Clinical trial NCT03257267
Conditions: Squamous Cell Carcinoma (SCC) Recurrent or Metastatic, Platinum-refractory Cervical Cancer
Sponsor: Regeneron Pharmaceuticals
Start date: 2017-09-05; Completion date: 2023-04-20
Enrollment: 608 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to compare overall survival (OS) for patients with recurrent or metastatic cervical cancer who have histology of squamous cell carcinoma (SCC) and who have any eligible histology treated with either cemiplimab or investigator's choice (IC) chemotherapy.

The secondary objectives performed among SCC patients and among all eligible histologies (SCC and adenocarcinoma/adenosquamous carcinoma (AC) are:

* To compare progression-free survival (PFS) of cemiplimab versus IC chemotherapy
* To compare objective response rate (ORR) (partial response \[PR\] + complete response \[CR\]) of cemiplimab versus IC chemotherapy per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* To compare the duration of response (DOR) of cemiplimab versus IC chemotherapy
* To compare the safety profiles of cemiplimab versus IC chemotherapy by describing adverse events (AE)
* To compare quality of life (QOL) for patients treated with cemiplimab versus IC chemotherapy using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Detailed description:

Arms: arm 1: Cemiplimab arm 2: Investigator choice (IC) chemotherapy
Interventions: intervention 1: Cemiplimab intervention 2: Investigator Choice (IC) Chemotherapy
Intervention descriptions: intervention 1: Intravenous (IV) administration every 3 weeks (Q3W) intervention 2: IC chemotherapy options include:

1. Antifolate: Pemetrexed
2. Topoisomerase 1 inhibitor: Topotecan or Irinotecan
3. Nucleoside analogue: Gemcitabine
4. Vinca alkaloid: Vinorelbine

The only chemotherapy treatments allowed in the control arm are any of the 5 drugs that are listed as IC options above.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R2810-ONC-1676 Amendment 7 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 145 
CONFIDENTIAL 
IND Number:  
 
Regeneron Pharmaceuticals, Inc. 
EudraCT number:  2017-000350-19 
Clinical Study Protocol 
AN OPEN-LABEL, RANDOMIZED, PHASE 3 CLINICAL TRIAL OF 
REGN2810 VERSUS INVESTIGATOR'S CHOICE OF 
CHEMOTHERAPY IN RECURRENT OR METASTATIC CERVICAL 
CARCINOMA 
Compound: 
REGN2810 (Cemiplimab)  
Clinical Phase: 
3 
Protocol Number: 
R2810-ONC-1676/GOG-3016 (CVP1601) ENGOT-cx9 
Protocol Version: 
R2810-ONC-1676/GOG-3016 (CVP1601) ENGOT-cx9 
Amendment 7 
Amendment 7 Date of Issue 
See appended electronic signature page 
Amendment 6 Date of Issue 
26 May 2020 
Amendment 5 Date of Issue 
08 Mar 2019
Amendment 4 Date of Issue 
16 Aug 2018 
Amendment 3JP Date of Issue 
27 Apr 2018 
Amendment 3 Date of Issue 
21 Mar 2018 
Amendment 2 Date of Issue: 
03 Nov 2017
Amendment 1 Date of Issue: 
14 Jul 2017 
Original Date of Issue: 
13 Apr 2017 
Scientific/Medical Monitors: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
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NCT03257267


Clinical Study Protocol 
R2810-ONC-1676 Amendment 7 
Regeneron Pharmaceuticals, Inc. 
 
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AMENDMENT HISTORY 
Amendment 7 
The Independent Data Monitoring Committee (IDMC) convened on 8 March 2021 to evaluate the 
data from a planned formal interim analysis of overall survival (OS).  The IDMC declared 
superiority of OS in patients receiving cemiplimab as compared to investigator’s choice (IC) 
chemotherapy.  As a result of the assessment, protocol Amendment 7 is being implemented to 
provide a mechanism for eligible patients randomized to chemotherapy to receive cemiplimab as 
part of a cemiplimab Extension Phase.   
Patients randomized to IC chemotherapy may screen to receive cemiplimab in the Extension Phase 
up to and including 30 June 2021.  Patients previously on IC chemotherapy may continue up to 96 
weeks on cemiplimab as per the Schedule of Events for the cemiplimab Extension Phase (Table 
3).   
All patients currently on cemiplimab may continue treatment up to 96 weeks.  All patients 
receiving cemiplimab will do so as per the Schedule of Events for the cemiplimab Extension Phase 
(Table 3).   
Patients currently receiving IC chemotherapy (pemetrexed, gemcitabine, topotecan, irinotecan, or 
vinorelbine) may continue to be treated as long as, in the opinion of the investigator, they are 
continuing to derive benefit from the assigned treatment. 
As of Amendment 7 retreatment is no longer an option.  As of Amendment 7, follow-up visits 
are no longer required. 
Detailed changes are in the following table: 
Description of Change 
Brief Rationale  
Section # and Name 
Added a cemiplimab 
Extension Phase so that 
patients previously 
randomized to the 
IC chemotherapy arm can 
receive cemiplimab 350 mg 
Q3W up to 96 weeks. 
Added language stating that 
patients currently on 
cemiplimab will also transition 
to the cemiplimab Extension 
Phase with pared-down 
assessments up to 96 weeks 
(inclusive of previous 
cemiplimab therapy). 
This is due to the observed 
superiority of OS in patients 
receiving cemiplimab as 
compared to 
IC chemotherapy at the 
second interim analysis.  
Cemiplimab continues to 
demonstrate a safety profile 
consistent in class. 
 
Clinical Study Protocol Synopsis: 
Study Design 
Section 5.1 Study Description and 
Duration 
Section 5.1.2  End of Study 
Definition 
Section 7.1.7 Note Regarding 
IDMC Interim Analysis 2 (new 
section) 
Section 7.1.7.1 Cemiplimab 
Extension Phase of the Study (new 
section) 
Table 3 Schedule of Events for 
Cemiplimab Extension Phase (new 
table) 
Section 7.1.7.2 Footnotes for the 
Schedule of Events Table 3 for the 
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Description of Change 
Brief Rationale  
Section # and Name 
Cemiplimab Extension Phase (new 
section) 
Section 15 Protocol Amendments 
Added language to remove 
option for retreatment upon 
disease progression for 
patients entering the 
cemiplimab Extension Phase. 
Based on limited data, the 
benefit of retreating patients 
with cemiplimab after 
progression on cemiplimab 
during the follow-up phase 
can’t be confirmed. 
Section 7.1.7 Note Regarding 
IDMC Interim Analysis 2 (new 
section) 
Added language to remove 
follow-up visits for patients 
entering the cemiplimab 
Extension Phase. 
This is due to the observed 
superiority of OS in patients 
receiving cemiplimab as 
compared to IC 
chemotherapy at the second 
interim analysis. 
Cemiplimab continues to 
demonstrate a safety profile 
consistent in class. 
Section 7.1.7 Note Regarding 
IDMC Interim Analysis 2 (new 
section) 
MedDRA Dictionary-Derived 
Preferred Terms for Potential 
immune-related adverse events 
(irAEs) list updated as per 
MedDRA version 23.0. 
The list was updated since 
the last amendment. 
Appendix 3 MedDRA 
Dictionary-Derived Preferred Terms 
for Potential irAEs 
 
Amendment 6 
Change and Rationale for Change 
Sections Changed 
Added European Network for Gynaecological 
Oncological Trial groups (ENGOT) number to 
Protocol Number and Protocol Version. 
Protocol Number 
Protocol Version 
Added 2 interim analyses to provide early 
efficacy assessment in this unmet-need 
population, and increased sample size to maintain 
90% power with 2 interim analyses.  
Interim efficacy analyses will be reviewed by 
Independent Data Monitoring Committee 
(IDMC). 
Clinical Study Protocol Synopsis: Study 
Design, Population, Statistical Plan 
Section 3.2.1 Rationale for Patient 
Population and Study Design 
Section 5.1 Study Description and 
Duration  
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Change and Rationale for Change 
Sections Changed 
Figure 2 Study Design Schematic 
Section 5.1.2 End of Study Definition 
Section 5.2 Planned Interim Analysis  
Section 5.3.1. Independent Data 
Monitoring Committee 
Section 6.1 Number of Patients Planned 
Section 7.1.5 Footnotes for the Schedule 
of Events Table for Post-Treatment 
Follow-up, footnote #2  
Section 8.8 Method of Treatment 
Assignment 
Section 10.2 Justification of Sample Size 
Section 10.4.5.1 Primary Efficacy 
Analysis 
Section 10.5 Interim Analysis 
Table 15 Alpha Spending in Group 
Sequential Design Using Lan-DeMets 
(O’Brien Fleming) Spending Function 
Section 10.6 Additional Statistical Data 
Handling Conventions 
Added language to meet a requirement under the 
guidance that has come out in the 
 
to address considerations related to 
conduct of a study during the COVID-19 
pandemic, including statistical analysis language. 
Section 5.4 Study Conduct in Response to 
COVID-19 (new) 
Section 7.1.1 COVID-19 Adaptation 
(new) 
Section 10 Statistical Plan 
Corrected typo regarding lymph nodes to have 
Inclusion Criteria #3 consistent with Appendix 1. 
Changed >15 mmto >15 mm. 
Section 6.2.1 Inclusion Criteria, #3 
Added language to clarify that peripheral blood 
mononuclear cell (PBMC) collection is optional 
and will only be done for patients receiving 
cemiplimab and who have signed the 
PBMC consent.  
Section 7.1.5 Footnotes for the Schedule 
of Events Table for Post-Treatment 
Follow-up, footnote #6  
Corrected typo in Appendix 1 to make consistent 
with Response Evaluation Criteria in Solid 
Tumors (RECIST) guidelines. 
Appendix 1.RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS: 
RECIST GUIDELINE (VERSION 1.1) 
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Amendment 5 
Change and Rationale for Change 
Sections Changed 
Updated background information on cemiplimab, 
including information regarding FDA approval in 
2018, to keep this section current.   
Section 1 Introduction 
Updated study population to cap enrollment of 
patients with adenocarcinoma histology and 
increase enrollment of patients with squamous 
cell histology (SCC) based on emerging internal 
data and early data from other oncology studies 
that PD-1/PD-L1 blockade is efficacious in 
squamous histology, and added a rationale for this 
change.  Increased enrollment to approximately 
534 in order to accommodate the new target 
enrollment of 436 patients with SCC histology. 
Updated the statistical plan to prioritize analysis 
of SCC over all histologies of cervical cancer. 
Clinical Study Protocol Synopsis: 
Objectives 
Clinical Study Protocol Synopsis: Study 
Design 
Clinical Study Protocol Synopsis: 
Population 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.1 Hypothesis 
Section 3.2.1 Rationale for Patient 
Population and Study Design 
Section 5.1 Study Description and 
Duration Figure Study Design Schematic 
Section 6.1 Number of Patients Planned 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria, #1 
Section 7.2.1 Procedures Performed at the 
Screening Visit 
Section 8.8 Method of Treatment 
Assignment 
Section 10.2 Justification of Sample Size 
Section 10.4.5.1 Primary Efficacy 
Analysis 
Section 10.4.5.2 Secondary Efficacy 
Analysis 
Section 10.4.5.5 Subgroup Analyses 
Section 10.4.6 Safety Analysis 
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Change and Rationale for Change 
Sections Changed 
Updated the total duration of study to 
accommodate increased enrollment needed to 
enroll 436 patients with SCC histology. 
Section 5.1.2 End or Study Definition 
Removed interim futility rule because the overall 
survival benefit of immune checkpoint blockers in 
oncology studies may not be evident in an early 
event analysis.  As clinical safety and efficacy of 
cemiplimab has been demonstrated in a variety of 
tumor types, including cutaneous squamous cell 
carcinoma (Migden 2018) and the clinical 
efficacy of PD-1 blockade in cervical carcinoma 
has recently been described (Chung 2018), an 
interim futility analysis is not warranted.   
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 5.2 Planned Interim Analysis 
Section 10.5 Interim Analysis  
Updated definitions of treatment and post-
treatment periods to align with updated company 
protocol template.  
Section 9.4.1 Adverse Events 
Section 9.4.2 Serious Adverse Events 
Section 10.4.6.1 Adverse Events 
Removed the text on sample size consideration 
and subgroup analyses of patients from Japan, as 
the Japan-specific information will be provided 
separately. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 10.2 Justification of Sample Size 
Section 10.4.5.1 Primary Efficacy 
Analysis 
Added statement that death due to disease 
progression will not be considered an adverse 
event but will be reported in efficacy endpoints 
such as PFS and OS, for consistency with updated 
company protocol template. 
Section 10.4.6.1 Adverse Events 
Added description of Trial Steering Committee 
Section 5.3.2 Trial Steering Committee 
(Section Added) 
Added statements to clarify that peripheral blood 
mononuclear cell (PBMC) collection is optional 
and will only be done for patients receiving 
cemiplimab. 
Table 1 Schedule of Events: Screening 
and Treatment Period 
Section 7.1.2 Footnotes for the Schedule 
of Events Table for Screening and 
Treatment, footnote 14 
Table 2 Schedule of Events, Post-
Treatment Follow-Up 
Section 7.1.5 Footnotes for the Schedule 
of Events Table for Post-treatment 
Follow-up, footnote 6 
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Change and Rationale for Change 
Sections Changed 
Section 7.2.7.3 Peripheral Blood 
Mononuclear Cells (optional) 
Added guidance stating “patients who fail 
screening may be screened one additional time 
and an ICF will need to be signed at re-screen. 
Some procedures may not need to be repeated if 
they were previously completed within 28 days 
prior to cycle 1 day 1.” 
Table 1 Schedule of Events: Screening 
and Treatment Period 
Section 7.1.2 Footnotes for the Schedule 
of Events Table for Screening and 
Treatment, footnote 1 (footnote added) 
Section 7.2.1 Procedures Performed at the 
Screening Visit 
Added clarifying language to the definition of 
“further progression after resumption of 
treatment.” 
Section 8.6 Treatment Beyond 
Progression in the Cemiplimab Treatment 
Group 
Updated definition of ORR from overall response 
rate to objective response rate to align with other 
protocols in the cemiplimab program.  
Clinical Study Protocol Synopsis: 
Objectives 
Section 2.2 Secondary Objectives 
Added language to clarify that dose modification 
recommendations pertain to treatment related 
adverse events (AEs) only.  
Section 8.3.1 Dose Modification 
Removed confirmatory scans at progressive 
disease, because per RECIST 1.1, progressive 
disease does not require confirmation. 
Appendix 1 Response Evaluation Criteria 
in Solid Tumors: RECIST Guideline 
(Version 1.1)  
Added a time point for vital sign check on day 15 
of each cycle of irinotecan, as standard of care 
dictates that vitals should be taken prior to 
administering each weekly infusion. 
Table 1 Schedule of Events: Screening 
and Treatment Period 
Updated footnotes to schedule of events to 
remove PK and ADA sample collection time 
points at the end of treatment and during 
follow-up. 
Section 7.1.2 Footnotes for the Schedule 
of Events Table for Screening and 
Treatment, footnotes 11 and 12 
Updated footnote to schedule of events describing 
ADA sample collection to include PK sample 
collection as well.  
Section 7.1.5 Footnotes for the Schedule 
of Events Table for Post-treatment 
Follow-up, footnote 4 
Removed statement that triplicate ECGs are not 
required. 
Section 7.2.5.3 Electrocardiogram 
Updated “follow up visit 2” to “end of study” in 
the Schedule of Events to clarify that survival 
follow-up starts after the end of study and that 
follow-up is quarterly. 
Section 7.1.5 Footnotes for the Schedule 
of Events Table for Post-treatment 
Follow-up, footnote 2 
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Change and Rationale for Change 
Sections Changed 
Minor language clarifications 
Section 4.2.1 Primary Endpoint 
Administrative changes 
Title Page: Scientific/Medical Monitor 
“REGN2810 (cemiplimab)” replaced with 
cemiplimab 
Throughout  
Amendment 4 
Amendment 4 incorporates all changes made for Amendment 3 JP, which were changes that 
were required to conduct the study in Japan.  In addition, the following changes were made in 
this amendment: 
Change 
Sections Changed 
Removed the requirement that patients must be 
platinum-refractory, which was defined as 
progression of disease within 6 months of last 
dose of platinum therapy.  Therefore, the term 
‘platinum-refractory’ used to describe the patient 
population was removed from the protocol. 
Face Page- Title 
Synopsis - Title 
Synopsis – Objectives 
Synopsis – Study Design 
Section 2.1 Primary Objective 
Section 3.2.1 Rationale for Patient 
Population and Study Design 
Section 5.1 Study Description and 
Duration 
Figure 2:  Study Design Schematic 
Revised inclusion requiring platinum-therapy.  
Patients must have had disease progression after 
prior platinum therapy in recurrent or metastatic 
disease setting, but without the requirement for 
progression within 6 months of last dose.   
Clinical Study Protocol Synopsis – Study 
Population 
Section 3.1 Hypothesis  
Section 6.2.1. Inclusion Criteria #2  
Revised and shortened the summary of prior 
studies regarding discussion of platinum-free 
interval.   
Section 3.2.1 Rationale for Patient 
Population and Study Design 
Deleted statement that follow-up will occur until 
death or study completion.  Replaced with 
clarification that patients will be followed for 
survival after the follow-up period.   
Clinical Study Synopsis – Study Design 
Section 5.1 Study Description and 
Duration 
Added clarification that patients who only 
received prior platinum-based therapy 
concurrently with radiation therapy for localized 
disease are not eligible. 
Clinical Study Protocol Synopsis – Study 
Population 
Section 6.2.1 Inclusion Criteria – 
Criterion  #2  
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Change 
Sections Changed 
Increased the duration of which the investigator is 
required to report a pregnancy, from ‘within 90 
days’ to ‘within 6 months,’ of the last dose of 
study drug.  This change was made to ensure 
consistency with Exclusion criterion #16 
(Section 6.2.2) to exclude women of childbearing 
potential who are unwilling to practice highly 
effective contraception for at least 6 months after 
the last dose of study drug. 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Added the description of patient population, to the 
appropriate section in the protocol body, for 
consistency with the corresponding section in the 
Clinical Study Protocol Synopsis 
Section 6.2 Study Population 
Added clarification that for patients who 
experience toxicity with a dose increase from 
100 mg/m2 to 125 mg/m2, the recommended first 
dose reduction should be to 100 mg/m2. 
Section 8.4.3 Irinotecan Dose 
Modifications 
Added clarification of the Dose Modification and 
Study Treatment Discontinuation Rules for 
Investigator’s Choice Chemotherapy that for other 
chemotherapy-related AEs that are not 
specifically addressed in these sections, the 
general approach for ≥ grade 3 treatment-related 
AEs is to hold chemotherapy until resolution of 
the event to ≤ grade 1 or baseline, and to reduce 
by one dose level on resumption of treatment. 
Section 8.4 Dose Modification and Study 
Treatment Discontinuation Rules for 
Investigator’s Choice Chemotherapy 
Added language regarding selection of 
Investigator’s Choice Chemotherapy when 
prescribing chemotherapy to patients on the 
control arm to give preference to regimens 
allowed by local regulations.  This addition was 
requested by the
 
.   
Section 8.1 Investigational and Reference 
Treatments 
Added clarification that the EORTC QLQ-C30 
assessment may be performed at any subsequent 
visit if the assessment is not performed on day 1. 
Table 1: Schedule of Events:  Screening 
and Treatment Period 
Section 7.1.2 Footnotes for the Schedule 
of Events Table for Screening and 
Treatment – Footnote #14 
Added a subgroup analysis by number of prior 
lines of systemic therapy for recurrent or 
metastatic disease (1 line or >1 line), which will 
Section 10.4.5.5 Subgroup Analysis  
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Change 
Sections Changed 
be performed for the primary and key secondary 
endpoints.  This planned analysis was in response 
to a request by the Independent Data Monitoring 
Committee.   
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Change 
Sections Changed 
Updated synopsis for consistency with 
Amendment 3 Japan, with addition of ‘for 
patients enrolling in Japan, there will be at least 
14 days of rest before subsequent irinotecan 
administration.’ 
Clinical Study Protocol Synopsis - 
Treatments 
Removed details on drug supply packaging and 
withdrawable volume and referred to the 
pharmacy manual 
Section 8.1.1 Experimental Group 
Treatment (REGN2810 [Cemiplimab]) 
Added clarification that laboratory assessment of 
glucose may be performed either fasting or non-
fasting 
Section 7.2.5.4 Laboratory Testing 
Clarified that the treatment days for gemcitabine 
dose reduction guidelines for myelosuppression 
refer to a 3-week treatment cycle 
Section 8.4.4 Gemcitabine Dose 
Modifications 
Revised text to simply state that Exclusion 
Criterion #10 was deleted in Amendment 3 
Section 6.2.2. Exclusion Criteria - 
Criterion #10  
Removed placeholder for footnote 1 of Table 1, 
which was deleted in Amendment 3 
Section 7.1.2  Footnotes for the Schedule 
of Events Table for Screening and 
Treatment- footnote 1 (deleted) 
Editorial revisions and corrections  
Clinical Study Protocol Synopsis – Site 
Locations 
Section 3.2.2 Rationale for REGN2810 
(Cemiplimab) Dose Selection 
Section 4.2.3 Other Secondary Endpoints 
Section 6.1 Number of Patients Planned 
Section 6.2.1 Inclusion Criteria – 
Criterion #3  
Section 7.2.5.4 Laboratory Testing 
Section 8.1 Investigational and Reference 
Treatments 
Section 8.8 Method of Treatment 
Assignment 
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Amendment 3 JP 
These changes apply to studies conducted in Japan 
Change 
Sections Changed 
Inclusion criterion #5 clarified to include the 
following statement:  
For patients enrolling in Japan who are ≥18 
and <20 years old, both the patient and 
parent/legal representative must provide 
signed informed consent. 
Section 6.2.1 Inclusion Criteria - Criterion #5  
Per standard of care in Japan, for patients 
enrolling in Japan, there will be at least 14 
days of rest before subsequent irinotecan 
administration. 
Section 8.1.2 Control Group Treatments 
(Investigator’s Choice) 
 
Section 8.1.2.3 Irinotecan 
Good Clinical Practice Statement section 
clarified to include the following text: 
The clinical study will be conducted in 
compliance with Pharmaceutical and Medical 
Device Act, Japanese GCP, and other relevant 
laws in Japan. 
Section 14.1 Good Clinical Practice 
Statement 
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Amendment 3 
Change 
Sections Changed 
The protocol is being amended to update the 
monitoring needed for investigators choice 
chemotherapy of vinorelbine treatment. 
These changes align with the standard of 
care. 
Table 1 Schedule of Events:  Screening and 
Treatment Period - hematology row under 
laboratory testing for day 8 and day 29 in all 
cycles 
Figure 2 revised to include ECOG 
stratification to align with the written text. 
Figure 2 Study Design Schematic 
The end of treatment definition was added in 
the text and deleted from Table 1 
The end of study definition was updated.   
Section 5.1.1 End of Treatment Definition 
Section 5.1.2 End of Study Definition 
Concomitant medications will be assessed on 
day 42 
Table 1 Schedule of Events:  Screening and 
Treatment Period 
Study drug indicates REGN2810 
(cemiplimab) or investigators choice of 
chemotherapy 
Section 6.2.2 Exclusion Criteria #4, #5, #8, 
#11, and #19 and throughout the protocol 
Exclusion criterion of known allergy to 
doxycycline or tetracycline was removed 
from the list of criteria – number of exclusion 
criterion kept in the list for formatting 
purposes 
Section 6.2.2 Exclusion Criteria, #10 
Following text added:  
All other "days” in the protocol refer to 
calendar days. 
Missed doses of study drug or visits will not 
be made up.  In the case of missed doses, 
response assessments should still follow 
original schedule.  If a patient is unable to 
undergo scans within the window due to 
logistical or medical reasons, response 
assessment will be obtained at the next 
available date and before subsequent study 
treatment. 
Section 7.1 Schedule of Events 
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Change 
Sections Changed 
Footnote #1 was deleted.  Footnote #3 
updated as follows: The first dose should be 
administered no later than 5 days after 
randomization (except for patient assigned to 
pemetrexed, for whom the first dose of 
pemetrexed may be given no later than 10 
days after randomization due to need for 
folate premedication for at least 5 days in the 
7 day period preceding the first dose of 
pemetrexed, as per Section 8.1.2.1 . 
Following text was added to Footnote #10: 
If surgical procedure for sterility was done 
≤30 days prior to signing ICF, serum 
pregnancy test must still be performed. 
Footnote #12 updated the ADA sample 
collection 
Section 7.1.2 Footnotes for the Schedule of 
Events Tables for Screening and Treatment, 
Footnote 3, 10, and 12  
Footnote #1 revised as follows: 
Post-treatment follow-up pertains to all 
patients (both treatment groups).  This 
pertains to patients who completed all 
16 cycles of planned treatment, and to 
patients who discontinue treatment prior to 
the completion of 16 cycles.  Follow-up visit 
1 occurs approximately 30 days (±10 days) 
from last dose of REGN2810 (cemiplimab) 
or IC of chemotherapy.  Follow-up visit 2 
occurs approximately 90 days (±10 days) 
after follow-up visit 1. 
Section 7.1.5 Footnotes for the Schedule of 
Events Table for Post-treatment Follow-up 
Survival status check deleted from Follow-up 
Visits 1 and 2 
Table 2 Schedule of Events Post-Treatment 
Follow-Up  
Any treatment administered, other than anti-
cancer therapy, from the time of informed 
consent until 90 days after the last study 
treatment will be considered concomitant 
treatment. 
Section 8.10 Concomitant Medications and 
Procedures 
Following text are added for statistical 
considerations regarding enrollment of 
patients from Japan: 
Section 10.2 Justification of Sample Size 
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Change 
Sections Changed 
Based on "Method 2" described in "Basic 
Principles on Global Clinical Trials" (Ministry 
of Health, Japan, 2007), the probability of 
observing a consistent trend across 2 regions 
(Japan vs. outside of Japan) is calculated.  
Assume the true treatment effect is uniform 
across the 2 regions and the natural logarithm 
of HR is normally distributed.  Per method of 
Kawai (Kawai, 2008), 33 OS events from 
Japan, or 10% of total 330 OS events, and 
approximately 44 Japanese patients are 
required for the primary analysis to yield a 
probability of 84.6% to observe an HR <1 
from both regions for the comparison of 
REGN2810 (cemiplimab) versus the IC 
chemotherapy options.   
Subgroup analyses of patients from Japan are 
included. 
Clinical Study Protocol Synopsis:  Statistical 
Plan 
Section 10.4.5.1 Primary Efficacy Analysis 
Section 10.4.5.5 Subgroup Analyses 
MedDRA Dictionary-Derived Preferred 
Terms for Potential irAEs list updated as per 
MedDRA version 20.1 
Appendix 3 MedDRA Dictionary-Derived 
Preferred Terms for Potential irAEs 
Minor editorial changes 
Throughout the protocol 
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CONFIDENTIAL 
Amendment 2 
The following table outlines the changes made to the protocol and the affected sections. 
Change 
Sections Changed 
Updated anti-drug antibody wording to 
be consistent with current practice 
Section 4.3.2 Anti-Dug Antibody Variables 
Section 7.1.2 Footnotes for the Schedule of Events 
Table for Screening and Treatment (footnote #12) 
Revised exclusion criteria per request 
from the
 
 
Section 6.2.2 Exclusion Criteria (#6, 7, 19, and 20) 
Added a window between 
randomization and start of treatment, to 
try to provide some flexibility 
Protocol Synopsis (Study Design) 
Section 5.1 Study Description and Duration 
Table 1 Schedule of Events (footnote reference #3) 
Section 7.1.2 Footnotes for the Schedule of Events 
Table for Screening and Treatment (added 
footnote #3) (new) 
Corrected length of study accrual and 
follow-up for consistency with other 
sections 
Section 5.1.1 End of Study Definition 
Clarified that some assessments didn’t 
need to be performed at cycle 1/day 1 if 
it was within 72 hours of screening, in 
order to decrease site and patient burden 
Table 1 Schedule of Events (footnote reference #6) 
Section 7.1.2 Footnotes for the Schedule of Events 
Table for Screening and Treatment (added 
footnote #6) (new) 
Reduced sampling of peripheral blood 
mononuclear cells, to minimize blood 
volume collection and to focus 
exploratory research in the earlier cycles 
Section 7.1.2 Footnotes for the Schedule of Events 
Table for Screening and Treatment (footnote #14 
[was previously #11]) 
Corrected number of planned cycles to 
be consistent across protocol 
Section 7.1.6 Option for Retreatment 
Revised wording to provide a window 
for a drug-free period during irinotecan 
dosing 
Protocol Synopsis (Treatments) 
Section 8.1.2.3 Irinotecan 
Section 8.4.3 Irinotecan Dose Modifications 
Added Eastern Cooperative Oncology 
Group (ECOG) performance status as a 
stratification factor for randomization to 
Section 8.8 Method of Treatment Assignment 
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Change 
Sections Changed 
balance treatment assignment, per 
request from the
 
  The ECOG 
performance status will not be included 
in the primary analysis model for 
efficacy. 
Revised the alternate statistical 
hypothesis at the request of 
 
 
Section 10.1 Statistical Hypothesis 
Updated sections to be consistent with 
the current protocol template 
Section 6.2.2 Exclusion Criteria (#21, new) 
Section 14.3 Patient Confidentiality and Data 
Protection (new section) 
Made minor editorial changes 
Section 5.1.1 End of Study Definition 
Section 7.1 Schedule of Events 
Section 7.1.2 Footnotes for the Schedule of Events 
Table for Screening and Treatment 
Section 7.1.5 Footnotes for the Schedule of Events 
Table for Post-treatment Follow-up 
Section 7.1.6 Option for Retreatment 
Section 8.1.2 Control Group Treatments 
(Investigator’s Choice) 
Section 8.1.2.5 Vinorelbine 
Section 8.5.1.1 Reasons for Permanent 
Discontinuation of Study Treatment 
Section 9.4.1 Adverse Events 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Section 9.4.4 Reporting Adverse Events Leading to 
Withdrawal from the Study 
Appendix 2 Recommended Dose Modification or 
Discontinuation and Supportive Care Guidelines 
for Specific Study Drug Related Adverse Events 
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Amendment 1 
The following table outlines the changes made to the protocol and the affected sections. 
Change 
Sections Changed 
An exclusion criterion has been added for the 
following reason:  Patients who have 
previously been treated with idelalisib will be 
excluded from treatment with REGN2810 as 
a result of the safety findings for 3 patients 
with indolent lymphoma previously treated 
with idelalisib, a phosphatidylinositol 
3-kinase (PI 3-K) inhibitor, in study 
R1979-ONC-1504.  Following a single dose 
of REGN2810 monotherapy in each case, 
2 patients experienced severe stomatitis 
and/or skin reactions.  The third patient 
experienced myositis and myasthenia gravis 
after 2 doses of REGN2810. 
Section 6.2.2 Exclusion Criteria #18 
Additional safety guidance language added 
for the management of patients developing 
stomatitis or mucositis 
Section 8.5.1 Study Drug Discontinuation 
An adverse event of special interest (AESI) 
has been added to the list of AESIs: 
An irAE of any grade in a patient previously 
treated with a PI 3-K inhibitor. 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................32 
1. 
INTRODUCTION ......................................................................................................35 
2. 
STUDY OBJECTIVES ..............................................................................................37 
2.1. 
Primary Objective .......................................................................................................37 
2.2. 
Secondary Objectives .................................................................................................37 
2.3. 
Exploratory Objectives ...............................................................................................38 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................38 
3.1. 
Hypothesis ..................................................................................................................38 
3.2. 
Rationale .....................................................................................................................38 
3.2.1. 
Rationale for Patient Population and Study Design ...................................................38 
3.2.2. 
Rationale for Cemiplimab Dose Selection .................................................................40 
3.2.3. 
Rationale for Investigator’s Choice Chemotherapy Options ......................................40 
4. 
STUDY VARIABLES................................................................................................43 
4.1. 
Demographic and Baseline Characteristics ................................................................43 
4.2. 
Primary and Secondary Endpoints..............................................................................43 
4.2.1. 
Primary Endpoint ........................................................................................................43 
4.2.2. 
Secondary Endpoints ..................................................................................................43 
4.2.3. 
Other Secondary Endpoints ........................................................................................43 
4.3. 
Exploratory Endpoints ................................................................................................44 
4.3.1. 
Pharmacokinetic Variables .........................................................................................44 
4.3.2. 
Anti-Drug Antibody Variables ...................................................................................44 
4.3.3. 
Other Exploratory Variables .......................................................................................44 
5. 
STUDY DESIGN .......................................................................................................44 
5.1. 
Study Description and Duration .................................................................................44 
5.1.1. 
End of Treatment Definition .......................................................................................46 
5.1.2. 
End of Study Definition ..............................................................................................46 
5.2. 
Planned Interim Analysis ............................................................................................46 
5.3. 
Study Committees .......................................................................................................46 
5.3.1. 
Independent Data Monitoring Committee ..................................................................46 
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5.3.2. 
Trial Steering Committee ...........................................................................................47 
5.4. 
Study Conduct in Response to COVID-19 .................................................................47 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............47 
6.1. 
Number of Patients Planned .......................................................................................47 
6.2. 
Study Population .........................................................................................................47 
6.2.1. 
Inclusion Criteria ........................................................................................................47 
6.2.2. 
Exclusion Criteria .......................................................................................................49 
6.3. 
Premature Withdrawal from the Study .......................................................................51 
6.4. 
Replacement of Patients .............................................................................................52 
7. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................52 
7.1. 
Schedule of Events .....................................................................................................52 
7.1.1. 
COVID-19 Adaptation ................................................................................................52 
7.1.2. 
Footnotes for the Schedule of Events Table for Screening and Treatment ................55 
7.1.3. 
Unscheduled Visits .....................................................................................................56 
7.1.4. 
Post-Treatment Follow-Up .........................................................................................56 
7.1.5. 
Footnotes for the Schedule of Events Table for Post-Treatment Follow-up ..............56 
7.1.6. 
Option for Retreatment ...............................................................................................57 
7.1.7. 
Note Regarding IDMC Interim Analysis 2 .................................................................58 
7.1.7.1. 
Cemiplimab Extension Phase of the Study .................................................................58 
7.1.7.2. 
Footnotes for the Schedule of Events Table 3 for the Cemiplimab Extension 
Phase ...........................................................................................................................60 
7.2. 
Study Procedures ........................................................................................................60 
7.2.1. 
Procedures Performed at the Screening Visit .............................................................60 
7.2.2. 
Efficacy Procedures ....................................................................................................61 
7.2.3. 
Survival Data Collection .............................................................................................61 
7.2.4. 
Quality of Life Questionnaires ...................................................................................61 
7.2.5. 
Safety Procedures .......................................................................................................62 
7.2.5.1. 
Vital Signs ..................................................................................................................62 
7.2.5.2. 
Physical Examination .................................................................................................62 
7.2.5.3. 
Electrocardiogram .......................................................................................................62 
7.2.5.4. 
Laboratory Testing ......................................................................................................63 
7.2.5.5. 
Anti-Drug Antibody Measurements and Samples ......................................................64 
7.2.5.6. 
Pharmacokinetic Samples ...........................................................................................64 
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7.2.6. 
Quality of Life Procedures ..........................................................................................64 
7.2.7. 
Biomarker Procedures ................................................................................................65 
7.2.7.1. 
Tumor Samples ...........................................................................................................65 
7.2.7.2. 
Serum/Plasma Samples ...............................................................................................65 
7.2.7.3. 
Peripheral Blood Mononuclear Cells (optional) .........................................................65 
7.2.8. 
Future Biomedical Research .......................................................................................66 
7.2.8.1. 
Genomics Sub-study - Optional..................................................................................66 
8. 
STUDY TREATMENTS............................................................................................66 
8.1. 
Investigational and Reference Treatments ..................................................................66 
8.1.1. 
Experimental Group Treatment (Cemiplimab) ...........................................................67 
8.1.2. 
Control Group Treatments (Investigator’s Choice) ....................................................67 
8.1.2.1. 
Pemetrexed, Alimta® ..................................................................................................68 
8.1.2.2. 
Topotecan ...................................................................................................................69 
8.1.2.3. 
Irinotecan ....................................................................................................................69 
8.1.2.4. 
Gemcitabine, Gemzar® ...............................................................................................70 
8.1.2.5. 
Vinorelbine .................................................................................................................70 
8.2. 
Pretreatments ..............................................................................................................71 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules for 
Cemiplimab .................................................................................................................71 
8.3.1. 
Dose Modification ......................................................................................................72 
8.3.2. 
Immune-Related Adverse Events (irAEs) ..................................................................74 
8.3.3. 
Resumption of Cemiplimab After Treatment Hold, or Discontinuation ....................76 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules for 
Investigator’s Choice Chemotherapy .........................................................................76 
8.4.1. 
Pemetrexed Dose Modifications .................................................................................76 
8.4.2. 
Topotecan Dose Modifications ...................................................................................77 
8.4.3. 
Irinotecan Dose Modifications ...................................................................................78 
8.4.4. 
Gemcitabine Dose Modifications ...............................................................................80 
8.4.5. 
Vinorelbine Dose Modifications .................................................................................81 
8.5. 
Study Treatment Discontinuation Rules, General Guidance ......................................82 
8.5.1. 
Study Drug Discontinuation .......................................................................................82 
8.5.1.1. 
Reasons for Permanent Discontinuation of Study Treatment.....................................82 
8.6. 
Treatment Beyond Progression in the Cemiplimab Treatment Group .......................82 
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8.7. 
Management of Acute Reactions ................................................................................83 
8.7.1. 
Acute Infusion Reactions ............................................................................................83 
8.7.1.1. 
Interruption of the Infusion .........................................................................................84 
8.7.1.2. 
Termination of the Infusion ........................................................................................84 
8.8. 
Method of Treatment Assignment ..............................................................................85 
8.8.1. 
Blinding ......................................................................................................................85 
8.9. 
Treatment Logistics and Accountability .....................................................................86 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................86 
8.9.2. 
Supply and Disposition of Treatments .......................................................................86 
8.9.3. 
Treatment Accountability ...........................................................................................86 
8.9.4. 
Treatment Compliance ................................................................................................86 
8.10. 
Concomitant Medications and Procedures .................................................................86 
8.10.1. 
Prohibited Medications and Procedures .....................................................................86 
8.10.2. 
Permitted Medications and Procedures ......................................................................87 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................87 
9.1. 
Obligations of Investigator .........................................................................................87 
9.2. 
Obligations of Sponsor ...............................................................................................87 
9.3. 
Definitions ..................................................................................................................88 
9.3.1. 
Adverse Event .............................................................................................................88 
9.3.2. 
Serious Adverse Event ................................................................................................88 
9.3.3. 
Adverse Events of Special Interest .............................................................................89 
9.3.4. 
Infusion Reactions ......................................................................................................89 
9.4. 
Recording and Reporting Adverse Events ..................................................................89 
9.4.1. 
Adverse Events ...........................................................................................................89 
9.4.2. 
Serious Adverse Events ..............................................................................................90 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................90 
9.4.3.1. 
Immune-Related Adverse Events ...............................................................................91 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................91 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................91 
9.4.6. 
Follow-up ....................................................................................................................91 
9.5. 
Evaluation of Severity and Causality .........................................................................92 
9.5.1. 
Evaluation of Severity ................................................................................................92 
9.5.2. 
Evaluation of Causality ...............................................................................................92 
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9.6. 
Safety Monitoring .......................................................................................................93 
9.7. 
Investigator Alert Notification ....................................................................................93 
10. 
STATISTICAL PLAN................................................................................................93 
10.1. 
Statistical Hypothesis ..................................................................................................93 
10.2. 
Justification of Sample Size........................................................................................94 
10.3. 
Analysis Sets ...............................................................................................................94 
10.3.1. 
Efficacy Analysis Sets ................................................................................................94 
10.3.2. 
Safety Analysis Set .....................................................................................................94 
10.3.3. 
Other Analysis Sets .....................................................................................................95 
10.4. 
Statistical Methods ......................................................................................................95 
10.4.1. 
Patient Disposition ......................................................................................................95 
10.4.2. 
Demography and Baseline Characteristics .................................................................95 
10.4.3. 
Medical History ..........................................................................................................96 
10.4.4. 
Prior Medications/Concomitant Medications .............................................................96 
10.4.5. 
Efficacy Analyses .......................................................................................................96 
10.4.5.1. 
Primary Efficacy Analysis ..........................................................................................96 
10.4.5.2. 
Secondary Efficacy Analysis ......................................................................................96 
10.4.5.3. 
Quality of Life Analysis .............................................................................................97 
10.4.5.4. 
Exploratory Efficacy Endpoint Analysis ....................................................................97 
10.4.5.5. 
Subgroup Analyses .....................................................................................................97 
10.4.6. 
Safety Analysis ...........................................................................................................97 
10.4.6.1. 
Adverse Events ...........................................................................................................98 
10.4.6.2. 
Other Safety ................................................................................................................98 
10.4.6.3. 
Treatment Exposure ....................................................................................................99 
10.4.6.4. 
Treatment Compliance ................................................................................................99 
10.4.7. 
Analysis of Drug Concentration Data .........................................................................99 
10.4.8. 
Analysis of Anti-Drug Antibody Data ........................................................................99 
10.4.9. 
Analysis of Biomarker Data .......................................................................................99 
10.5. 
Interim Analysis ..........................................................................................................99 
10.6. 
Additional Statistical Data Handling Conventions ...................................................100 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .......101 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................101 
11.1. 
Data Management .....................................................................................................101 
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11.2. 
Electronic Systems ....................................................................................................101 
12. 
STUDY MONITORING ..........................................................................................102 
12.1. 
Monitoring of Study Sites .........................................................................................102 
12.2. 
Source Document Requirements ..............................................................................102 
12.3. 
Case Report Form Requirements ..............................................................................102 
13. 
AUDITS AND INSPECTIONS ...............................................................................102 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................103 
14.1. 
Good Clinical Practice Statement .............................................................................103 
14.2. 
Informed Consent .....................................................................................................103 
14.3. 
Patient Confidentiality and Data Protection .............................................................103 
14.4. 
Institutional Review Board/Ethics Committee .........................................................104 
15. 
PROTOCOL AMENDMENTS ................................................................................104 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................104 
16.1. 
Premature Termination of the Study .........................................................................104 
16.2. 
Close-out of a Site ....................................................................................................104 
17. 
STUDY DOCUMENTATION .................................................................................105 
17.1. 
Certification of Accuracy of Data .............................................................................105 
17.2. 
Retention of Records ................................................................................................105 
18. 
CONFIDENTIALITY ..............................................................................................105 
19. 
FINANCING AND INSURANCE ...........................................................................106 
20. 
PUBLICATION POLICY ........................................................................................106 
21. 
REFERENCES .........................................................................................................107 
22. 
INVESTIGATOR’S AGREEMENT ........................................................................111 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................145 
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LIST OF TABLES 
Table 1: 
Schedule of Events:  Screening and Treatment Period ...............................................53 
Table 2: 
Schedule of Events, Post-Treatment Follow-Up ........................................................56 
Table 3: 
Schedule of Events for Cemiplimab Extension Phase ................................................59 
Table 4: 
General Guidelines for Cemiplimab Treatment Modifications or 
Discontinuations Due to Adverse Events ...................................................................73 
Table 5: 
General Treatment Hold Guidelines for Immune Related Adverse Events ...............74 
Table 6: 
Cemiplimab Dose Reductions ....................................................................................74 
Table 7: 
Dose Reductions for Pemetrexed:  Hematologic Toxicity .........................................77 
Table 8: 
Dose Reductions for Pemetrexed:  Nonhematologic Toxicity ...................................77 
Table 9: 
Dose Reductions for Topotecan ..................................................................................78 
Table 10: Recommended Dose Modifications for Irinotecan Monotherapya .............................79 
Table 11: Dose Modifications for Gemcitabine for Myelosuppression on Day of 
Treatment ....................................................................................................................80 
Table 12: Gemcitabine Dose Modifications for Myelosuppression in Preceding Cycle ............80 
Table 13: Vinorelbine Dose Modifications for Neutropenia ......................................................81 
Table 14: Vinorelbine Dose Modifications for Elevated Bilirubin ............................................81 
Table 15: Alpha Spending in Group Sequential Design Using Lan-DeMets 
(O’Brien-Fleming) Spending Function .....................................................................100 
 
LIST OF FIGURES 
Figure 1: 
TCGA Immune Signatures Using CD8A/PD-1/PD-L1 Expression ...........................37 
Figure 2: 
Study Design Schematic .............................................................................................45 
 
LIST OF APPENDICES 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: 
RECIST GUIDELINE (VERSION 1.1) ...................................................................112 
APPENDIX 2. RECOMMENDED DOSE MODIFICATION OR 
DISCONTINUATION AND SUPPORTIVE CARE GUIDELINES FOR 
SPECIFIC CEMIPLIMAB RELATED ADVERSE EVENTS ................................118 
APPENDIX 3. MEDDRA DICTIONARY-DERIVED PREFERRED TERMS FOR 
POTENTIAL IRAES ................................................................................................132 
APPENDIX 4. FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF ADVERSE EVENTS TO STUDY DRUG, STUDY CONDUCT, 
INFUSION PROCEDURE, OR STUDY PROCEDURE ........................................144 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
An Open-Label, Randomized, Phase 3 Clinical Trial of REGN2810 Versus 
Investigator's Choice of Chemotherapy in Recurrent or Metastatic Cervical 
Carcinoma 
Site Location(s) 
 
Principal Investigator 
Patients will be enrolled at approximately 100 sites globally. 
The Principal Investigator is to be determined. 
Objectives 
The primary objective is to compare overall survival (OS) for patients with 
recurrent or metastatic cervical cancer who have histology of squamous cell 
carcinoma (SCC) and who have any eligible histology, treated with either 
REGN2810 (cemiplimab) or investigator’s choice (IC) chemotherapy. 
The secondary objectives performed among SCC patients and among all 
eligible histologies (SCC and adenocarcinoma/adenosquamous carcinoma 
[AC]) are: 
• 
To compare progression-free survival (PFS) of cemiplimab versus 
IC chemotherapy 
• 
To compare objective response rate (ORR) (partial response [PR] + 
complete response [CR]) of cemiplimab versus IC chemotherapy 
per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
• 
To compare the duration of response (DOR) of cemiplimab versus 
IC chemotherapy 
• 
To compare the safety profiles of cemiplimab versus IC 
chemotherapy by describing adverse events (AE) 
• 
To compare quality of life (QOL) for patients treated with 
cemiplimab versus IC chemotherapy using the European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) 
Study Design 
This is an open-label, randomized, multi-center, phase 3 trial comparing 
cemiplimab versus IC of chemotherapy in patients with recurrent or 
metastatic cervical cancer.  Approximately 590 patients will be randomized 
to either the experimental cemiplimab treatment arm or the IC of 
chemotherapy control treatment arm.  In the experimental group, 
cemiplimab will be administered intravenously (IV) as a flat dose of 350 mg 
every 3 weeks (Q3W).  In the control group, IC chemotherapy options are 
4 classes: 
(1) 
antifolate 
- 
pemetrexed, 
(2) 
topoisomerase 1 
inhibitor - topotecan or irinotecan, (3) nucleoside analogue – gemcitabine, 
and (4) vinca alkaloid - vinorelbine.  The only chemotherapy treatments 
allowed in the control arm are any of the 5 drugs that are listed as IC options.  
Other agents in these classes are not permitted in this study. 
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The study includes 3 periods:  screening, treatment, and follow-up.  The 
screening period begins with the signing of the informed consent form 
(ICF).  The screening period ends when the patient has been confirmed as 
fully eligible for the study and is randomized, or with confirmation that the 
patient is ineligible and is a screen failure.  The treatment period begins 
within 5 days of randomization to 1 of the treatment arms.  Cycle length is 
6 weeks, and tumor imaging is planned to be conducted on day 42 (±7 days) 
of cycles 1–4, 6, 8, 10, 12, 14, and 16.  Planned treatment is for up to 
96 weeks.  The treatment phase ends when the patient discontinues study 
therapy.  There is no cross-over during this study.  After completion of the 
treatment period, patients enter the follow up period.  After the follow-up 
period, patients will be followed for survival.   
The second interim analysis demonstrated survival advantage for patients 
treated with cemiplimab over IC chemotherapy.  As such, Amendment 7 
will allow for an cemiplimab Extension Phase.  Patients randomized to 
IC chemotherapy will have the option to receive monotherapy with 
cemiplimab.  All randomized patients are eligible for this option provide 
they meet criteria per Section 7.1.7.1 and have not received anticancer 
immunotherapy. 
Patients randomized to and continuing treatment with cemiplimab will also 
enter the cemiplimab Extension Phase.  Retreatment is no longer an option 
as of Amendment 7. 
Study closeout procedures will be implemented following the last patient 
last visit of the cemiplimab Extension Phase  
Study Duration 
The duration of the study treatment period for a patient is up to 96 weeks 
(up to 16 cycles of 6 weeks each), excluding the screening period.  The 
follow-up period continues until death or study completion, per the sponsor 
and the Gynecologic Oncology Group (GOG). 
Population 
 
 
Sample Size: 
Approximately 460 SCC patients will be randomized 1:1 (230 per treatment 
arm) at approximately 100 sites globally.  Approximately 590 patients in the 
overall population are projected to have accrued when the enrollment of 
SCC patients is completed.  However, the actual number of patients in the 
overall population depends on the proportion of adenocarcinoma patients in 
the patient population and the time when Amendment 5 is implemented at 
each of the study sites. 
 
Target Population: 
The study will enroll women ≥18 years old with recurrent, persistent, and/or 
metastatic cervical cancer that has progressed after platinum-containing 
chemotherapy given to treat recurrent or metastatic cervical cancer.  Patients 
who only received prior platinum-based therapy concurrently with radiation 
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therapy for localized disease are not eligible. Starting with Amendment 5, 
only patients with squamous histology will be enrolled. 
Treatments 
 
 
Cemiplimab 
 
Dose/Route/Schedule: 
Cemiplimab will be administered IV as a flat dose of 350 mg Q3W, for up 
to 96 weeks of treatment 
 
IC chemotherapy 
 
Dose/Route/Schedule: 
Pemetrexed will be administered IV at a dose of 500 mg/m2 Q3W, for up to 
96 weeks of treatment 
 
IC chemotherapy 
 
Dose/Route/Schedule: 
Topotecan will be administered IV at a dose of 1 mg/m2 daily for 5 days, 
every 21 days, for up to 96 weeks of treatment 
 
IC chemotherapy 
 
Dose/Route/Schedule: 
Irinotecan will be administered IV at a dose of 100 mg/m2 on days 1, 8, 15, 
and 22, followed by 10 to 14 days of rest, for a 42-day (6-week cycle), for 
up to 96 weeks of treatment.  For patients enrolling in Japan, there will be 
at least 14 days of rest before subsequent irinotecan administration 
 
IC chemotherapy 
 
Dose/Route/Schedule: 
Vinorelbine will be administered IV at a dose of 30 mg/m2 on days 1 and 8, 
every 21 days, for up to 96 weeks of treatment. 
 
IC chemotherapy 
 
Dose/Route/Schedule: 
Gemcitabine will be administered IV at a dose of 1000 mg/m2 on days 1 and 
8, every 21 days, for up to 96 weeks of treatment 
Endpoints 
 
 
Primary: 
The primary endpoint is OS, defined as the time from randomization to the 
date of death.  A patient who has not died will be censored at the last known 
date of contact. 
 
Secondary: 
The key secondary endpoints are PFS and ORR. 
Other secondary endpoints will include DOR, QOL, and the safety and 
tolerability of cemiplimab. 
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 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 
• 
Biomarkers (serum, plasma, tumor tissue) 
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• 
Peripheral blood mononuclear cells 
• 
Quality of life assessments 
Statistical Plan 
The primary OS endpoint will be tested in patients with SCC first.  If the 
null hypothesis is rejected in the SCC patients, then OS will be tested in the 
overall population.  The sample size and power are calculated using 
East® version 6.4.1 statistical software. 
The sponsor assumes a median OS of 7 months for SCC patients treated with 
IC chemotherapy and a median OS of 10 months for SCC patients treated 
with cemiplimab.  The assumptions correspond to an approximately 42.8% 
increase in median OS and a hazard ratio (HR) of 0.7 if OS is distributed 
exponentially in both treatment groups. 
Two interim efficacy analyses are planned using Lan-DeMets 
(O’Brien-Fleming) spending function at 70% and 85% of the total 
OS events, respectively.  A total of 340 OS events in SCC patients will yield 
approximately 90% power to detect an HR of 0.7 with an overall type I error 
of 0.025 (1-sided).  The first interim efficacy analysis will be performed 
after observing approximately 238 OS events (70% of total OS events).  It 
is projected that an observed HR of 0.729 or lower would result in a 
statistically significant improvement in OS at the 1-sided nominal type I 
error of 0.0074 at the first interim efficacy analysis.  The second interim 
efficacy analysis will be performed after observing approximately 289 OS 
events (85% of total OS events).  It is projected that an observed HR of 0.769 
or lower would result in a statistically significant improvement in OS at the 
1-sided nominal type I error of 0.0129 at the second interim efficacy 
analysis.  The final efficacy analysis will be performed after observing 
approximately 340 OS events.  It is projected that an observed HR of 0.801 
or lower would result in a statistically significant improvement in OS at the 
1-sided nominal type I error of 0.0202 at the final analysis.  The actual alpha 
spending will be based on the actual number of OS events included in the 
analyses and determined by the O’Brien-Fleming spending function at the 
time of interim and final analyses. 
Considering the enrollment rate (2 patients/month for months 1 to 5, 
9 patients/month for months 6 to 16, 20 patients/month for months 17 to 23, 
22 patients/month for month 24 and beyond) and 10% dropout rate per year, 
enrollment of 460 randomized SCC patients will yield 340 OS events 
approximately 42 months after the first SCC patient is randomized.  
At the time when 460 SCC patients are enrolled in the study, a total 
enrollment in the study of approximately 590 patients is projected (SCC + 
non-SCC).  The actual number of patients to be enrolled will depend on the 
proportion of adenocarcinoma patients in the patient population and the time 
when Amendment 5 is implemented at each of the study sites.  If the HR is 
0.7, the power for testing OS in the overall population will be higher than 
90%.  
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The primary endpoint of OS will be analyzed in patients with SCC first by 
stratified log-rank test using geographic region (North America versus Asia 
versus Rest of World [ROW]) as a stratification factor.  The HR and its 95% 
confidence interval (CI) will be estimated by a stratified Cox regression 
model using the treatment as covariate.  
If the final analysis of OS is statistically significant in the SCC patients, then 
the analysis of OS will be performed in the overall population by stratified 
log-rank test using histology and geographic region. If statistically 
significant, the secondary endpoints PFS and ORR will be tested using a 
hierarchical procedure. The order of hierarchical testing for secondary 
endpoints will be specified in the statistical analysis plan (SAP) before 
database lock (DBL).   
Analysis of PFS and ORR will be performed at the time of OS analysis.  The 
PFS will be analyzed using the same statistical method as the analysis of 
OS.  The ORR will be analyzed using Cochran-Mantel-Haenszel test 
stratified by the same stratification factors used in analysis of OS.  An 
associated odds ratio and 95% CI will be calculated.  Objective response 
rate and the corresponding 95% exact CI will be calculated by the Clopper-
Pearson method for each treatment arm.  
The change in EORTC QLQ-C30 scores from baseline to the end of the 
study will be summarized descriptively at each post-baseline time point and 
compared using a mixed effect model, if appropriate. 
Safety observations and measurements including drug exposure, AEs, 
laboratory data, vital signs, and Eastern Cooperative Oncology Group 
performance status will be summarized and presented in tables and listings. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition of Term 
AC 
Adenosquamous carcinoma 
ADA 
Anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
βHCG 
β-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete response 
CRF 
Case report form (electronic or paper) 
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
DOR 
DBL 
Duration of response 
Database Lock 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ENGOT 
European Network for Gynaecological Oncological Trial 
EORTC QLQ30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GOG 
Gynecologic Oncology Group 
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Abbreviation 
Definition of Term 
Gy 
Gray 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HCG 
β-human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
HR 
Hazard ratio 
IC 
Investigator’s choice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PFS 
Progression-free survival 
PI 3-K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
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Abbreviation 
Definition of Term 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QOL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
ROW 
Rest of world 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SOC 
System organ class 
TCGA 
The Cancer Genome Atlas 
TEAE 
Treatment-emergent adverse event 
TSC 
Trial Steering Committee 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of child-bearing potential 
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1. 
INTRODUCTION 
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 13000 new cases and 4100 deaths annually (Siegel 2016).  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). 
For patients with locally advanced disease, 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, there is no standard of care.  Non-randomized phase 2 trials have demonstrated survival 
times of 7.4 to 8.1 months (N = 29 and 43 patients, respectively) with single agent pemetrexed 
monotherapy (Lorusso 2010) (Miller 2008).  Gemcitabine monotherapy yielded median overall 
survival (OS) of 6.5 months in a phase 2 study of women (N = 22 patients) with previously treated 
cervical cancer (Schilder 2005).  In a phase 2 study (N = 45 patients) of topotecan in which most 
patients had received prior platinum, median OS was 6.6 months (Bookman 2000).  In phase 
2 studies of vinorelbine for patients who could have received 1 prior chemotherapy regimen for 
squamous or non-squamous advanced cervical cancer, observed response rates were 13% 
(6/44 patients) and 7% (2/28 patients), respectively (Muggia 2004) (Muggia 2005).  Weekly 
dosing of irinotecan yielded a response rate of 13% (6/45 patients) in a phase 2 study for women 
with recurrent squamous cervical cancer in the US (Look 1998), and a response rate of 24% 
(13/55 patients) in a phase 2 study for women with cervical cancer in Japan (Takeuchi 1991).  New 
systemic therapy options are needed for this patient population. 
Cemiplimab (the INN for REGN2810) is a hinge-stabilized IgG4P anti-PD-1 (programmed cell 
death 1) monoclonal antibody that has demonstrated encouraging efficacy and favorable 
tolerability in a phase 1 study that is now enrolling patients in multiple expansion cohorts 
(Papadopoulos 2016) (NCT02383212).  Cemiplimab is also being evaluated in various clinical 
trials and indications globally.  On 28 September 2018, cemiplimab was approved in the US by 
the Food and Drug Administration (FDA) as LIBTAYO® (cemiplimab-rwlc) for the treatment of 
patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC 
who are not candidates for curative surgery or curative radiation. 
The current study seeks to evaluate the clinical efficacy of cemiplimab in patients with recurrent 
or metastatic cervical cancer that has progressed after platinum-based therapy.   Programmed cell 
death 1 is expressed on activated T-cells, and binding of PD-1 to its ligands, PD-L1 and PD-L2, 
imparts inhibition of cytotoxic T-cell activity (Francisco 2010).  Upregulated expression of 
PD-1/PD-L1 checkpoint signaling in the tumor microenvironment plays a role in resistance to 
antitumor immune responses (Zou 2008).  The clinical study of cemiplimab in cervical cancer is 
supported by both preclinical and clinical observations regarding the role of PD-1/PD-L1 
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checkpoint signaling in the suppression of anti-tumor immune responses against this and other 
HPV-associated cancers. 
First, almost all cervical squamous cell carcinomas are associated with high risk strains of HPV 
(The Cancer Genome Atlas Research Network).  Tumors that express viral antigen appear to be 
responsive to PD-1 blockade as a strategy to enhance the antitumor immune response, as 
demonstrated by positive clinical trial results in patients with HPV-associated head and neck 
squamous cell carcinoma and in polyomavirus-associated Merkel Cell carcinoma, with nivolumab 
and pembrolizumab, respectively (Gillison 2016) (Nghiem 2016).  Secondly, cervical squamous 
carcinomas may evade immune response by expression of PD-L1 ligand, which was detectable by 
immunohistochemistry (>5% staining) in 54% (83/154) of squamous tumors, and in 14% (7/49) 
of adenocarcinomas (Heeren 2016). 
Thirdly, preliminary clinical data demonstrate efficacy of PD-1 blockade against cervical cancer.  
In a cohort of 24 cervical cancer patients with PD-L1+ recurrent or metastatic cervical cancer 
treated with pembrolizumab, objective responses were observed in 17% (4/24) of patients and 
median OS was 9 months (95% confidence interval [CI]:  4 to 12 months) (Frenel 2016).  In the 
first-in-human (FIH) study of cemiplimab, 3 patients with cervical squamous cancer were enrolled 
in dose escalation cohorts to receive cemiplimab plus hypofractionated radiation therapy (9 gray 
[Gy] X 3 fractions or 6 Gy X 5 fractions) (Papadopoulos 2016).  Two of these patients have 
experienced durable responses.  Radiation therapy was administered in week 2, and cemiplimab 
was administered intravenously (IV) every 2 weeks (Q2W) for up to 48 weeks or until progression 
of disease or unacceptable toxicity.  Non-radiated lesions were evaluated for response.  One patient 
has experienced a radiologic complete response (CR), and another has experienced an overall 
partial response (CR in target lesions, with a non-target lesion that persisted).  Both patients 
completed 48 weeks of treatment, and entered post-treatment follow up.  The cervical cancer 
patient with partial response experienced progressive disease (PD) with an enlarging 
supraclavicular node after approximately 8 months of post-treatment follow up, and this was 
biopsy-proven.  This patient resumed treatment with cemiplimab monotherapy (no radiation) and 
experienced a partial response at the first response assessment (8 weeks) after resuming treatment. 
Fourth, analysis of gene expression data in The Cancer Genome Atlas (TCGA) 
(The Cancer Genome Atlas Research Network) demonstrates similarities between cervical cancer 
and other tumor types for which anti-PD-1 therapy achieves therapeutic advantage.  Briefly, 
average expression of 3 genes (CD8A, PD-1, and PD-L1) in each tumor type is normalized to 
standard distribution across all tumor types.  Tumors are organized according to Z-scores using 
hierarchical clustering (Figure 1).  Cervical cancer clusters with non-small cell lung cancer, 
melanoma, renal clear cell carcinoma, and head and neck squamous cell carcinoma.  Programmed 
cell death 1 blockade improved OS in each of these tumor types in randomized phase 3 studies 
(Ferris 2016) (Motzer 2015) (Trivedi 2015). 
Taken together, these observations suggest that a prospective randomized trial of PD-1 inhibition 
with cemiplimab is warranted for patients with recurrent/metastatic cervical cancer to potentially 
improve OS. 
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Figure 1: 
TCGA Immune Signatures Using CD8A/PD-1/PD-L1 Expression 
 
Source:  Regeneron Molecular Profiling analysis of TCGA RNA-Seq data. 
Color key of z value is shown. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To compare OS for patients with recurrent or metastatic cervical cancer who have histology of 
squamous cell carcinoma (SCC) and who have any eligible histology, treated with either 
cemiplimab or investigator’s choice (IC) chemotherapy. 
2.2. 
Secondary Objectives 
The secondary objectives of the study performed among SCC patients and among all eligible 
histologies (SCC and adenocarcinoma/adenosquamous carcinoma [AC]) are: 
• To compare progression-free survival (PFS) of cemiplimab versus IC chemotherapy 
• To compare objective response rate (ORR) (partial response [PR] + CR) of 
cemiplimab versus IC chemotherapy per Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 (Appendix 1) 
• To compare the duration of response (DOR) of cemiplimab versus IC chemotherapy 
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• To compare the safety profiles of cemiplimab versus IC chemotherapy by describing 
adverse events (AE) 
• To compare quality of life (QOL) for patients treated with cemiplimab versus IC 
chemotherapy using European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
2.3. 
Exploratory Objectives 
• To measure concentrations of cemiplimab in serum and characterize the 
pharmacokinetics (PK) of cemiplimab 
• To assess the immunogenicity of cemiplimab 
• To explore associations between the clinical efficacy of cemiplimab and molecular 
features in pretreatment tumor samples 
• To explore the pharmacodynamic activity of cemiplimab on the immune system in 
peripheral blood samples 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Human papillomavirus viral proteins are recognized as foreign antigens by effector T cells in 
cervical cancer, and an anti-tumor immune response can be unleashed by blockade of the PD-1 
immune checkpoint.  Cemiplimab will improve OS compared to IC chemotherapy for cervical 
cancer patients who experienced progression of disease after treatment with platinum 
chemotherapy that was administered in the recurrent or metastatic disease setting, in SCC and in 
the overall population. 
3.2. 
Rationale 
3.2.1. 
Rationale for Patient Population and Study Design 
This is an open-label, randomized, phase 3 trial of cemiplimab versus IC chemotherapy in patients 
with recurrent or metastatic cervical cancer that has progressed after platinum-containing 
chemotherapy.  The GOG240 study established the efficacy of first line-therapy for recurrent or 
metastatic cervical cancer with the regimen of platinum + paclitaxel + bevacizumab (Tewari 2014).  
There is no standard-of-care regimen in the second line setting.  Agents that may be considered in 
this setting are the IC options in this study:  pemetrexed, topotecan, irinotecan, gemcitabine, and 
vinorelbine.  Despite the availability of various chemotherapy options, patients treated with these 
agents for cervical cancer have a median survival time of approximately 7 months (Section 3.2.3).   
A concept of “platinum-refractory” disease has been described in the cervical cancer literature, 
and is related to time since prior platinum therapy (Nishino 2016) (McLachlan 2016) 
(Tanioka 2011).  However, it is not typical clinical practice to re-treat cervical cancer patients with 
platinum-based chemotherapy if they have already received it in the setting of recurrent or 
metastatic disease.  The chemotherapy regimens in the control arm of this study represent the 
current treatment options for cervical cancer patients who have received prior platinum in the 
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setting of recurrent or metastatic disease.  Regardless of the time interval between prior platinum 
therapy (for recurrent or metastatic cervical cancer) and subsequent progression, such patients have 
unmet medical need and are appropriate for consideration of the clinical study.  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 in this study.   
NOTE:  The term persistent disease is sometimes used to refer to disease for which there 
was never documentation of complete resolution after chemoradiation.  For such patients, 
first line therapy is the same as that for patients with recurrent or metastatic disease 
(ie, platinum + paclitaxel ± bevacizumab).  As a convention in this study, patients with 
persistent disease are considered included in the category of “recurrent or metastatic” 
disease any time that term is used in the protocol.  
The study population will have received prior paclitaxel and prior bevacizumab, refused such 
treatment, or been unsuitable for such treatment (or, in the case of bevacizumab, not had access).  
For patients who received prior paclitaxel and/or prior bevacizumab, disease progression at any 
time after prior paclitaxel and/or bevacizumab is an acceptable reason for discontinuation of 
paclitaxel and/or bevacizumab. 
The study design is a randomized comparison of cemiplimab versus IC chemotherapy, with an OS 
endpoint.  For patient populations in which there is no widely accepted standard of care, and in 
which randomization to a placebo or best-supportive care arm is considered unethical or 
unfeasible, health authorities have accepted IC as a comparator in studies that have led to 
regulatory approvals based on OS endpoints (Donoghue 2012) (Ferris 2016).  Blinding is not 
practical in the current study due to differences in schedule and differences in AE profiles between 
cemiplimab and the IC options (ie, immune-related adverse events [irAEs] with cemiplimab and 
white blood cell count suppression with chemotherapy). 
Overall survival directly measures clinical benefit, is not biased, and is not a surrogate endpoint.  
As such, OS has been selected as the primary endpoint, and this open-label study will compare 
cemiplimab versus IC chemotherapy in patients with cervical cancer who have progressed after 
prior treatment with a platinum containing regimen that was given in the recurrent or metastatic 
disease setting.   
Rationale for Further Enrollment of only Patients with Squamous Histology  
The International Collaboration of Epidemiological Studies of Cervical Cancer analyzed data from 
23 published studies that included 9052 cervical cancer patients; histologic data was available for 
8575 patients (Appleby 2006).  In the overall analysis of studies globally, approximately 85% of 
cases had squamous histology, although this did appear to vary by geographic region. 
Emerging data from anti-PD-1 studies in cervical cancer suggests that efficacy of these agents in 
cervical cancer may be associated with squamous histology.  The phase 1 study of cemiplimab 
(R2810-ONC-1423) contained expansion cohorts for cervical cancer patients (Rischin 2018).  Data 
from these expansion cohorts, combined with the results of 3 cervical cancer patients in the dose 
escalation portion of the study (Papadopoulos 2016), suggest an efficacy difference associated 
with histology:  ORR among squamous cell cancer patients was 31% (4/13), and ORR among 
patients with adenocarcinoma/other histology was 0% (0/10) (Regeneron, data on file).  Results 
with pembrolizumab also support the efficacy of PD-1 blockade in cervical cancer patients with 
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squamous histology.  The accelerated approval of pembrolizumab for cervical cancer patients in 
the US was based on a data set (N = 77 patients) in which 92% of the patients had squamous 
histology (KEYTRUDA 2018).  The observation in cervical cancer that PD-L1 expression is 
higher in squamous cell histology than in adenocarcinoma histology may partially account for the 
observed association of anti-PD-1 efficacy with histology in this disease (Heeren 2016).   
These observations support a protocol amendment to improve the ability of the study to test for 
efficacy in the squamous population, and also to increase the probability that the proportion of 
patients with squamous histology in the total study population will be consistent with the global 
proportions of histologies in cervical cancer.  As such, Amendment 5 sets forth that enrollment 
will only be allowed for patients with squamous histology and that enrollment will continue until 
460 patients with squamous histology are enrolled per Amendment 6.  Based on current and 
projected enrollment trends and anticipated time to implementation of Amendments 5 and 6 at 
study sites, total enrollment to the study will be approximately 590 patients, and approximately  
80% of patients will have squamous histology.  This is consistent with global distribution of 
cervical cancer histologies described above (Appleby 2006).  
See Section 10 for details regarding statistical analysis considerations regarding histology.   
3.2.2. 
Rationale for Cemiplimab Dose Selection  
In this phase 3 clinical study in cervical cancer, cemiplimab monotherapy at a dose of 350 mg 
every 3 weeks (Q3W) is being proposed, to allow for compatibility with many standard 
chemotherapeutic regimens that are dosed on a Q3W schedule, and to improve patient 
convenience.  This cemiplimab dose of 350mg Q3W was chosen based on the safety and 
preliminary anti-tumor activity observed in the ongoing FIH study R2810-ONC-1423 
(NCT02383212), and was supported by modeling of cemiplimab exposure in serum based on data 
collected in the FIH study. 
Simulations of cemiplimab exposure in 1000 patients using population PK analyses indicated that 
1) the variability in cemiplimab exposure (CV%) was similar with body-weight adjusted as 
compared to fixed doses, therefore supporting the fixed dose selection, and 2) that a 350 mg Q3W 
dose resulted in similar (≤20% difference) Ctrough, AUC12W and Cmax as compared to a 3 mg/kg 
Q2W dose, used in the FIH study.  cemiplimab concentrations exceeded those observed at 1 mg/kg 
Q2W dose, which demonstrated clinical efficacy in the FIH study and Ctrough values exceeded 
concentrations of approximately 5 mg/L to 20 mg/L above which saturation of PD-1 target 
occupancy is expected to occur, based on animal data.  The 350 mg Q3W dose of cemiplimab is 
therefore being proposed as the optimal dose in the phase 3 studies in patients with cervical cancer 
and across the cemiplimab program. 
3.2.3. 
Rationale for Investigator’s Choice Chemotherapy Options 
The IC chemotherapy agents in this study are in 4 classes: (1) antifolate - pemetrexed, 
(2) topoisomerase 1 inhibitor – topotecan or irinotecan, (3) nucleoside analogue – gemcitabine, 
and (4) vinca alkaloid - vinorelbine.  These agents have all been evaluated as monotherapies in 
single arm, non-randomized, phase 2 studies, and are included as possible treatment options in the 
National Comprehensive Cancer Network (NCCN) Guidelines for recurrent or metastatic cervical 
cancer (NCCN 2017).  No systemic treatment agents have been associated with a survival 
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advantage in this patient population, and the IC option in this study comprises a group of treatments 
that are commonly used in clinical practice as monotherapy options. 
In a phase 2 study of pemetrexed (900 mg/m2 every 21 days), patients (N = 27) who had 1 prior 
chemotherapy regimen for recurrent or metastatic cervical cancer had an ORR of 15% and a 
median OS of 7.4 months (Miller 2008).  In another phase 2 trial of pemetrexed (500 mg/m2 every 
21 days) for patients (N = 43) with recurrent or metastatic cervical cancer that had been previously 
treated with 1 prior chemotherapy regimen in any setting (including concurrent chemoradiation), 
ORR was 14% and median OS was 8 months (Lorusso 2010).  The dose and schedule of 
pemetrexed (500 mg/m2 IV every 21 days with folic acid and vitamin B12 support) that is used in 
the current protocol is the same pemetrexed monotherapy regimen that has been approved by the 
FDA for non-small cell lung cancer (Hanna 2004). 
Topotecan is an FDA-approved agent for the treatment of cervical cancer when given in 
combination with cisplatin.  Topotecan plus cisplatin, compared to cisplatin alone, improved OS 
for women with stage IVB, recurrent, or persistent cervical cancer that was not amenable to 
curative treatment with surgery or radiation therapy in GOG179 (Long 2005).  A phase 2 study 
evaluated topotecan monotherapy for patients with recurrent or metastatic cervical cancer who had 
received no more than 1 prior chemotherapy regimen for metastatic disease.  The regimen was 
topotecan 1.5 mg/m2 per day for 5 consecutive days of a 21-day cycle.  Of 41 evaluable patients, 
34 had received prior chemotherapy, generally including cisplatin.  The ORR was 12.5% and the 
median OS was 6.6 months (Bookman 2000).  The 21-day topotecan monotherapy regimen 
(topotecan 1.5 mg/m2 per day for 5 consecutive days of a 21-day cycle) was subsequently approved 
in small cell lung cancer (von Pawel 1999) and in ovarian cancer (ten Bokkel Huinink 2004).  
Topotecan monotherapy is recognized as a palliative option for patients with recurrent or 
metastatic cervical cancer (NCCN 2017). 
However, in cervical cancer patients who have received prior platinum-based chemotherapy, the 
topotecan regimen of 1.5 mg/m2 per day for 5 consecutive days is associated with unacceptable 
hematologic toxicity, including 68% and 39% incidence rates of grade 4 neutropenia and grade 
4 thrombocytopenia, respectively (Bookman 2000).  Even among patients who had not received 
prior systemic therapy for recurrent, persistent, or metastatic cervical cancer, the incidence rates 
of grade 4 neutropenia and grade 4 thrombocytopenia with this regimen were 68% and 18%, 
respectively (Muderspach 2001).  To optimize patient safety, the starting topotecan dose and 
schedule in this protocol is 1 mg/m2 per day for 5 consecutive days, which is acceptable in routine 
clinical practice. 
A phase 2 study of gemcitabine administered over a 28-day treatment course (800 mg/m2, 3 weeks 
on, 1 week rest) enrolled 22 patients who had received 1 prior regimen for metastatic, persistent, 
or recurrent cervical cancer (Schilder 2005).  The ORR was 4.5% and median OS was 6.5 months.  
In the current protocol, the IC regimen for gemcitabine is 1000 mg/m2 on days 1 and 8 of a 21-day 
treatment course, which is the FDA-approved dose and schedule for gemcitabine in combination 
with carboplatin in ovarian cancer (Pfisterer 2006).  Gemcitabine also has monotherapy activity in 
ovarian cancer (Mutch 2007).  The FDA approval in ovarian cancer provides toxicity management 
guidelines that are specific for this dose and schedule of gemcitabine (see Section 8.4.3).  Over 
12 weeks, this 21-day treatment course provides similar exposure to gemcitabine (8000 mg) as the 
28-day treatment course in the Schilder study (7200 mg).  Gemcitabine monotherapy is 
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recommended as a palliative treatment option in recurrent or metastatic cervical cancer 
(NCCN 2017). 
Vinorelbine monotherapy (30 mg/m2 days 1 and 8, every 21 days) has been evaluated in two 
phase 2 studies for women with advanced cervical cancer (recurrent or persistent) who could have 
received one prior systemic therapy.  Among 44 patients with squamous histology, the observed 
response rate was 13% (5 partial responses, 1 complete response).  Grade 3 or 4 neutropenia 
occurred in 41% of patients (Muggia 2004).  Among 22 patients with nonsquamous histology, the 
observed response rate was 7% (2 partial responses), and grade 3 or 4 neutropenia occurred in 32% 
of subjects (Muggia 2005).  Neither vinorelbine study presented survival data, but the 6 squamous 
responders received a median of 24 weeks (range, 12 to 30 weeks) of treatment (Muggia 2004), 
and the 2 nonsquamous responders received 18 weeks of therapy before progression 
(Muggia 2005).  The weekly dosing schedule (days 1 and 8, every 21 days) facilitates safe 
administration for this regimen as regards neutropenia and other potential drug-related AEs. 
Irinotecan (CPT-11) monotherapy has been studied in several phase 2 clinical trials in advanced 
cervical cancer (Look 1998) (Takeuchi 1991) (Irvin 1998) (Verschraegen 1997).  A phase 2 study 
evaluated weekly dosing (125 mg/m2 x 4 weeks, followed by 2 rest weeks) among women with 
recurrent cervical cancer who could have only received prior chemotherapy as a radiosensitizer 
(Look 1998).  Response rate was 13% (6/45 evaluable patients).  Survival data was not presented, 
but duration of response was 8.8 months in 1 patient with complete response and median duration 
of response was 4.8 months (range, 3.2 to 12+ months) among 5 patients with partial responses.  
Grade 3 or 4 gastrointestinal toxicity occurred in 39% of patients.  In a phase 2 study that evaluated 
the same regimen in cervical cancer patients who could have received 1 prior chemotherapy for 
recurrent or metastatic disease, response rate was 21% (9/42) and overall median survival was 
6.4 months.  Dose reduction was required in 77% of patients (Verschraegen 1997). 
In a Japanese phase 2 study of CPT-11 in cervical cancer and ovarian cancer, the observed response 
rate was 24% (13/55 patients) in the cervical cancer group, including 5 complete responses.  Two 
regimens were used in the study, but no significant differences were observed between the 
regimens of 100 mg/m2 weekly dosing or 150 mg/m2 every 2 week dosing (Takeuchi 1991).  The 
regimen of irinotecan 100 mg/m2 (weekly for 4 weeks, followed by 2 weeks rest) is approved in 
Japan for women with recurrent and metastatic cervical cancer.  Because the patient population in 
this protocol will include patients who may have received more than 1 prior line of therapy, this 
100 mg/m2 weekly dosing regimen (weekly x 4, followed by 2 rest weeks) is selected as the starting 
dose for this IC option to optimize patient safety. 
In clinical practice, other possible monotherapy options exist for palliation of advanced cervical 
cancer, including paclitaxel, bevacizumab, ifosfamide, mitomycin, and 5-fluorouracil 
(NCCN 2017).  Paclitaxel or other taxane is not included as an IC chemotherapy option in this 
protocol because it is anticipated that most study patients will have received prior paclitaxel in the 
context of prior first-line therapy for recurrent, persistent, or metastatic cervical cancer with 
cisplatin plus paclitaxel ± bevacizumab as per the GOG240 regimen (Tewari 2014).  Most patients 
with access to bevacizumab will also have received it as part of the GOG240 regimen.  Because 
no survival advantage has been established in this setting for any monotherapy option, the IC 
options in this protocol (pemetrexed, topotecan, irinotecan, gemcitabine, and vinorelbine) were 
selected based on relatively favorable safety profiles and the Gynecologic Oncology Group’s 
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(GOG) impression that the older agents (ifosfamide, mitomycin, and 5-fluoruracil) are less 
commonly used in contemporary practice for cervical cancer. 
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, and height) and 
disease characteristics, tumor histology (squamous versus adenocarcinoma/adenosquamous), and 
geographic region, as well as medical and oncology history.  Oncologic history will include prior 
treatments with platinum agents, paclitaxel, and bevacizumab (or reason why paclitaxel or 
bevacizumab was not given previously). 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint is OS, defined as the time from randomization to the date of death.  A patient 
who has not died will be censored at the last known date of contact. 
4.2.2. 
Secondary Endpoints 
The key secondary endpoints are PFS and ORR. 
Progression-free survival will be defined as the time from randomization to the date of the first 
documented tumor progression using RECIST 1.1, or death due to any cause.  Patients will be 
censored according to rules listed below: 
1. Patients who do not have a documented tumor progression or death will be censored on the 
date of their last evaluable tumor assessment. 
2. Patients who do not have any evaluable tumor assessments after randomization and do not 
die will be censored on the date of randomization. 
Overall response rate will be defined as the number of patients with a best overall response of 
confirmed CR or PR divided by the number of patients in the efficacy analysis set.  Best overall 
response will be defined as the best overall response between the date of randomization and the 
date of the first objectively documented progression or the date of subsequent anti-cancer therapy, 
whichever comes first. 
4.2.3. 
Other Secondary Endpoints 
Other secondary endpoints will include DOR and QOL.  Duration of response will be defined as 
the time between the date of first response (CR or PR) to the date of the first documented tumor 
progression (per RECIST 1.1) or death due to any cause.  Quality of life will be measured by the 
EORTC QLQ-C30. 
Other secondary endpoints will also include the safety and tolerability of cemiplimab.  To evaluate 
the safety and tolerability of cemiplimab IC chemotherapy, the incidence of AEs, serious adverse 
events (SAEs), deaths, and laboratory abnormalities will be assessed. 
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4.3. 
Exploratory Endpoints 
4.3.1. 
Pharmacokinetic Variables 
Cemiplimab concentrations in the serum will be assessed at multiple time points throughout the 
treatment and follow-up periods. 
Pharmacokinetic variables may include, but are not limited to, the following: 
• Ceoi – concentration at end of infusion 
• Ctrough 
4.3.2. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status of ADA response and titer as follows: 
• Treatment-emergent ADA response - defined as any positive response post-treatment 
when baseline results are negative or missing 
Treatment-boosted ADA response - defined as any post treatment ADA response that 
is at least 9-fold over baseline titer levels when baseline results are positive 
• Titer values (titer value category) 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
• Samples that are positive in the ADA assay may be analyzed for the neutralizing 
activities 
4.3.3. 
Other Exploratory Variables 
Relationships between efficacy endpoints and candidate biomarkers in tumor and peripheral blood 
will be described. 
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This is an open-label, randomized, multi-center, phase 3 trial comparing cemiplimab versus IC of 
chemotherapy in patients with recurrent or metastatic cervical cancer.  Approximately 590 patients 
will be randomized to either the experimental cemiplimab treatment arm or the IC of chemotherapy 
control treatment arm.  In the experimental group, cemiplimab will be administered as a flat dose 
of 350 mg Q3W.  In the control group, IC chemotherapy options are in 4 classes: 
(1) antifolate - pemetrexed, (2) topoisomerase 1 inhibitor – topotecan or irinotecan, (3) nucleoside 
analogue – gemcitabine, and (4) vinca alkaloid - vinorelbine.  A schematic diagram of the study 
design is presented in Figure 2.  The only chemotherapy treatments allowed in the control arm are 
any of the 5 drugs that are listed as IC options.  Other agents in these classes are not permitted in 
this study. 
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Figure 2: 
Study Design Schematic 
 
Q42D=every 42 days 
Study Population: Patients 
with recurrent or metastatic 
cervical cancer that has 
progressed after platinum 
therapy for recurrent or 
metastatic cervical cancer 
Screening, Randomization, 
and Stratification (N = 590):  
Randomization – 1:1 
Stratification: 
•
Histology–  Squamous 
versus adenocarcinoma/ 
adenosquamous 
•
Geographic region 
•
Prior bevacizumab (Y/N) 
•
ECOG PS 0 vs 1 
Duration of Treatment: 
Treatment until PD, 
unacceptable toxicity, or  
until 96 weeks (16cycles, 
each 6 weeks) 
•
Option for treatment 
beyond progression 
with cemiplimab 
•
Option for 
retreatment for 
patients who 
complete 16 cycles 
and then experience 
PD in post-treatment 
follow up 
Post-Treatment  
Follow-up: 
For safety, progression 
events, and OS 
Study Endpoints: 
Primary:  OS 
Key Secondary: PFS, 
ORR 
Experimental Therapy 
Cemiplimab 
350 mg IV Q3W 
Control Therapy,  
Investigator’s Choice   
Any of the following, given IV Q3W: 
•
Anti-folate: 
Pemetrexed 500 mg/m2 on  
Day 1(Q3W) 
•
Topoisomerase inhibitor 
Topotecan 1.0 mg/m2 on Days 1-5 
(Q3W) 
OR 
Irinotecan 100 mg/m2 weekly x4 
followed by 10-14 days’ rest 
(Q42D) 
•
Nucleoside analog: 
Gemcitabine 1000 mg/m2 on 
Days 1 and 8 (Q3W) 
•
Vinca alkaloid: 
Vinorelbine 30 mg/m2 on 
 days 1 and 8 (Q3W) 
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The study includes 3 periods:  screening, treatment, and follow-up.  The screening period begins 
with the signing of the informed consent form (ICF).  The screening period ends when the patient 
has been confirmed as fully eligible for the study and is randomized, or with confirmation that the 
patient is ineligible and is a screen failure.  The treatment period begins within 5 days of 
randomization to 1 of the treatment arms.  Cycle length is 6 weeks, and tumor imaging is planned 
to be conducted on day 42 (±7 days) of cycles 1-4, 6, 8, 10, 12, 14, and 16.  Planned treatment is 
for up to 96 weeks.  The treatment phase ends when the patient discontinues study therapy.  There 
is no cross-over during this study.  After completion of the treatment period, patients enter the 
follow-up period.  After the follow-up period, patients will be followed for survival.   
Study closeout procedures will be implemented after last patient last visit of the cemiplimab 
Extension Phase (Section 7.1.7.1).  
5.1.1. 
End of Treatment Definition 
There is an end of treatment disposition point for each patient, as reflected by treatment 
completion/discontinuation case report form (CRF).  The end of treatment occurs for each 
individual patient after the patient completes or discontinues from the treatment (Table 1), but 
before follow-up visits 1 and 2 (Table 2). 
5.1.2. 
End of Study Definition 
The end of study for the study as a whole is planned to occur when approximately 340 deaths have 
occurred in squamous cell patients, as per Section 10.2.  The total duration of study from start of 
randomization to final analysis of OS is expected to be approximately 42 months (33 months of 
accrual plus 11 months of follow-up).  There is an end of study disposition point for each patient, 
as reflected by study completion/discontinuation CRF.  The end of study occurs for each individual 
patient after the patient completes or discontinues from the treatment (Table 1) and/or follow-up 
visit 1 and 2 portion of Table 2, but before the survival follow-up portion of Table 2.   
Due to survival benefit, for patients on the cemiplimab arm on second interim analysis, a 
cemiplimab Extension Phase was added (Section Section 7.1.7).  Therefore, end of study is now 
planned to occur after last patient last visit of the cemiplimab Extension Phase. 
5.2. 
Planned Interim Analysis 
Two interim efficacy analyses are planned using Lan-DeMets (O’Brien-Fleming) spending 
function.  The first interim efficacy analysis will be performed after observing approximately 
238 OS events (70% of total OS events).  The second interim efficacy analysis will be performed 
after observing approximately 289 OS events (85% of total OS events).  The details are provided 
in Section 10.5. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) composed of members who are independent 
from the sponsor and the study investigators will monitor patient safety by conducting formal 
reviews of accumulated safety data and available efficacy data.  The IDMC will also monitor and 
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review the interim efficacy analyses for OS.  If requested, the IDMC may have access to the 
treatment allocation code or any other requested data for the purposes of a risk-benefit assessment. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution.  The IDMC will act in an advisory capacity to Regeneron.  Regeneron 
will have responsibility for the overall design and conduct of the study including communication 
of the data. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
5.3.2. 
Trial Steering Committee 
All activities of the Trial Steering Committee (TSC) are described in the TSC charter. 
5.4. 
Study Conduct in Response to COVID-19 
Included in amendment 6 of the protocol are measures to account for the “Coronavirus Disease 
2019” (COVID-19) pandemic and to minimize the risks to the patients in the study as well as 
healthcare providers.  
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 460 SCC patients will be randomized 1:1 (230 per treatment arm) at approximately 
100 sites globally.  Approximately 590 patients in the overall population are projected to have 
accrued when the enrollment for SCC patients is completed.  However, the actual number of 
patients in the overall population depends on the proportion of adenocarcinoma patients in the 
patient population and the time when Amendment 5 is implemented at each of the study sites. 
6.2. 
Study Population 
The study will enroll women ≥18 years old with recurrent, persistent, and/or metastatic cervical 
cancer that has progressed after platinum-containing chemotherapy given to treat recurrent or 
metastatic cervical cancer.  Patients who have only received prior platinum-based therapy 
concurrently with radiation therapy for localized disease are not eligible.  Starting with 
Amendment 5, only patients with squamous histology will be enrolled. 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Recurrent, persistent, and/or metastatic cervical cancer with squamous cell histology, for 
which there is not a curative-intent option (surgery or radiation therapy with or without 
chemotherapy).   
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a. Patients with acceptable histologies (squamous carcinoma, adenocarcinoma, and AC) 
will be enrolled from the original protocol through protocol Amendment 4.  For the 
purpose of this study, AC will be stratified as adenocarcinoma. 
b. Starting with protocol Amendment 5, only patients with squamous cell histology are 
eligible to enroll. 
2. Tumor progression or recurrence after treatment with platinum 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.   
3. Patient must have measurable disease as defined by RECIST 1.1.  Measurable disease is 
defined as at least one 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. 
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
5. ≥18 years old 
NOTE:  For patients enrolling in Japan who are ≥18 and <20 years old, both the patients 
and parent/legal representative must provide signed informed consent. 
6. Hepatic function: 
a. Total bilirubin ≤1.5x upper limit of normal (ULN; if liver metastases ≤3x ULN).  
Patients with Gilbert’s Disease and total bilirubin up to 3x ULN may be eligible after 
communication with and approval from the medical monitor. 
b. Transaminases ≤3x ULN (or ≤5.0x ULN, if liver metastases) 
c. Alkaline phosphatase ≤2.5x ULN (or ≤5.0x ULN, if liver or bone metastases) 
NOTE: For patients with hepatic metastases, if transaminase levels (aspartate 
aminotransferase [AST] and/or alanine aminotransferase [ALT]) >3x but ≤5x ULN, total 
bilirubin must be ≤1.5x ULN.  If total bilirubin >1.5x but ≤3x ULN, both transaminases 
(AST and ALT) must be ≤3x ULN. 
7. Renal function: Serum creatinine ≤1.5x ULN or estimated creatinine clearance >45 mL/min 
8. Bone marrow function: 
a. Hemoglobin ≥9.0 g/dL 
b. Absolute neutrophil count (ANC) ≥1.5x 109/L 
c. Platelet count ≥75 x 109/L 
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9. Anticipated life expectancy >12 weeks 
10. Willing and able to comply with clinic visits and study-related procedures 
11. Provide signed informed consent 
12. Able to understand and complete study-related questionnaires 
13. Patients must meet at least one of the following criteria regarding prior bevacizumab therapy: 
a. Received prior bevacizumab-containing therapy, which was discontinued due to 
progression of disease 
b. Received prior bevacizumab-containing therapy, which was discontinued due to 
toxicity 
c. Was deemed unsuitable for prior bevacizumab therapy for one of the following reasons: 
(i) unacceptable risk of fistula formation, (ii) poorly controlled hypertension, (iii) “low 
risk” disease according to the Moore Criteria (Tewari 2015) 
d. Refused prior bevacizumab therapy 
e. Did not have access to bevacizumab therapy due to logistical reasons (eg, lived in a 
region in which bevacizumab was not commercially available for patients with cervical 
cancer, or did not have insurance coverage for bevacizumab) 
14. Patients must meet at least one of the following criteria regarding prior paclitaxel therapy: 
a. Received prior paclitaxel-containing therapy, which was discontinued due to 
progression of disease 
b. Received prior paclitaxel-containing therapy, which was discontinued due to toxicity 
c. Was deemed unsuitable for prior paclitaxel therapy for one of the following reasons: 
(i) neuropathy (ii) allergy to paclitaxel or its components 
d. Refused prior paclitaxel therapy 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required 
treatment with systemic immunosuppressive treatments, which may suggest higher risk for 
severe irAEs.  The following are not exclusionary:  vitiligo, childhood asthma that has 
resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, 
or psoriasis that does not require systemic treatment. 
2. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway. 
3. Prior treatment with other systemic immune-modulating agents that was (a) within fewer 
than 4 weeks (28 days) of the enrollment date, or (b) associated with irAEs 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 
or erythropoietin), or agents that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), 4-1BB 
(CD137), PI 3-K-delta, LAG3, or OX-40. 
4. Known history of brain metastasis(es) that may be considered active (screening imaging of 
brain is not required unless there is clinical suspicion of brain metastases).  Patients with 
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previously treated brain metastases may participate provided that the lesions are stable 
(without evidence of progression for at least 6 weeks on 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 ( cemiplimab or IC chemo).  
5. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
4 weeks prior to the first dose of study drug (cemiplimab or IC chemo).   
NOTE: Patients who require brief courses of steroids (eg, as prophylaxis for imaging 
studies due to hypersensitivity to contrast agents) are not excluded. 
6. Active bacterial, viral, fungal or mycobacterial infection requiring therapy, including known 
infection with human immunodeficiency virus (HIV), or active infection with hepatitis B 
virus (HBV) or hepatitis C virus (HCV). 
NOTE:  Active infection with HBV is defined as having positive surface antigen. 
7. History of pneumonitis within the last 5 years. 
NOTE:  Pneumonitis is inclusive of interstitial pneumonitis and active, non-infectious 
pneumonia, including interstitial lung disease. 
8. Any anticancer treatment (chemotherapy, targeted systemic therapy, photodynamic therapy), 
investigational, or standard of care, within 30 days of the initial administration of study drug 
(cemiplimab or IC chemo) or planned to occur during the study period (patients receiving 
bisphosphonates or denosumab are not excluded).   
NOTE:  Any radiation therapy must be discontinued at least 14 days prior to initial 
administration of study drug (cemiplimab or IC chemo). 
9. History of documented allergic reactions or acute hypersensitivity reaction attributed to 
antibody treatments. 
10. Criterion deleted in Amendment 3.   
11. Concurrent malignancy other than cervical cancer and/or history of malignancy other than 
cervical cancer within 3 years of date of first planned dose of study drug (cemiplimab or IC 
chemo), except for tumors with negligible risk of metastasis or death, such as adequately 
treated cutaneous squamous cell carcinoma or basal cell carcinoma of the skin or ductal 
carcinoma in situ of the breast.  Patients with hematologic malignancies (eg, chronic 
lymphocytic leukemia) are excluded. 
12. Any acute or chronic psychiatric problems that, in the opinion of the investigator, make the 
patient ineligible for participation. 
13. Patients with a history of solid organ transplant (patients with prior corneal transplant(s) may 
be allowed to enroll after discussion with and approval from the medical monitor). 
14. Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or 
clinical laboratory abnormality that, in the opinion of the investigator, renders the patient 
unsuitable for participation in a clinical trial due to high safety risks and/or potential to affect 
interpretation of results of the study. 
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15. Pregnant or breastfeeding women. 
16. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial study drug treatment, during the study, and for at least 
6 months after the last dose.  Highly effective contraceptive measures include 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; intrauterine device; intrauterine hormone-releasing system; bilateral tubal 
ligation; vasectomized partner; and or sexual abstinence†, ‡. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  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 
treatments.  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, and 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. 
17. Patients committed to an institution by virtue of an order issued by either the judicial or the 
administrative authorities will be excluded from this study. 
18. Prior treatment with idelalisib. 
19. Prior treatment with live vaccines within 30 days of initial administration of study drug 
(cemiplimab or IC chemo).  Patients must not be treated with live vaccines during the study 
and up to 5 half-lives following the last dose of study drug. 
20. Patients with prior treatment on any clinical trial within 30 days of the initial administration 
of study drug.  Non-interventional and observational trials are acceptable. 
21. Member of the clinical site study team and/or his or her immediate family. 
6.3. 
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/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 7.1.4.  Patients who discontinue study drug will, as feasible, 
remain in the study, to complete the follow-up procedures (Section 7.1.4).  When patients 
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withdraw from the study (eg, to pursue treatment options not allowed in the study), they should be 
encouraged to provide consent for OS follow-up.  Patients who specifically withdraw consent for 
follow-up should notify the investigator of this decision in writing whenever possible.  The 
withdrawal of consent should be explained in detail in the medical records by the investigator, and 
should include whether it is from further treatment only, or also from study procedures and follow-
up.  It should also be entered in the appropriate case report form (CRF) page.  If survival is being 
assessed, use of publicly available information should only be in accordance with local law. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.5. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
7. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
7.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 and Table 2.  
The allowable window for all visit days and assessments is ±3 business days (excluding weekends 
and holidays), unless otherwise stated in the protocol.  All other "days" in the protocol refer to 
calendar days.  For response assessments (CT or MRI), the window is ±7 days from planned scan 
dates (day 42 of cycles 1-4, 6, 8, 10, 12, 14, and 16).  
Missed doses of study drug or visits will not be made up.  In the case of missed doses, response 
assessments should still follow original schedule.  If a patient is unable to undergo scans within 
the window due to logistical or medical reasons, response assessment will be obtained at the next 
available date and before subsequent study treatment. 
7.1.1. 
COVID-19 Adaptation  
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 in response to 
COVID-19, 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 1: 
Schedule of Events:  Screening and Treatment Period 
 
 
Cycles 1 through 16 (cycle length = 6 weeks) 
Study Procedure 
Screening Visit X 
Day 
1 
Day 8 
Day 15 
Day 
22 
Day 29 
Day 42 
Screening1  
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
Informed consent2 
X 
 
 
 
 
 
 
Genomics sub-study informed 
consent (optional) 
X 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
Tumor tissue sample 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
Cemiplimab (experimental) 
 
X3 
 
 
X 
 
 
Pemetrexed 
 
X3 
 
 
X 
 
 
Topotecan 
 
Days 
1-53 
 
 
Days 
22-26 
 
 
Irinotecan 
 
X3 
X 
X 
X 
 
 
Gemcitabine 
 
X3 
X 
 
X 
X 
 
Vinorelbine 
 
X3 
X 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Efficacy (Radiologic): 
 
 
 
 
 
 
 
CT scan and/or MRI 
X 
 
 
 
 
 
X  
(cycles 1-4, 6, 8, 10, 12, 14, 
and 16) 
Safety: 
 
 
 
 
 
 
 
Vital signs4 
X 
X 
Only for 
gemcitabine, 
irinotecan, 
and 
vinorelbine 
Only for 
irinotecan 
X 
Only for gemcitabine 
and vinorelbine 
 
Weight and height (height at 
screening only)5 
X 
X6 
 
 
 
 
 
Complete physical examination7 
X 
 
 
 
 
 
 
Limited physical examination8 
 
X 
 
 
X 
 
 
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Cycles 1 through 16 (cycle length = 6 weeks) 
Study Procedure 
Screening Visit X 
Day 
1 
Day 8 
Day 15 
Day 
22 
Day 29 
Day 42 
Adverse events 
 
←          ←          ←         Continuous Monitoring for Adverse Events         →           →           
→ 
Laboratory Testing: 
 
 
 
 
 
 
 
 
Hematology 
X 
X6, 9 
Only for 
gemcitabine 
and 
vinorelbine 
Only for 
irinotecan 
X 
Only for gemcitabine 
and vinorelbine 
 
Blood chemistry 
X 
X6, 9 
 
Only for 
irinotecan 
X 
 
 
Prothrombin time, Activated partial 
thromboplastin time 
X 
 
 
 
 
 
 
TSH (with reflex T3, free T4) 
X 
 
 
 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
Pregnancy test for WOCBP10 
X 
X6 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
PK, ADA, Biomarkers 
PK, ADA, soluble biomarkers, and PBMC are collected from patients randomized to cemiplimab 
PK 
 
X11 
 
 
 
 
 
ADA sample 
 
X12 
 
 
 
 
 
Soluble biomarkers 
(serum/plasma)13 
 
X 
 
 
 
 
 
PBMC only for cemiplimab arm 
(optional)  
 
X14 
 
 
 
 
 
Genomic DNA sample (optional 
sub-study) 
 
X 
 
 
 
 
 
Quality of Life 
EORTC QLQ-C30 
X 
X6, 15 
 
 
 
 
 
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7.1.2. 
Footnotes for the Schedule of Events Table for Screening and Treatment 
1. Patients who fail screening may be screened one 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. 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.  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. 
3. The first dose should be administered no later than 5 days after randomization (except for 
patient assigned to pemetrexed, for whom the first dose of pemetrexed may be given no later 
than 10 days after randomization due to need for folate premedication for at least 5 days in 
the 7 day period preceding the first dose of pemetrexed, as per Section 8.1.2.1). 
4. Only for patients assigned to cemiplimab:  At cycle 1 day 1 and cycle 1 day 22, vital signs 
will be collected prior to infusion, and approximately 30 minutes after the completion of the 
infusion.  For all other cemiplimab infusions, vital signs are collected prior to infusion, and 
approximately 15 minutes after the completion of the infusion.  The allowable window for 
each specified time point is ±10 minutes. 
5. For the IC options, doses are weight-based.  For cycle 1/day 1, the investigator should use 
screening height and weight to calculate dose, but cycle 1/day 1 weight is also allowed to be 
used, per investigator discretion.  Weight is measured at start of each cycle.  If there is a 
≥10% change in weight, the IC chemotherapy dose should be re-calculated.   
6. If cycle 1/day 1 is within 72 hours of screening, this assessment does not need to be repeated 
at cycle 1/day 1. 
7. Complete physical examination includes head and neck, lungs, heart, abdomen, lymph nodes, 
extremities, and skin.  A brief neurologic examination should also be performed.  The exam 
(and measurement of weight) may be performed ≤72 hours prior to study treatment. 
8. Limited physical exam includes lungs, heart, abdomen, and skin.  The exam (and easement 
of weight) may be performed ≤72 hours prior to study treatment. 
9. Hematology and chemistry samples may be obtained ≤72 hours prior to study treatment. 
10. Pre-dose serum β-human chorionic gonadotropin (HCG) at screening up to 72 hours prior to 
first administration.  Subsequent predose pregnancy tests (up to 72 hours before the dose) 
may be urine β-HCG.  Serum pregnancy test and urine pregnancy test are requirements for 
women of child bearing potential only.  If surgical procedure for sterility was done ≤30 days 
prior to signing ICF, serum pregnancy test must still be performed.  
11. The PK samples are collected predose (pre-infusion) and at the end of infusion on day 1 of 
cycle 1.  PK samples are collected at pre-infusion and at the end of infusion on day 1 of 
cycles 2 through 6, 7, 9, 11, 13, and 15.  The PK samples are to be obtained only from patients 
randomized to receive cemiplimab.  “End of infusion” includes up to within 10 minutes after 
completion of the infusion. 
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12. The ADA samples for immunogenicity are collected pre-infusion on day 1 of cycle 1, 3, 7, 
11, and 15.  The ADA samples for immunogenicity are to be obtained only from patients 
randomized to receive cemiplimab. 
13. The biomarker samples are collected pre-infusion on day 1 of cycles 1 through 8. 
14. Peripheral blood mononuclear cell (PBMC) collection is optional.  If pre-treatment PBMC 
is not collected on day 1/cycle 1, PBMC should not be collected at future dates.  If PBMC 
are collected, this sample should be collected prior to treatment on day 1 of cycles 1 through 
3.  Samples are to be obtained only from patients randomized to receive cemiplimab. 
15. The EORTC QLQ-C30 assessment may be performed at any subsequent visit within the 
same treatment cycle if the assessment is not performed on day 1. 
7.1.3. 
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. 
7.1.4. 
Post-Treatment Follow-Up 
Table 2: 
Schedule of Events, Post-Treatment Follow-Up 
Study Procedure 
Follow-up Visits 1 
and 21 
Survival Follow-Up 
Assessments2 
Survival status 
 
X 
Limited physical exam3 
X 
 
Concomitant medications 
X 
 
Vital signs 
X 
 
Electrocardiogram 
X 
 
Adverse events 
X 
 
Laboratory Testing 
Hematology 
X 
 
Blood chemistry 
X 
 
Pregnancy test for WOCBP 
X 
 
TSH (with reflex T3, free T4) 
X 
 
ADA 
X4 
 
PK 
X4 
 
Soluble biomarkers (serum/plasma) 
X 
 
PBMC (optional) 
X6 
 
Quality of Life 
EORTC QLQ-C30 
X 
 
 Efficacy (Radiology) 
CT and/or MRI5 
X 
X 
7.1.5. 
Footnotes for the Schedule of Events Table for Post-Treatment Follow-up 
1. Post-treatment follow-up pertains to all patients (both treatment groups).  This pertains to 
patients who completed all 16 cycles of planned treatment, and to patients who discontinue 
treatment prior to the completion of 16 cycles.  Follow-up visit 1 occurs approximately 
30 days (±10 days) from last dose of cemiplimab or IC of chemotherapy.  Follow-up visit 
2 occurs approximately 90 days (±10 days) after follow-up visit 1. 
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2. After the end of study, survival follow-up assessments will occur every 90 days (±10 days) 
until death or study termination per sponsor and GOG.  It is preferable for survival follow-up 
assessments to occur in the clinic, but telephone assessments are acceptable.  Regeneron may 
request that survival data be collected on all randomized participants outside of the 90-day 
specified window.  At the time of this request, each participant will be contacted to determine 
their survival status unless the patient has withdrawn consent for all contact. 
3. Limited physical exam includes heart, lung, abdomen, and skin. 
4. During the follow-up period, after end of treatment of cemiplimab, PK and ADA samples 
are collected at follow-up 1 visit.  PK and ADA samples may be collected at follow-up 
visit 2 (approximately 4 months post last treatment of cemiplimab).  In response to adverse 
events of special interest (AESIs), such as anaphylaxis or hypersensitivity, ADA samples 
may be collected closer to the event, based on the judgment of the investigator and/or 
medical monitor.  
5. Radiologic imaging in the post-treatment follow-up period is only required for patients who 
have not experienced prior PD.  Tumor assessments should occur every 90 days (±10 days) 
until PD. 
6. PBMC samples are to be obtained only from patients randomized to receive cemiplimab and 
have signed optional PBMC consent. 
7.1.6. 
Option for Retreatment 
Patients who complete 16 cycles of treatment (Table 1) enter the follow up period (Table 2).  If 
they have not experienced PD during the study, radiologic assessments will continue until PD, as 
per Table 2.  If a patient experiences PD during the follow-up period, retreatment with the same 
drug that was given during the treatment period is an option.  A patient who was initially 
randomized to receive cemiplimab may be considered for resumption of cemiplimab.  A patient 
who was initially randomized to IC of chemotherapy may be considered for resumption of the 
same chemotherapy that they received in the treatment period.  Resumption of treatment due to 
PD during the follow-up period may be allowed if: 
• The patient received no other anticancer systemic therapy during the follow-up period. 
• The reason for discontinuation of study treatment was the completion of 16 planned 
cycles, not for toxicity. 
• The patient provides written informed consent prior to initiating retreatment by signing 
the current version of the ICF (eg, the patient repeats the written informed consent 
process that was performed prior to study enrollment). 
• All screening period assessments (with the exception of providing tumor pathology 
material) are repeated, and the patient meets all study eligibility criteria (with the 
exception of the exclusion regarding prior anti-PD-1 therapy if the patient was 
randomized to cemiplimab). 
Patients who resume study treatment will follow the schedule of events in Table 1, for up to 
8 cycles total with the same treatment to which they were originally randomized.  Cycles will be 
counted as 17 through 24.  However, PK, ADA, research blood samples, and PBMC samples are 
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not required for these patients during retreatment. In response to AESIs like anaphylaxis or 
hypersensitivity, ADA samples closer to the event may be collected and analyzed, based on the 
judgement of the medical investigator and/or medical monitor. 
There is no treatment crossover in this study.   
7.1.7. 
Note Regarding IDMC Interim Analysis 2 
The Independent Data Monitoring Committee (IDMC) convened on 8 March 2021 to evaluate the 
data from a planned formal interim analysis of OS.  The IDMC declared superiority of OS in 
subjects receiving cemiplimab as compared to IC chemotherapy.  As a result of the assessment, 
Protocol Amendment 7 is being implemented to provide a mechanism for eligible subjects 
randomized to chemotherapy to receive subsequent cemiplimab as part of the cemiplimab 
Extension Phase (Section 7.1.7.1). 
Patients randomized to IC chemotherapy may screen to receive cemiplimab in the cemiplimab 
Extension Phase up to and including 30 June 2021.  Patients previously on IC chemotherapy may 
receive up to 96 weeks on cemiplimab as per the Schedule of Events for the cemiplimab Extension 
Phase as per Table 3.   
All patients currently on cemiplimab may continue treatment up to 96 weeks.  All patients 
receiving cemiplimab will do so as per the Schedule of Events for the cemiplimab Extension Phase 
as per Table 3.   
Subjects currently receiving IC chemotherapy (pemetrexed, gemcitabine, topotecan, irinotecan, or 
vinorelbine) may continue to be treated with IC as long as, in the opinion of the investigator, they 
are continuing to derive benefit from the assigned treatment.  Patients who opt to continue 
receiving IC chemotherapy will do so as per routine clinical practice.   
As of Amendment 7, retreatment is no longer an option (Section 7.1.6).  As of Amendment 7, 
follow-up visits are no longer required (Section 7.1.4). 
7.1.7.1. 
Cemiplimab Extension Phase of the Study  
All patients currently on cemiplimab will transition to cemiplimab Extension Phase (Table 3) as 
of Amendment 7.  
This section also provides a mechanism for patients randomized to the IC chemotherapy arm to 
receive cemiplimab 350 mg Q3W.  
All patients randomized to IC chemotherapy are eligible for crossover to receive cemiplimab in 
the cemiplimab Extension Phase of the study, as long as eligibility criteria (Section 6.2) are met.  
Patients with squamous histology or adenocarcinoma/adenosquamous histology may be eligible 
for the cemiplimab Extension Phase.  The following criteria are not exclusionary for patients to 
enter the cemiplimab Extension Phase of the study:  
• Exclusion criteria #5: Steroids applied as supportive medications for IC chemotherapy 
will not be exclusionary. 
• Exclusion criteria #20: Patients currently enrolled in R2810-ONC-1676 are not excluded.  
Patients must complete screening assessments as set forth in Table 3, including signing the ICF.  
Patients will follow the Schedule of Events in Table 3.  Cycle length in the cemiplimab Extension 
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Phase is approximately 6 weeks, corresponding to two Q3W cemiplimab treatments (+/- 3-day 
treatment window).  The principle of “time marches on” applies in the Extension Phase: Treatment 
not administered in the treatment window will not be made up.  Treatment beyond progression is 
allowed in the cemiplimab Extension Phase if the conditions set forth in Section 8.6 are met. 
Table 3: 
Schedule of Events for Cemiplimab Extension Phase 
   
Screening 
Period for 
Extension 
Phase (28 days) 
1,2  
Extension  
Cycle 1/Day 
1 (EC1D1) 
Every 3 
weeks, ±3 
days  
(EC1D22 
through 
EC16D22)  
End of 
Extension 
Phase (up to 
96 weeks)3 
30 days 
±7 days after 
last dose of 
cemiplimab 
Survival 
Follow-Up4 
Inclusion//Exclusi
on 
X 
 
 
 
 
Informed 
Consent1 
X 
 
 
 
 
Serious Adverse 
Events 
X 
X 
X 
X 
 
Cemiplimab 
350 mg IV 
 
X 
X 
 
 
Complete 
Physical 
Examination 
X 
After the Screening Period, these assessments should be 
done as clinically appropriate. 
ECOG PS 
X 
Limited Physical 
Exam 
 
Vital Signs 
X 
Hematology 
X 
Blood Chemistry 
X 
Pregnancy Test 
for WOCBP 
X 
TSH (with 
reflex T3, free 
T4)  
X 
CT and/or MRI 
X 
Concomitant 
Medications 
X 
Concomitant 
Procedures 
X 
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Screening 
Period for 
Extension 
Phase (28 days) 
1,2  
Extension  
Cycle 1/Day 
1 (EC1D1) 
Every 3 
weeks, ±3 
days  
(EC1D22 
through 
EC16D22)  
End of 
Extension 
Phase (up to 
96 weeks)3 
30 days 
±7 days after 
last dose of 
cemiplimab 
Survival 
Follow-Up4 
CT=computed tomography; ECOG PS=Eastern Cooperative Oncology Group Performance Status;  
IV=intravenous; MRI=magnetic resonance imaging; TSH=thyroid stimulating hormone; 
WOCBP=women of childbearing potential 
7.1.7.2. 
Footnotes for the Schedule of Events Table 3 for the Cemiplimab Extension 
Phase 
1. Written informed re-consent for the cemiplimab Extension Phase must be provided prior 
to the initiation of screening procedures and must be obtained within 45 days prior to first 
dose of cemiplimab in the Extension Phase of the study.  All screening assessments must 
be performed within 28 days prior to first dose of cemiplimab in the Extension Phase.  
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 do not need to be 
repeated for eligibility. 
2. Patients who are currently receiving cemiplimab will transition to the cemiplimab 
Extension Phase.  Their Extension Phase treatment day should correspond to their current 
treatment day, such that they may receive up to 96 weeks of total cemiplimab therapy 
(inclusive of cemiplimab received prior to the cemiplimab Extension Phase).  These 
patients do not need to repeat screening procedures. 
3. Total duration of cemiplimab therapy is up to 96 weeks, or PD, or unacceptable toxicity. 
4. After the end of treatment, survival follow-up assessments will occur every 90 days 
(±10 days) until death or study termination per sponsor.  Telephone assessments are 
acceptable.  Regeneron may request that survival data be collected on all randomized 
participants outside of the 90-day specified window.  At the time of this request, each 
participant will be contacted to determine their survival status unless the patient has 
withdrawn consent for all contact. 
7.2. 
Study Procedures 
7.2.1. 
Procedures Performed at the Screening Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: 
• Serum β-HCG (result must be ≤72 hours before first dose) 
• HBV, HCV, and HIV screening: hepatitis B surface antigen, hepatitis C positive RNA 
(positive hepatitis C antibody test will require hepatitis C RNA test to rule out active 
infection), HIV-1, or HIV-2 serum antibody 
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• Documentation 
of 
pathologic 
confirmation 
of 
cervical 
cancer 
(SCC 
or 
adenocarcinoma/AC prior to Amendment 5; squamous cell histology only starting with 
Amendment 5) 
• Pathology material (formalin-fixed, paraffin-embedded [FFPE] block or 20 slides from 
the sample in the submitted pathology report).  This material will be used for correlative 
science studies (Section 7.2.7). 
• Patients who fail screening may be screened one 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. 
7.2.2. 
Efficacy Procedures 
For all patients, disease will be measured radiologically according to RECIST 1.1 criteria 
(Appendix 1; Eisenhauer 2009).  The CT or MRI for tumor assessment will be performed in 
screening, during treatment, and during follow-up, as detailed in Table 1 and Table 2.  During the 
treatment period, tumor response assessments are performed at end of cycles 1 through 4, 6, 8, 10, 
12, 14, and 16 (Table 1).  During follow-up, tumor response assessments are performed at follow-
up visits 1 and 2 (Table 2).  The choice of whether the imaging is by CT or MRI is an investigator 
decision.  Once the choice of CT scan or MRI has been made, subsequent assessments should be 
made using the same modality whenever possible. 
• Whole-body (chest/abdomen/pelvis) imaging is performed at the baseline assessment 
and is strongly recommended at each response assessment.  A CT or MRI of the neck 
should be performed in patients with metastases to neck.  At a minimum, all 
radiologically measurable target lesions (RECIST 1.1) should be imaged at each 
response assessment.  The same radiologic imaging modality should be used at each 
response assessment. 
• Brain imaging – MRI brain with gadolinium (or CT brain with contrast, if MRI is not 
feasible) will be performed in the screening period for patients with history of brain 
metastases, or for whom there is clinical suspicion of brain metastases.  Patients with 
brain metastases that are “not active” (see Section 6.2.2) who are enrolled on the study 
should have brain imaging at each response assessment, or sooner if there is clinical 
suspicion of worsening brain metastases during treatment. 
All radiological scans will be submitted to central depository and may be reviewed centrally. 
7.2.3. 
Survival Data Collection 
Every effort will be made to collect survival data on all patients, including patients who withdraw 
from the study for any reason but have not withdrawn consent to collect survival information.  If 
the death of a patient is not reported, the date of the last patient contact in this study will be used 
in the determination of the patient’s last known date of being alive. 
7.2.4. 
Quality of Life Questionnaires 
Patient-reported outcomes will be measured at a frequency indicated in Table 1 and Table 2 using 
the validated patient self-administered EORTC QLQ-C30 questionnaire.  Patients will be asked to 
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complete these questionnaires prior to any study procedures being performed at a given study visit 
(during the on-study/treatment and follow-up periods). 
7.2.5. 
Safety Procedures  
7.2.5.1. 
Vital Signs 
Vital signs, including temperature, resting blood pressure, pulse, and respiration, will be collected 
at time points according to Table 1 and Table 2. 
NOTE:  blood pressure should be measured after the patient has been resting quietly for at 
least 5 minutes. 
Only for patients assigned to cemiplimab:  At cycle 1 day 1 and cycle 1 day 22, vital signs will be 
collected prior to infusion, and approximately 30 minutes after the completion of the infusion.  For 
all other cemiplimab infusions, vital signs are collected prior to infusion, and approximately 
15 minutes after the completion of the infusion.  The allowable window for each specified time 
point is ±10 minutes. 
7.2.5.2. 
Physical Examination 
A thorough complete or limited physical examination will be performed at visits specified in 
Table 1 and 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, 
lymph nodes, extremities, and skin.  A brief neurologic examination also should be performed. 
Limited physical examination will include lungs, heart, abdomen, and skin. 
7.2.5.3. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) should be performed during the screening period. 
The patient should be relaxed and in a recumbent or semi-recumbent position at least 5 minutes 
before recording an ECG.  The ECG strips or reports will be retained with the source.  The ECG 
will be reviewed by the investigator (paper or electronic tracing) and will be available for 
comparison with subsequent ECGs by the investigator.  The following will be recorded on the 
CRF: 
• PR interval (msec) 
• QRS interval (msec) 
• QT interval (msec) 
• Heart rate (beats per minute; recorded from the ventricular rate) 
There is not a required time window for ECGs; they may be performed at any time on the study 
days according to Table 1 and Table 2 (±3 days). 
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7.2.5.4. 
Laboratory Testing 
Hematology, blood chemistry, urinalysis, and pregnancy testing samples will be collected at time 
points according to Table 1 and Table 2, and will be analyzed by the site’s local laboratory. 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
Blood Chemistry 
Sodium 
Total protein, serum 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN)* 
Alkaline phosphatase 
Carbon dioxide (bicarbonate)** 
Total bilirubin 
 
Calcium 
Albumin 
 
Glucose (fasting or non-fasting) 
 
 
* 
At ex-US centers at which a urea assay is performed instead of BUN, the urea assay will be acceptable. 
** At ex-US centers at which the bicarbonate assays is not performed as part of the routine chemistry panel, it 
may be omitted. 
Hematology 
Hemoglobin 
Differential: 
White bloods cells (WBCs) 
 
Neutrophils 
Platelet count 
 
Lymphocytes 
 
 
Monocytes 
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Urinalysis (Dipstick) 
Glucose 
pH 
Ketones 
Blood 
Specific gravity 
Spot urine protein 
Other Laboratory Tests  
• Prothrombin time, Activated partial thromboplastin time 
• HBV, HCV, HIV testing 
• Serum β-HCG 
• Thyroid-stimulating hormone (TSH) (+ reflex T3 and free T4).  Thyroid-stimulating 
hormone will be analyzed by the site’s local laboratory.  If TSH is abnormal, a T3 and 
free T4 should be measured at the investigative site’s local laboratory. 
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 monitor 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 AEs are provided in Section 9.4.5. 
7.2.5.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected prior to dosing at time points shown in Table 1 and 
during the follow-up period as shown in Table 2.  Any unused samples collected for ADA 
assessment may be used for exploratory research or to investigate unexpected AEs. 
7.2.5.6. 
Pharmacokinetic Samples 
Samples for PK assessment will be collected prior to dosing and at end of infusion (or within 
10 minutes of the end of infusion) at time points shown in Table 1 and during the follow-up period 
as shown in Table 2.  Any unused samples collected for PK assessment may be used for 
exploratory research or to investigate unexpected AEs. 
7.2.6. 
Quality of Life Procedures 
Quality of life questionnaires (EORTC QLQ-C30) will be collected according to the time points 
shown in Table 1 and Table 2. 
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7.2.7. 
Biomarker Procedures 
7.2.7.1. 
Tumor Samples 
On-treatment tumor biopsies for correlative science research purposes do not occur in this study.  
However, for all study patients, a pretreatment tumor sample (preferably a recent FFPE tissue 
block, or alternatively, 20 unstained FFPE slides) is required.  This should be provided in central 
lab in the screening period, but a patient’s enrollment would not be delayed if sample is not 
received in screening period.  An archived tumor sample may satisfy this requirement.  Tumor 
samples should be of sufficient size to ensure an adequate amount of tissue for analysis (excisional, 
incisional, or core needle; fine needle aspirates are not acceptable).  If sufficient archived material 
is not available, fresh biopsy (excisional, incisional, or core needle) should be performed in the 
screening period to obtain adequate tumor material (preferably an FFPE tissue block, or 
alternatively, 20 unstained FFPE slides) if the investigator deems the biopsy can be safely 
performed.  Invasive procedures that require general anesthesia should not be performed to satisfy 
the biopsy requirement.  However, if surgery is performed for a clinical indication, excess tumor 
material from the surgical procedure could be used to satisfy the required for pretreatment tumor 
material.  Complete instructions on the collection, processing, handling, and shipment of all 
samples will be provided in the laboratory manual. 
Candidate biomarkers will be analyzed in archived (pretreatment) tumor samples.  
Immunohistochemistry (IHC) will be performed to determine PD-L1 expression levels in archived 
tumor specimens.  This approach may provide a better understanding of the performance of PD-
L1 expression level as a predictive biomarker of response to cemiplimab.  Of special interest is 
PD-L1 expression across different cell types including tumor cells, stroma cells, and infiltrating 
immune cells.  After completion of PD-L1 expression analysis, the remaining tumor tissue may be 
used to study candidate biomarkers associated with clinical response to cemiplimab, including 
characterization of expression of other immune-related or cervical cancer-related genes (DNA, 
RNA and/or protein), tumor-infiltrating lymphocytes and other immune cell populations, HPV 
status and subtype, human leukocyte antigen variants and antigen processing components, tumor 
genetic mutation profile, and T cell receptor repertoire.  Methodologies that may be employed 
include, but are not limited to, IHC, RNA sequencing, RNAscope®, fluorescence in situ 
hybridization, and whole exome DNA sequencing. 
7.2.7.2. 
Serum/Plasma Samples 
Serum/plasma samples will be collected from all patients enrolled in this study at multiple time 
points to study the potential pharmacodynamics or predictive biomarkers of response to 
cemiplimab (refer to the laboratory manual). 
7.2.7.3. 
Peripheral Blood Mononuclear Cells (optional) 
Peripheral blood mononuclear cells 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. 
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7.2.8. 
Future Biomedical Research 
The biomarker samples unused 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 of cervical cancer and other diseases.  No additional 
samples will be collected for future biomedical research.  After 15 years, any residual samples will 
be destroyed. 
7.2.8.1. 
Genomics Sub-study - Optional 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF before collection of the samples.  Patients are not required to participate 
in the genomics sub-study in order to enroll in the primary study.  Samples for DNA extraction 
should be collected on cycle 1 day 1 (baseline/predose) but may be collected at any study visit.   
The DNA samples for the genomics sub-study will be double-coded as defined by the International 
Council for Harmonisation (ICH) guideline E15.  Sub-study samples will be stored for up to 
15 years after the final date of the database lock and may be used for research purposes.  The 
purpose of the genomic analyses is to identify genomic associations with clinical or biomarker 
response, other clinical outcome measures, and possible AEs.  In addition, associations between 
genomic variants and prognosis or progression of other 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 treatment or other 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, 
and DNA copy number, may also be performed.  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. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
The term “investigational product” (study drug) includes the experimental treatment cemiplimab 
(REGN2810) and the IC chemotherapy treatments.  In this protocol, the investigational products 
(study drugs) are: 
• Cemiplimab (experimental group) 
• Antifolate:  Pemetrexed (an IC option in the control group) 
• Topoisomerase inhibitor:  Topotecan or irinotecan (IC options in the control group) 
• Nucleoside analogue:  Gemcitabine (an IC option in the control group) 
• Vinca alkaloid:  Vinorelbine (an IC option in the control group) 
The only chemotherapy treatments allowed in the control arm are any of the 5 drugs that are listed 
as IC options.  Other agents in these classes are not permitted in this study.  Preference should be 
given to regimens that are allowed by local regulations. 
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Regeneron will provide cemiplimab.  Investigator’s choice chemotherapy (pemetrexed, topotecan, 
irinotecan, gemcitabine, and vinorelbine) should be procured by investigative sites as local 
commercial product, where allowed by local regulations.  In countries in which local regulations 
do not allow IC chemotherapy to be procured as local commercial product for the study, Regeneron 
may provide the chemotherapy to the study sites.  The sites will also procure any supplies needed 
for administration of investigational product, including IV bags, diluents, lines, and filters.  
Investigational product will be stored in a secure area according to local regulations. 
8.1.1. 
Experimental Group Treatment (Cemiplimab) 
Open-label cemiplimab will be supplied as a liquid in sterile, single-use vials.  Each vial will 
contain cemiplimab at a concentration of 50 mg/mL.  Instructions on dose preparation are provided 
in the pharmacy manual. 
Open-label cemiplimab will be administered in an outpatient setting as a 30-minute IV infusion.  
Each patient’s dose will be administered as a flat dose of 350 mg Q3W. 
A pharmacist or other qualified individual will be identified at each site to prepare cemiplimab for 
administration.  The prepared infusion bag should be kept no more than 6 hours at room 
temperature, or no more than 24 hours at 2°C to 8°C.  Detailed preparation and administration 
instructions will be provided to the sites in the pharmacy manual. 
8.1.2. 
Control Group Treatments (Investigator’s Choice) 
Patients assigned to the control arm will receive one of the Investigator’s Choice chemotherapy 
options, as follows: 
• Antifolate:  Pemetrexed, 500 mg/m2 IV every 21 days, for up to 96 weeks of treatment.  
Vitamin B12 and folate support will be provided according to standard of care with 
pemetrexed (Lorusso 2010) 
• Topoisomerase 1 inhibitor:  Topotecan, 1 mg/m2 daily IV for 5 days, every 21 days, for 
up to 96 weeks of treatment (Bookman 2000); or irinotecan 100 mg/m2 IV weekly x 4, 
followed by 10 to 14 days’ rest, for up to 96 weeks of treatment (Look 1998) 
(Takeuchi 1991).  For patients enrolling in Japan, there will be at least 14 days of rest 
before subsequent irinotecan administration 
NOTE:  For patients without significant toxicity during the first 21-day course of 
topotecan, subsequent courses may be increased to 1.25 mg/m2 x 5 days, every 21 days. 
NOTE:  For patients without significant toxicity during the first 42-day course of 
irinotecan, subsequent courses may be increased to 125 mg/m2 IV weekly x 4, followed 
by 2 weeks rest 
• Nucleoside analogue:  Gemcitabine, 1000 mg/m2 IV on days 1 and 8 and every 21 days, 
for up to 96 weeks of treatment (Mutch 2007) (Schilder 2005) 
• Vinca alkaloid:  Vinorelbine 30 mg/m2 IV on days 1 and 8 and every 21 days, for up to 
96 weeks of treatment (Muggia 2004) (Muggia 2005) 
The only chemotherapy treatments allowed in the control arm are any of the 5 drugs that are listed 
as IC options.  Other agents in these classes are not permitted in this study. 
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See Section 3.2.3 for rationale regarding doses and schedules for Investigator’s Choice options. 
For pemetrexed, topotecan, irinotecan, gemcitabine, and vinorelbine, instructions for storage, 
handling, and administration are to be found in the appropriate Summary of Product 
Characteristics or package insert or pharmacy reference sheets. 
For the IC options, doses are weight-based.  For cycle 1/day 1, the investigator should use 
screening height and weight to calculate dose, but cycle 1/day 1weight is also allowed to be used, 
per investigator discretion.  Weight is measured at start of each cycle.  If there is a ≥10% change 
in weight, the IC chemotherapy dose should be re-calculated. 
8.1.2.1. 
Pemetrexed, Alimta® 
Drug Class and Mechanism of Action 
Pemetrexed is a folate analogue that inhibits multiple enzymes involved in both purine and 
pyrimidine synthesis, including thymidylate synthase, dihydrofolate reductases, and glycinamide 
ribonucleotide formyl transferase.  Pemetrexed is not metabolized to an appreciable extent, and is 
primarily eliminated in the urine. 
Supplier/How Handled 
See pharmacy manual. 
Solution Preparation 
See pharmacy manual. 
Storage/Stability 
See pharmacy manual. 
Administration 
Pemetrexed will be administered at a dose of 500 mg/m2 as an IV infusion over 10 minutes 
(±5 minutes) on day 1 of each 21-day cycle (Lorusso 2010) for up to 96 weeks of treatment.  See 
Section 3.2.3 for rationale in support of IC chemotherapy regimens. 
To reduce toxicity, patients treated with pemetrexed must be instructed to take a low dose oral 
folic acid preparation or multivitamin with folic acid on a daily basis (usual dose, 400 μg/day; 
range, 350 μg/day to 1000 μg/day).  At least 5 daily doses of folic acid must be taken in the 7-day 
period preceding the first dose of pemetrexed.  Daily folic acid dosing should continue during the 
entire period of pemetrexed treatment and for 21 days after the last dose of pemetrexed.  Patients 
must also receive 1 intramuscular injection of 1000 μg vitamin B12 in the week preceding the first 
dose of pemetrexed, and with every third pemetrexed dose thereafter (every 9 weeks, if no delays 
in pemetrexed dosing).  Subsequent 1000 μg vitamin B12 injections may be given on the same day 
as pemetrexed infusions.  
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Adverse Effects 
See FDA/European Medicines Agency (EMA)-approved (or local equivalent) pemetrexed 
prescribing information for a comprehensive list of AEs associated with pemetrexed. 
8.1.2.2. 
Topotecan 
Drug Class and Mechanism of Action 
Topotecan is a cell cycle-specific inhibitor of the nuclear enzyme topoisomerase I.  It has a mean 
half-life of approximately 3 hours.  Topotecan’s metabolism and clearance are complex but it is 
estimated that approximately 40% of the drug undergoes renal clearance. 
Supplier/How Supplied 
See pharmacy manual. 
Solution Preparation 
See pharmacy manual. 
Storage/Stability 
See pharmacy manual. 
Administration 
Topotecan 1 mg/m2 will be administered by IV infusion over 30 minutes (±10 minutes) daily for 
5 consecutive days, starting on day 1 of a 21-day course (Bookman 2000) for up to 96 weeks of 
treatment.  See Section 3.2.3 for rationale in support of IC chemotherapy regimens.  For patients 
who do not experience significant toxicity with the first course of topotecan, subsequent courses 
may be increased to topotecan 1.25 mg/m2 daily x 5 days, every 21 days. 
Adverse effects 
See FDA/EMA-approved (or local equivalent) topotecan prescribing information for a 
comprehensive list of AEs associated with topotecan. 
8.1.2.3. 
Irinotecan 
Drug Class and Mechanism of Action 
Irinotecan is a derivative of camptothecin.  Camptothecins interact specifically with the enzyme 
topoisomerase 1, which relieves torsional strain in DNA by inducing reversible single-strand 
breaks.  Irinotecan and its active metabolite SN-38 bind to the topoisomerase 1-DNA complex and 
prevent relegation of these single strand breaks.  Cytotoxicity of irinotecan is thought be due to 
double-stranded damage during DNA synthesis when replication enzymes interaction with ternary 
complex formed by DNA/topoisomerase 1/irinotecan or SN-38.  Mammalian cells cannot efficient 
repair these double-strand breaks. 
Supplier/How Supplied 
See pharmacy manual. 
Stability/Storage 
See pharmacy manual. 
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Preparation 
See pharmacy manual. 
Administration 
Irinotecan 100 mg/m2 will be administered IV over approximately 90 minutes (±15 minutes) on 
days 1, 8, 15, and 22, followed by 10 to 14 days of rest, for a 42-day (6-week cycle), for up to 
96 weeks of treatment.  For patients enrolling in Japan, there will be at least 14 days of rest before 
subsequent irinotecan administration.  See Section 3.2.3 for rationale for dose and schedule of IC 
chemotherapy regimens.   
For patients who do not experience significant toxicity with the first course of irinotecan, 
subsequent courses may be increased to irinotecan 125 mg/m2 on days 1, 8, 15, and 22, followed 
by 10 to 14 days of rest.  For patients enrolling in Japan, there will be at least 14 days of rest before 
subsequent irinotecan administration.   
Adverse Effects 
See FDA/EMA-approved (or local equivalent) irinotecan prescribing information for a 
comprehensive list of AEs associated with irinotecan. 
8.1.2.4. 
Gemcitabine, Gemzar® 
Drug Class and Mechanism of Action 
Gemcitabine HCl is a nucleoside analog that exhibits anti-tumor activity.  Gemcitabine is a 
pyrimidine antimetabolite that is anabolized into a diphosphate form, which inhibits ribonucleotide 
reductase, and a triphosphate form, which is incorporated into DNA resulting in chain termination. 
Supplier/How Supplied 
See pharmacy manual. 
Stability/Storage 
See pharmacy manual. 
Preparation 
See pharmacy manual. 
Administration 
Gemcitabine 1000 mg/m2 will be administered IV over approximately 30 minutes (±10 minutes) 
on days 1 and 8 and every 21 days, for up to 96 weeks of treatment.  See Section 3.2.3 for rationale 
for dose and schedule of IC chemotherapy regimens. 
Adverse effects 
See FDA/EMA-approved (or local equivalent) gemcitabine prescribing information for a 
comprehensive list of AEs associated with gemcitabine. 
8.1.2.5. 
Vinorelbine 
Drug Class and Mechanism of Action 
Vinorelbine is a vinca alkaloid compound that interferes with microtubule assembly. 
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Supplier/How Supplied 
See pharmacy manual. 
Stability/Storage 
See pharmacy manual. 
Preparation 
See pharmacy manual. 
Administration 
Vinorelbine 30 mg/m2 will be administered IV over approximately 6 to 10 minutes (±5 minutes) 
on days 1 and 8, every 21 days, for up to 96 weeks of treatment.  See Section 3.2.3 for rationale 
for dose and schedule of IC chemotherapy regimens. 
Adverse Events 
See FDA/EMA-approved (or local equivalent) vinorelbine prescribing information for a 
comprehensive list of AEs associated with vinorelbine. 
8.2. 
Pretreatments 
No premedications are to be administered for the first dose of cemiplimab.  If needed, 
premedication will be allowed for subsequent doses of cemiplimab to manage any observed low-
grade infusion reactions. 
For the IC chemotherapy options, appropriate premedication for study treatments may be 
administered at the investigator’s discretion as per usual clinical practice and in accordance with 
institutional guidelines.  Premedications should be procured by the investigative sites where 
allowed by local regulations.  In countries in which local regulations do not allow premedications 
to be procured as local commercial product for the study, Regeneron may provide the 
premedications to the study sites. 
For patients who receive pemetrexed, premedications should include folate and vitamin B12, per 
manufacturer’s instructions.  At least 5 daily doses of folic acid (usual dose, 400 μg/day; range, 
350 μg/day to 1000 μg/day) must be taken in the 7-day period preceding the first dose of 
pemetrexed.  Patients must also receive 1 intramuscular injection of 1000 μg vitamin B12 in the 
week preceding the first dose of pemetrexed.  Skin rashes have been reported to be more severe in 
patients not pretreated with corticosteroid prior to pemetrexed.  Pretreatment with dexamethasone 
(or equivalent) reduces the incidence and severity of cutaneous reaction to pemetrexed.  
Dexamethasone 4 mg (or equivalent) should be given twice daily on the day before, the day of, 
and the day after pemetrexed infusion. 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules for 
Cemiplimab 
Adverse events are to be reported according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. 
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8.3.1. 
Dose Modification 
The general approach regarding missed doses of cemiplimab (eg, due to AEs) is “time marches 
on.”  Missed doses of systemic therapy will not be made up, unless ≤3 business days from the 
scheduled date. 
The planned dose and schedule is a 350 mg flat dose of cemiplimab IV over approximately 
30 minutes (±10 minutes) Q3W.  Patients will generally remain on the assigned dosage of 
cemiplimab throughout the course of study treatment.  The general approach to cemiplimab 
toxicity management is dose interruption rather than dose modification.  Cemiplimab treatment 
may be held at any time upon occurrence of a treatment-related AE.  General guidelines for 
cemiplimab treatment modifications due to treatment-related AEs and irAEs are provided in 
Table 4 and Table 5.  These recommendations should be seen as guidelines, and the treating 
physician should exercise clinical judgment based on the symptoms and condition of the individual 
patient.  For additional information regarding irAEs, reference Section 8.3.2 and Appendix 2.  
Acute infusion reactions to cemiplimab are discussed separately in Section 8.7. 
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Table 4: 
General Guidelines for Cemiplimab Treatment Modifications or 
Discontinuations Due to Adverse Events 
Toxicity 
Grade 
Hold 
Treatment? 
Restarting 
Criteria 
Discontinuation Criteria 
Hematological Toxicity (other 
than grade 3 thrombocytopenia 
greater than 7 days or associated 
with bleeding) 
1, 2, 3 
No 
N/A 
N/A 
 
4 
Yes 
Toxicity 
resolves to 
grade ≤1 or 
baseline 
Toxicity does not resolve 
within 84 days of last 
infusion 
Permanent discontinuation 
should be considered for 
any severe or life-
threatening event 
Grade 
3 
thrombocytopenia 
greater than 7 days or associated 
with bleeding 
3 
Yes 
Toxicity 
resolves to 
grade ≤1 or 
baseline 
Toxicity does not resolve 
within 84 days of last 
infusion 
Permanent discontinuation 
should be considered for 
any severe or life-
threatening event 
Nonhematological Toxicity 
1 
No 
N/A 
N/A 
NOTE: Exceptions to be treated as 
for Grade 1 toxicity: 
• 
Grade 2 alopecia 
• 
Grade 2 fatigue 
• 
Clinically insignificant 
lab abnormality not 
meeting AE criteria 
2 
Consider 
withholding for 
persistent 
symptoms 
Toxicity 
resolves to 
grade 0–1 or 
baseline 
Toxicity does not resolve 
within 84 days of last 
infusion 
 
3 
Yes 
Toxicity 
resolves to 
grade 0–1 or 
baseline 
Toxicity does not resolve 
within 84 days of last 
infusion 
 
4 
Yes 
N/A 
Patient must be 
discontinued 
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Table 5: 
General Treatment Hold Guidelines for Immune Related Adverse Events 
Severity Withhold/Discontinue Treatment? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold treatment 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3  
Grade 4 
Withhold treatment 
Discontinue if unable to reduce 
corticosteroid dose to <10 mg per 
day prednisone equivalent within 12 
weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 
to 2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
For any severe (grade 3-4) irAE, if symptoms 
worsen or do not improve on adequate 
corticosteroids within 48 to 72 hours, consider 
adding additional immunosuppressive agents (to be 
selected from agents such as infliximab, 
cyclophosphamide, cyclosporine, mycophenolate 
mofetil).  Referral of the patient to a specialized unit 
for assessment and treatment should be considered. 
In the limited circumstances in which cemiplimab dose modifications are called for in the toxicity 
management guidelines, the dose reductions will be as per Table 6.  The medical monitor should 
be notified of dose reductions. 
Table 6: 
Cemiplimab Dose Reductions 
Dose Level 
Reduction Order 
Dose 
Dose Level -1 
First dose reduction 
120 mg flat dose cemiplimab Q3W 
Dose Level -2 
Second dose reduction 
60 mg flat dose cemiplimab Q3W 
A patient who requires dose reduction below dose level -2 will be permanently discontinued from 
the study. 
8.3.2. 
Immune-Related Adverse Events (irAEs) 
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs, as the onset of symptoms of irAEs (eg, pneumonitis) may be subtle.  Detailed guidance of 
management of irAEs is provided in Appendix 2.  In the event of irAEs that are not addressed in 
Appendix 2, general guidance is provided in Table 5.  The recommendations in Table 5 and 
Appendix 2 should be seen as guidelines, and the treating physician should exercise clinical 
judgment based on the symptoms and condition of the individual patient. 
NOTE: Regarding irAEs, for any AE that is of a type known to be potentially immune-related 
(eg, rash, colitis, elevated transaminases, endocrine), but is deemed not to be an irAE by the 
investigator, the sponsor may request additional information. 
Based on the emerging safety profile of cemiplimab and other antibodies targeting the PD-1/PD-L1 
axis (Weber 2015) (Naidoo 2015), the following working case definitions are provided to help 
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investigators distinguish irAEs from non-immune AEs.  These case definitions pertain to the more 
commonly reported irAEs associated with PD-1 inhibition (Weber 2015) (Naidoo 2015), and is 
not exhaustive of all possible irAEs.  Clinical presentations of less common irAEs, including 
neurologic, musculoskeletal, cardiac, renal, and ocular events (Zimmer 2016) (Hofmann 2016), 
should be reviewed in patients with concerning presentations. 
The case definitions below have not been validated, and are intended only as guidance for 
investigators to help distinguish irAEs from non-immune AEs.  Investigators’ clinical judgment 
may include other factors when determining immune-relatedness.  The case definitions for irAEs 
may evolve as clinical experience increases with cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis. 
a. Immune-related rash:  Skin examination demonstrates a rash that is usually 
maculopapular, but other presentations may occur, including papulopustular, follicular, or 
urticarial dermatitis.  Consider dermatologic consultation and biopsy for atypical 
presentations.  Exclude other cause such as virally-induced rash or contact dermatitis. 
b. Immune-related diarrhea/colitis:  These events are on a continuum, with diarrhea defined 
as increased stool frequency, and colitis involves abdominal pain and/or radiologic evidence 
of colonic inflammation (Naidoo 2015).  Onset at 4 to 6 weeks is common (Weber 2015).  
A CT scan usually demonstrates diffuse colitis (Tirumani 2015).  Exclude Clostridium 
difficile or other infectious etiologies and exclude laxative misuse. 
c. Immune-related hepatitis:  Laboratory studies are notable for elevated ALT and/or AST 
that is usually asymptomatic.  Viral or other drug-induced hepatitis is excluded.  Exclude 
alcohol-related liver toxicity.  If clinically appropriate, consider radiologic imaging to 
exclude malignant causes.  If clinically appropriate, exclude worsening of underlying 
cirrhosis. 
d. Immune-related hypothyroidism:  Laboratory studies are notable for elevated TSH 
associated with low serum free thyroxine (free T4).  If elevated TSH is detected, it is 
recommended that free T4 level also be tested.  Elevated TSH with low free T4 establishes 
the diagnosis of hypothyroidism.  Hypothyroidism may be asymptomatic or associated with 
symptoms such as fatigue, constipation, cold intolerance, dry skin, weight gain, and/or 
bradycardia.  Exclude other causes of hypothyroidism, such as prior radiation therapy to the 
neck.  In patients with prior history of hypothyroidism, exclude noncompliance with thyroid 
replacement medication. 
e. Immune-related hyperthyroidism:  Hyperthyroidism should be managed with standard 
antithyroid pharmacotherapy, and consultation with an endocrinologist is recommended. 
f. Immune-related pneumonitis: Pneumonitis, defined as inflammation of the lung 
parenchyma, may present as shortness of breath, cough, fever, and/or chest pain.  Median 
time from start of anti-PD-1 therapy to onset of pneumonitis is 2.6 months (Nishino 2016), 
but delayed onset of pneumonitis has been reported.  The most common radiologic pattern 
on CT chest has been described as cryptogenic organizing pneumonia, but other 
radiographic patterns may occur (Nishino 2016).  If performed, biopsy may demonstrate 
lymphocyte-predominant interstitial pneumonitis with areas of organizing pneumonia 
(Nishino 2016).  Exclude infectious causes of pneumonitis. 
Adverse events that meet the criteria above should be entered using the appropriate terms 
(see Appendix 3 for terms corresponding to common potential irAEs), and attributing them as 
related to cemiplimab.  Such related events will be assumed to be irAEs in the database (unless 
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medical review of data raises questions regarding the attribution and are queried).  If AEs 
corresponding to the common terms are attributed as NOT related to (cemiplimab), additional 
information should be provided substantiating 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. 
8.3.3. 
Resumption of Cemiplimab After Treatment Hold, or Discontinuation 
Resumption of cemiplimab after resolution of adverse event to ≤grade 1 (or baseline) is allowed 
at the discretion of the investigator in accordance with the toxicity management guidelines in this 
protocol if resumption of treatment is thought to be in best interest of the patient.  Treatment after 
an AE may resume, at the discretion of the investigator, if the AE is felt to be manageable through 
supportive/medical therapy (eg, grade 3 hypertension that can be controlled with the addition of a 
second anti-hypertensive agent).  However, cemiplimab treatment resumption is not allowed in the 
following circumstances: 
• Patients with events that require cemiplimab to be permanently discontinued or held 
for more than 84 days from last scheduled dose 
• Patients with ≥grade 2 uveitis.  Patients with grade 2 uveitis will generally be 
discontinued from cemiplimab treatment, unless there is resolution to ≤grade 1 AND 
approval from the medical monitor at the sponsor prior to resumption of treatment. 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
should continue follow-up in the study without additional treatment until PD, completion of all 
study assessments, or closure of the study (Section 6.3).  After PD, all patients should be followed 
for survival. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules for 
Investigator’s Choice Chemotherapy 
Adverse events are to be reported according to the NCI-CTCAE version 4.03.  Dose adjustments 
at the start of a subsequent cycle should be based on nadir observed hematologic counts or 
maximum nonhematologic toxicity from the preceding cycle of therapy.  Treatment may be 
delayed to allow sufficient time for recovery.  Upon recovery, patients should be retreated using 
guidelines in the following subsections.  The general approach regarding missed doses of IC 
chemotherapy (eg, due to AEs) is "time marches on.”  Missed doses of IC chemotherapy will not 
be made up, unless ≤3 business days from the scheduled date. 
The following section provides toxicity management guidelines for selected AEs that are 
characteristic for the IC agents, pemetrexed, topotecan, irinotecan, gemcitabine, and 
vinorelbine.  For other chemotherapy-related AEs that are not specifically addressed in the 
following sections, the general approach for ≥ grade 3 chemotherapy treatment-related AEs is to 
hold chemotherapy until resolution of the event to ≤ grade 1 or baseline, and to reduce by one dose 
level on resumption of treatment. 
8.4.1. 
Pemetrexed Dose Modifications 
The dose reduction guidelines for hematologic toxicity are in Table 7. 
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Table 7: 
Dose Reductions for Pemetrexed:  Hematologic Toxicity 
Toxicity 
Dose Modification 
Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3 
75% of previous dose 
Nadir platelets <50,000/mm3 without bleeding regardless of 
nadir ANC 
75% of previous dose 
Nadir platelets <50,000/mm3 with bleeding regardless of nadir 
ANC 
50% of previous dose 
If patients develop nonhematologic toxicity ≥grade 3, treatment should be held until resolution to 
less than or equal to the patient’s pretherapy value.  Treatment should be resumed according to the 
guidelines in Table 8. 
Table 8: 
Dose Reductions for Pemetrexed:  Nonhematologic Toxicity 
Toxicity 
Dose Modification 
Any grade 3a or 4 toxicities except mucositis 
75% of previous dose 
Any diarrhea requiring hospitalization (regardless of grade) or 
grade 3 or 4 diarrhea 
75% of previous dose 
Grade 3 or 4 mucositis 
50% of previous dose 
a Excluding grade 3 transaminase elevation, for which no dose modification is required 
Pemetrexed therapy should be discontinued if patient experiences any hematologic or 
nonhematologic grade 3 or 4 toxicity (except transaminase elevations) after 2 dose reductions, and 
immediately for grade 3 or 4 neurologic toxicity at any time. 
Renally impaired patients:  In clinical studies, patients with creatinine clearance ≥45 mL/min 
required no dose adjustments other than those required for all patients.  Insufficient numbers of 
patients with creatinine clearance <45 mL/min have been treated to make dosage recommendations 
for this group.  Therefore, pemetrexed should not be administered to patients with creatinine 
clearance <45 mL/min using the standard Cockcroft and Gault formula.  Caution should be used 
in administering pemetrexed concurrently with nonsteroidal anti-inflammatory drugs to patients 
with creatinine clearance <80 mL/min. 
Cockcroft and Gault Formula: 
Creatinine Clearance, Males (mL/min) =  
[140 – Age in years] * [Actual Body Weight in kg]/ 
 
 
 
 
 
 
72 * [Serum Creatinine, mg/dL] 
Creatinine Clearance, Females (mL/min) = estimate creatinine clearance for males * 0.85 
8.4.2. 
Topotecan Dose Modifications 
The dose reduction guidelines for topotecan are in Table 9. 
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Table 9: 
Dose Reductions for Topotecan 
Toxicity 
Dose Modification 
ANC ≤1000/mm3 or 
Platelet count of ≤100,000/mm3 or  
Hemoglobin <9.0 g/dL or 
Serum creatinine >1.5 mg/dL 
Delay next cycle of topotecan until hematologic 
or renal recovery.  No dose reduction unless 
criteria below are met. 
ANC <500/mm3 in preceding cycle 
Permanently reduce topotecan dose to 0.75 mg/m2 
or administer prophylactic granulocyte colony-
stimulating factor during subsequent cycles 
Platelets <25,000/mm3 in preceding cycle 
Permanently reduce topotecan dose to 0.75 mg/m2 
Creatinine clearance 20 mL/min to 39 mL/min in 
preceding cycle 
Permanently reduce topotecan dose to 0.75 mg/m2 
Special safety considerations for topotecan: 
• Topotecan-induced neutropenia can lead to neutropenic colitis, which can be fatal.  In 
patients presenting with neutropenia, fever, and a compatible pattern of abdominal 
pain, consider the possibility of neutropenic colitis. 
• For patients for whom dose was increased to 1.25 mg/m2 after the first course and 
then experienced any toxicity requiring dose reduction, the recommended first dose 
reduction is to 1.0 mg/m2. 
• Topotecan can cause interstitial lung disease (ILD), which can be fatal.  Monitor 
patients for symptoms indicative of interstitial lung disease (cough, fever, dyspnea, 
or/or hypoxia), and discontinue topotecan if a new diagnosis of ILD is confirmed. 
8.4.3. 
Irinotecan Dose Modifications 
The starting dose for irinotecan is 100 mg/m2 weekly x 4, followed by 10 to 14 days of rest.  
Patients who experience toxicity at 100 mg/m2 will undergo a first dose reduction (dose level -1) 
to 75 mg/m2.  Patients who experience toxicity at 75 mg/m2 will undergo a second dose reduction 
to dose level -2) of 50 mg/m2.   
For patients who experience toxicity with 125 mg/m2 after an increase from the starting dose of 
100 mg/m2 (described in Section 8.1.2.3), the recommended first dose reduction is to 100 mg/m2. 
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, 
and the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea has fully 
resolved.  Treatment should be delayed for 1 to 2 weeks to allow for recovery of irinotecan-related 
toxicities.  If the patient has not recovered after a 2-week delay, consideration should be given to 
discontinuing irinotecan.  Dose modifications of irinotecan for specific toxicities are provided in 
Table 10. 
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Table 10: 
Recommended Dose Modifications for Irinotecan Monotherapya 
Worst Toxicity, NCI 
Gradeb 
During a Cycle of Therapy 
At Start of Next Cycle of Therapy 
(after adequate recovery), 
Compared with the Starting Dose 
of the Previous Cycle 
Neutropenia 
1 (1500 – 1999/mm3) 
2 (1000 – 1499/mm3) 
3 (500 – 999/mm3) 
4 (<500/mm3) 
 
Maintain dose level 
↓ 25 mg/m2 
Omit dose level until resolved to ≤ grade 2, then 
↓ 25 mg/m2 
Omit dose level until resolved to ≤ grade 2, then 
↓ 50 mg/m2 
 
Maintain dose level 
Maintain dose level 
↓ 25 mg/m2 
 
↓ 50 mg/m2 
Neutropenic Fever 
Omit dose level until resolved, then ↓ 50 mg/m2 
↓ 50 mg/m2 
Other Hematologic 
Toxicities 
Dose modifications for leucopenia, thrombocytopenia, and anemia during a cycle of 
therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity 
criteria and are the same as those recommended for neutropenia above  
Diarrhea 
1 (2 – 3 stools/day)c 
2 (4 – 6 stools/day)c 
3 (7 – 9 stools/day)c 
 
4 (≥10 stools/day)c 
 
Maintain dose level 
↓ 25 mg/m2 
Omit dose level unit resolved to ≤ grade 2, then 
↓ 25 mg/m2 
Omit dose level until resolved to ≤ grade 2, then 
↓ 50 mg/m2 
 
Maintain dose level 
Maintain dose level 
↓ 25 mg/m2 
 
↓ 50 mg/m2 
 
Other nonhematologic 
toxicitiesd 
1 
2 
3  
 
4 
 
 
Maintain dose level 
↓ 25 mg/m2 
Omit dose level until resolved to ≤ grade 2, then 
↓ 25 mg/m2 
Omit dose level until resolved to ≤ grade 2, then 
↓ 50 mg/m2 
 
 
Maintain dose level 
Maintain dose level 
↓ 25 mg/m2 
 
↓ 50 mg/m2 
a All dose modifications should be made based on the worst preceding toxicity. 
b National Cancer Institute Common Toxicity Criteria (version 4.0) 
c All numbers refer to increase over number of pre-treatment number of stools/day 
d Excludes anorexia, alopecia, fatigue, asthenia, and laboratory abnormalities that are not felt to be clinically 
significant 
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8.4.4. 
Gemcitabine Dose Modifications 
The dose reduction guidelines for myelosuppression on days 1 and 8 (of a 3-week treatment course 
of gemcitabine) are in Table 11. 
Table 11: 
Dose Modifications for Gemcitabine for Myelosuppression on Day of 
Treatment 
Treatment Day  
Absolute Neutrophil 
Count 
(X 106/L) 
 
Platelet Count 
(X 106/L) 
% of Full Dose 
Day 1 
≥1500 
<1500 
And 
Or 
≥100 000 
<100 000 
100% 
Hold 
Day 8 
≥1500 
1000-1499 
<1000 
And 
Or 
Or 
≥100 000 
75000-99999 
<75000 
100% 
50% 
Hold 
The dose reduction guidelines for myelosuppression (of a 3-week treatment course of gemcitabine) 
on in the preceding cycle are in Table 12. 
Table 12: 
Gemcitabine Dose Modifications for Myelosuppression in Preceding Cycle 
Occurrence  
Myelosuppression During Treatment Cycle 
Dose Modification 
Initial 
Occurrence 
ANC <500 x 106/L for more than 5 days 
ANC <100 x 106/L for more than 3 days 
Febrile Neutropenia 
Platelets <25000 x 106/L 
Cycle delay >1 week due to toxicity 
Permanently reduce gemcitabine 
to 800 mg/m2 on days 1 and 8 
Subsequent 
Occurrence 
If any of the above toxicities occurred after the 
initial dose reduction 
Permanently reduce gemcitabine 
to 800 mg/m2 on day 1 only  
Permanently discontinue gemcitabine for any of the following: 
• Unexplained dyspnea or other evidence of severe pulmonary toxicity 
• Severe hepatic toxicity 
• Hemolytic-Uremic Syndrome 
• Capillary Leak Syndrome 
• Posterior reversible encephalopathy syndrome 
Withhold gemcitabine or reduce dose by 50% for other severe (grade 3 or 4) nonhematologic 
toxicity until resolved.  No dose modifications are recommended for alopecia, nausea, or vomiting. 
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8.4.5. 
Vinorelbine Dose Modifications 
Hematologic Toxicity 
Hold or decrease the dose of vinorelbine in patients with decreased neutrophil counts using the 
schema in Table 13. 
Table 13: 
Vinorelbine Dose Modifications for Neutropenia 
Neutrophils on Day of Treatment 
(cells/mm3) 
Percentage of Starting Dose of Vinorelbine 
≥1500 
100% 
1000 - 1499 
50% 
<1000 
Do not administer vinorelbine.  Repeat neutrophil 
count in 1 week.  If 3 consecutive weekly doses are 
held because neutrophil count is <1000/mm3, 
discontinue vinorelbine 
NOTE:  For patients who experience fever and/or sepsis while neutrophil count is <1500 or had 
2 consecutive weekly doses held due to neutropenia, subsequent doses of vinorelbine should be: 
≥1500 
75% 
1000 - 1499 
37.5% 
<1000 
Do not administer vinorelbine.  Repeat neutrophil 
count in 1 week. 
Hepatic Impairment/Toxicity 
Reduce vinorelbine dose in patients with elevated serum total bilirubin concentration according to 
the schema in Table 14. 
Table 14: 
Vinorelbine Dose Modifications for Elevated Bilirubin 
Serum total bilirubin concentration (mg/ml) 
Percentage of starting dose of vinorelbine 
≤2.0 
100% 
2.1 to 3.0 
50% 
>3.0 
25% 
Concurrent Hematologic Toxicity with Hepatic Impairment 
In patients with both hematologic toxicity and hepatic impairment, administer the lower of the 
doses based on the corresponding starting dose of vinorelbine determined from the respective 
schemas in Table 13 and Table 14. 
Neurologic Toxicity 
Discontinue vinorelbine for NCI CTCAE grade 2 or higher peripheral neuropathy or autonomic 
neuropathy causing constipation. 
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8.5. 
Study Treatment Discontinuation Rules, General Guidance 
Guidelines for discontinuation of cemiplimab or IC chemotherapy due to AEs are provided in 
Sections 8.3 and 8.4, respectively.  This section provides general guidance on protocol 
requirements after discontinuation of either cemiplimab or IC chemotherapy. 
8.5.1. 
Study Drug Discontinuation  
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 7.1.4. 
Any patient currently receiving cemiplimab who was previously treated with a 
phosphatidylinositol 3-kinase (PI 3-K) inhibitor and who develops stomatitis or mucositis should 
temporarily suspend study treatment.  If this or any other immune-related AE occurs among these 
patients, the sponsor should be informed as soon as possible to discuss further management of the 
patient.  An irAE of any grade in a patient previously treated with a PI 3-K inhibitor should be 
reported as an AESI. 
8.5.1.1. 
Reasons for Permanent Discontinuation of Study Treatment 
Reasons for permanent discontinuation of study treatment may include, but are not limited to: 
• An infusion reaction of grade ≥3 severity during or directly following infusion 
• 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) 
• Evidence of pregnancy 
• Progression of disease 
• Unacceptable toxicity 
• Treatment delay of ≥84 consecutive days from last dose of cemiplimab or IC of 
chemotherapy due to toxicity 
8.6. 
Treatment Beyond Progression in the Cemiplimab Treatment Group  
For a small percentage of cancer patients treated with anti-PD-1 therapy, unconventional responses 
may occur in which radiologic evidence of progression on therapy occurs before subsequent 
radiologic response.  To account for this possibility in the cemiplimab treatment group, treatment 
beyond progression may be allowed after consultation with the medical monitor at Regeneron if 
the following conditions are met: 
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• The patient has stable performance status 
• The patient does not have rapid progression of disease 
• The patient has not experienced adverse events that would require permanent 
discontinuation of cemiplimab 
• The 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).  
• 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. 
8.7. 
Management of Acute Reactions 
8.7.1. 
Acute Infusion Reactions 
Acute infusion reactions are defined as any AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  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 9.4.1) and graded using the grading scales as instructed in Section 9.5.1. 
In the event of an infusion reaction of grade 3 or greater severity during or directly following 
cemiplimab infusion, dosing should be stopped and the patient must be permanently discontinued 
from cemiplimab treatment. 
To assist investigators in identifying cemiplimab-related infusion reactions, 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 2 hours after the 
infusion is completed 
• Vital signs may be notable for hypotension and/or tachycardia 
The investigator’s clinical judgment may include other factors when evaluating a possible 
cemiplimab-related infusion reaction.  For example, rarely, an infusion reaction may occur up to 
24 hours after initiation of the infusion. 
Case report forms must capture start and stop time of the event, signs and symptoms, and 
management interventions (medications, interruption of infusion, rate reduction). 
Patients who experience grade ≥3 acute infusion reactions to IC chemotherapy should discontinue 
treatment. 
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8.7.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• cough 
• rigors/chills 
• rash, pruritus (itching) 
• urticaria (hives, welts, wheals) 
• diaphoresis (sweating) 
• hypotension 
• dyspnea (shortness of breath) 
• vomiting 
• flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
For patients who experience infusion-related hypersensitivity reactions that are less than grade 3 
and who plan to continue treatment, premedication will be required 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 cemiplimab infusions. 
For grade 2 symptoms (moderate reaction that requires therapy or infusion interruption, but for 
which symptoms resolve promptly with appropriate treatment such as antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, corticosteroids, and/or IV fluids; prophylactic medications 
indicated ≤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 cemiplimab infusions.  If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
8.7.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• anaphylaxis 
• laryngeal/pharyngeal edema 
• severe bronchospasm 
• chest pain 
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• 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 
discontinuation of the infusion 
8.8. 
Method of Treatment Assignment 
Approximately 590 patients will be randomized in a 1:1 ratio to receive either cemiplimab or IC 
of chemotherapy, according to a central randomization scheme provided by an interactive voice 
response system (IVRS)/interactive web response system (IWRS) to the designated study 
pharmacist (or qualified designee).  Randomization will be stratified according to: 
1. Histology (squamous cell carcinoma versus adenocarcinoma). Adenosquamous histology 
be considered adenocarcinoma for purposes of stratification. 
2. Geographic Region:  North America versus Asia versus Rest of World (ROW) 
3. Prior bevacizumab (yes/no) 
4. ECOG performance status (0,1) 
The stratification factors of “prior bevacizumab use” and “ECOG performance status” are used for 
balancing treatment assignment only and will not be included in the statistical model for analysis 
of the primary endpoint. 
After it is confirmed that the patient meets all eligibility criteria, she will be enrolled in IVRS.  The 
following information must be provided at time of enrollment, prior to randomization: 
• Patient number 
• Date of birth 
• Histology (squamous cell carcinoma versus adenocarcinoma). Adenosquamous 
histology will be considered adenocarcinoma for purposes of stratification and 
analysis. Starting with Amendment 5, only squamous cell patients will be enrolled 
• Geographic region 
• Prior bevacizumab (yes/no) 
• ECOG performance status (0,1) 
• Choice of Investigator’s Choice treatment 
After a patient is enrolled in IWRS with this information, she will be randomized (1:1) to either 
cemiplimab or Investigator’s Choice of chemotherapy. 
8.8.1. 
Blinding 
Not applicable. 
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8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage  
Open-label study drug will display the product lot number on the label. 
Cemiplimab will be stored at the site at a temperature of 2oC to 8oC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments 
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 cemiplimab will be destroyed or returned to the 
sponsor or designee. 
8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened cemiplimab.  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. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures 
Any treatment administered, other than anti-cancer therapy, from the time of informed consent 
until 90 days after the last study treatment will be considered concomitant treatment.  This includes 
medications and other therapies for which administration started before 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.  All concomitant treatments must be recorded in the study CRF with the generic name, 
dose, dose unit, frequency, indication, and start/stop date, as appropriate. 
8.10.1. 
Prohibited Medications and Procedures 
While participating in this study, a patient may not receive any anti-cancer treatment other than 
the treatment assigned at randomization:  cemiplimab or IC of chemotherapy.  Patients must not 
receive live vaccines during the study and for up to 5 half-lives after the last dose of study drug.  
Any other medication which is considered necessary for the patient’s welfare, and which is not 
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expected to interfere with the evaluation of the assigned treatment (cemiplimab or IC of 
chemotherapy), may be given at the discretion of the investigator. 
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.  For 
patients on the cemiplimab arm, 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 emergency and/or to treat an irAE. 
NOTE:  Bisphosphonates and denosumab are not prohibited. 
8.10.2. 
Permitted Medications and Procedures 
Physiologic replacement doses of systemic corticosteroids are permitted, even if >10 mg/day 
prednisone equivalents.  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. 
NOTE:  Bisphosphonates and denosumab are not prohibited. 
Radiation therapy is not part of the study regimen in either the experimental group or the control 
group.  Patients for whom radiation therapy is planned are not eligible.  If, during the course of the 
study, a patient develops a symptomatic lesion for which palliative radiation therapy is deemed 
appropriate by the investigator, this will be deemed PD, and generally, the patient would be 
removed form study.  Palliative radiation therapy may be allowed in certain circumstances in 
patients who have been on study for at least 24 weeks.  Palliative radiation is only allowed to a 
non-target lesion in this study. 
If the investigator feels that palliative radiation therapy to a non-target lesion, followed by 
resumption of the assigned treatment (cemiplimab or IC of chemotherapy) after radiation is in the 
best interest of the patient, such cases must be discussed with and approved by the medical monitor 
prior to initiation of palliative radiation therapy.  The patient will be deemed to have experienced 
PD if radiation therapy is instituted, but will be followed for OS. 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction), to the health authorities, IRBs/ECs as appropriate, and to the investigators.  
Any AE not listed as an expected event in the Reference Safety Information section of the 
cemiplimab Investigator’s Brochure or in the reference safety document for the IC chemotherapy 
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(United States Package Insert for pemetrexed, gemcitabine, vinorelbine, irinotecan, and topotecan) 
will be considered as unexpected. 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRB/EC as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered, related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
Progression of underlying malignancy will not be considered an AE if it is clearly consistent with 
the typical progression pattern of the underlying cancer (including time course, affected organs, 
etc.).  Similarly, death due to progression of malignancy will be considered a study endpoint but 
not an AE. Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit the 
expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to progression of the underlying malignancy, 
it should be reported as an AE or SAE as outlined in Section 9.4. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
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• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Hospitalization or death due solely to manifestations consistent with typical progression of 
underlying malignancy will not be considered an SAE. 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3). 
9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after the 
infusion is completed.  All infusion reactions must be reported as AEs (see Section 9.4.1) and 
graded using the grading scale as instructed in Section 9.5.1. 
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will seek information on AEs at each patient contact, and record all 
AEs that occur from the time the informed consent is signed until 90 days after the last 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, pemetrexed, gemcitabine, vinorelbine, irinotecan, and 
topotecan. 
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Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
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. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female 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 9.4.2.  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 reaction 
• Grade ≥3 irAEs (see Section 8.3.2) 
• An irAE of any grade in a patient previously treated with a PI 3-K inhibitor 
NOTE (Applicable to cemiplimab only):  An irAE can occur shortly after the 
first dose or several months after the last dose of treatment.  All AEs of unknown 
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etiology associated with drug exposure should be evaluated to determine possible 
immune etiology.  If an irAE is suspected, efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling 
an AE as an irAE. 
9.4.3.1. 
Immune-Related Adverse Events 
Detailed guidance of management of irAEs is provided in Section 8.3.2 and Appendix 2. 
NOTE: Regarding irAEs, 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 irAE by the 
investigator, the sponsor may request additional information. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• 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 9.5.1. 
9.4.6. 
Follow-up 
Information for any non-SAE that starts during the treatment period or within 90 days after last 
treatment will be collected from the time of the event until resolution of the event, or until the 
patient’s last study visit, whichever comes first. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
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9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs (including test findings classified as AEs) will be graded using the current 
version of the NCI-CTCAE grading system.  Adverse events not listed in the NCI-CTCAE will be 
graded according to the following scale: 
1 (Mild): 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
2 (Moderate): Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*.  
3 (Severe): 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
4 (Life–threatening): Life-threatening consequences; urgent intervention indicated. 
5 (Death): 
Death related to AE 
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs or SAEs to study drug will be assessed by the investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE or SAE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs or SAEs to study drug is 
provided in Appendix 4. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs or SAEs to study conduct will be assessed by the investigator, and will be 
a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE or SAE may have been caused by study conduct? 
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The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs or SAEs to study conduct is 
provided in Appendix 4. 
The investigator should justify the causality assessment of each SAE. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
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. 
10.1. 
Statistical Hypothesis  
The primary analysis of OS will be performed for the following null (H0) and alternative 
hypotheses (H1): 
• H0:  The survival curve of OS for cemiplimab is the same as that for IC chemotherapy 
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• H1:  The survival curve of OS for cemiplimab is superior to that for IC chemotherapy. 
10.2. 
Justification of Sample Size 
The primary endpoint will be overall survival among patients treated with cemiplimab versus IC 
of chemotherapy.  After progression on platinum-taxane based chemotherapy, there is no standard 
of care.  The median OS has been reported in range of 6.5 months to 8.1 months in the 
phase 2 setting (Lorusso 2010) (Miller 2008) (Schilder 2005) (Bookman 2000). 
The primary OS endpoint will be tested in patients with SCC first.  If the null hypothesis is rejected 
in SCC patients, then OS will be tested in the overall population.  The sample size and power are 
calculated using East® version 6.4.1 statistical software.  
The sponsor assumes a median OS of 7 months for SCC patients treated with IC chemotherapy 
and a median OS of 10 months for SCC patients treated with cemiplimab.  The assumptions 
correspond to an approximately 42.8% increase in median OS and a hazard ratio (HR) of 0.7 if OS 
is distributed exponentially in both treatment groups.   
Two interim efficacy analyses are planned using Lan-DeMets (O’Brien-Fleming) spending 
function at 70% and 85% of the total OS events, respectively.  A total of 340 OS events in SCC 
patients will yield approximately 90% power to detect an HR of 0.7 with an overall type I error of 
0.025 (1-sided).  The details of alpha spending at interim and final analyses based on the planned 
number of OS events are provided in Section 10.5.  
Considering the enrollment rate (2 patients/month for months 1 to 5, 9 patients/month for 
months 6 to 16, 20 patients/month for months 17 to 23, and 22 patients/month for month 24 and 
beyond) and 10% dropout rate per year, enrollment of 460 randomized SCC patients will yield 
340 OS events for analysis of OS around 42 months after the first SCC patient is randomized.   
At the time when 460 SCC patients are enrolled in the study, a total enrollment in the study of 
approximately 590 patients is projected (SCC plus non-SCC). The actual number of patients to be 
enrolled will depend on the proportion of adenocarcinoma patients in the patient population and 
the time when Amendment 5 is implemented at each of the study sites.  If the HR is 0.7, the power 
for testing OS in the overall population will be higher than 90%. 
10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients.  This is the intention to treat 
population.  The FAS is based on the treatment allocated (as randomized).  All efficacy endpoints 
will be analyzed using the FAS. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug.  This 
population is based on the treatment received (as treated).  Treatment compliance/administration 
and all clinical safety variables will be analyzed using the SAF. 
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10.3.3. 
Other Analysis Sets 
The PK population includes all randomized patients (safety population) who received cemiplimab 
and who had at least 1 non-missing cemiplimab concentration following the first dose of 
cemiplimab up to the end of the study. 
The ADA analysis set includes all treated patients who received any study drug and had at least 
1 non-missing post-baseline ADA assay result following the first dose of study drug. 
The biomarker analysis set includes all treated patients who had at least 1 sample assayed. 
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, standard deviation, minimum, and 
maximum.  In addition, 25% percentile and 75% percentile may be provided if needed. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
The descriptive summary of time-to-event data will include median time to event and its 95% CI 
using the Kaplan-Meier method. 
10.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized subjects:  received a randomization number 
• The total number of patients in the FAS 
• The total number of patients in the SAF 
• The total number of patients who discontinued treatment and the reasons for treatment 
discontinuation 
• The total number of patients who discontinued the study and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment and study, along with 
reasons for discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and by all patients combined. 
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10.4.3. 
Medical History 
Medical history will be summarized by primary system organ class (SOC) and preferred term (PT) 
for each treatment group, with the table sorted by decreasing frequency of SOC, followed by PT 
based on the overall incidence between treatment groups. 
10.4.4. 
Prior Medications/Concomitant Medications 
Number and proportion of patients taking prior/concomitant medication will be summarized by 
decreasing frequency of anatomical therapeutic chemical (ATC) level 2 and ATC level 4 according 
to the current version of the World Health Organization Drug Dictionary, based on the overall 
incidence between treatment groups. 
Listings of pretreatment medication and concomitant medications include generic name, ATC 
levels 2 and 4, indication, study day onset, the study end date (defined similarly as for study onset 
day), ongoing status, dose, frequency, and route. 
For medications started before treatment, the study day onset is defined as date of medication start 
- date of the first dose; for medications started on or after treatment, the study day onset is defined 
as the date of medication start - date of the first dose + 1. 
10.4.5. 
Efficacy Analyses 
10.4.5.1. Primary Efficacy Analysis 
The primary analysis of OS will be implemented after the pre-specified numbers (Table 15) of 
OS events have been reported in patients with SCC. The analyses will include all survival 
information available at the time.      
The primary endpoint of OS will be analyzed in SCC patients first by stratified log-rank test using 
geographic region (North America versus Asia-Pacific versus ROW) as a stratification factor. 
The HR and its 95% CI will be estimated by a stratified Cox regression model using the treatment 
as covariate. 
If the analysis of OS is statistically significant in the SCC patients, then the analysis of OS will be 
performed in the overall population by stratified log-rank test using the following stratification 
factors: 
1. Histology: SCC versus adenocarcinoma. Adenosquamous histology will be considered 
adenocarcinoma for the purpose of stratification. 
2. Geographic Region: North America versus Asia Pacific versus ROW. 
The HR and its 95% CI will be estimated by a stratified Cox regression model using the treatment 
as covariate. 
10.4.5.2. Secondary Efficacy Analysis 
The multiplicity is controlled by a hierarchical testing procedure as follows:  The primary endpoint 
OS will be tested in SCC patients first.  If statistically significant, OS will be tested in the overall 
population.  If statistically significant, the secondary endpoints PFS and ORR will be tested.  The 
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order for hierarchical testing in secondary endpoints will be specified in the SAP before database 
lock (DBL).  
Analysis of PFS and ORR will be performed at the time of OS analysis.  The PFS will be analyzed 
using the same statistical method as the analysis of OS.  The ORR will be analyzed using the 
Cochran-Mantel-Haenszel test stratified by the same stratification factors used in analysis of OS.  
An associated odds ratio and 95% CI will be calculated.  Objective response rate and the 
corresponding 95% exact CI will be calculated by Clopper-Pearson method for each treatment 
arm. 
10.4.5.3. Quality of Life Analysis 
The change in EORTC QLQ-C30 scores from first assessment to the end of the study will be 
summarized descriptively at each post-baseline time point and compared using a mixed effect 
model, if appropriate. 
10.4.5.4. Exploratory Efficacy Endpoint Analysis 
Relationships between efficacy endpoints and candidate biomarkers will be described. 
10.4.5.5. Subgroup Analyses  
To determine the consistency of treatment effect across various demographic and baseline 
subgroups, the estimate of the between-group treatment effect (with a nominal 95% CI) for the 
primary and key secondary endpoints will be estimated and plotted within each category of the 
following subgroup variables: 
• Age category (≤65 years, >65 years) 
• Choice of IC chemotherapy:  (1) Antifolate - pemetrexed, (2) Topoisomerase 1 
inhibitor - topotecan or irinotecan, (3) Nucleoside analogue - gemcitabine, or (4) 
Vinca alkaloid - vinorelbine 
• Race (white, non-white) 
• ECOG status (0, 1) 
• Histology adenocarcinoma/adenosquamous 
• Geographic region (North America, Asia, ROW) 
• Geographic region (Japan, outside of Japan) 
• Prior bevacizumab use(Y/N) 
• Number of prior lines of systemic therapy for recurrent or metastatic disease (1 line or 
>1 line) 
10.4.6. 
Safety Analysis 
Safety will be assessed in the overall population.  Safety observations and measurements including 
drug exposure, AEs, laboratory data, vital signs, and ECOG performance status will be 
summarized and presented in tables and listings. 
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10.4.6.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment period is defined as the day from first dose of study drug to the day of 
the last dose of study drug plus 90 days, or to the day before the patient commences 
another anticancer systemic therapy, whichever comes first. 
• The post-treatment period is defined as the time starting one day after the treatment 
period ends.   
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period.  In 
addition, the study drug related AEs occurring anytime are considered as TEAEs.  
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the PT, and the primary SOC will be listed. 
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 (according to the grading scale outlined in Section 9.5.1), presented 
by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group.  Death due to disease 
progression will not be considered an AE, but will be reported in efficacy endpoints such as PFS 
and OS. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
10.4.6.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
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Number and percentage of patients with a potentially clinically significant value at any post 
randomization time point 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. 
Listings will be provided with flags indicating the out of range laboratory values. 
10.4.6.3. Treatment Exposure 
Treatment duration, dose intensity, and number of cycles administered will be summarized by 
treatment group. 
10.4.6.4. Treatment Compliance 
Treatment compliance, which is defined as (number of doses patients received X scheduled dose 
interval)/divided by total duration of study drug X 100%, will be summarized by treatment group. 
10.4.7. 
Analysis of Drug Concentration Data 
No formal statistical analysis will be performed.  Descriptive statistics are planned, with least 
square mean analysis for concentration at steady state.  See Section 4.3 for PK variables. 
10.4.8. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.3.2 will be summarized using descriptive statistics in 
the ADA analysis set of the experimental therapy (cemiplimab-treated) group.  Frequency tables 
of the proportion of patients with treatment-emergent, treatment-boosted, persistent ADA 
response, neutralizing antibody status in the neutralizing antibody assay, and titers will be 
presented as absolute occurrence (n) and percent of patients (%),in the experimental therapy 
(cemiplimab treated) group.  Listings of all ADA peak titer levels and neutralizing antibody status 
will be provided for patients positive in the ADA assay. 
Plots of drug concentrations will be examined and the influence of ADAs on individual 
concentration-time profiles may be evaluated.  Assessment of impact of ADA on safety and 
efficacy may be provided. 
10.4.9. 
Analysis of Biomarker Data 
Biomarker analyses in this study will be exploratory in nature and results will be summarized in a 
separate report.  Detailed description of statistical methods that will be used for biomarker data 
analyses will be provided in a separate biomarker statistical analytical plan. 
10.5. 
Interim Analysis 
Two interim efficacy analyses are planned using Lan-DeMets (O’Brien-Fleming) spending 
function at 70% and 85% of the total OS events in SCC patients, respectively.  The first interim 
efficacy analysis will be performed after observing approximately 238 OS events in SCC patients 
(70% of total OS events).  It is projected that an observed HR of 0.729 or lower would result in a 
statistically significant improvement in OS at the 1-sided nominal type I error of 0.0074 at the first 
interim efficacy analysis. The second interim efficacy analysis will be performed after observing 
approximately 289 OS events in SCC patients (85% of total OS events).  It is projected that an 
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observed HR of 0.769 or lower would result in a statistically significant improvement in OS at the 
1-sided nominal type I error of 0.0129 at the second interim efficacy analysis.  The final efficacy 
analysis will be performed after observing approximately 340 OS events in SCC patients.  It is 
projected that an observed HR of 0.801 or lower would result in a statistically significant 
improvement in OS at the 1-sided nominal type I error of 0.0202 at the final analysis. Table 15 
summarizes the alpha spending for interim and final analyses based on planned number of 
OS events.  The actual alpha spending will be based on the actual number of OS events included 
in the analyses and determined by the O’Brien-Fleming spending function at the time of interim 
and final analyses. 
Table 15: 
Alpha Spending in Group Sequential Design Using Lan-DeMets 
(O’Brien-Fleming) Spending Function 
1st Interim Efficacy Analysis 
2nd Interim Efficacy Analysis 
Final Efficacy Analysis 
# Events 
needed 
1-sided 
Nominal Alpha  
# Events 
needed 
1-sided 
Nominal Alpha  
# Events  
needed 
1-sided Nominal 
Alpha  
238 
(70%) 
0.0074 
289 
(85%) 
0.0129 
340 
(100%) 
0.0202 
In the event the primary endpoint is met during interim or final analysis, all pre-specified endpoints 
will be analyzed at that time at all remaining alpha. 
10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
• Unless otherwise specified, the last assessment before the initial administration of 
cemiplimab will be considered the baseline evaluation for safety measurements. And 
the last assessment before the randomization will be considered the baseline evaluation 
for efficacy measurements. 
General rules for handling missing data: 
• Unless otherwise specified, there will be no imputations for the missing data. 
• The pattern of missing data and potential prognostic factors for missing data (QOL, 
clinical neurologic assessment, and mental status) will be examined to guide the use of 
proper statistical models. 
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study drug except if an incomplete 
date (eg, month and year) clearly indicates that the event started prior to treatment.  If 
the partial date indicates the same month or year of the intake of study drug date, then 
the start date by the study drug intake date will be imputed; otherwise, the missing day 
or month by the first day or the first month will be imputed. 
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• Assessments taken outside of protocol allowable windows will be displayed according 
to the CRF assessment recorded by the investigator. 
Unscheduled assessments: 
• Extra assessments (laboratory data or vital signs associated with non-protocol-defined 
clinical visits or obtained in the course of investigating or managing AEs) will be 
included in listings, but not by visit summaries.  If more than 1 laboratory value is 
available for a given visit, the first observation will be used in summaries, and all 
observations will be presented in listings. 
10.7. 
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 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, and releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, and medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool.  User 
training must be documented before the user is granted access to the EDC system. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture 
• Statistical Analysis System – statistical review, analysis, and reporting 
• Pharmacovigilance safety database 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each site 
prior to enrollment of the first patient, and periodically during the study. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
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. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each patient 
enrolled in the study.  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. 
13. 
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 
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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. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
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.  The clinical study will be conducted in compliance with Pharmaceutical and 
Medical Device Act, Japanese GCP, and other relevant laws in Japan. 
14.2. 
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. 
• Patient who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patient who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, 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. 
14.3. 
Patient 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 their initials and a patient identification 
number, only, on CRFs or other documents submitted to the sponsor.  Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
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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. 
14.4. 
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 subjects 
(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 patients, 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. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment or formal notification from the sponsor in the event of 
recommendations from the IDMC. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
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. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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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. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRFs that will be provided to the sponsor. 
17.2. 
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 consult with the sponsor before discarding or 
destroying any essential study documents 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 and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
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19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, “An Open-Label, Randomized, Phase 3 Clinical Trial of 
REGN2810 Versus Investigator's Choice of Chemotherapy in Recurrent or Metastatic Cervical 
Carcinoma,” 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. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS: RECIST GUIDELINE (VERSION 1.1) 
For the purposes of this study, patients should be re-evaluated for response at day 42 (±7 days) in 
cycles 1 through 4, 6, 8, 10, 12, 14, and 16. Confirmatory scans should also be obtained 4 weeks 
following initial documentation of objective response. 
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. 
Selection of Lesions 
• Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm 
(≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At 
baseline and in follow-up, only the short axis will be measured and followed. 
• Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to 
<15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
• Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion, which 
can be measured reproducibly, should be selected.  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. If lymph nodes are to be included in the 
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sum, then only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
• Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions 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.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 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. 
• Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (eg, skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (eg, skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
• Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable.  
• Conventional CT and MRI.  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If 
CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situation. 
• PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions 
over time. Note, however, that the PET portion of the CT introduces additional data, 
which may bias an investigator if it is not routinely or serially performed. 
• Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
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the course of the study, confirmation by CT or MRI is advised. If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following CR or surgical resection is an endpoint. 
• Tumor markers.  Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
• Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and CR in rare cases (eg, residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease 
• 
18F-fluorodeoxyglucose positron emission tomography (FDG-PET).  While 
FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
NOTE: A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
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Response Criteria 
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 (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Evaluation of Non-Target Lesions 
• Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
NOTE: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
• Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target 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 “non-target” 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 Principal Investigator). 
Evaluation of Overall Response Criteria 
The best overall response is the best response recorded from the start of the treatment until 
PD/recurrence (taking as reference for PD the smallest measurements recorded since the treatment 
started). The patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. Revised Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 (Eisenhauer 2009) are summarized in the table:  
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Response According to Revised Response Evaluation Criteria in Solid Tumors 
(Version 1.1) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Requireda 
CR 
CR 
No 
CR 
>4 weeks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
SD 
Non-PD/not all evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
a.  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
(NE) at that time point.  If only a subset of lesion measurements are made at an assessment, usually 
the case is also considered NE at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) would not change the assigned time point 
response.  This would be most likely to happen in the case of progressive disease.  For example, if 
a patient had a baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 lesions 
were assessed, but those gave a sum of 80 mm, the patient will have achieved progressive disease 
status, regardless of the contribution of the missing lesion. 
Best Overall Response:  All Time Points 
The best overall response is determined once all the data for the patient is known.  Best response 
determination in trials where confirmation of complete or partial response IS NOT required:  Best 
response in these trials is defined as the best response across all time points (for example, a patient 
who has SD at first assessment, PR at second assessment, and progressive disease on last 
assessment has a best overall response of PR).  When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline.  If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments.  For example, a patient who has SD at first assessment, progressive 
disease at second and does not meet minimum duration for SD, will have a best response of 
progressive disease.  The same patient lost to follow-up after the first SD assessment would be 
considered inevaluable. 
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Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).  The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
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APPENDIX 2. RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC CEMIPLIMAB RELATED 
ADVERSE EVENTS 
Section 8.3 provides the dose level reductions. 
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Grade 1
Bowel obstruction 
Colitis
Colitis microscopic
No change in REGN2810 
dose
•
For diarrhea, treat symptomatically (loperamide, oral 
hydration, electrolyte substitution and ADA colitis 
diet).  Endoscopy is recommended if symptoms persist.
•
Grade 1 diarrhea that persist for >1 week should be 
treated with the addition of oral diphenoxylate 
hydrochloride and atropine sulfate four times daily and 
budesonide 9 mg daily
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
bacterial or parasitic 
infection, viral 
gastroenteritis, or the 
first manifestation of 
an inflammatory 
bowel disease by 
examination for stool 
leukocytes, stool 
cultures, and a 
Clostridium difficile 
titer
Grade 2
Enterocolitis 
hemorrhagic 
Gastrointestinal (GI) 
perforation
Necrotizing colitis
Diarrhea:
All patients who 
experience
diarrhea should be 
advised 
to drink liberal 
quantities of clear 
fluids.  
If sufficient oral 
fluid intake is
not feasible, 
fluid and 
Electrolytes
should be 
substituted via 
IV infusion.
Hold until ≤Grade 1.
•
GI consultation and endoscopy is recommended to 
confirm or rule out colitis for grade 2 diarrhea that 
persists >1 week or grade 1-2 diarrhea with rectal 
bleeding (additional guidelines for the treatment of 
persistent colitis are provided below). 
•
Grade 2 diarrhea should be treated with the addition of 
oral diphenoxylate hydrochloride and atropine sulfate 
four times daily and budesonide 9 mg daily.
•
Grade 2 diarrhea with diffuse ulceration and bleeding 
seen on endoscopy may require oral steroids with 
prolonged taper and represent an increased risk for the 
development of bowel perforation.
•
When symptoms improve to grade 1 or less, steroid 
taper should be started and continued over no less than 
4 weeks.
•
In patients with Grade 2 enterocolitis, REGN2810 
should be withheld and anti-diarrheal treatment should 
be started. If symptoms are persistent for more than 
one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent). 
When symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and continued 
over at least 1 month.
Diagnostic 
Considerations
COLITIS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
Colitis Adverse Event Management
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Grade 3-4
Withhold REGN2810
Discontinue if unable 
to reduce 
corticosteroid dose to 
<10 mg per day 
prednisone equivalent 
within 12 weeks of 
toxicity
•
Patients with Grade 3 enterocolitis, drug will be 
permanently discontinued and treatment with systemic 
corticosteroids should be initiated at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent. When symptoms 
improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month.
For Grade 3-4 diarrhea (or Grade 2 diarrhea that persists 
after initial steroid treatment),
•
Rule out bowel perforation. Imaging with plain films or 
computed tomography (CT) can be useful.
•
Consider consultation with gastroenterologist and 
confirmation biopsy with endoscopy.
•
Treat with intravenous (IV) steroids (methylprednisolone 
125 mg) followed by high-dose oral steroids (prednisone 
1-2 mg/kg once per day or dexamethasone 4 mg every 4 
hours). When symptoms improve to grade 1 or less, 
steroid taper should be started and continued over no 
less than 4 weeks. Taper over 6-8 weeks in patients with 
diffuse and severe ulceration and/or bleeding.
•
If IV steroids followed by high-dose oral steroids does not 
reduce initial symptoms within 48-72 hours, consider 
treatment with infliximab at 5 mg/kg once every 2 weeks.  
Discontinue infliximab upon symptom relief and initiate a 
prolonged steroid taper over 45-60 days. If symptoms 
worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg 
followed by a more prolonged taper and administer 
infliximab. CAUTION: infliximab is contraindicated in 
patients with bowel perforation or sepsis.
•
If symptoms persist despite the above treatment a 
surgical consult should be obtained.
Diagnostic 
Considerations
COLITIS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
bacterial or parasitic 
infection, viral 
gastroenteritis, or the 
first manifestation of 
an inflammatory 
bowel disease by 
examination for stool 
leukocytes, stool 
cultures, and a 
Clostridium difficile 
titer
If symptoms are 
persistent And/or 
severe, endoscopic 
evaluation should be 
considered
Colitis Adverse Event Management
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Grade 1-2
No change in REGN2810 
dose
Grade 3-4
Hold until on stable 
replacement dose as 
determined by 
resolution of 
symptoms and 
normalization of 
hormone levels.
• Consider endocrine consultation.
• Rule out infection and sepsis with appropriate 
cultures and imaging.
• Replacement of thyroid hormone or thyroid 
suppression therapy as indicated.
• Monitor thyroid function or other hormonal level 
tests and serum chemistries more frequently 
(every 3-6 weeks) until returned to baseline 
values.
• Replacement of thyroid hormone or thyroid 
suppression therapy as indicated.
All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection.  An 
endocrinology 
consultation is 
recommended
Hyperthyroidism
Hypothyroidism
Thyroid disorder
Thyroiditis
Diagnostic 
Considerations
ENDOCRINE 
EVENTS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
Hyperthyroidism
Hypothyroidism
Thyroid disorder
Thyroiditis
Endocrine Adverse Event Management
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Grade 1-4
Hold until on stable 
replacement dose 
• Thyroid hormone and/or steroid replacement 
therapy to manage adrenal insufficiency.
• If Grade 1–2 hypophysitis is considered, pituitary 
gland imaging should be considered (magnetic 
resonance imaging [MRIs] with gadolinium and 
selective cuts of the pituitary can show 
enlargement or heterogeneity and confirm the 
diagnosis).
• Grade 3–4 hypophysitis with clinically significant 
adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such 
as hyponatremia and hyperkalemia) constitutes 
adrenal crisis. Hospitalization and IV 
methylprednisolone should be initiated.
All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection.  An 
endocrinology 
consultation is 
recommended
Adrenal insufficiency
Hypophysitis
Hypopituitarism
Pan-hypopituitarism
Diagnostic 
Considerations
ENDOCRINE 
EVENTS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
Endocrine Adverse Event Management (Cont)
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Grade 1
Pneumonitis
Interstitial lung 
disease
Acute interstitial 
pneumonitis
Consider hold of 
therapy. REGN2810 
may be continued with 
close monitoring.
Grade 2
Pneumonitis
Interstitial lung 
disease
Acute interstitial 
pneumonitis
Hold REGN2810
To rule out other causes such as infection:
•
Consider pulmonary consultation with bronchoscopy and 
biopsy/bronchoalveolar lavage (BAL).
•
Consider pulmonary function tests.
•
Follow radiologic findings on serial imaging studies every 
1-3 days
If the patient is determined to have study drug associated 
pneumonitis:
•
Monitor symptoms daily; consider hospitalization.
•
Treat with systemic corticosteroids at a dose of 1–2 mg/kg/day 
prednisone or equivalent.  When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over 
no less than 4 weeks.  
•
Treatment with REGN2810 may be resumed if the event 
improves to ≤Grade 1 within 12 weeks and corticosteroids 
have been reduced to the equivalent of methylprednisolone 
10 mg by mouth daily or less.  Repeat chest imaging monthly 
as clinically indicated.
For Grade 2 pneumonitis that improves to ≤Grade 1 within 12 
weeks, the following rules should apply:
•
First episode of pneumonitis: May increase dosing interval by 
one week in subsequent cycles.
•
Second episode of pneumonitis: Discontinue REGN2810 if 
upon rechallenge the patient develops a second episode of 
≥Grade 2 pneumonitis.
• Radiologic findings should be followed on serial 
imaging studies at least every 3 weeks.
• Monitor for symptoms every 2–3 days.
• Consider pulmonary consultation and/or 
bronchoscopy if clinically indicated.
Diagnostic 
Considerations
PNEUMONITIS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
bacterial or viral 
infection.
Pneumonitis Adverse Event Management
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Grade 3-4
Pneumonitis
Interstitial lung 
disease
Acute interstitial 
pneumonitis
Discontinue REGN2810 
• Consider pulmonary function tests with 
pulmonary consult.
• Bronchoscopy with biopsy and/or BAL is 
recommended.
• Treat with IV steroids (methylprednisolone 125 
mg). When symptoms improve to grade 1 or less, 
a high-dose oral steroid (prednisone 1-2 mg/kg 
once per day or dexamethasone 4 mg every 4 
hours) taper should be started and continued over 
no less than 4 weeks.
• Add prophylactic antibiotics for opportunistic 
infections
• If IV steroids followed by high-dose oral steroids 
does not reduce initial symptoms within 48-72 
hours, treat with infliximab at 5 mg/kg once every 
2 weeks. Discontinue infliximab upon symptom 
relief and initiate a prolonged steroid taper over 
45-60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting 
at a higher dose of 80 or 100 mg followed by a 
more prolonged taper and administer infliximab.
Diagnostic 
Considerations
PNEUMONITIS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
bacterial or viral 
infection.
Pneumonitis Adverse Event Management (Cont)
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Grade 1
Nephritis
Nephritis 
autoimmune
Consider withholding 
REGN2810 if event 
does not improve with 
symptomatic 
treatment
• Provide symptomatic treatment.
• Monitor creatinine weekly; when it returns to 
baseline, resume routine creatinine monitoring 
per protocol.
Diagnostic 
Considerations
RENAL EVENTS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should 
be made to rule out 
other causes such as 
obstructive 
uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents.  A renal 
consultation is 
recommended.
Grade 2
Renal failure
Consider withholding 
REGN2810
• Systemic corticosteroids at a dose of 
1-2 mg/kg/day of prednisone or equivalent may 
be indicated.  When symptoms improve to Grade 
1 or less, corticosteroid taper should be started 
and continued over at least 1 month.
• Consider prophylactic antibiotics for opportunistic 
infections.
• Consider renal biopsy.
• If elevations persist >7 days or worsen, treat as 
Grade 4.
Grade 3-4
•Renal failure  acute
Discontinue REGN2810 
• Renal consultation with consideration of 
ultrasound and/or biopsy as appropriate.
• Monitor creatinine daily.
• Treat with systemic corticosteroids at a dose of 1–
2 mg/kg prednisone or equivalent once per day.  
• When symptoms improve to grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks.  
• Discontinue REGN2810 if unable to reduce 
corticosteroid dose for irAEs to ≤10 mg.
• REGN2810 treatment may be restarted and the 
dose modified as specified in the protocol.
Renal Adverse Event Management
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Grade 1 - 2 
No change in dose
Diagnostic 
Considerations 
Thrombocyto -
penia
CTCAE v4.03 Grade 
Cemiplimab Dosing 
Management
Action and Guidelines
Grade 3
See Table 4 
Grade 4 
See Table 4 
Hematologic Adverse Event Management
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Grade 1 - 3 
No change in dose
Diagnostic 
Considerations 
Neutropenia 
CTCAE v4.03 Grade
Cemiplimab Dosing 
Management
Action and Guidelines
Grade 4
Hold until resolves to 
Grade 1.  May 
increase the dosing 
interval by 1 week.
Discontinue if 
toxicities do not 
resolve within 
12 weeks. 
Hematologic Adverse Event Management (Cont.)
For neutropenia, see general guidelines on 
hematological toxicity in Table 4
For neutropenia, see general guidelines on 
hematological toxicity in Table 4 
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CONFIDENTIAL 
 
Dermatologic Adverse Event Management
Grade 1-2
Dermatitis 
exfoliative
Erythema 
multiforme
Stevens-Johnson 
syndrome
Toxic epidermal 
necrolysis
No change in dose
• Symptomatic treatment should be given such as 
topical glucocorticosteroids (eg, betamethasone 
0.1% cream or hydrocortisone 1%) or urea-
containing creams in combination with oral 
antipruritics (eg, diphenhydramine HCl or 
hydroxyzine HCl). 
• Treatment with oral steroids is at investigator 
discretion for Grade 2 events.
Diagnostic 
Considerations
SKIN EVENTS
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, or allergic 
dermatitis.
Grade 3
If considered to be
immune related,
≥Grade 3 or result in 
dose modification
or discontinuation:
Pruritus, Rash
Rash generalized
Rash maculo-papular
•
Vitiligo
hold REGN2810
• Consider dermatology consultation and biopsy for 
confirmation of diagnosis.
• Treatment with oral steroids is recommended, 
starting with 1 mg/kg prednisone or equivalent 
once per day or dexamethasone 4 mg four times 
orally daily.  When symptoms improve to Grade 1 
or less, steroid taper should be started and 
continued over no less than 4 weeks.
Grade 4
Permanently 
discontinue REGN2810 
• Dermatology consultation and consideration of 
biopsy and clinical dermatology photograph.
• Initiate steroids at 1-2 mg/kg prednisone or 
equivalent.  When symptoms improve to grade 1 
or less, steroid taper should be started and 
continued over no less than 4 weeks.
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CONFIDENTIAL 
 
Grade 1-2
Hepatitis 
Hepatitis, 
Autoimmune
Withhold REGN2810 if 
there is a treatment-
emergent concurrent 
elevation of ALT and 
bilirubin that 
corresponds to an 
upward shift of 2 or 
more grades in both 
parameters.
•
Monitor liver function tests more frequently until 
returned 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 3-4
Discontinue 
REGN2810 when AST 
or ALT >5.0 times ULN 
and/or total bilirubin 
>3.0 times ULN.
•
Consider appropriate consultation and liver biopsy to 
establish etiology of hepatic injury, if necessary.
•
Treat with high-dose IV glucocorticosteroids for 24–48 
hours.  When symptoms improve to grade 1 or less, a 
steroid taper with dexamethasone 4 mg every 4 hours 
or prednisone at 1–2 mg/kg should be started and 
continued over no less than 4 weeks. 
•
If serum transaminase levels do not decrease 48 hours 
after initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg every 12 hours may be 
given.  Infliximab is not recommended due to its 
potential for hepatotoxicity.
•
Several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is 
decreased
Diagnostic 
Considerations
Hepatitis
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
Hepatitis Adverse Event Management
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CONFIDENTIAL 
 
Ophthalmologic (Uveitis) Adverse Event Management
Grade 1
iritis, iridocyclitis
Discontinue REGN2810 
if symptoms persist 
despite treatment with 
topical 
immunosuppressive 
therapy 
• Evaluation by an ophthalmologist is strongly 
recommended.
• Treat with topical steroids such as 1% 
prednisolone acetate suspension and 
iridocyclitics.
Diagnostic 
Considerations
Uveitis
CTCAE v4.03 Grade
REGN2810 Dosing
Management
Action and Guidelines
All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, or other 
ocular disease 
(e.g., glaucoma or 
cataracts).
Grade 2
Discontinue REGN2810 
if symptoms persist 
despite treatment with 
topical 
immunosuppressive 
therapy and do not 
improve to Grade 1 
within the retreatment 
period OR requires 
systemic treatment.
• Evaluation by an ophthalmologist is strongly 
recommended.
• Treat with topical steroids such as 1% 
prednisolone acetate suspension and 
iridocyclitics.
Grade 3-4
Discontinue REGN2810
• Treat with systemic corticosteroids such as 
prednisone at a dose of 1-2 mg/kg per day.  When 
symptoms improve to ≤Grade 1, steroid taper 
should be started and continued over no less than 
4 weeks
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CONFIDENTIAL 
 
Grade 1
No change in dose
Diagnostic 
Considerations
Nausea and
Vomiting
CTCAE v4.0 Grade
REGN2810 Dosing
Management
Action and Guidelines
Grade 2
Hold until ≤Grade 1.  
Resume at same dose 
level.  May increase 
dosing interval by 1 
week if it takes more 
than 4 weeks for 
toxicities to resolve. 
• Nausea and vomiting should be treated 
aggressively, and consideration should be given in 
subsequent cycles to the administration of 
prophylactic antiemetic therapy according to 
standard institutional practice.  Patients should be 
strongly encouraged to maintain liberal oral fluid 
intake.
Grade 3
Hold until <Grade 2.  
May increase dosing 
interval by 1 week for 
each occurrence.
Discontinue if 
toxicities do not 
resolve within 
12 weeks.
Nausea and Vomiting Adverse Event Management
Grade 4
Off protocol therapy
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CONFIDENTIAL 
APPENDIX 3. MEDDRA DICTIONARY-DERIVED PREFERRED 
TERMS FOR POTENTIAL IRAES 
MedDRA v23.0 Preferred Terms (N=267) 
Addison’s disease 
Adrenal androgen deficiency 
Adrenal atrophy 
Adrenal insufficiency 
Adrenal suppression 
Adrenocortical insufficiency acute 
Glucocorticoid deficiency 
Hypoaldosteronism 
Mineralocorticoid deficiency 
Primary adrenal insufficiency 
Secondary adrenocortical insufficiency 
Antinuclear antibody increased 
Antinuclear antibody positive 
Arthralgia 
Arthritis 
Autoimmune arthritis 
Immune-mediated arthritis 
Polyarthritis 
Rheumatoid arthritis 
Autoimmune demyelinating disease 
Axonal neuropathy 
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Chronic inflammatory demyelinating polyradiculoneuropathy 
Demyelinating polyneuropathy 
Demyelination 
Autoimmune disorder 
Autoimmune eye disorder 
Blood alkaline phosphatase increased 
Blood creatine phosphokinase increased 
Blood thyroid stimulating hormone decreased 
Blood thyroid stimulating hormone increased 
Cardiac amyloidosis 
Central nervous system inflammation 
Chronic gastritis 
Cutaneous vasculitis 
Duodenitis 
Encephalitis 
Encephalomyelitis 
Encephalitis allergic 
Encephalitis autoimmune 
Immune-mediated encephalitis 
Noninfective encephalitis 
Noninfective encephalomyelitis 
Autoimmune encephalopathy 
Encephalopathy 
Immune-mediated endocrinopathy 
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CONFIDENTIAL 
Autoimmune endocrine disorder 
Episcleritis 
Gastrointestinal perforation 
Guillain-Barre syndrome 
Hepatic amyloidosis 
Basedow’s disease 
Hyperthyroidism 
Immune-mediated hyperthyroidism 
Marine Lenhart syndrome 
Primary hyperthyroidism 
Secondary hyperthyroidism 
Thyrotoxic crisis 
Thyrotoxic periodic paralysis 
Toxic goitre 
Toxic nodular goitre 
Hypoglossal nerve paralysis 
Hypophysitis 
Lymphocytic hypophysitis 
Hypopituitarism 
Autoimmune hypothyroidism 
Hypothyroidic goitre 
Hypothyroidism 
Immune-mediated hypothyroidism 
Myxoedema 
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CONFIDENTIAL 
Primary hypothyroidism 
Secondary hypothyroidism 
Tertiary hypothyroidism 
Immune-mediated adverse reaction 
Autoimmune anaemia 
Autoimmune aplastic anaemia 
Autoimmune haemolytic anaemia 
Acute haemorrhagic ulcerative colitis 
Allergic colitis 
Autoimmune colitis 
Autoimmune enteropathy 
Colitis 
Colitis erosive 
Colitis ischaemic 
Colitis microscopic 
Colitis ulcerative 
Crohn’s disease 
Diarrhoea 
Diarrhoea haemorrhagic 
Enterocolitis 
Enterocolitis haemorrhagic 
Eosinophilic colitis 
Immune-mediated enterocolitis 
Inflammatory bowel disease 
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CONFIDENTIAL 
Necrotising colitis 
Neutropenic colitis 
Acute hepatic failure 
Autoimmune cholangitis 
Autoimmune hepatitis 
Hepatic failure 
Hepatic function abnormal 
Hepatitis 
Hepatitis acute 
Hepatotoxicity 
Hyperbilirubinaemia 
Immune-mediated cholangitis 
Immune-mediated hepatic disorder 
Immune-mediated hepatitis 
Jaundice 
Liver injury 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Blood bilirubin increased 
Gamma-glutamyltransferase increased 
Hepatic enzyme increased 
Liver function test abnormal 
Transaminases increased 
Autoimmune hyperlipidaemia 
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CONFIDENTIAL 
Autoimmune inner ear disease 
Blood creatinine increased 
Glomerular filtration rate decreased 
Acute kidney injury 
Autoimmune nephritis 
Chronic autoimmune glomerulonephritis 
Immune-mediated nephritis 
Immune-mediated renal disorder 
Lupus nephritis 
Nephritis 
Nephritis haemorrhagic 
Perinephritis 
Renal failure 
Renal impairment 
Tubulointerstitial nephritis 
Tubulointerstitial nephritis and uveitis syndrome 
Autoimmune neutropenia 
Autoimmune pancytopenia 
Immune-mediated pancytopenia 
Acute interstitial pneumonitis 
Autoimmune lung disease 
Immune-mediated pneumonitis 
Interstitial lung disease 
Pneumonitis 
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CONFIDENTIAL 
Autoimmune retinopathy 
Rash pustular 
Perineal rash 
Acute generalised exanthematous pustulosis 
Autoimmune blistering disease 
Autoimmune dermatitis 
Dermatitis 
Dermatitis acneiform 
Dermatitis bullous 
Dermatitis exfoliative 
Dermatitis exfoliative generalised 
Dermatitis herpetiformis 
Drug eruption 
Drug reaction with eosinophilia and systemic symptoms 
Dyshidrotic eczema 
Erythema 
Erythema multiforme 
Erythema nodosum 
Exfoliative rash 
Immune-mediated dermatitis 
Lichen planus 
Oculomucocutaneous syndrome 
Palmoplantar keratoderma 
Parapsoriasis 
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CONFIDENTIAL 
Pemphigoid 
Pemphigus 
Psoriasis 
Rash 
Rash erythematous 
Rash generalised 
Rash macular 
Rash maculo-papular 
Rash maculovesicular 
Rash morbilliform 
Rash papular 
Rash pruritic 
Rash rubelliform 
Rash scarlatiniform 
Rash vesicular 
Skin reaction 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
Toxic skin eruption 
Autoimmune heparin-induced thrombocytopenia 
Heparin-induced thrombocytopenia 
Immune thrombocytopenia 
Immune thrombocytopenic purpura 
Insulin autoimmune syndrome 
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CONFIDENTIAL 
Iridocyclitis 
Iritis 
Keratitis 
Ulcerative keratitis 
Meningitis 
Meningitis aseptic 
Motor dysfunction 
Mucosal inflammation 
Muscular weakness 
Myalgia 
Ocular myasthenia 
Myasthenia gravis 
Myasthenia gravis crisis 
Myasthenic syndrome 
Myelitis 
Noninfectious myelitis 
Myelitis transverse 
Autoimmune myocarditis 
Immune-mediated myocarditis 
Myocarditis 
Blood creatine phosphokinase MB increased 
Troponin increased 
Autoimmune myositis 
Immune-mediated myositis 
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CONFIDENTIAL 
Myositis 
Polymyositis 
Dermatomyositis 
Autoimmune neuropathy 
Immune-mediated neuropathy 
Neuritis 
Neuropathy peripheral 
Peripheral sensory neuropathy 
Polyneuropathy 
Oral lichen planus 
Autoimmune pancreatitis 
Immune-mediated pancreatitis 
Pancreatitis 
Pancreatitis acute 
Paraneoplastic encephalomyelitis 
Autoimmune pericarditis 
Pericarditis 
Polymyalgia rheumatica 
Pruritus 
Pruritus allergic 
Pruritus generalised 
Pseudopolyposis 
Psoriatic arthropathy 
Idiopathic pulmonary fibrosis 
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Pulmonary fibrosis 
Raynaud’s phenomenon 
Sarcoidosis 
Pulmonary sarcoidosis 
Sjogren’s syndrome 
Epidermal necrosis 
Skin necrosis 
Stomatitis 
Systemic inflammatory response syndrome 
Thyroid dermatopathy 
Autoimmune thyroid disorder 
Thyroid disorder 
Autoimmune thyroiditis 
Immune-mediated thyroiditis 
Thyroiditis 
Thyroiditis acute 
Thyroiditis chronic 
Thyroiditis fibrous chronic 
Thyroiditis subacute 
Trigeminal nerve paresis 
Diabetes mellitus 
Diabetic ketoacidosis 
Latent autoimmune diabetes in adults 
Type 1 diabetes mellitus 
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Autoimmune uveitis 
Immune-mediated uveitis 
Uveitis 
Vasculitis 
Vitiligo 
Vocal cord paralysis 
 
 
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CONFIDENTIAL 
APPENDIX 4. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG, STUDY CONDUCT, INFUSION PROCEDURE, OR 
STUDY PROCEDURE 
Is there a reasonable possibility that the event may have been caused by the study drug, study 
conduct, infusion procedure, or study procedure? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug  
• do not reappear or worsen when dosing with study drug or study procedure resumed 
• are not a suspected response to the study drug or study procedure based upon 
preclinical data or prior clinical data 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the time of administration of the 
dose of study drug or study procedure 
• resolve or improve after discontinuation of study drug or study procedure 
• reappear or worsen when dosing with study drug or study procedure is resumed 
• are known or suspected to be a response to the study drug or study procedure based 
upon preclinical data or prior clinical data 
NOTE:  This list is not exhaustive. 
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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this document accurately describes the conduct of the study. 
Study Title: 
An Open-Label, Randomized, Phase 3 Clinical Trial of REGN2810 
versus Investigator's Choice of Chemotherapy in Recurrent or 
Metastatic Cervical Carcinoma 
Protocol Number: 
R2810-ONC-1676/GOG-3016 (CVP1601) ENGOT-cx9 
Protocol Version: 
R2810-ONC-1676/GOG-3016 (CVP1601) ENGOT cx9 
Amendment 7 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00146791 v1.0
Signature Page for VV-RIM-00146791 v1.0 Approved
ESig Approval
000
ESig Approval
21 14:14:43 GMT+0000
ESig Approval
r-2021 14:35:22 GMT+0000
ESig Approval
-2021 14:46:23 GMT+0000
ESig Approval
-2021 16:10:37 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION 3.0 
CONFIDENTIAL 
Page 1 of 37 
 
Title: 
AN OPEN-LABEL, RANDOMIZED, PHASE 3 CLINICAL TRIAL OF 
REGN2810 VERSUS INVESTIGATOR'S CHOICE OF CHEMOTHERAPY IN 
RECURRENT OR METASTATIC CERVICAL CARCINOMA 
Protocol: R2810-ONC-1676 
Investigational product:  REGN2810 (Cemiplimab, anti-PD-1 mAb) 
Sponsor:  Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Study Team Leader: 
 
Study Medical Directors:  
 
Version: 3.0    
Date:  Feburary 17, 2020 
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Protocol Number R2810-ONC-1676 
Statistical Analysis Plan  
 
CONFIDENTIAL 
Page 2 of 37 
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 
Study Biostatistician 
 (Author) 
 
See appended electronic signature page 
Study Medical Director 
 (Approver) 
 
See appended electronic signature page 
Head of BDM or designee 
 (Approver)  
 
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Protocol Number R2810-ONC-1676 
Statistical Analysis Plan  
 
CONFIDENTIAL 
Page 3 of 37 
TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITIONS ......................................................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.1.1. 
Background ...................................................................................................................8 
1.1.2. 
Rationale .......................................................................................................................9 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objective .........................................................................................................9 
1.2.1.1. 
Secondary Objectives....................................................................................................9 
1.2.2. 
Exploratory Objectives ...............................................................................................10 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ......................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design ...............................................................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................12 
3. 
ANALYSIS POPULATIONS .....................................................................................13 
3.1. 
Full Analysis Set (FAS) ..............................................................................................13 
3.2. 
Safety Analysis Set (SAF) ..........................................................................................13 
3.3. 
PK Analysis Set (PKS) ...............................................................................................13 
3.4. 
Anti-Drug Antibody Set (ADA) .................................................................................13 
3.5. 
Biomarker Analysis Set (BAS) ...................................................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
4.2. 
Medical History ..........................................................................................................14 
4.3. 
Pre-Treatment/Concomitant Medication ....................................................................15 
4.4. 
Efficacy Variable ........................................................................................................15 
4.4.1. 
Primary Efficacy Variable ..........................................................................................15 
4.4.2. 
Key Secondary Efficacy Variables .............................................................................15 
4.4.3. 
Other secondary efficacy variables .............................................................................16 
4.5. 
Safety Variables ..........................................................................................................16 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................16 
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4.5.2. 
Adverse Events of Special Interest (applicable to cemiplimab only): ........................17 
4.5.3. 
Laboratory Safety Variables .......................................................................................17 
4.5.4. 
Vital Signs ..................................................................................................................18 
4.5.5. 
12-Lead Electrocardiography (ECG) ..........................................................................18 
4.5.6. 
Physical Examination Variables .................................................................................19 
4.6. 
Pharmacokinetic Variables and Immunogenicity Variables .......................................19 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior/Concomitant Medications ..................................................................................22 
5.4. 
Subject Disposition .....................................................................................................22 
5.5. 
Protocol Deviations ....................................................................................................23 
5.6. 
Measurement of Compliance ......................................................................................23 
5.7. 
Exposure to Investigational Product ...........................................................................23 
5.8. 
Analyses of Efficacy Variables ...................................................................................24 
5.8.1. 
Analysis of Primary Efficacy Variable .......................................................................24 
5.8.2. 
Analysis of Key Secondary Efficacy Variables ..........................................................25 
5.8.3. 
Analysis of Patient-Reported Outcomes .....................................................................26 
5.8.4. 
Analysis of Other Secondary Variables ......................................................................27 
5.8.5. 
Subgroup Efficacy Analysis ........................................................................................27 
5.9. 
Analysis of Safety Data...............................................................................................27 
5.9.1. 
Adverse Events ...........................................................................................................28 
5.9.2. 
Clinical Laboratory Measurements and Vital Signs ...................................................30 
5.9.3. 
Analysis of Vital Signs ...............................................................................................30 
5.9.4. 
Analysis of 12-Lead ECG ...........................................................................................30 
5.9.5. 
Physical Exams ...........................................................................................................30 
5.10. 
Analysis of Pharmacokinetic and Antibody Data .......................................................31 
5.10.1. 
Analysis of Pharmacokinetic Data ..............................................................................31 
5.10.2. 
Analysis of Anti-Drug Antibody Data ........................................................................31 
5.10.3. 
Analysis of Exploratory Biomarker Data ....................................................................31 
6. 
DATA CONVENTIONS ............................................................................................31 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................31 
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Statistical Analysis Plan  
 
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6.2. 
Data Handling Convention for Efficacy Variables .....................................................32 
6.3. 
Data Handling Convention for Missing Data .............................................................32 
6.4. 
Unscheduled Assessments ..........................................................................................33 
7. 
MULTIPLICITY CONSIDERATIONS .....................................................................34 
7.1. 
Type I error control for interim and final analyses of OS in SCC patients 
using group sequential design .....................................................................................34 
7.2. 
Type I error control for OS, PFS, QoL and ORR  in SCC and overall 
population using hierarchical testing procedure .........................................................34 
8. 
INTERIM ANALYSIS ...............................................................................................35 
9. 
SOFTWARE ...............................................................................................................35 
REFERENCES ..............................................................................................................................36 
 
LIST OF TABLES 
Table 1: 
Alpha Spending in Group Sequential Design Using Lan-DeMets (O’Brien-
Fleming) Spending Function for OS in SCC Patients ................................................34 
 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
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ABBREVIATIONS AND DEFINITIONS 
ADA  
Anti-drug antibody 
ADL  
Activities of daily living 
AE  
 
Adverse event 
AESI  
Adverse event of special interest 
ALK  
Anaplastic lymphoma kinase 
ALT 
 
Alanine aminotransferase 
ALP 
 
Alkaline phosphatase 
AST 
 
Aspartate aminotransferase 
ATC  
Anatomical therapeutic chemical 
BAS 
 
Biomarker analysis set 
BOR  
Best overall response 
BUN  
Blood urea nitrogen 
CI  
 
Confidence interval 
CSR 
 
Clinical study report 
CR  
 
Complete response 
CRF 
 
Case report form  
DoR           Duration of response 
ECG  
Electrocardiogram 
ECOG  
East Cooperative Oncology Group 
EORTC     European Organization for Research and Treatment of Cancer 
EOS 
 
End of study 
FAS 
 
Full analysis set 
HR  
 
Hazard ratio 
IC              Investigator’s choice 
ICH 
 
International Conference on Harmonisation 
irAE 
 
Immune-related adverse event 
IWRS   
Interactive web response system 
LDH  
Lactate dehydrogenase 
MAA  
Marketing authorization application 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
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MedDRA Medical Dictionary for Regulatory Activities 
NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Events  
NE  
 
 
Not evaluable  
ORR  
 
Objective response rate 
OS  
 
 
Overall survival 
PD  
 
 
Progression Disease 
PD-1  
 
Programmed death-1 (receptor) 
PD-L1  
 
Programmed death ligand 1 
PFS 
 
 
Progression-free survival 
PK  
 
 
Pharmacokinetic 
PR  
 
 
Partial response 
PT  
 
 
Preferred term 
QLQ-C30        Quality of Life Questionnaire-Core30 
ROW  
 
Rest of world 
SAE 
 
 
Serious adverse event 
SAF 
 
 
Safety analysis set 
SAP 
 
 
Statistical analysis plan 
SAS 
 
 
Statistical Analysis Systems (software) 
SCC                Squamous cell carcinoma 
SD  
 
 
Stable disease 
SI  
 
 
Standard international 
SOC  
 
System organ class 
TEAE  
 
Treatment-emergent adverse event 
WHODD  
World Health Organization drug dictionary 
WBC  
 
White blood cell 
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Statistical Analysis Plan  
 
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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 the database 
lock. The SAP is intended to be a comprehensive and detailed description of strategy and 
statistical technique to be used to realize the analysis of data for R2810-ONC-1676 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 
For patients with locally advanced disease, curative intent therapy is definitive radiation with 
concurrent cisplatin. 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, most patients with recurrent or metastatic cervical cancer after failure of 
platinum-based chemotherapy die within one year, and none of the chemotherapy options in this 
setting have been widely accepted as standard of care (McLachlan 2016). Non-randomized phase 
2 trials have demonstrated survival times of 7.4 to 8.1 months (N = 29 and 43 patients, 
respectively) with single agent pemetrexed monotherapy (Lorusso 2010, Miller 2008). 
Gemcitabine monotherapy yielded median overall survival (OS) of 6.5 months in a phase 2 study 
of women (N = 22 patients) with previously treated cervical cancer (Schilder 2005). In a phase 2 
study (N = 45 patients) of topotecan in which most patients had received prior platinum, median 
OS was 6.6 months (Bookman 2000). In phase 2 studies of vinorelbine for patients who could 
have received 1 prior chemotherapy regimen for squamous or non-squamous advanced cervical 
cancer, observed response rates were 13% (6/44 patients) and 7% (2/28 patients), respectively 
(Muggia 2004, Muggia 2005).  Weekly dosing of irinotecan yielded a response rate of 13% 
(6/45 patients) in a phase 2 study for women with recurrent squamous cervical cancer in the US 
(Look 1998), and response rate of 24% (13/55 patients) in a phase 2 study for women with 
cervical cancer in Japan (Takeuchi 1991).  New systemic therapy options are needed for this 
patient population. 
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1.1.2. 
Rationale 
This is an open-label, randomized, phase 3 trial of cemiplimab versus Investigator’s choice (IC) 
chemotherapy in patients with recurrent or metastatic cervical cancer that has progressed after 
platinum-containing chemotherapy. Investigator’s choice chemotherapy in this study are in 4 
classes: (1) antifolate - pemetrexed, (2) topoisomerase 1 inhibitor – topotecan or irinotecan, (3) 
nucleoside analogue – gemcitabine, and (4) vinca alkaloid - vinorelbine. Despite the availability 
of various chemotherapy options, most patients with platinum-refractory cervical cancer have a 
median survival time of approximately 7 months. After progression on platinum-taxane based 
chemotherapy, there is no widely accepted standard of care for subsequent systemic therapy.   
There is no standard of care for patients who progress after platinum in the recurrent, persistent, 
or metastatic setting. These patients have an unmet medical need and are appropriate for 
consideration of the clinical study.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to compare overall survival (OS) for the patient population 
with recurrent or metastatic cervical cancer who have histology of squamous cell carcinoma 
(SCC) and then the overall population who have any eligible histology (SCC or 
adenocarcinoma/adenosquamous carcinoma [AC]), between those treated with either cemiplimab 
or IC chemotherapy. 
1.2.1.1. 
Secondary Objectives 
The secondary objectives of the study performed among SCC patients and among all eligible 
histologies (SCC and adenocarcinoma/adenosquamous carcinoma) are: 
• To compare progression-free survival (PFS) of cemiplimab versus IC chemotherapy 
• To compare overall response rate (ORR) (partial response [PR] + CR) of cemiplimab 
versus IC chemotherapy per Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1  
• To compare the duration of response (DOR) of cemiplimab versus IC chemotherapy 
• To compare the safety profiles of cemiplimab versus IC chemotherapy by describing 
adverse events (AE) 
• To compare quality of life for patients treated with cemiplimab versus IC 
chemotherapy using European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), ), as measured by mean 
change from baseline in the global health status/quality of life and physical 
functioning scales.  
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1.2.2. 
Exploratory Objectives  
• To measure concentrations of cemiplimab in serum and characterize the 
pharmacokinetics (PK) of cemiplimab 
• To characterize the immunogenicity of cemiplimab 
• To explore associations between the clinical efficacy of cemiplimab and molecular 
features in pretreatment tumor samples 
• To explore the pharmacodynamic activity of cemiplimab on the immune system in 
peripheral blood samples 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
This study is a pivotal trial with intent to support registration of cemiplimab monotherapy for 
patients with recurrent or metastatic cervical cancer. Accordingly, revision to this plan will only 
be made if deemed necessary to the furtherance of the trial objectives. Such revision, if 
necessary, will be completed prior to the final database lock.  
1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
SAP vesion 
Changes 
SAP v3.0 
This SAP was updated to include additional PRO endpoints: 
1. Section 5.8.3,  the adjusted mean estimates at cycle 2 was added. 
2. Section 7.2, the PRO endpoints will be tested in SCC and then in overall 
population in the hierarchy.  
SAP v2.0 
This SAP was updated according to R2810-ONC-1676 all Protocol 
Amendements, up to Amendement 6. 
The major changes include: 
1. Section 2.2, updated sample size with interim analysis, targeted 
population and enrollement rate. 
2. Section 5.8.1, the primary efficacy analysis will be performed with a 
hierarchical order of SCC patients, then overall population. 
3. Sections 7 and 8, added multiplicity control to reflect interim analyses 
using Lan-DeMets O’Brien-Fleming alpha spending function, and 
hierarchical order in testing the primary endpoints and secondary 
endpoints.  
SAP v0.2 
This is the original version of SAP 
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Statistical Analysis Plan  
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
This is an open-label, randomized, multi-center, phase 3 trial comparing cemiplimab versus IC 
chemotherapy in patients with recurrent or metastaticcervical cancer. Patients will be randomized 
to either the experimental cemiplimab treatment arm or the IC of chemotherapy control treatment 
arm. In the experimental group, cemiplimab will be administered as a flat dose of 350 mg Q3W. 
In the control group, IC chemotherapy options are in 4 classes: (1) antifolate - pemetrexed, (2) 
topoisomerase 1 inhibitor – topotecan or irinotecan, (3) nucleoside analogue – gemcitabine, and 
(4) vinca alkaloid - vinorelbine.   
The study includes 3 periods:  screening, treatment, and follow-up.  The screening period begins 
with the signing of the informed consent form (ICF).  The screening period ends when the patient 
has been confirmed as fully eligible for the study and is randomized, or with confirmation that 
the patient is ineligible and is a screen failure.  The treatment period begins within 5-10 days of 
randomization to 1 of the treatment arms.  Cycle length is 6 weeks, and tumor imaging is planned 
on day 42 (±7 days) of cycles 1-4, 6, 8, 10, 12, 14, and 16.  Planned treatment is for up to 
96 weeks.  The treatment phase ends when the patient discontinues study therapy.  There is no 
cross-over during this study.  After completion of the treatment period, patients enter the 
follow-up period. After the follow up period, patients will be followed for survival.  Study 
closeout procedures will be implemented after the 340th  OS event has been reported in SCC 
patients. 
2.2. 
Sample Size and Power Considerations   
The primary endpoint will be overall survival among all patients treated with cemiplimab versus 
IC chemotherapy.  For IC chemotherapy, the median OS has been reported in range of 
6.5 months to 8.1 months in the phase 2 setting (Lorusso 2010, Miller 2008, Schilder 2005, 
Bookman 2000). 
The primary OS endpoint will be tested in patients with SCC first.  If the null hypothesis is 
rejected in SCC patients, then OS will be tested in the overall population.  The sample size and 
power are calculated using East® version 6.4.1 statistical software. 
Assumes a median OS of 7 months for SCC patients treated with IC chemotherapy and a median 
OS of 10 months for SCC patients treated with cemiplimab. The assumptions correspond to an 
approximately 42.8% increase in median OS and a hazard ratio (HR) of 0.7 if OS is distributed 
exponentially in both treatment groups.  
Two interim efficacy analyses are planned using the Lan-DeMets (O’Brien-Fleming) spending 
function at 70% and 85% of the total OS events, repectively. A total of 340 OS events on SCC 
patients will yield approximately 90% power to detect an HR of 0.7 with an overall type I error 
of 0.025 (1-sided). 
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Considering the enrollment rate (2 patients/month for months 1 to 5, 9 patients/month for 
months 6 to 16, 20 patients/month for months 17 to 23, and 22 patients/month for month 24 and 
beyond) and 10% dropout rate per year, enrollment of 460 randomized SCC patients will yield 
340 OS events for analysis of OS around 42 months after the first SCC patient is randomized.   
At the time when 460 SCC patients are enrolled in the study, a total enrollment in the study of 
approximately 590 patients is projected (SCC plus non-SCC). The actual number of patients to 
be enrolled will depend on the proportion of adenocarcinoma patients in the patient population 
and the time when Amendment 5 is implemented at each of the study sites.  If the HR is 0.7, the 
power for testing OS in the overall population will be higher than 90%. 
2.3. 
Study Plan 
After completion of screening period and randomization, patients assigned to the cemiplimab 
treatment group will receive cemiplimab 350 mg as an intravenous (IV) infusion every 3 weeks 
for up to 96 weeks or until RECIST 1.1 defined progressive disease, unacceptable toxicity, death, 
or withdrawal of consent. Patients on the cemiplimab arm who experienced progression per 
RECIST were allowed to continue  treatment with cemiplimab providing they met all criteria in 
Section 8.6 of the protocol.  
Patients assigned to chemotherapy will receive one of the IC chemotherapies specified in the 
protocol for up to 96 weeks or until RECIST 1.1 defined progressive disease, unacceptable 
toxicity, death, or withdrawal of consent.  
Radiographic tumor assessments will be obtained in all patients on day 42 (±7 days) of cycles 1-
4, 6, 8, 10, 12, 14, and 16.   
There is no cross-over in this study. After completion of the treatment period, patients enter the 
follow-up period. If a patient experiences PD during the follow-up period, retreatment with the 
same drug that was given during the treatment period is an option.  
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Statistical Analysis Plan  
 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH 1998), the following analysis sets will be used for 
statistical analysis. A patient is deemed eligible and enrolled after the patient completes the 
screening process and the investigator deems that the subject is eligible, and the investigator 
requsted randomization number and treatment assignment in interactive web response system 
(IWRS). 
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients. This is the intention to treat 
population.  The FAS is based on the treatment allocated (as randomized).  All efficacy endpoints 
will be analyzed using the FAS.  
3.2. 
 Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug. This 
set is based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF.  
3.3. 
PK Analysis Set (PKS) 
The PK analysis set includes all randomized patients (safety population) who received 
cemiplimab and who had at least one non-missing cemiplimab concentration following the first 
dose of cemiplimab. 
3.4. 
Anti-Drug Antibody Set (ADA) 
The anti-drug antibody (ADA) set includes all patients who have received cemiplimab and who 
have at least one non-missing ADA result following the first dose of cemiplimab. 
The neutralizing anti-drug antibody (NAb) set includes all treated patients who received 
cemiplimab, with at least one non-missing NAb result (either assigned or assessed) following the 
first dose of cemiplimab or ADA negative during the study. 
3.5. 
Biomarker Analysis Set (BAS) 
The biomarker analysis set (BAS) includes all treated patients who have at least one sample 
assayed.  
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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 years) 
• Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander, and Other) 
• Ethnicity (Hispanic/Latino or not) 
• Geographic region (North America, Asia and Rest of World) 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• Histology (squamous or adenocarcinoma/adenosquamous) 
• ECOG performance status (0, 1) 
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 MedDRA. 
• Cervical cancer history and diagnosis (cervical cancer histology/cytology; histologic 
grade, etc.) 
• Prior Systemic Cancer Therapy 
• Time from last platinum in metastatic setting to randomization 
• Prior Cancer Related Surgery 
• Prior Cancer Radiotherapy 
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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. Medications will be coded to the anatomical therapeutic chemical (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. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug, particularly, prior cancer related surgery, prior cancer 
radiotherapy, and prior systemic cancer therapy will be summarized.  
Concomitant medications/procedures: any treatment administered, other than anti-cancer therapy, 
from the time of informed consent until 90 days after the last study treatment will be considered 
concomitant treatment. This includes medications and other therapies for which administration 
started before 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. All concomitant treatments must be recorded 
in the study case report form (CRF) with the generic name, dose, dose unit, frequency, indication, 
and start/stop date, as appropriate. 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable 
The primary efficacy variable is overall survival (OS). Overall survival will be defined as the 
time from randomization to the date of death.  A patient who has not died will be censored at the 
last known alive date.   
4.4.2. 
Key Secondary Efficacy Variables 
Progression free survival (PFS): PFS is assessed by investigator using RECIST 1.1 
(Eisenhauer 2009).  PFS will be defined as the time from randomization to the date of the first 
documented tumor progression (radiographic) or death due to any cause.  Patients who do not 
have a documented tumor progression or death will be censored on the date of their last 
evaluable tumor assessment. Patients who do not have any evaluable tumor assessments after 
randomization and do not die will be censored on the date of randomization.  
 Objective Response Rate (ORR): ORR will be defined as the number of patients with a best 
overall response (BOR) of confirmed CR or PR divided by the number of patients in the Full 
Analysis Set.  
BOR is defined as the best response between the date of randomization and the date of the first 
objectively documented progression or the date of subsequent anti-cancer therapy, whichever 
comes first. 
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4.4.3. 
Other secondary efficacy variables 
Duration of response (DOR) is determined for patients with best overall response of CR or PR. 
Duration of response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date of progressive disease (radiographic), or death 
due to any cause. Patients who never progress while being followed will be censored at the last 
valid tumor measurement. 
Patient-reported quality of life is measured by the EORTC QLQ-C30 (Aaronson. 1993, 
Fayers 2001). The instrument includes 5 functional scales, 8 symptom scales/items, 1 global 
health status/quality of life (GHS/QoL) scale and 1 financial impact scale. Most items are scored 
1 (“not at all”) to 4 (“very much”) except for the items contributing to the global health 
status/QoL, which are scored 1 (“very poor”) to 7 (“excellent”). The recall period for each 
question is “during the past week”. An outcome variable consisting of a score from 0 to 100 is 
derived for each of the scales. Higher scores on symptoms indicate a worse health state. Higher 
scores on the global health status and functioning scales indicate better health status/function. 
Analyses supporting assessment of quality of life are indicated in section 5.8.3. 
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. Unless otherwise noted, the baseline value 
is defined as the last available value before the first dose of study treatment. 
4.5.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to 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). 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. A Serious Adverse Event (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 version 
4.03 of the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) grading system. Adverse events not listed in the NCI-CTCAE will be graded according 
to the following scale:  
1. (Mild):  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
2. (Moderate): 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*.  
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Statistical Analysis Plan  
 
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3. (Severe): Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**.  
4. (Life–threatening):   Life-threatening consequences; urgent intervention indicated.  
5. (Death): 
Death related to AE.  
*   Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
The relationship of AEs to study drug 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: 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): 
An AE of special interest (AESI) must be reported within 24 hours of identification. AEs of 
special interest for this study include: 
• Grade 2 or greater infusion-related reactions 
• Grade 2 or greater allergic/hypersensitivity reactions 
• Grade 3 immune-related AEs (irAEs) 
• An irAE of any grade in a patient previously treated with a PI 3-K inhibitor 
Note: An irAE 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 irAE is suspected, efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior 
to labeling an AE as an irAE. 
4.5.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, and urinalysis. 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: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN)* 
Alkaline phosphatase 
Carbon dioxide (bicarbonate)** 
Total bilirubin 
 
Calcium 
Albumin 
 
Glucose 
 
 
*At ex-US centers at which a urea assay is performed instead of BUN, the urea assay will be acceptable. 
**At ex-US centers at which the bicarbonate assays is not performed as part of the routine chemistry panel, it may be 
omitted. 
Hematology 
• Hemoglobin  
• White blood cells (WBCs)  
• Platelet count  
• Differential:  Neutrophils, Lymphocytes, Monocytes 
Urinalysis 
• Glucose  
• pH  
• Ketones 
• Blood  
• Specific gravity  
• Spot urine protein 
4.5.4. 
Vital Signs 
Vital signs will be collected  at time points specified in the study protocol: 
• Body temperature (oC) 
• 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 specified in the study protocol.  The 
ECG strips or reports will be retained with the source. The ECG will be reviewed by the 
investigator (paper or electronic tracing) and will be available for comparison with subsequent 
ECGs by the investigator: 
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• PR Interval (msec) 
• QRS Interval (msec) 
• QT Interval (msec) 
• Heart Rate (BPM; 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. 
4.5.6. 
Physical Examination Variables 
A thorough 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 skin, head, eyes, nose, throat, neck, 
joints, lungs, heart, pulse, abdomen (including liver and spleen), lymph nodes, and extremities, as 
well as a brief neurologic examination.  
Limited physical examination will include lungs, heart, abdomen, and skin. 
4.6. 
Pharmacokinetic Variables and Immunogenicity Variables  
Cemiplimab concentrations in serum of patients randomized to the cemiplimab treatment group 
will be assessed at multiple time points throughout the treatment and follow-up periods. PK 
variables may include, but are not limited to, the following: 
• Ctrough – pre-infusion concentration 
• Ceoi – concentration at end-of-infusion 
Immunogenicity assessment will include the assessment of anti-drug antibody (ADA) and the 
assessment of neutralizing ADA (NAb).  ADA variables will be measured in samples from 
patients randomized to the cemiplimab treatment group and will include status (positive or 
negative) and titer as follows: 
• Total number of patients whose response in the ADA assay is negative at all times  
• Pre-existing immunoreactivity – defined either as a positive ADA assay response at 
baseline with all post-treatment ADA results negative, or a positive assay response at 
baseline with all post-treatment ADA assay responses less than 9-fold over baseline 
titer levels 
• Treatment emergent – defined as any positive response post-treatment when baseline 
results are negative or missing 
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• Treatment boosted – defined as any post treatment positive ADA assay response that 
is greater than 9-fold over the baseline titer level when baseline is positive in the 
ADA assay.  
• Titer category is defined based on values as (titer value category): 
− Low (titer < 1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer > 10,000)  
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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. 
Although the study is open-label, summaries and analysis generated based on actual treatment or 
randomized treatment assignment will be documented. 
The data cut-off for the two planned interim efficacy analyses of OS will be at the time when 
70%  and 85% of  total OS events in SCC patients are reached, repectively. The data cut-off for 
planned final analysis for primary efficacy endpoint of OS will be at the time when 340 OS 
events in SCC patients are observed. At the time, all OS events occurring by the end of data cut-
off date will be incuded in analysis. A patient with no OS event or with OS event occurring after 
the date of data cut-off will be censored at the last known date of alive or the date of data cut-off, 
whichever occurs first.   
5.1. 
Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics variables will be summarized by treatment 
based on the FAS population.  
Assessments made before or on the randomization date will be used as baseline measurements 
for the demographics and baseline characteristics unless otherwise specified. 
5.2. 
Medical History 
Medical history will be listed which includes SOC, PT, investigator verbatim and start and end 
dates and summarized by SOC and PT. Summary tables will be sorted by decreasing frequency 
of SOC followed by PT. 
Cervical cancer history and diagnosis will be listed and summarized with histology, histological 
grade at initial diagnosis.  
Prior cancer related surgery will be listed with type of procedure, surgery location, and date of 
surgery.  
Prior cancer related radiotherapy will be listed with type, site, total dose, and start and end dates.  
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Prior systemic cancer therapy will be listed and summarized. 
5.3. 
Prior/Concomitant Medications  
Prior/concomitant medications will be listed including generic name and ATC levels 2 and 4, 
indication, study day onset (for medications started before treatment, the study day onset is 
defined as date of medication start - date of the first dose; for medications started on or after 
treatment, the study day onset is defined as date of medication start - date of the first dose+1), the 
study end date (defined similarly as for study onset day), ongoing status, dose, frequency, and 
route. Number and proportion of subjects taking concomitant medications, prohibited 
medications/procedures and rescue medications/procedures will be summarized, sorted by 
decreasing frequency of ATC Level 2 and ATC level 4 according to the current version of the 
World Health Organization Drug Dictionary, based on the overall incidence between treatment 
groups.   
New anti-cancer treatment received after disease progression will be listed and summarized.  
The total number of patient who received post-treatment Immunotherapy after progression will  
be listed and summarized. 
5.4. 
Subject Disposition 
For subject disposition, the following summaries by table will be provided: 
• The total number of screened patients 
• The total number of randomized patients 
• The total number of patients in the FAS (as randomized) 
• The total number of patients in the SAF (as treated) 
• The total number of patients who discontinued treatment and the reasons for treatment 
discontinuation 
• The total number of patients who discontinued the study and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized. Summary table will be 
provided if applicable 
• A listing of patients prematurely discontinued from treatment and study, along with 
reasons for discontinuation 
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Listing of patient disposition will include dates of the first and the last study treatment 
administration, date of the end of treatment and end of study visits, and reasons for treatment and 
study discontinuation. 
5.5. 
Protocol Deviations 
Protocol deviations will be recorded in a separate protocol deviation definition document which 
includes a listing of all patients with protocol deviations and the reasons for deviation. The major 
protocol deviations, such as violation of inclusion/exclusion criteria; post-enrollment deviations 
which will impact assessment of efficacy or safety endpoints, will be determined before database 
lock and be summarized by treatment group. 
5.6. 
Measurement of Compliance 
Compliance with study drug will be calculated as follows: 
Treatment Compliance =  
(Number of doses of study drug administered during treatment period) / (Number of doses of 
study drug planned to be administered during period) × 100% 
where temporary dose discontinuation is ignored. 
The percentage of subjects who have <60%, 60-80%, 80-100%, and >100% compliance will be 
summarized for each group. 
5.7. 
Exposure to Investigational Product 
Exposure to study treatment will be examined for each subject and the following variables will 
be summarized: 
• The total number of study doses administered  
• The total dosage of cemiplimab administered  
• Duration of treatment exposure (in weeks) calculated as the minimum of  
1. [date of last dose – date of first dose + x days] / 7  
or  
2. [date of clinical data cut-off or date of death – date of first dose + 1] / 7 
x = 21 for cemiplimab and Pemetrexed 
x= 7 for Topotecan, Irinotecan, Gemcitabine, and Vinorelbine 
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• The number of subjects exposed to study drug will be presented by specific time point 
periods for each group. The time periods of interest are weeks 3, 6, 12, 18, 24, 36, 48, 
72 and 96. 
• The actual dose intensity = total dose received / duration of treatment exposure 
(week)  
• The relative dose intensity = actual dose intensity / planned dose intensity, 
5.8. 
Analyses of Efficacy Variables 
The efficacy analyses will be performed based on the FAS according to assigned treatment 
group.  
5.8.1. 
Analysis of Primary Efficacy Variable 
The primary analysis of OS will be performed with an overall one-sided alpha of 0.025 for the 
following null and alternative hypothesis. 
H0: The survival curve of OS for cemiplimab is the same as that for IC chemotherapy 
H1: The survival curve of OS for cemiplimab is superior to that for IC chemotherapy 
The multiplicity is controlled by a hierarchical testing procedure at one-sided 0.025 level as 
follows:  The primary endpoint OS will be tested in SCC patients first.  If statistically significant, 
OS will be tested in the overall population.   
The primary endpoint of OS will be analyzed in SCC patients by stratified log-rank test using 
geographic region (North America versus Asia-Pacific versus ROW) as a stratification factor. 
The HR and its 95% CI will be estimated by a stratified Cox regression model with Efron’s 
method for tie handling and using the treatment as covariate.  
The distribution of OS will be estimated using the Kaplan-Meier method. The median OS along 
with its 95% CI will be presented by treatment group and Kaplan-Meier estimates with 2-sided 
95% CIs at specific time points (for example, 6, 12, 18 and 24 months) will be summarized. The 
Kaplan-Meier curves will be displayed by treatment group. 
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If the analysis of OS is statistically significant in the SCC patients, then the analysis of OS will 
be performed in the overall population by stratified log-rank test using the following stratification 
factors. And the HR and its 95% CI will be estimated by a stratified Cox regression model with 
Efron’s method for tie handling and using the treatment as covariate. The Kaplan-Meier estimate 
of median OS with its 95% CI and the estimates with the 95% CIs at specific time points (for 
example, 6, 12, 18 and 24 months) will be summarized by treatment group. The 
Kaplan-Meier curves will be displayed by treatment group. 
1. Histology: SCC versus adenocarcinoma per IWRS. Adenosquamous histology will be 
considered adenocarcinoma for the purpose of stratification. 
2. Geographic Region: North America versus Asia Pacific versus ROW. 
Note: Since Amendment 5, only squamous patients were randomized. Patients randomized prior 
to Amendment 5 were stratified by histology (squamous versus adeno/adenosquamous).  
Sensitivity analyses will be performed for OS.  
• The first sensitivity analysis will be performed using the stratification information 
(i.e., histology) collected in the clinical database. 
• The second sensitivity analysis may be performed using the Rank Preserving 
Structural Failure Time (RPSFT) model to account for the effect of the PD-1/PD-L1 
treatments 
after 
disease 
progression 
in 
the 
chemotherapy 
arm 
(Robins and Tsiatis, 1991).  
• The third sensitivity analysis will be performed to account for the effect of the post-
treatment immune check-point inhibitors (including PD1/PDL1, and others) in both 
arms after primary study period. Patients who received post-treatment immune check-
point inhibitors will be censored on the start date of post-treatment immune check-
point inhibitors.  
5.8.2. 
Analysis of Key Secondary Efficacy Variables 
The analysis of PFS will be analyzed using the same statistical method as described for the 
primary analysis of OS with regard to SCC and overall population.  
Sensitivity analyses will be performed for PFS. 
• The first sensitivity analysis is the same as the main analysis except that it considers 
initiation of new anti-cancer therapy as a progressive disease event for patients 
without documented radiological PD or death on or prior to initiation of new anti-
cancer treatment.  
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• The second sensitivity analysis is the same as the main analysis except that it 
considers clinical progression as a progressive disease event for patients without 
documented radiological PD or death on or prior to clinical progression. 
The ORR will be analyzed using Cochran-Mantel-Haenszel test stratified by the same 
stratification factors used in analysis of OS with regard to the SCC and overall population. ORR 
and the corresponding 95% exact CI will be calculated by Clopper-Pearson method 
(Clopper 1934) for each treatment arm. 
Best overall response: CR/PR/SD/PD/NE will be summarized by group: 
• Not evaluated response includes the missing and unknown response 
• CR/PR must be confirmed by repeated assessments no less than 4 weeks apart 
• SD criteria must be met at least once for a minimum duration of 4 weeks after first 
dose date 
Patients with the best overall response of NE will be considered as non-responder. 
One sensitivity analysis will be performed using the same method as above in ORR eligible 
patients, defined as all randomized patients who had baseline and at least one valid post-baseline 
tumor evaluation. 
5.8.3. 
Analysis of Patient-Reported Outcomes 
Patient disposition by treatment group for all PRO assessment timepoints will be provided. PRO 
completion rate at each visit will be calculated among patients who are expected to have PRO 
assessments.  At each PRO assessment, the mean and mean change scores of each component of 
QLQ-C30 will be summarized descriptively and graphically depicted by longitudinal plots. 
Longitudinal change from baseline at each PRO assessment in the GHS/QoL and PF scales will 
be analysed using a mixed models repeated measures (MMRM) model.  Pairwise comparison of 
the overall adjusted mean estimates, giving each visit equal weight, and adjusted mean estimates 
at Cycle 2, will be conducted for Cemiplimab vs IC chemotherapy. The model includes fixed 
effects of treatment, visit, baseline PRO score, geographical region, histology (overall population 
only), treatment-by-visit interaction and baseline PRO score-by-visit interaction and generates 
least squares (LS) mean estimates, standard errors, 95% CIs and p-values (where applicable) for 
mean changes from baseline to each PRO assessment. The model will assume unstructured 
covariance among the within-patient repeated measurements. If the algorithm does not converge, 
a heterogeneous Toeplitz (the TOEPH option in SAS PROC MIXED) will be tried first and then 
AR(1) as a covariance structure to achieve convergence. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom.  Partial missing data will be handled by the 
scoring algorithm.  No additional imputations will be conducted for missing data. Additional 
PRO analyses (e.g. pattern mixture model) will be described in a separate SAP. 
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5.8.4. 
Analysis of Other Secondary Variables 
All analyses for other secondary variables are descriptive. 
Duration of response will be summarized by median and range, and displayed by Kaplan-Meier 
approach and by treatment group. 
5.8.5. 
Subgroup Efficacy Analysis 
Subgroup primary and key sencondary efficacy analyses will be performed based on the 
following factors, using the  stratified Cox regression model. Within each subgroup per the 
clinical database, the treatment effect in terms of HR and its two-sided 95%CI generated from the 
cox regression model will be summarized and ploted using Forest plot. 
• age group (<65, ≥65) 
• race (White, Non-white) 
• geographic region (North America, Asia and ROW) 
• geographic region (Japan, outside of Japan) 
• histology (Squamous, adenocarcinoma/adenosquamous)  
• prior Bevacizumab use (Yes, No) 
• baseline ECOG status (0, 1) 
• choice of IC chemotherapy 
• number of prior lines of systemic therapy for recurrent or metastatic disease (1 line,  
>1 line) 
As subgroup analyses do not have enough power for hypothesis tests, the analysis will be 
descriptive only. 
5.9. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. The 
safety analysis will be based on the reported AEs and other safety information (clinical laboratory 
evaluations, vital signs and 12-lead ECG). The analysis will comprise the basis upon which 
conclusions will be drawn regarding the safety of cemiplimab. The AEs of special interest will be 
determined by the list provided by medical monitors. 
The summary of safety results will be presented by treatment group and in overall total. 
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5.9.1. 
Adverse Events  
The verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be 
displayed in subject listings. Summaries that include number and proportions of patients 
reporting AEs will include the PTs and the SOCs. 
Period of observation: The observation period will be divided into three segments: pre-treatment, 
on-treatment and post-treatment.  
• The pre-treatment period is defined as the time between when the subjects give 
informed consent and before the start of study treatment.  
• The treatment period is defined as the time from first dose of study treatment up to 90 
days after the last dose of study treatment, or to the day before the patient commences 
another anticancer systemic therapy, whichever comes first.   
• The post-treatment period is defined as the time starting one day after the treatment 
period ends. 
Day 1 is the first day of patient receiving study treatment, Day –1 is the day before, and there is 
no Day 0. 
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• Pre-treatment AEs are defined as AEs that developed during the pre-treatment period. 
• Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened 
during the treatment period. In addition, the study drug related AEs occurring anytime 
are considered as TEAEs. 
• 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. 
The focus of adverse event reporting in the CSR will be on TEAEs. For details on handling 
missing data and partial dates, see Section 6.  
Summaries of TEAEs will include: TEAEs, Treatment related TEAEs, Serious TEAEs, 
Treatment-related Serious TEAEs and AESIs (grade 2 or greater infusion-related reactions, grade 
2 or greater allergic/hypersensitivity reactions, and grade 3 or greater irAEs). For TEAEs, the 
following will be summarized: 
• The number and proportions of patients reporting at least 1 TEAE, presented by SOC 
and PT 
• TEAEs by severity (CTCAE, version 4.03 grade), presented by SOC and PT 
• Treatment related TEAEs, presented by SOC and PT 
• TEAEs occurring in ≥ 5% patients, presented by PT 
• Serious and treatment related serious TEAEs, presented by SOC and PT 
• TEAEs leading to permanent treatment discontinuation, presented by SOC and PT 
• TEAEs leading to death, presented by SOC and PT 
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. 
For AE listings, the following variables will be displayed:  
• Age /race 
• Verbatim Term  
• PT 
• SOC  
• AE start date and end date/ongoing (and corresponding study day) 
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• AE duration 
• Relationship to study drug: unrelated or related 
• Seriousness (Serious AE or not) 
• National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) grade 
• Action taken 
• Treatment: none, medication, procedure/surgery  
• Outcome: recovered/resolved, recovered/resolved with sequelae, recovering/ 
resolving, not recovered/not resolved, fatal, or unknown 
Counts will be provided for each patient within each SOC and PT. Percentages will be calculated 
using the number of patients from the SAF in each group. 
5.9.2. 
Clinical Laboratory Measurements and Vital Signs 
Listings of laboratory values, normal ranges, grade, by dose cohort, date, and visit/cycle will be 
provided. For numeric lab variables and change from baseline to each visit/cycle and overall will 
be summarized. Listings of abnormal lab values and clinical significance (NCI-CTCAE) by 
patient and visit/cycle will also be constructed.  
Summary tables for new or worsened laboratory results by NCI CTCAE v4.03 all grade and 
grade ≥ 3 will be generated.  
Summary of Shift tables from baseline to post-treatment worst NCI CTCAE v4.03 grade will be 
generated.  
5.9.3. 
Analysis of Vital Signs 
Vital signs (pulse, sitting blood pressures, and temperature) will be listed and summarized by 
Baseline and change from Baseline to each scheduled assessment time with descriptive statistics.  
5.9.4. 
Analysis of 12-Lead ECG 
ECG status (i.e. normal, abnormal but not clinically significant, abnormal and clinically 
significant) will be reported. Shift tables will be provided to present the post-baseline status 
according to the baseline status (normal or missing / abnormal) by group. 
5.9.5. 
Physical Exams 
Physical examination findings at baseline as well as post-treatment abnormal findings by body 
system and status (normal, abnormal and not done) will be provided with Listing. 
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5.10. 
Analysis of Pharmacokinetic and Antibody Data 
5.10.1. 
Analysis of Pharmacokinetic Data  
Concentrations of cemiplimab in serum will be measured at multiple time points throughout the 
study treatment and follow-up periods, and the PK variables will be determined. 
Summaries of study drug concentrations will be presented by nominal time point (ie, the time 
points specified in the protocol) and group. Pharmacokinetic variables, including Ceoi and Ctrough 
will be presented as individual values with descriptive statistics. 
5.10.2. 
Analysis of Anti-Drug Antibody Data 
Formation of ADA will be assessed in individual patients and per group as follows: 
• Possible relationship between changes in PK profile and treatment-emergent positive 
responses in the ADA assay will be assessed to evaluate a potential impact of 
anti-cemiplimab antibodies on drug exposure. 
• Possible relationship between AEs and treatment-emergent positive responses in the 
ADA assay will be assessed to evaluate a potential impact of anti-cemiplimab 
antibodies on the incidence of Grade 3 and 4 AEs, atypical AEs, and SAEs. 
Cases of ADA positivity will be listed and summarized as appropriate. 
5.10.3. 
Analysis of Exploratory Biomarker Data  
Biomarker analyses in this study will be exploratory in nature and results will be summarized in a 
separate report. Detailed description of statistical methods that will be used for biomarker data 
analyses will be provided in a separate Biomarker Analytical Plan.  
More details on exploratory analysis of PDL1 expression may be added to the SAP as an 
addendum before the PDL1 expression data become available. 
6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analyses.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment for all safety measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. The 
baseline assessment for all efficacy measurements will be the latest available taken prior to the 
randomization, except that the baseline for quality of life assessment will be the latest available 
prior to the administration of investigational product. 
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6.2. 
Data Handling Convention for Efficacy Variables 
For OS, patients who are lost to follow up after randomization will be censored at the date of 
randomization. 
For PFS, patients who do not die and do not have a valid tumor assessment post baseline will be 
censored at the date of randomization. 
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. 
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. 
Last known alive day will be derived from all assessments (e.g., tumor assesments, etc) and 
actual event dates (e.g., AEs, biopsy, etc). If year is missing, the assessment/actual event date will 
not be imputed. If month is missing, the assessment/actual event date will be imputed as Jan 1 of 
the year. If day is missing, the assessment/actual event date will be imputed as 1st day of the 
month. 
No other missing data imputation is planned in this study unless specified otherwise. 
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 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.  
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6.4. 
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. 
The determination of baselines and values at the end of treatment 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 by visit 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 
The multiplicity is controlled at one-sided 0.025 level by group sequential design for interim and 
final analyses for OS in SCC patients and a hierarchical testing procedure for OS, PFS, QoL and 
ORR in SCC and overall population. 
7.1. 
Type I error control for interim and final analyses of OS in SCC 
patients using group sequential design 
Two interim efficacy analyses are planned for the primary endpoint of OS in SCC patients using 
Lan-DeMets (O’Brien-Fleming) spending function at 70% and 85% of the total OS, respectively. 
The first interim efficacy analysis will be performed after observing approximately 238 OS 
events in SCC patients (70% of total OS events). OS will be tested at the 1-sided nominal type I 
error of 0.0074. The second interim efficacy analysis will be performed after observing 
approximately 289 OS events in SCC patients (85% of total OS events). OS will be tested at the 
1-sided nominal type I error of 0.0129. The final efficacy analysis will be performed after 
observing approximately 340 OS events in SCC patients. OS will be tested at the 1-sided 
nominal type I error of 0.0202. Table 1 summarizes the alpha spending for interim and final 
analyses based on planned number of OS events in SCC patients. The actual alpha spending will 
be based on the actual number of OS events included in the analyses and determined by the 
O’Brien-Fleming spending function at the time of interim and final analyses. 
Table 1: 
Alpha Spending in Group Sequential Design Using Lan-DeMets (O’Brien-
Fleming) Spending Function for OS in SCC Patients  
1st Interim Efficacy Analysis 
2nd Interim Efficacy Analysis 
Final Efficacy Analysis 
# Events 
needed 
1-sided  
Nominal Alpha  
# Events 
needed 
1-sided 
Nominal Alpha  
# Events  
needed 
1-sided Nominal 
Alpha  
238 
(70%) 
0.0074 
289 
(85%) 
0.0129 
340 
(100%) 
0.0202 
7.2. 
Type I error control for OS, PFS, QoL and ORR  in SCC and overall 
population using hierarchical testing procedure 
A hierarchical testing strategy will be applied to perform confirmatory analysis of primary 
endpoints and secondary endpoints in the following sequence: 
1. OS in SCC patients 
2. OS in overall population 
3. PFS in SCC patients 
4. Mean change from baseline in GHS/QoL scale in SCC patients 
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5. Mean change from baseline in physical functioning scale in SCC patients 
6. ORR in SCC patients 
7. PFS in overall population 
8. ORR in overall population 
9. Mean change from baseline to cycle 2 in GHS/QoL scale in SCC patients 
10. Mean change from baseline  to cycle 2 in in physical functioning scale in SCC patients 
11. Mean change from baseline in GHS/QoL scale in overall population 
12. Mean change from baseline in physical functioning scale in overall population  
13. Mean change from baseline to cycle 2 in GHS/QoL scale in overall population 
14. Mean change from baseline  to cycle 2 in in physical functioning scale in overall 
population  
If the OS is significant in SCC patients, statistical testing from 2 to 14 will be performed as final 
analysis at norminal alpha of one-sided 0.025 level. 
8. 
INTERIM ANALYSIS 
 Two interim efficacy analyses are planned, please refer Section 7 for detailed information. 
9. 
SOFTWARE 
All statistical analyses will be done using SAS Version 9.4 or above. 
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