 
dose of study drug plus 90 days, or 1 day prior to starting a new treatment for cervical 
cancer, whichever is first. 
• The posttreatment period is defined as the day after the on-treatment period until 1 year 
after the end of the on-treatment period or the start of a new treatment for cervical 
cancer.  
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (NCI-CTCAE, version 5.0 grade), presented by SOC and PT 
• Treatment-related TEAEs, presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
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11.4.5.2. Deaths, other SAEs, and TEAEs leading to permanent treatment discontinuation 
will be summarized.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. 
Number and percentage of patients with a potentially clinically significant value (PCSV) will be 
summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.5.3. Treatment Exposure 
Duration of exposure, number of doses administered, and dose intensity will be summarized. 
11.4.5.4. Treatment Compliance 
Patients will be administered study drug, and treatment compliance will be defined in detail in the 
SAP. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
Serum samples for cemiplimab will be collected from all patients as follows: 
• Pre-dose (Ctrough) on cycle 1 day 1 and every other cycle for the first 2 years of 
treatment 
• Pre-dose (Ctrough) every 6 months (24 weeks) thereafter during therapy and at EOT. 
The concentrations of total cemiplimab over time will be summarized by descriptive statistics. 
No formal statistical hypothesis testing will be performed.  
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The association of PD-L1 expression in tumor and infiltrating immune cells with clinical efficacy 
and available data on changes is HPV antigen specific T cell responses in a subset of patients will 
be included in the CSR. Analysis of all other exploratory pharmacodynamic and baseline 
predictive biomarker data will be included in a separate biomarker analysis report. 
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11.4.8. 
Analysis of Immunogenicity Data 
Immunogenicity for cemiplimab will be characterized by the ADA response observed:  
• ADA negative, defined as ADA negative response in the ADA assay for all time points 
regardless of any missing samples 
• 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. 
• 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)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
positivity presented by patient and time point will be provided. Incidence of treatment-emergent 
ADA 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 on individual PK profiles 
evaluated.  Assessment of impact of ADA on safety and efficacy may be provided. 
11.5. 
Interim Analysis 
There will be no formal interim analysis in this study.  
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. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at the sponsor. 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• Interactive Response Technology (IRT)/IVRS/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, contract research organization [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 
CRF 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. 
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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 CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required CRFs 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 CRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature. 
A copy of each patient CRF 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 CRF will be entered in the CRF 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, CRFs, 
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. 
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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 
eCRFs that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, 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. 
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. 
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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. 
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 CRFs or other documents and data 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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Bevacizumab in Advanced Cervical Cancer. New England Journal of Medicine 2014; 370(8):734-743. 
 
Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, et al. Bevacizumab for 
advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, 
open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017; 390(10103):1654-1663. 
 
Thompson JA. New NCCN Guidelines: Recognition and Management of Immunotherapy-Related 
Toxicity. J Natl Compr Canc Netw 2018; 16(5s):594-596. 
 
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Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J,Jemal A. Global cancer statistics, 2012. CA: A 
Cancer Journal for Clinicians 2015; 65(2):87-108. 
 
van Poelgeest MI, Welters MJ, Vermeij R, Stynenbosch LF, Loof NM, Berends-van der Meer DM, et al. 
Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance 
Is Related to the Strength of the T-Cell Response. Clin Cancer Res 2016; 22(10):2342-2350. 
 
Weber JS, Yang JC, Atkins MB,Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol 
2015; 33(18):2092-2099. 
 
Welters MJP, Ma W, Santegoets S, Goedemans R, Ehsan I, Jordanova ES, et al. Intratumoral HPV16-
Specific T Cells Constitute a Type I-Oriented Tumor Microenvironment to Improve Survival in HPV16-
Driven Oropharyngeal Cancer. Clin Cancer Res 2018; 24(3):634-647. 
 
Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, 
musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60:210-225. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2 Study of Cemiplimab, an Anti-PD-1 Monoclonal 
Antibody, and ISA101b Vaccine in Patients with Recurrent/Metastatic HPV16 Cervical Cancer 
Who Have Experienced Disease Progression after First Line Chemotherapy 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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APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
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 
Source: (Oken, 1982) 
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APPENDIX 2. GUIDELINES FOR MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS 
Select immune-mediated adverse events (imAEs) and their management are described in this appendix. Additionally, the following 
general principles apply to management of imAEs, if not described in detail in this appendix: 
Grade 1: Continue study treatment with close monitoring and provide symptomatic management.   
Grade 2: Consider withholding study treatment 
Grade 3: Withhold study treatment 
Grade 4: Discontinue study treatment. 
Temporary hold and resumption. Except as described for select imAEs, if cemiplimab is withheld for grade ≤3 imAE, consider 
resuming when the imAE improves to grade 0 or 1 after corticosteroid taper to ≤ prednisone 10 mg/day or equivalent.  
Permanent discontinuation. Except as described for select imAEs, give an initial dose of 1 to 2 mg/kg/day prednisone or equivalent 
followed by a taper and permanently discontinue study treatment for: 
• Grade 4 adverse reactions (excluding endocrinopathies) 
• Recurrent Grade 3 imAEs 
• Grade 2 or 3 imAEs persistent for ≥12 weeks after the last study treatment  
• Requirement for ≥10 mg per day prednisone or equivalent lasting ≥12 weeks after the last study treatment. 
For guidance in addition to that provided here, please refer to regional imAE management guidelines, such as those provided by NCCN 
or ESMO. In countries where cemiplimab has a marketing authorization the local product information may be consulted. Note that local 
and regional treatment guidelines and cemiplimab product information may be updated periodically and the latest version should always 
be reviewed. 
 
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Recommended Adverse Event Management for Colitis/Diarrhea 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
• Colitis: 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
• Diarrhea: Increase of <4 
stools per day over 
baseline; mild increase in 
ostomy output compared 
to baseline 
• No change  
 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and American Dietic 
Association colitis diet)  
• Consider consultation with gastroenterologist for 
prolonged symptoms  
• If symptoms are persistent, consider endoscopic 
evaluation 
• If persists for >2 weeks, treat as grade 2  
 
 
 
• All attempts 
should be 
made to rule 
out other 
causes such as 
metastatic 
disease, 
bacterial or 
parasitic 
infection, or 
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CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 2 
• Colitis: Abdominal pain; 
mucus or blood in stool 
• Diarrhea: Increase of 4 
to 6 stools per day over 
baseline; moderate 
increase in ostomy output 
compared to baseline; 
limiting instrumental 
ADL 
• Withhold study treatment 
until colitis or diarrhea 
improves and remains at 
grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and American Dietetic 
Association colitis diet) 
• Consultation with gastroenterologist  
• Consider colonoscopy ± 
esophagogastroduodenoscopy (EGD), or endoscopy  
• Consider stool evaluation to rule out infectious 
etiology 
• Consider stool inflammatory marker evaluation (ie, 
lactoferrin and calprotectin) to differentiate 
functional vs. inflammatory diarrhea 
• Consider abdominal and pelvic CT with contrast 
• Treatment with systemic corticosteroids (1 to 
2 mg/kg/day prednisone or equivalent) until 
resolution to grade ≤1 and taper over at least a 
month 
• If no improvement within 2 to 3 days, treat as grade 
3 
viral 
gastroenteritis 
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CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 3 
• Colitis: Severe 
abdominal pain; 
peritoneal signs 
• Diarrhea: Increase of ≥7 
stools per day over 
baseline; hospitalization 
indicated; severe increase 
in ostomy output 
compared to baseline; 
limiting selfcare ADL 
• Withhold study treatment 
until colitis or diarrhea 
improves and remains at  
grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Permanently discontinue 
study treatment if patient 
develops a second episode 
of grade 3 colitis or diarrhea 
upon re-challenge 
 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and American Dietetic 
Association colitis diet) 
• Consultation with gastroenterologist  
• Consider colonoscopy ± 
esophagogastroduodenoscopy (EGD), or endoscopy  
• Consider stool evaluation to rule out infectious 
etiology 
• Consider stool inflammatory marker evaluation (ie, 
lactoferrin and calprotectin) to differentiate 
functional vs. inflammatory diarrhea 
• Consider abdominal and pelvic CT with contrast 
• Inpatient care for close monitoring and supportive 
care 
• Treatment with systemic corticosteroids (1 to 2 
mg/kg/day prednisone or equivalent) until resolution 
to grade ≤1 and taper over at least 1 month 
• If no improvement with corticosteroid within 2 to 3 
days, consider additional immunosuppressive 
therapy ie, mycophenolate 0.5 to 1g BID, infliximab 
5 mg/kg IV  
Grade 4 or Recurrent 
Grade 3 
• Colitis: Life-threatening 
consequences: urgent 
intervention indicated 
• Diarrhea: Life-
threatening 
consequences; urgent 
intervention indicated 
• Permanently discontinue 
study treatment 
 
• Same as above 
• Consider lower GI endoscopy if symptoms are 
refractory despite treatment or there is concern of 
new infections 
 
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Recommended Adverse Events Management for Dermatologic Toxicities 
Immune-related skin toxicities include maculopapular rash, dermatitis, rash generalized, dermatitis bullous, drug eruption, erythema, 
rash erythematous, rash macular, rash pruritic, and skin reaction. Guidance here is provided for maculopapular rash. For other 
immune-related skin toxicities, see expert consensus guidelines cited in Section 8.3. 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
or 
Grade 2 lasting 1 
week or less 
• No change  
 
• Treatment with mild to moderate potency topical steroids  
• Treatment with oral antihistamine 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, contact 
dermatitis, effect of 
another drug, or a 
skin condition linked 
to another systemic 
disease 
 
Grade 2 lasting 
longer than 1 week 
or 
Grade 3 
or 
Suspected Stevens-
Johnson syndrome 
(SJS), toxic 
epidermal 
necrolysis (TEN) or 
Drug rash with 
eosinophilia and 
systemic symptoms 
(DRESS) 
• Withhold study 
treatment until skin 
reaction improves 
and remains at 
grade 0 to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Consider consultation with dermatologist and skin biopsy for 
diagnosis of bullous dermatitis 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least one month 
• Consider treatment with medium to high potency topical 
steroids  
• Treatment with oral antihistamine 
Grade 4 
or 
Confirmed SJS,  
TEN, or DRESS 
• Permanently 
discontinue study 
treatment  
• Consultation with dermatologist and skin biopsy 
• Treatment with high potency topical steroids and with 
systemic corticosteroids (1 to 2 mg/kg/day prednisone or 
equivalent) until resolution to ≤ grade 1 and taper over at 
least one month 
 
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Immune-Mediated Skin 
Adverse Reactions or other 
Immune-Related Adverse 
Reactions in Patients with 
Prior Treatment with 
Idelalisib 
CTCAE v5.0 Grade  
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
• No change 
• Treatment as clinically indicated 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, contact 
dermatitis, effect of 
another drug, or a 
skin condition 
linked to another 
systemic disease 
 
Grade 2 
• Withhold study treatment until 
skin reaction or other 
immune-related adverse 
reaction improves and remains 
at grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Consider consultation with dermatologist 
and skin biopsy for diagnosis of bullous 
dermatitis 
• Immediate symptom management, 
including systemic corticosteroids (1 to 2 
mg/kg/day prednisone or equivalent) until 
resolution to ≤ grade 1 and taper over at 
least one month 
• Consider treatment with medium to high 
potency topical steroids and/or oral 
antihistamine for skin reactions  
Grade 3 or 4 (excluding 
endocrinopathies) 
or  
Recurrent Grade 2 
• Permanently discontinue 
study treatment  
• Consultation with dermatologist and skin 
biopsy for skin reactions 
• Treatment with high potency topical 
steroids if skin reaction 
• Treatment with systemic corticosteroids (1 
to 2 mg/kg/day prednisone or equivalent) 
until resolution to ≤ grade 1 and taper over 
at least one month 
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Recommended Adverse Events Management for Endocrine Events: Hypothyroidism 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor thyroid function more frequently (every 3 to 6 
weeks) until resolution to baseline 
• There should be low index of suspicion for immune-related 
endocrinopathy including checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically appropriate 
• Immune-related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
Grade 2 
 
• Withhold study 
treatment if 
clinically necessary 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Replacement of thyroid hormone as indicated 
Grade 3 or 4 
• Withhold study 
treatment until 
hypothyroidism 
improves and 
remains at grade 0 
to 1 or is otherwise 
clinically stable 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Replacement of thyroid hormone as indicated 
 
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Recommended Adverse Events Management for Endocrine Events: Hyperthyroidism 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor thyroid function more frequently (every 2 to 3 
weeks) until resolution to baseline 
• There should be low index of suspicion for immune-related 
endocrinopathy including checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically appropriate 
• Immune-related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
Grade 2 
 
• Withhold study 
treatment if 
clinically necessary 
• Same as above 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Consider -blocker for symptomatic relief 
• For persistent hyperthyroidism (> 6weeks), consider work up 
for Graves disease and refer to endocrinology for Graves 
disease 
Grade 3 or 4 
• Withhold study 
treatment until 
hyperthyroidism 
improves and 
remains at grade 0 
to 1 or is otherwise 
clinically stable 
• Same as above 
• For severe symptoms, inpatient care and consider systemic 
corticosteroids treatment (1 to 2 mg/kg/day prednisone or 
equivalent) until resolution to ≤ grade 1 and taper over 1 to 2 
weeks in consultation with endocrinology 
• Consider use of saturated solution of potassium iodide 
(SSKI) or thionamide 
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Recommended Adverse Events Management for Endocrine Events: Hypophysitis or Adrenal Insufficiency 
CTCAE v5 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• There should be low index of suspicion for 
immune-related endocrinopathy including 
checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically 
appropriate 
• Immune related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
Grades 2 to 4 
• Withhold study treatment 
until hypophysitis or adrenal 
insufficiency improves and 
remains at grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent or is otherwise 
clinically stable 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
• Initial dose of 1 to 2 mg/kg/day prednisone or 
equivalent followed by a taper 
• Replacement of relevant hormone(s) as indicated 
 
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Recommended Adverse Events Management for Endocrine Events: Type I Diabetes Mellitus 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor glucose level more frequently until 
resolution to baseline 
• There should be low index of suspicion for 
immune-related endocrinopathy including 
checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically 
appropriate 
 
• Immune related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
 
Grade 2 
• Withhold study treatment if 
clinically necessary until 
glucose control is obtained 
• Same as above 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
 
Grade 3 or 4 
(hyperglycemia) 
• Withhold study treatment 
until diabetes mellitus returns 
to grade 0 to 1 or is otherwise 
clinically stable 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
• Initiate treatment with anti-hyperglycemics as 
clinically indicated 
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Recommended Adverse Events Management for Hepatitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change 
• Monitor liver function tests (LFT) more frequently until 
resolution to baseline values 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
progressive liver 
disease, viral 
hepatitis, alternative 
drug toxicity, 
infectious causes 
and/or myositis  
 
Grade 2 with: 
Elevated ALT & 
AST >3 and ≤5x 
ULN  
Or total bilirubin 
>1.5x and ≤3x ULN 
 
• Withhold study 
treatment until 
hepatitis improves 
and remains at 
grade 0 to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent or 
returns to baseline 
AST or ALT after 
completion of 
corticosteroid taper 
• Monitor LFT more frequently until resolution to baseline 
values 
• Consider appropriate consultation with hepatologist and liver 
biopsy to establish etiology of hepatic injury, if necessary 
• Consider inpatient monitoring for patients with ALT/AST 
>8x ULN and or elevated total bilirubin >3x ULN 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least 1 month 
• If no improvement within 3 days after initiation of systemic 
steroids, consider additional immunosuppressive therapy ie, 
mycophenolate mofetil 0.5 to 1 g BID 
• Several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased 
Grade 3 or 4 with: 
Elevated ALT & 
AST >5x ULN 
or total bilirubin ˃3x 
ULN 
 
• Permanently 
discontinue study 
treatment 
• Same as above 
 
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Recommended Adverse Events Management for Neurotoxicity 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
• Closely monitor the patient 
• If worsening, treat as grade 2 or 3 to 4, as clinically 
appropriate 
• If immune-mediated 
encephalitis is 
suspected, consider 
radiologic assessment 
and, if possible, 
cerebrospinal fluid 
(CSF) assessment for 
auto-immune 
antibodies 
Grade 2 
• Withhold study 
treatment until 
improves and 
remains at grade 0 
to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Treat symptoms per local guidelines, eg 0.5 to 1 mg/kg/day 
methylprednisolone IV or oral (PO) equivalent 
• If worsening, treat as grades 3 to 4 
• Consider neurology consult 
Grade 3 or 4 
 
• Permanently 
discontinue study 
treatment  
• Neurology consult required 
• Treat symptoms per local guidelines AND give 1 to 2 
mg/kg/day methylprednisolone IV 
• If improves to grade 2: taper with corticosteroids over at least 
4 weeks 
• Consider adding prophylactic antibiotics for opportunistic 
infections 
• If worsening or atypical presentation, consider intravenous 
immunoglobulin (IVIG) or other immunosuppressive 
therapies per local guidelines 
 
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Recommended Adverse Events Management for Pneumonitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
• Consider 
withholding study 
treatment 
• Monitor symptoms every 2 to 3 days 
• Consider consultation with pulmonologist 
• Consider chest imaging (chest CT or chest x-ray) followed by 
serial imaging at least every 3 weeks to monitor resolution or 
progression 
• May resume study treatment upon improvement or 
resolution. If no improvement, treat as grade 2 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
bacterial or viral 
infection  
Grade 2 
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL 
• Withhold study 
treatment until 
pneumonitis 
improves and 
remains at grade 0 
to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Permanently 
discontinue study 
treatment if patient 
develops a second 
episode of ≥ grade 
2 pneumonitis upon 
re-challenge 
• Monitor symptoms daily; consider hospitalization 
• Consider consultation with pulmonologist 
• Consider chest imaging (chest CT or chest x-ray) followed by 
serial imaging at least every 3 weeks to monitor resolution or 
progression 
• Consider bronchoscopy with bronchoalveolar lavage (BAL) 
to rule out infection and malignant lung infiltration 
• Consider pulmonary function tests and laboratory work up 
for infections 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• If symptoms do not improve within 48 to 72 hours of 
corticosteroid treatment, treat as grade 3 
• Consider empiric antibiotics if infection has not yet been 
fully excluded 
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CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 3 or 4 or 
Recurrent Grade 2 
 
Grade 3: 
Severe symptoms; 
limiting selfcare 
ADL; oxygen 
indicated 
 
Grade 4: 
Life-threatening 
respiratory 
compromise; urgent 
intervention 
indicated (eg, 
tracheotomy or 
intubation) 
 
• Permanently 
discontinue study 
treatment 
 
• Inpatient care 
• Consultation with pulmonologist and infectious disease 
specialties 
• Treatment with systemic corticosteroids (2 to 4 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least 6 weeks 
• If symptoms do not improve within 48 to 72 hours of 
corticosteroid treatment, consider additional 
immunosuppressive treatment ie, mycophenolate mofetil 1 to 
1.5 g BID, infliximab 5 mg/kg IV 
• If symptoms worsen during steroid reduction, initiate a re-
tapering of steroids starting at a higher dose of 80 or 100 mg 
followed by a more prolonged taper 
• Consider bronchoscopy with bronchoalveolar lavage (BAL) 
to rule out infection and malignant lung infiltration 
• Empiric antibiotics if infection has not yet been fully 
excluded 
• Consider adding prophylactic antibiotics for opportunistic 
infections 
 
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Recommended Adverse Events Management for Renal Events 
Immune-Mediated 
Nephritis with 
renal dysfunction 
 CTCAE v5 Grade  
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
• Provide symptomatic treatment.  
• Monitor creatinine weekly; when it returns to baseline, 
resume routine creatinine monitoring per protocol 
• All attempts should 
be made to rule out 
other causes such as 
obstructive uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents 
 
Grade 2 
Blood creatine 
increased > 1.5 to 
3.0 X baseline or 
ULN 
 
• Withhold study 
treatment until 
nephritis improves 
and remains at 
grade 0 to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Consultation with nephrologist 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• Consider prophylactic antibiotics for opportunistic infections 
• Consider renal biopsy 
• If elevations persist >7 days or worsen, treat as severe AE 
Grade 3  
Blood creatinine 
increased > 3.0 X 
baseline or > 3.0 to 
6.0 x ULN 
 
Grade 4 
Blood creatine 
increased > 6.0 X 
ULN 
• Permanently 
discontinue study 
treatment 
• Consultation with nephrologist in consideration of ultrasound 
and/or biopsy as appropriate 
• Consider inpatient care and monitor creatinine daily 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• If no improvement within 7 days after initiation of systemic 
steroids, consider additional immunosuppressive therapy ie, 
mycophenolate mofetil 0.5 to 1 g BID  
 
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Recommended Adverse Events Management for Uveitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
 
• No change 
• Consultation with ophthalmologist within 1 week 
• Treatment with artificial tears 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, or other 
ocular disease 
(eg, glaucoma or 
cataracts) 
Grade 2 
 
• Withhold study treatment  
• Urgent consultation with ophthalmologist 
• Treatment with topical/periocular/intravitreal 
corticosteroids and/or systemic corticosteroids 
guided by ophthalmologist  
• May resume study treatment if resolved to ≤ grade 1 
and systemic steroid is reduced to ≤10 mg. 
Topical/ocular steroids are permitted during study 
treatment 
Grade 3 or 4 
• Permanently discontinue 
study treatment  
• Same as above 
• If severe or refractory to steroid treatment, consider 
infliximab 
 
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Recommended Adverse Events Management for Myocarditis or Pericarditis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 or 2 
• Consider withholding study 
treatment 
• Immediate consultation with cardiologist 
• Inpatient care 
• Consider ECG, telemetry monitoring, cardiac MRI 
• Consider cardiac biomarker assessment (creatine 
kinase and troponin) or inflammatory biomarkers 
(ESR, CRP, WBC count, etc) 
• May offer immediate transfer to a coronary care 
unit for patient with elevated troponin or 
conduction abnormalities 
• Treatment with systemic corticosteroids (1 to 
2 mg/kg/day prednisone or equivalent) initiated 
rapidly (oral or IV depending on symptoms) until 
resolution to baseline and taper over 4 to 6 weeks 
• Manage cardiac symptoms according to American 
College of Cardiology (ACC)/AHA guidelines and 
with guidance from cardiology 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease 
and viral infection 
Grade 3 or 4 
  
• Permanently discontinue 
study treatment  
 
• Same as above 
• Consider 1 g methylprednisolone pulse dose 
• If severe or refractory to steroid treatment, consider 
additional immunosuppressive agents 
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APPENDIX 3. 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) or magnetic resonance imaging (MRI) scan 
(slice thickness recommended to be no greater than 5 mm)  
− 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)  
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT or MRI scan (slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
1.2. 
Nonmeasurable Disease   
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis), are considered nonmeasurable 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 nonmeasurable. 
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 
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or MRI can be considered 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 malignant lesions (neither measurable nor nonmeasurable) since they are, by definition, 
simple cysts.  “Cystic lesions” thought to represent cystic metastases can be considered measurable 
lesions, if they meet the definition of measurability described above.  However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
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 tumor 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 for body 
scans except chest. MRI is preferred for brain 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 larger size are 
generally preferred), be representative of all involved organs, have better defined boundaries, 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 or MRI 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 
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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 of 
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, 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 (eg, 2 mm).  If the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. However, 
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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:  i.e. not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
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 
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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.  If repeat scans confirm there is definitely a new lesion, then 
progression should be declared using the date of the initial scan.  
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 taking into account any requirement for confirmation.   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 When Confirmation is 
Required 
Target 
Lesions 
Non-target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required 
CR 
CR 
No 
CR 
≥4 weeks confirmation 
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 
Documented at least once 
≥4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Yes or no 
PD 
No prior SD, PR, or CR 
Any 
PD** 
Yes or no 
PD** 
Any 
Any 
Yes 
PD 
 
Abbreviations:  CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease; NE=not 
evaluable. 
*For non-target disease, ‘non-CR/non-PD’ is preferred over ‘SD’ since SD is increasingly used as endpoint for 
assessment of efficacy in some trials, so to assign this category when no lesions can be measured is not advised. 
**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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Best Overall Response When Confirmation of CR and PR are Required 
Overall Response, First 
Time Point 
Overall Response, 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR* 
CR 
SD 
SD if minimum criteria for SD duration 
met, otherwise PD 
CR 
PD 
SD if minimum criteria for SD duration 
met, otherwise PD 
CR 
NE 
SD if minimum criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD if minimum criteria for SD duration 
met, otherwise PD 
PR 
NE 
SD if minimum criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
Adapted from (Eisenhauer, 2009) 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease; NE=not 
evaluable. 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
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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 planned conduct of the study. 
Study Title: 
 A Phase 2 Study of Cemiplimab, an Anti-PD-1 Monoclonal Antibody, and 
ISA101b Vaccine in Patients with Recurrent/Metastatic HPV16 Cervical Cancer Who Have 
Experienced Disease Progression after First Line Chemotherapy  
Protocol Number: 
R2810-ONC-ISA-1981 
Protocol Version: 
R2810-ONC-ISA-1981 Amendment 2 
 
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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Signature Page for VV-RIM-00164906 v1.0
Signature Page for VV-RIM-00164906 v1.0 Approved
ESig Approval
27-Aug-2021 17:22:00 GMT+0000
ESig Approval
28-Aug-2021 10:13:06 GMT+0000
ESig Approval
30-Aug-2021 13:15:09 GMT+0000
ESig Approval
31-Aug-2021 08:20:53 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 33 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION 2.0 FINAL 
Clinical Study Protocol Title: A Phase 2 Study of Cemiplimab, an Anti-PD-1 Monoclonal 
Antibody, and ISA101b Vaccine in Patients with 
Recurrent/Metastatic HPV16 Cervical Cancer who Have 
Experienced Disease Progression after First Line Chemotherapy 
Compound: 
Cemiplimab (REGN2810 [anti-PD-1 mAb]) 
ISA101b 
Protocol Number: 
R2810-ONC-ISA-1981 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Study Lead:  
 
Study Medical Director: 
 
Version/Date:  
Version 2.0 / October 12, 2022 
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Statistical Analysis Plan 
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Page 2 of 33 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
 
 
See appended electronic signature page 
 
  
 
 
 
 
See appended electronic signature page 
  
 
 
 
 
 
 
See appended electronic signature page 
  
 
 
 
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Page 3 of 33 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.1.1. 
Background ...................................................................................................................8 
1.1.2. 
Rationale .......................................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objectives .................................................................................................9 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design ...............................................................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Full Analysis Set (FAS) ..............................................................................................13 
3.2. 
The Pharmacokinetic Analysis Set .............................................................................13 
3.3. 
Immunogenicity Analysis Set .....................................................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
4.2. 
Medical History ..........................................................................................................14 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................14 
4.4. 
Efficacy Variable ........................................................................................................15 
4.4.1. 
Primary Efficacy Variable ..........................................................................................15 
4.4.2. 
Secondary Efficacy Variables .....................................................................................15 
4.4.3. 
Exploratory Efficacy Variables ..................................................................................16 
4.5. 
Safety Variables ..........................................................................................................16 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................17 
4.5.2. 
Adverse Events of Special Interest (applicable to cemiplimab only) .........................18 
4.5.3. 
Laboratory Safety Variables .......................................................................................18 
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Page 4 of 33 
4.5.4. 
Vital Signs ..................................................................................................................19 
4.5.5. 
12-Lead Electrocardiography (ECG) ..........................................................................19 
4.5.6. 
Physical Examination Variables .................................................................................19 
4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables (ADA) ....................20 
4.6.1. 
Pharmacokinetic Variables .........................................................................................20 
4.6.2. 
Immunogenicity Variables ..........................................................................................20 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior/concomitant Medications and Procedures .........................................................21 
5.4. 
Subject Disposition .....................................................................................................21 
5.5. 
Protocol Deviation ......................................................................................................21 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................22 
5.6.1. 
Measurement of Compliance ......................................................................................22 
5.6.2. 
Exposure to Investigational Product ...........................................................................22 
5.7. 
Analyses of Efficacy Variables ..................................................................................22 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................22 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................23 
5.7.3. 
Subgroup Efficacy Analysis .......................................................................................23 
5.8. 
Analysis of Safety Data ..............................................................................................23 
5.8.1. 
Adverse Events ...........................................................................................................23 
5.8.2. 
Clinical Laboratory Measurements.............................................................................24 
5.8.3. 
Analysis of Vital Signs ...............................................................................................24 
5.8.4. 
Analysis of 12-Lead ECG ...........................................................................................24 
5.9. 
Analysis of Pharmacokinetic and Antibody Data .......................................................25 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................25 
5.9.2. 
Analysis of Anti-Drug Antibody Data ........................................................................25 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................26 
5.10.1. 
Immunogenicity and Exposure ...................................................................................26 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................26 
5.11. 
Analysis of Exploratory Biomarker Data ...................................................................26 
6. 
DATA CONVENTIONS ............................................................................................27 
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Page 5 of 33 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................27 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................27 
6.3. 
Definition of Study Day ..............................................................................................27 
6.4. 
Data Handling Convention for Missing Data .............................................................27 
6.5. 
Unscheduled Assessments ..........................................................................................27 
7. 
MULTIPLICITY CONSIDERATIONS .....................................................................29 
8. 
INTERIM ANALYSIS ...............................................................................................30 
9. 
SOFTWARE ...............................................................................................................31 
10. 
REFERENCES ...........................................................................................................32 
 
LIST OF TABLES 
Table 1: 
The 2-sided 95% Confidence Intervals for Observed ORR Based on a 
Sample Size of 105 Patients .......................................................................................11 
 
 
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Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CR 
Complete response 
CRF 
Case report form (electronic or paper) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRR 
Infusion-related reaction 
ISA 
ISA Pharmaceuticals B.V. 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
ORR 
Objective response rate 
OS 
Overall survival 
PD-1 
Programmed death-1 (receptor) 
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PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
Q3W 
Every 3 weeks 
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 
SC 
Subcutaneous 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
WBC 
White blood cell 
WHO 
World Health Organization 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock.  
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for R2810-ONC-ISA-1981 study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses.  The final plan, if revised, will document all changes and be issued prior to database 
lock. 
1.1. 
Background/Rationale 
1.1.1. 
Background 
The global annual incidence of cervical cancer is approximately 527,000 cases per year, and 
there are approximately 265,000 deaths (Torre, 2015). Most cases are due to infection with 
human papillomavirus (HPV). Although vaccination against high risk strains of HPV is projected 
to gradually decrease the global incidence of cervical cancer in the next 15 years, the burden of 
this disease remains profound (Bray, 2012). Internationally, the etiologic fraction of HPV-
associated malignancy, based on HPV detection, varies by geography and anatomic site, but 
overall suggests that 70% of cervical cancers are caused by HPV16/18, and HPV16 is the 
primary oncogenic virus in other anogenital and oropharyngeal cancers. 
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 
20 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. LIBTAYO® (cemiplimab) is approved 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. 
ISA101b is a therapeutic vaccine targeting the HPV type 16 E6/E7 proteins. The HPV16 
synthetic long peptides in ISA101b act as a therapeutic vaccine that stimulates the actions of 
both CD4+ T-helper cells and CD8+ cytotoxic T-cells against the known oncogenic sequences of 
the HPV16 virus. 
1.1.2. 
Rationale 
Combination therapy may stimulate convergent aspects of host immunity by employing 
complementary immunomodulators and immune-stimulatory aspects of conventional modalities. 
Combination therapy may result in the development of more effective cancer therapies.  
Treatment with the PD-1 inhibitor pembrolizumab has shown initial efficacy as monotherapy in 
recurrent or metastatic cervical cancer after disease progression on or after chemotherapy (FDA, 
2018). While the response rates with monotherapy Pembrolizumab are similar to chemotherapy 
in the 2L or greater setting, responses with pembrolizumab have shown greater durability  
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(Takeuchi , 1991; Look, 1998; Bookman, 2000; Muggia, 2004; Muggia, 2005; Schilder, 2005; 
Miller, 2008; Lorusso, 2010; Chung, 2019). 
ISA101 has demonstrated a robust and clinically active immune responses against HPV16 E6/E7 
in HPV16 positive patients with pre-malignant lesions, such as vulvar intraepithelial neoplasia 
(VIN) (Kenter, 2009; van Poelgeest , 2016). A single arm study in women with HPV16+ 
advanced cervical cancer receiving ISA101/101b after carboplatin and paclitaxel showed a 
potent and durable immune response to HPV16 epitopes. An increase in OS was associated with 
strength of induced vaccine responses (Melief, 2020). Data from a combination study with 
ISA101b and nivolumab in a variety of recurrent/metastatic incurable HPV16 positive 
malignancies showed an ORR of 33% with a safety profile consistent with PD-1 inhibitors 
(Gillison, 2016). 
These data together support a single arm phase 2 trial with combination therapy of ISA101b and 
cemiplimab in recurrent/metastatic cervical cancer. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b 
after progression on first line chemotherapy, as assessed by objective response rate (ORR).   
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To characterize the safety profile of cemiplimab + ISA101b 
• To assess preliminary efficacy of cemiplimab + ISA101b as measured by duration of 
response (DOR), progression-free survival (PFS), and overall survival (OS) 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To correlate clinical efficacy with baseline tumor tissue immune biomarkers 
including PD-L1, immune cell subsets, MHC class I/II, gene expression profile and 
tumor mutational burden. 
• To correlate clinical efficacy with on-treatment changes in HPV antigen specific 
T cell responses, immune cell subsets and serum cytokine biomarkers  
• Explore novel molecular and cellular predictive and pharmacodynamic biomarkers 
associated with clinical efficacy, including cellular and molecular parameters in 
tumor tissue and peripheral blood.  
• To assess the immunogenicity of cemiplimab when combined with ISA101b 
• To explore other HPV serotypes present in HPV16+ tumors 
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1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
TTR, DCR, and dDCR were added as secondary endpoints. 
1.2.5. 
Revision History for SAP Amendments 
This is the second version of the SAP, based on the study protocol of R2810-ONC-ISA-1981 
Amendment 2 dated August 31, 2021. 
The main changes from SAP 1.0 dated November 3, 2020 (based on the original protocol) 
include:  
• Updated the sample size to 105 patients per protocol amendment 2 
• Removed statistical hypothesis testing and added the option for an administrative efficacy 
review per protocol amendment 2 
• Removed safety analysis set per protocol amendment 2. The full analysis set will be used 
to summarize efficacy, safety, and baseline variables. 
 
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
This is a single-arm, phase 2, global study of treatment with cemiplimab + ISA101b in HPV16 
positive cervical cancer patients with disease progression on first line chemotherapy in the 
recurrent or metastatic setting. 
2.2. 
Sample Size and Power Considerations 
The planned total sample size for this study is 105 patients. 
The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b 
after progression on first line chemotherapy, as assessed by objective response rate (ORR). 
With105 patients, Table 1  below presents various response rates and associated 2-sided 95% CIs 
using a normal approximation of the binomial distribution, and precision of estimation defined as 
distance from the boundary to the center (i.e., half-width of the 95% CI). If observed ORR 
ranges from 20.0% to 34.3%, the precision estimation using 105 patients ranges from 7.7% to 
9.1%. 
Table 1: 
The 2-sided 95% Confidence Intervals for Observed ORR Based on a 
Sample Size of 105 Patients 
Number of Responders 
Observed ORR 
95% CI 
Precision 
21 
20.0% 
(12.4, 27.7) 
7.7% 
24 
22.9% 
(14.8, 30.9) 
8.0% 
27 
25.7% 
(17.4, 34.1) 
8.4% 
31 
29.5% 
(20.8, 38.3) 
8.8% 
36 
34.3% 
(25.2, 43.4) 
9.1% 
2.3. 
Study Plan 
After a screening period of up to 28 days, all patients will receive the following regimen:  
• ISA101b 100 μg/peptide by SC injection on Day 1, Day 29, and Day 50 (total of 
3 doses). 
• Cemiplimab 350 mg given by IV infusion over 30 minutes every 3 weeks (Q3W) on 
Days 8 and 29 in Cycle 1, on Days 1 and 22 in Cycles 2 through 4, and on Days 1, 22, 
and 43 in all subsequent cycles or until disease progression or discontinuation of 
study drug for any other reason. 
Cycle 1 will be 7 weeks long, Cycles 2 through 4 will be 6 weeks long, and all subsequent cycles 
will be 9 weeks long. 
Patients will be assessed for response at week 7, then every 6 weeks for 3 cycles, then every 9 
weeks in all subsequent cycles or until disease progression or discontinuation of study drug for 
any other reason. Patients with confirmed CR after a minimum of 48 weeks of treatment may elect 
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to discontinue treatment and continue with all relevant study assessments (eg, efficacy 
assessments).  
There will be a 90-day safety follow-up after the last dose of cemiplimab. Patients who discontinue 
study drug for reasons other than progression will be followed approximately every 4 months by 
scans until disease progression or until the patient commences another anticancer systemic therapy, 
whichever comes first. After progression, survival follow-up should occur approximately every 4 
months. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all enrolled patients who received any study drug. Efficacy, 
safety, and baseline variables will be analyzed or summarized using the FAS. 
3.2. 
The Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any study drug and who had at 
least 1 non-missing result following the first dose of cemiplimab. 
3.3. 
 Immunogenicity Analysis Set 
The ADA analysis set includes all patients who received cemiplimab and had at least 1 non-
missing ADA result following the first cemiplimab dose. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Age at screening in years (quantitative and qualitative variable: <65, ≥65 - < 75, ≥75) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic/Latino or not) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) calculated from weight and height: weight (kg) / [height 
(m)]^2 
• ECOG performance status (0, 1) 
Baseline tumor characteristics variables include: 
• Primary diagnosis 
• Time from initial diagnosis to first study dose 
• Histologic grade 
• Cancer stages at initial diagnosis 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until 90 days after 
the last study treatment or 1 day prior to starting a new treatment for cervical cancer, whichever 
is first. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. 
Prior cancer related medications/procedures: medications taken, or procedures performed prior to 
administration of the study drug, particularly, prior cancer related surgery, prior cancer related 
radiotherapy, and prior cancer related systemic therapy will be summarized. 
Pre-treatment medications/procedures: non-study medications for which administration started 
and discontinued before a patient received the first dose of study drug. 
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Concomitant medications/procedures: any treatment administered from the time of informed 
consent until 90 days after the last study treatment or start of another systemic anticancer 
therapy, whichever comes first, will be considered concomitant treatment. This includes 
medications and other therapies for which administration started 30 days before the first dose of 
the study and will continue during the study, as well as any therapies started in the follow-up 
period to treat a study-drug-related AE.  
Post treatment anti-cancer medications/procedures: anti-cancer medications and other anti-cancer 
therapies that started after discontinuation of the study drug. 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable  
Overall response is determined by RECIST version 1.1 (Eisenhauer, 2009). 
Best overall response (BOR) is determined once all the overall response data for the patient are 
known. The best overall response is the best response recorded during the study: 
• Best overall response of CR or PR must be confirmed by consecutive evaluations of 
overall response of CR or PR at time points at least 4 weeks apart. 
• Best overall response of SD must have met the response SD criteria at least once ≥ 42 
days (7 weeks - 7 days) after start of study treatment. Best overall response of (early) 
PD does not require confirmation using the RECIST. 
• The best overall response for patients who do not have any post-baseline tumor 
assessment will be not evaluable (NE). Patients with best overall response of NE will 
be considered as not reaching an objective response of CR or PR. 
Objective response rate (ORR) is determined by the proportion of patients with best overall 
response of CR or PR in the FAS.  
4.4.2. 
Secondary Efficacy Variables 
Duration of response (DOR) is determined for patients with BOR of CR or PR. DOR is 
measured from the time measurement criteria are first met for CR/PR (whichever is first 
recorded) until the first date of recurrent or progressive disease (radiographic), or death due to 
any cause. 
• Patients who do not have a documented tumor progression or death will be censored 
at the last evaluable tumor assessment. 
• Patients who do not have a documented tumor progression or death before initiation 
of new anti-cancer therapy will be censored at the last evaluable tumor assessment 
prior to or on the date of new anti-cancer therapy. 
Progression-free survival (PFS) is measured from the start of treatment until the first date of 
recurrent or progressive disease (radiographic), or death due to any cause. 
• Patients who do not have a documented tumor progression or death will be censored 
at the last evaluable tumor assessment. 
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• Patients who do not have a documented tumor progression or death before initiation 
of new anti-cancer therapy will be censored at the last evaluable tumor assessment 
prior to or on the date of new anti-cancer therapy. 
• Patients who do not have any evaluable post-baseline tumor assessment and do not 
die will be censored on the date of first study treatment. 
Overall survival (OS) is measured from the start of treatment until death due to any cause. 
Patients who do not die will be censored at the last date that patient is documented to be alive. As 
many patients may receive new anti-cancer therapy after disease progression, a sensitivity 
analysis of OS will be conducted by censoring patients at the first date of a new anti-cancer 
therapy is taken. 
Time to tumor response (TTR) is determined for patients with BOR of CR or PR. TTR is 
measured from the start of treatment until the time measurement criteria are first met for CR/PR 
(whichever is first recorded). 
For all the above time-to-event variables, the time to event (day) is the date of event/censor - the 
date of first study treatment + 1. 
Disease control rate (DCR) is determined by the portion of patients with BOR of CR, PR, or 
SD. 
Durable disease control rate (dDCR) is defined as the proportion of patients best overall 
response of CR, PR, or SD without progression for at least 12 weeks. 
4.4.3. 
Exploratory Efficacy Variables 
The following exploratory efficacy variables will be analyzed. 
• Association of clinical efficacy endpoints with baseline tumor biomarker parameters 
(PD-L1, immune cell subsets, MHC class I/II, gene expression profile and tumor 
mutational burden) 
• In a subset of study sites: Association of clinical efficacy endpoints with post-
treatment changes in frequency and clonal repertoire of HPV antigen specific T cells, 
peripheral blood immune cell subsets (Teff, Treg, myeloid, dendritic and NK cells) 
and serum cytokine levels when available  
• Cemiplimab immunogenicity as measured by anti-drug antibodies (ADA) to 
cemiplimab 
• HPV serotyping of archival tumor 
4.5. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG, and physical exam.  
Period of observation: The observation period will be divided into three segments: pretreatment, 
on-treatment, and posttreatment. 
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• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to the last 
dose of study drug plus 90 days, or 1 day prior to starting a new treatment for cervical 
cancer, whichever is first. 
− The period from the first dose of ISA 101b to the first dose of cemiplimab reflects  
the on-treatment period associated with ISA 101b alone. 
• The posttreatment period is defined as the day after the on-treatment period until 1 
year after the end of the on-treatment period or the start of a new treatment for 
cervical cancer, whichever is first. 
4.5.1. 
Adverse Events and Serious Adverse Events 
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. 
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 CRF: 
• Serious Adverse Events (SAEs) 
• Events associated with a protocol-mandated intervention and which are not drug 
related (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 CRF. 
All AEs after initiation of study treatment and until 90 days after the last dose of study treatment 
or 1 day prior to starting a new treatment for cervical cancer, whichever is first, regardless of 
relationship to study treatment, will be reported on the AE CRF. Additionally, any SAE or AE 
that the investigator believes may be related to study drug(s) and that occurs later than 90 days 
after last dose of study drug should be reported. 
Pre-treatment AEs are defined as AEs that developed during the pretreatment period and are 
not treatment-emergent as defined below. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
on-treatment period and treatment-related AEs that occur during post-treatment period. 
Post-treatment AEs are defined as AEs that developed or worsened during the post-treatment 
period and are not considered drug related by the investigator. 
All AEs are to be coded to a Preferred Term (PT) and associated primary System Organ Class 
(SOC) according to the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). 
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A SAE is an AE that is classified as serious according to the criteria specified in the protocol. 
The severity of AEs (including test findings classified as AEs) will be graded using the current 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
grading system (v5.0). Adverse events not listed in the NCI-CTCAE v5.0 will be graded 
according to the following scale:  
• 1 (Mild): Mild AE (minor; no specific medical intervention; asymptomatic laboratory 
findings only, radiographic findings only; marginal clinical relevance)  
• 2 (Moderate): Moderate AE (minimal intervention; local intervention; noninvasive 
intervention [packing, cautery]) 
• 3 (Severe): Severe and undesirable AE (significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation) 
• 4 (Life-threatening): Life-threatening or disabling AE (complicated by acute, life 
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis. Life-threatening physiologic consequences; need for intensive 
care or emergent invasive procedure; emergent interventional radiological procedure, 
therapeutic endoscopy or operation) 
• 5 (Death): Death associated with an AE.  
The relationship of AEs to study drugs will be assessed by the investigator and be determined 
based on protocol specified criteria. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: for example, symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.5.2. 
Adverse Events of Special Interest (applicable to cemiplimab only) 
All AEs of special interest (AESI), serious and nonserious, must be reported to the Sponsor 
within 24 hours of identification. AEs of special interest for this study include: 
• Grade ≥2 infusion-related reaction (IRR) 
• Grade ≥2 allergic/hypersensitivity reactions 
• Grade ≥3 immune-medicated adverse event (imAE) 
• An imAE of any grade in a patient previously treated with a PI3-Kinase inhibitor  
Note: An imAE can occur shortly after the first dose, several months after the last 
dose of treatment, or any time in-between. All AEs of unknown etiology associated 
with drug exposure should be evaluated to determine possible immune etiology. If an 
imAE is suspected, efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an AE as an imAE. 
4.5.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis and other. 
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Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional units may be provided. Functions are defined as 
follows: 
Blood Chemistry: Sodium, Potassium; Chloride; Calcium; Glucose; Albumin; Total protein, 
serum; Creatinine; Aspartate aminotransferase (AST); Alanine aminotransferase (ALT); Alkaline 
phosphatase; Carbon dioxide (bicarbonate); Blood urea nitrogen (BUN); Bilirubin (total/direct); 
Uric acid 
Hematology: Hemoglobin; White blood cells (WBCs); Platelet count; Differential (Neutrophils, 
Lymphocytes, Monocytes) 
Urinalysis: pH; Ketones; Glucose; Specific gravity; Protein; Blood 
Other Laboratory Tests: Thyroid Function Tests; Coagulation Tests; Viral Serology Tests; 
Pregnancy Tests 
4.5.4. 
Vital Signs 
Vital signs will be collected according to  the protocol: Body temperature (°C); Resting systolic 
blood pressure and diastolic blood pressure (mmHg); Pulse (beats/minute); Respiratory rate 
(breaths/minute) 
4.5.5. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at time points according to  the protocol. 12-Lead 
ECG parameters include PR, QRS, RR, and QT (identify QTcB or QTcF) intervals; Heart Rate 
(recorded from the ventricular rate) 
Any ECG finding that is judged by the investigator as a clinically significant change (worsening) 
compared to the baseline value will be considered an AE, recorded, and monitored. If a clinically 
significant finding is identified and assessed as not related to study drugs by the investigator, an 
alternative aetiology for the abnormality should be provided in the AE page. 
4.5.6. 
Physical Examination Variables 
A complete or limited physical examination will be performed at visits specified in the protocol. 
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 (including liver and spleen), lymph nodes, extremities, and skin, as well as a brief 
neurologic examination.  
Limited physical examination will include examination of lungs, heart, abdomen, skin, and other 
organ systems. 
Any finding that is judged by the investigator as a clinically significant change (worsening) 
compared to the baseline value will be considered an AE, recorded, and monitored. If a clinically 
significant finding is identified and assessed as not related to study drugs by the investigator, an 
alternative aetiology for the abnormality should be provided in the AE page. 
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4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables 
(ADA)  
4.6.1. 
Pharmacokinetic Variables 
Serum samples for cemiplimab will be collected from all patients as follows: 
• Pre-dose (Ctrough) on cycle 1 day 1 and every other cycle for the first 2 years of 
treatment 
• Pre-dose (Ctrough) every 6 months (24 weeks) thereafter during therapy and at EOT. 
4.6.2. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Serum samples for 
ADA will be collected at the clinic visits specified in the table 1of the protocol. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. In 
addition, 25th percentile and 75th percentile will be provided. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
The denominator will be determined by the analysis population used for the summary. 
For time-to-event variables, median time-to-event (and the survival rate at a fixed time point) 
and its two-sided 95% confidence intervals will be summarized by the Kaplan-Meier method, 
unless otherwise specified. 
5.1. 
Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics variables listed in Section 4.1 will be 
summarized descriptively.  
5.2. 
Medical History 
Medical history will  be summarized by SOC and PT. Tables will be sorted by decreasing 
frequency of SOC followed by PT. 
5.3. 
Prior/concomitant Medications and Procedures 
Prior medications and procedures will be summarized.  
The number and percentage of patients who received any prior cancer related medications, prior 
cancer related radiotherapy, or prior cancer related surgery will be summarized.  
Concomitant medications will be summarized by ATC level 2 and ATC level 4. Concomitant 
procedures will be summarized by SOC and PT. 
5.4. 
Subject Disposition 
For subject disposition, the following summaries will be provided: 
• The total number of screened patients 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study treatment and the reasons for 
the treatment discontinuation 
• The total number of patients who discontinued the study, and the reasons for the 
study discontinuation 
 
5.5. 
Protocol Deviation 
Protocol deviations will be defined in separate protocol deviation plan (PDP). Listing of all 
patients with protocol deviations and the reason of deviation will be provided. The important 
protocol deviation, such as violation of inclusion/exclusion criteria; post-enrollment deviations 
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which will impact assessment of efficacy or safety endpoints, will be determined before database 
lock and be summarized. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Drug compliance records, including actual drug administration will be provided. 
5.6.2. 
Exposure to Investigational Product 
Exposure to ISA 101b and cemiplimab will be examined for each subject and the following 
variables will be calculated: 
• The total number of study doses administered  
• The total dosage of study drug administered  
• Duration of treatment exposure (in weeks) calculated as the minimum of  
− [date of last dose – date of first dose + 21 days] /7  
or 
− [date of clinical data cut-off or date of death - date of first dose + 1] /7 
The  number and percentage of subjects exposed to cemiplimab will be presented by 
specific time point of interest. 
• The actual dose intensity (μg /week) = total dose received (μg) / duration of treatment 
exposure (week) for ISA 101b 
The actual dose intensity (mg /week) = total dose received (mg) / duration of 
treatment exposure (week) for cemiplimab 
• The relative dose intensity = actual dose intensity / planned dose intensity 
− Planned dose intensity (μg /week) = planned dose (μg) /3 for ISA 101b 
− Planned dose intensity (mg /week) = planned dose (mg) /3 for cemiplimab 
5.7. 
Analyses of Efficacy Variables 
The analysis of efficacy data will be performed based on the FAS, as defined in Section 3.1. 
5.7.1. 
Analysis of Primary Efficacy Variable 
Primary efficacy analysis will be performed when the last patient enrolled has had the 
opportunity for at least 4 tumor assessments. 
The ORR according to investigator review will be summarized and the corresponding 2-sided 
95% confidence interval will be derived using a normal approximation of the binomial 
distribution. 
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5.7.2. 
Analysis of Secondary Efficacy Variables 
DOR: The distribution of DOR will be estimated using the Kaplan-Meier method. The median 
DOR along with its 95% CI will be presented and Kaplan-Meier estimates with 2-sided 95% CIs 
at specific time points will be summarized. DOR will also be summarized descriptively by range. 
Number and percentage of patients with DOR at specific time periods of interest will be 
summarized. 
PFS: The distribution of PFS will be estimated using the Kaplan-Meier method. The median 
PFS along with its 95% CI will be presented and Kaplan-Meier estimates with 2-sided 95% CIs 
at specific time points will be summarized.  
OS: The distribution of OS will be estimated using the Kaplan-Meier method. The median OS 
along with its 95% CI will be presented and Kaplan-Meier estimates with 2-sided 95% CIs at 
specific time points will be summarized. A variant of OS defined by censoring patients at the 
start date of subsequent therapy will be summarized and displayed by Kaplan-Meier approach as 
a sensitivity analysis. 
TTR will be summarized descriptively and at specific time periods of interest. 
DCR and dDCR will be summarized and the corresponding 2-sided 95% confidence intervals 
will be derived using a normal approximation of the binomial distribution. 
The duration of response and the best percentage change from baseline in target lesions will be 
presented by swimmer plot and waterfall plot, respectively. 
5.7.3. 
Subgroup Efficacy Analysis 
Subgroup efficacy analyses will be performed based on the following factors, respectively: 
• Age group (<65, ≥65 - < 75, ≥75) 
• Race 
• Geographical region  
• Number of prior systemic therapies  
• ECOG (0, 1) 
• Prior radiotherapy (Yes, No) 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the FAS, as defined in Section 3.1 . 
5.8.1. 
Adverse Events  
Summaries that include frequencies and proportions of patients reporting AEs will include the 
PTs and the SOCs. 
Summaries of TEAEs will include: TEAEs, Treatment related TEAEs, Serious TEAEs, 
Treatment-related Serious TEAEs, treatment-emergent AESI, and imAEs. For TEAEs, the 
following will be summarized: 
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• The number and proportions of patients reporting at least 1 TEAE, presented by SOC 
and PT 
• TEAEs by severity (NCI-CTCAE, version 5.0), presented by SOC and PT 
• TEAEs related to treatment, presented by SOC and PT 
• SAEs, presented by SOC, PT and NCI-CTCAE grade 
• TEAEs leading to permanent treatment discontinuation, presented by SOC, PT and 
NCI-CTCAE grade 
• TEAEs leading to death, presented by SOC and PT 
• IRRs by SOC, PT and NCI-CTCAE grade 
• Injection site reaction by SOC, PT, and NCI-CTCAE grade 
• AESIs by SOC, PT and NCI-CTCAE grade 
• Treatment-emergent imAEs by SOC, PT and NCI-CTCAE grade 
For each TEAE summary presented by SOC and PT, the summary table will be sorted by 
decreasing frequency of SOC and PT. For TEAE summary presented by PT, the summary table 
will be sorted by decreasing frequency of PT. 
5.8.2. 
Clinical Laboratory Measurements  
Laboratory test results will be summarized by baseline and change from baseline to each visit 
with descriptive statistics. 
Summary tables for worst laboratory values during on-treatment period with NCI CTCAE all 
grade and grade ≥ 3 will be generated. Shift tables from baseline to worst post-treatment NCI 
CTCAE grade during on-treatment period will be generated. 
5.8.3. 
Analysis of Vital Signs 
Vital signs (pulse, sitting blood pressures, and temperature) will be summarized by Baseline and 
change from Baseline to each scheduled assessment time with descriptive statistics.    
5.8.4. 
Analysis of 12-Lead ECG 
ECG parameters will be summarized by Baseline and change from Baseline to each scheduled 
assessment time with descriptive statistics.      
ECG status (ie, normal, abnormal, not clinically significant, and abnormal clinically significant) 
will be reported. Shift tables from baseline to worst post-baseline findings (normal, abnormal not 
clinically significant, and abnormal clinically significant) during on-treatment period will be 
generated. 
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5.9. 
Analysis of Pharmacokinetic and Antibody Data  
5.9.1. 
Analysis of Pharmacokinetic Data  
The concentrations of total cemiplimab will be assessed at multiple time points throughout the 
study treatment and summarized by descriptive statistics and listed by patient, timepoint, and 
dose. 
5.9.2. 
Analysis of Anti-Drug Antibody Data 
The immunogenicity variables described in Section 4.6.2 will be summarized using descriptive 
statistics. Immunogenicity for cemiplimab will be characterized by the ADA response observed: 
• ADA Negative, defined as ADA negative response in the REGN2810 ADA assay at 
all time points, regardless of any missing samples. 
•  Pre-existing immunoreactivity, defined as a positive response in the cemiplimab 
ADA assay 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 response in the 
cemiplimab ADA assay when the baseline results are negative 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate. 
− Persistent Response – Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least 16-
week period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment boosted ADA response, defined as any post-dose positive response in 
cemiplimab ADA assay 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)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
positivity presented by patient and time point will be provided. Incidence of treatment-emergent 
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ADA will be assessed as absolute occurrence (N) and percent of patients (%), grouped by study 
cohorts and ADA titer level. 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to cemiplimab will be 
explored. Plots of individual cemiplimab concentration time profiles may be provided to 
examine the potential impact of ADA category and maximum titer category on these profiles.   
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:   
• Infusion reactions   
• Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow])  
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot).   
The safety and efficacy analyses mentioned above will be conducted using the following 
categories:  
• ADA Positive  
− Treatment-emergent  
− Treatment-boosted  
• Maximum post-baseline titer category in ADA positive patients 
5.11. 
Analysis of Exploratory Biomarker Data  
The association of PD-L1 expression in tumor and infiltrating immune cells with clinical 
efficacy and available data on changes is HPV antigen specific T cell responses in a subset of 
patients will be included in the CSR. Analysis of all other exploratory pharmacodynamic and 
baseline predictive biomarker data will be included in a separate biomarker analysis report. 
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6. 
DATA CONVENTIONS  
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product.  
6.2. 
Data Handling Convention for Efficacy Variables  
Patients who are deemed NE according to RECIST version 1.1. will be considered as not 
reaching PR/CR in calculating ORR, i.e. they are not considered as responders in the numerator 
of ORR, but they are counted in the denominator of ORR. 
6.3. 
Definition of Study Day 
Study day 1 is the day of patient receiving first dose of study drug. Study day –1 is the day 
before patient receiving first dose of study drug. There is no Day 0. 
For events prior to the first day a patient receiving study drug, the study day is defined as date of 
the date of event - first dose of study drug; for events on or after the first dose of study drug, the 
study day is defined as date of event - date of the first dose of study drug +1. 
6.4. 
Data Handling Convention for Missing Data 
No missing data imputation is planned in this study unless specified otherwise. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Medication missing/partial dates 
To determine whether a medication is prior, concomitant or post-treatment medication, the 
missing medication start date is estimated as early as possible up to date of the first study 
treatment, and the missing medication end date is estimated as late as possible. If the medication 
start date is missing, the onset day will not be imputed in medication listings. 
Date of first / last study treatment 
Date of first injection or infusion is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted.  
6.5. 
Unscheduled Assessments  
Unscheduled visit measurements may be used to provide a measurement for a baseline or 
endpoint value if appropriate according to their definition. The measurements may also be used 
to determine abnormal laboratory or ECG values. 
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The determination of baselines and worst post-baseline values for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments. 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations 
will be presented in listings. 
 
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7. 
MULTIPLICITY CONSIDERATIONS  
Adjustments to the significance level for the purposes of multiple testing are not applicable for 
this study. 
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8. 
INTERIM ANALYSIS  
No formal interim analysis is planned for the primary endpoint. Administrative efficacy review 
may be performed when at least 4 tumor assessments are collected for the first 53 patients.  
 
 
 
 
 
 
 
 
 
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9. 
SOFTWARE  
All statistical analyses will be done using SAS Version 9.4 or above. 
 
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10. 
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Response.', Clin Cancer Res. 22(10):2342-50. 
 
 
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