Clinical trial NCT03444376
Conditions: Cervical Cancer
Keywords: KEYTRUDA® pembrolizumab GX-188E TDS-IM device KEYNOTE-567
Sponsor: Genexine, Inc.
Start date: 2018-06-19; Completion date: 2023-12-21
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Multi-Center, Open-label Phase Ib-II Trial of the Combination of GX-188E Vaccination and Pembrolizumab in Patients with Advanced, Non-Resectable HPV-Positive Cervical Cancer

Detailed description:
This is an open-label Phase Ib-II trial to evaluate the safety and efficacy of GX-188E (IM administration using Ichor TDS-IM device) + pembrolizumab (P) in patients with advanced HPV-16+ or HPV-18+ cervical cancer.

Arms: arm 1: GX-188E: 1st day of week 1,2,4,7,13,19, 46/ 2mg KEYTRUDA® : Day 1 q3 weeks/ 200mg
Interventions: intervention 1: GX-188E intervention 2: KEYTRUDA®
Intervention descriptions: intervention 1: GX-188E (1.0mg/0.5ml/vial), Intramuscular administration using electroporator, Ichor TDS-IM device intervention 2: pembrolizumab(100mg/4mL/vial), Intravenous administration

Protocol documents:
Prot_000.pdf: 
GX-188E/Pembrolizumab 
[Protocol Number: GX-188E-005] Amended (V4.0)_ 29Aug2022 
 
 
CONFIDENTIAL 
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 Title  
A Multi-Center, Open-label Phase Ib-II Trial of the combination of GX-
188E Vaccination and Pembrolizumab in Patients with Advanced, Non-
Resectable  HPV type 16 and/or 18 Positive Cervical Cancer 
Protocol Number GX-188E-005 
IND Number 
12053  
Primary Sponsor Genexine, Inc. 
Genexine-Progen Bio Innovation Park Bldg., 
172 Magokjungang-ro, Ganseo-gu, 
Seoul, 07789, Korea 
Medical Monitor Jong Sup Park  
Date/Version 
29Aug2022 / Amended (V4.0)  
 
 
Confidentiality Statement 
 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a clinical 
study for the Sponsor. You may disclose the contents of this document only to study personnel under 
your supervision, institutional review boards (IRBs)/independent ethics committees (IECs), or duly 
authorized representatives of regulatory agencies for this purpose under the condition that they maintain 
confidentiality. The contents of this document may not be used in any other clinical study, disclosed to 
any other person or entity, and/or published without the prior written permission of the Sponsor. The 
foregoing shall not apply to disclosure required by any regulations; however, you will give prompt 
notice to the Sponsor of any such disclosure. All other nonpublic information provided by the Sponsor 
and any information that may be added to this document also is confidential and proprietary to the 
Sponsor and must be kept in confidence in the same manner as the contents of this document. 
 
 


GX-188E/Pembrolizumab 
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Protocol Acknowledgement 
I have read this Protocol and agree that it contains all necessary details for carrying out the 
study described. I understand that it must be reviewed by the Independent Ethics Committee 
overseeing the conduct of the study and approved or given favorable opinion before 
implementation.  
 
The signature of the Principal Investigator and Sponsor below constitute their approval of this 
protocol and proved the necessary assurances that this study will be conducted according to the 
Declaration of Helsinki, GCP, ICH guidelines, local legal and regulatory regulations as well as 
to all stipulations of the protocol in both the clinical and administrative sections, including 
statements regarding confidentiality. 
 
 
__________________________________                ______________________ 
Investigator’s name and signature 
Date 
 
__________________________________                ______________________ 
Medical Monitor’s name and signature 
Date 
 
 
__________________________________                 ______________________ 
Clinical Development Division Head’s name and signature Date 
 
 
 


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Table of Contents 
 
 
PROTOCOL ACKNOWLEDGEMENT ............................................................. 2 
 
TABLE OF CONTENTS ...................................................................................... 3 
 
LIST OF TABLES ................................................................................................. 6 
 
LIST OF FIGURE ................................................................................................. 6 
 
CONTACTS ........................................................................................................... 8 
 
Emergency Contacts .................................................................................... 8 
 
Additional Contacts ..................................................................................... 8 
 
SAE Reporting Contact................................................................................ 8 
 
LIST OF ABBREVIATIONS ............................................................................... 9 
 
STUDY SYNOPSIS ............................................................................................. 11 
 
INTRODUCTION................................................................................................ 21 
 
Background on HPV-16 and 18 Positive Cervical Cancer ........................ 21 
 
Background on the Compounds ................................................................. 22 
 
GX-188E: Promoting HPV-16 and 18-Specific Anti-Tumor 
Immunity ................................................................................... 22 
 
Pembrolizumab ......................................................................... 25 
 
HYPOTHESIS AND STUDY OBJECTIVES ................................................... 29 
 
Hypothesis.................................................................................................. 29 
 
Study Objectives ........................................................................................ 29 
 
STUDY DESIGN .................................................................................................. 30 
 
Description and Rationale for Study Design ............................................. 30 
 
Part A: Evaluation of Safety and Tolerability............................................ 30 
 
Part B: Exploratory Efficacy Evaluation of GX-188E + P ........................ 31 
 
Part C: Efficacy Evaluation in Larger Number of Patients ........................ 31 
 
Number of Patients .................................................................................... 31 
 
Number of Study Centers........................................................................... 32 
 
Selection of Study Population .................................................................... 32 
 
Inclusion Criteria ....................................................................... 32 
 
Exclusion Criteria...................................................................... 34 
 
Duration of Patient Participation ............................................................... 36 
 
Duration of Study ....................................................................................... 37 
 
INVESTIGATIONAL TREATMENTS-PRODUCT INFORMATION ........ 37 
 
GX-188E Product Information .................................................................. 37 
 
Storage and Handling of GX-188E ........................................... 38 
 
Dispensing of GX-188E ............................................................ 38 
 
Records of GX-188E Disposition at Investigational Site(s) ..... 39 


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Return and Destruction of GX-188E......................................... 40 
 
TDS-IM ®  Electroporation Device Use and Accountability ...................... 40 
 
Pembrolizumab Product Information ......................................................... 41 
 
INVESTIGATIONAL TREATMENT PLAN-ROUTE AND REGIMEN ..... 41 
 
Part A: Establishing Recommended Phase 2 Treatment Schedule ............ 41 
 
Starting Treatment Schedule ..................................................... 41 
 
Reduction Level 1 Treatment Schedule .................................... 43 
 
General Dosing Adjustments and Delays and Supportive Care 
Instructions ................................................................................................. 43 
 
Dose Modification and Toxicity Management for Immune-
related AEs Associated with Pembrolizumab ........................... 44 
 
Dose modification and toxicity management of infusion-
reactions related to pembrolizumab .......................................... 48 
 
Other Allowed Dose Interruption for Pembrolizumab.............. 50 
 
Supportive Care Guidelines for Events of Clinical Interest and 
Immune-related Adverse Events (irAEs) .................................. 50 
 
PRIOR TREATMENT ........................................................................................ 50 
 
MEALS AND DIETARY RESTRICTIONS ..................................................... 51 
 
CONCOMITANT TREATMENTS ................................................................... 51 
 
Acceptable Concomitant Medications ....................................................... 51 
 
Prohibited Concomitant Medications ........................................................ 52 
 
STUDY PROCEDURES AND OBSERVATIONS ........................................... 53 
 
Screening Evaluation ................................................................................. 53 
 
Week 1 Day 1............................................................................................. 54 
 
Week 2 Day 1 (± 3 days) ........................................................................... 55 
 
Week 3 Day 1 (±3 days) ............................................................................ 56 
 
Week 4 Day 1 (± 3 days) ........................................................................... 56 
 
Week 7 Day 1 (±3Days) ............................................................................ 57 
 
Week 10 Day 1 (± 3 days) ......................................................................... 57 
 
Week 13 Day 1 (± 3 days) ......................................................................... 58 
 
Week 16 Day 1 (± 3 days) ......................................................................... 59 
 Week 19 Day 1 (±3 days) .......................................................................... 59 
 Other Schedules Subsequent to Week 19 Day 1 ........................................ 60 
 
Every 3 Weeks (after Week 19 Day 1)(± 3 days) ..................... 60 
 
Every 9 Weeks (after Week 19 Day 1) (± 1 week) ................... 61 
 
Week 46 Day 1 (± 1 week, GX-188E optional administration) 61 
 End of Study (EOS) ................................................................................... 62 
 Long-Term Follow-Up............................................................................... 63 
 
PATIENT IDENTIFICATION AND TRACKING .......................................... 63 
 
SCREEN FAILURES .......................................................................................... 64 


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DISCONTINUATION/WITHDRAWAL CRITERIA ..................................... 64 
 
Discontinuation of Study Treatment ...................................................... 64 
 
SAFETY REPORTING AND DOCUMENTATION OF CLINICAL 
RESULTS ............................................................................................................. 64 
 
Safety Evaluations ..................................................................................... 64 
 
Physical Examination ................................................................ 65 
 
Vital Signs ................................................................................. 65 
 
Safety Laboratory Determinations ............................................ 65 
 
Pain Assessment ........................................................................ 65 
 
Adverse Events (AE) ................................................................................. 66 
 
Serious Adverse Event (SAE) .................................................................... 68 
 
Other Reportable Information .................................................................... 70 
 
Contraception and Pregnancy ................................................... 70 
 
Pregnancy .................................................................................. 71 
 
Use in Nursing Women ............................................................. 72 
 
Unexpected AE and SAE ........................................................................... 72 
 
Reporting and Follow-Up Requirements for Adverse Events, Serious 
Adverse Events and Other Reportable Safety Events ................................ 72 
 
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ....................................... 72 
 
Serious Adverse Event (SAE)-Specific and Expedited Reporting ............ 73 
 
Events of Clinical Interest (ECI) ................................................................ 74 
 
Treatment of Pembrolizumab Overdose .................................................... 74 
 
DOSE-LIMITING TOXICITIES (DLTS) ......................................................... 75 
 
EVALUATION AND REPORTING OF EFFICACY DATA ......................... 76 
 
Tumor Imaging and Assessment of Disease .............................................. 76 
 
Initial Tumor Imaging ............................................................... 76 
 
Tumor Imaging During the Study ............................................. 76 
 
End of Treatment and Follow-Up Tumor Imaging ................... 77 
 
RECIST 1.1 Assessment of Disease .......................................................... 78 
 
iRECIST Assessment of Disease ............................................................... 80 
 
CORRELATIVE STUDIES AND BIOMARKER EVALUATIONS ............. 85 
 
Tumor Tissue for Biomarker Analyses ...................................................... 85 
 
Planned Peripheral Blood Biomarker Analyses ......................................... 86 
 
STATISTICAL ANALYSIS ............................................................................... 86 
 
Statistical Plan Summary ........................................................................... 86 
 
General Statistical Considerations ............................................................. 88 
 
Sample Size and Power .............................................................................. 89 
 
Analysis Populations .................................................................................. 90 
 
Efficacy Analysis ....................................................................................... 91 


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Safety Analysis .......................................................................................... 93 
 
Interim Analysis ......................................................................................... 93 
 
Final Analysis ............................................................................................ 94 
 
GENERAL STUDY MANAGEMENT INFORMATION ............................... 94 
 
Informed Consent....................................................................................... 94 
 
Institutional Review Board and Institutional Biosafety Committee 
Approvals ................................................................................................... 94 
 
Pre-Study Documentation .......................................................................... 95 
 
Protocol Amendments ................................................................................ 96 
 
Direct Access, Data Handling, and Record Keeping ................................. 96 
 
Confidentiality .......................................................................... 96 
 
Case Report Forms (CRFs) ....................................................... 96 
 
Oversight and Monitoring ......................................................... 97 
 
Study Suspension, Termination, and Completion...................................... 98 
 
PROTECTION OF HUMAN PATIENTS......................................................... 98 
 
Protection from Unnecessary Harm ........................................................... 98 
 
Protection of Privacy.................................................................................. 98 
 
REFERENCES ................................................................................................... 100 
APPENDIX 1: SCHEDULE OF EVENTS (SCREENING -WEEK 10) ................... 103 
APPENDIX 2: LIST OF LIVE VACCINES. .............................................................. 109 
APPENDIX 3: MOORE’S CRITERIA FOR DETERMINING PROGNOSIS IN 
CERVICAL CANCER ...................................................................................... 110 
APPENDIX 4. CLINICAL LABORATORY TESTS ................................................. 111 
APPENDIX 5: RECIST CRITERIA VERSION 1.1 .................................................. 112 
APPENDIX 6: DESCRIPTION OF THE IRECIST PROCESS FOR ASSESSMENT 
OF DISEASE STATUS AND DISEASE PROGRESSION ........................... 121 
 
 
 
 
LIST OF TABLES 
Table 1: Organ Function Requirements for Eligibility .................................................................................... 33 
Table 2. Investigational Treatment Product Details ........................................................................................ 37 
Table 3. Investigational Treatment Schedules ................................................................................................... 43 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab. ............................................................................................................................ 45 
Table 5. Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines ............ 49 
Table 6. Imaging and Treatment after First Radiologic Evidence of Progressive Disease ............... 82 
Table 7. Determination of Patients to be Included in Efficacy Evaluable. ............................................... 91 
 
 
 
LIST OF FIGURE 
Figure 1. pGX27-E6E7 plasmid DNA map ............................................................................................................ 23 


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Figure 2. GFP expression in muscle cross sections with or without EP (Ichor) ................................... 24 
Figure 3. TDS-IM ®  Cartridge and Integrated Applicator ............................................................................. 39 
Figure 4. Numeric Pain Rating Scale ....................................................................................................................... 66 
Figure 5: Imaging and Treatment for Clinically Stable Participants Treated with pembrolizumab 
after First Radiologic Evidence of PD Assessed by the Investigator ......................................................... 84 
 
 


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Contacts 
 
Emergency Contacts 
Primary Medical Monitor   
Jong Sup Park, Genexine, Inc. 
 
Safety Physician and Back-Up Medical Monitor 
Charu Gautam, IQVIA 
 
Additional Contacts 
Clinical Project Manager/Lead Clinical Research Associate 
Yoon Jeong Choi, Genexine, Inc. 
 
 
 
SAE Reporting Contact 
IQVIA Lifecycle Safety 
E-mail: QLS_GX188E@IQVIA.com / Fax : 00798-14-800-4270 


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List of Abbreviations 
Abbreviation or Term1 Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
aPTT 
Activated Partial thromboplastin time 
AST 
Aspartate aminotransferase 
BICR 
Blinded Independent Central Review 
BID 
Twice daily 
BORR 
Best Overall Response Rate 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
CR 
Complete response 
CRF 
Case Report Form 
CT 
Computed tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Toxicity Criteria for Adverse Events 
D/C 
Discontinue 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EOT 
End of Treatment 
EP 
Electroporation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HCO3- 
Bicarbonate 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
HR 
Heart rate 
Hr 
Hour or hours 


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Abbreviation or Term1 Definition/Explanation 
IBC 
Institutional Biosafety Committee 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Events 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria In Solid Tumors for Immunotherapeutics  
IU 
International Unit 
IV 
Intravenous, intravenously 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
ORR 
Overall Response Rate 
PD 
Progressive disease 
PFS 
Progression Free Survival 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumor 
SAE 
Serious adverse event 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SOC 
Standard of Care 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
WBC 
White blood cell 
WOCBP 
Women of child-bearing potential 
1 
All of these abbreviations may or may not be used in protocol. 
 


GX-188E/Pembrolizumab 
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  Study Synopsis 
TITLE 
A Multi-Center, Open-label Phase Ib-II Trial of the Combination of GX-188E Vaccination and 
Pembrolizumab in Patients with Advanced, Non-Resectable HPV-Positive Cervical Cancer 
 
OBJECTIVES 
Part A: Evaluation of Safety and Tolerability of GX-188E + Pembrolizumab (P) in Patients 
with HPV 16+ and/or 18+ Advanced Cervical Cancer 
 
Primary Objective: 
 To establish the safety and tolerability of GX-188E +P, and to identify the recommended 
Phase 2 treatment regimen 
Secondary Objectives: 
 Objective Response Rate within 24 weeks (ORR24) by RECIST v1.1 and Response 
Evaluation Criteria In Solid Tumors for Immunotherapeutics (iRECIST) 
 Best Overall Response Rate (BORR) 
 Time-to-Best Response (TTR) 
 Duration of Response (DOR) 
 Disease Control Rate (DCR) 
 Progression-Free Survival (PFS): median PFS and 6 month PFS rate 
 Overall Survival (OS): median OS 
 
Part B: Simon Two-Stage Design to Evaluate the Exploratory Efficacy of Recommended 
Phase 2 GX-188E + P Regimen in Patients with HPV 16+ and/or 18+ Advanced Cervical 
Cancer 
  
Primary Objective: 
 ORR24 by RECIST v1.1 
Secondary Objectives: 
 Safety and tolerability 
 BORR by RECIST v1.1 and iRECIST 
 TTR, DOR, DCR, 6-month PFS rate, median PFS and median OS 
 
Part C: To Evaluate the Efficacy of Recommended Phase 2 GX-188E + P Regimen in Larger 
Number of Patients with HPV 16+ and/or 18+ Advanced Cervical Cancer 
 
 Primary Objective: 
 ORR24 by RECIST v1.1 
Secondary Objectives: 
 Safety and tolerability 
 BORR by RECIST v1.1 and iRECIST 
 TTR, DOR, DCR, 6-month PFS rate, median PFS and median OS 
 
 
 
All Parts, Exploratory/Biomarker Objectives: 


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 To evaluate the ability of GX-188E to induce a systemic HPV-16 and HPV-18-specific 
T-cell response that includes, but is not limited to, expansion of CD4+ and CD8+ T-cells 
that recognize E6 or E7 peptide epitopes 
 To investigate whether GX-188E vaccination promotes a Th1-polarized anti-tumor 
immune response 
 To assess whether GX-188E vaccination increases tumor immunogenicity (e.g. increased 
expression of antigen presentation and processing machinery, increased TILs) 
 Identification of biomarkers that has possibility to implicate clinical response and safety 
and/or mechanism of action of GX-188E and pembrolizumab. 
SAMPLE SIZE 
Approximately 46 patients will be enrolled and treated with the investigational combination in 
Parts A and B. It is expected that Part A will enroll between 6- and 18 patients, based upon the 
incidence of dose-limiting toxicities. 
If at least 8 of the 28 subjects enrolled in Part B, experience an objective response who are 
considered to be evaluable for efficacy, it will be considered that ORR satisfies the criteria for 
study expansion and additional 17 subjects (at least) will be enrolled in Part C to evaluate 
efficacy further in larger population (N=60). Refer to the Section 24.3 Sample Size and Power 
for detailed assumptions for sample size estimation. 
STUDY DESIGN 
This is an open-label Phase Ib-II trial to evaluate the safety and efficacy of GX-188E + 
pembrolizumab (P) in patients with advanced HPV-16+ or HPV-18+ cervical cancer. 
 
Study Design. This study is separated into Parts A, B and C.  
 
Part A. Initial Safety Evaluation  
The study will begin with Part A, a safety run-in, employing a “6+3 design”, to ensure that the 
study treatment is not associated with unacceptable acute toxicities.  
 
The starting dose in Part A for GX-188E will be 2mg (1mg/site x 2 vaccination sites). Six (6) 
vaccination days are planned.(week 1, week 2, week 4, week 7, week 13 and week 19). An 
optional GX-188E administration may be given at week 46 if it is in the best interests of the 
patient, as determined by the investigator, once the patient has completed 37 weeks of treatment.  
Additional GX-188E administration(s) may be given to the subject after discussion with the 
sponsor.” 
 
GX-188E will be administered on Day 1 of the following schedule: 
 Weeks 1, 2, 4, 7, 13, 19 and 46 (Optional) 
 
The standard dose of pembrolizumab (200 mg every 3 weeks) will be administered.. No dose 
escalation of either agent is planned.  
 
The first 6 patients will be enrolled and evaluated for the first 3 weeks (prior to Week 4 Day 1 
visit)  for dose-limiting toxicities (DLTs). A DLT is defined as any AE that is not clearly due to 
progression of the patient’s malignancy, that occurs within the first 21 days of treatment 
initiation (prior to Week 4 Day 1 visit), and that meets at least one of the non-hematologic or 
hematologic criteria below:  
 
Non-Hematologic DLT: 


GX-188E/Pembrolizumab 
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 ≥ Grade 3 non-hematologic toxicity according to the Common Toxicity Criteria for 
Adverse Events (CTCAE) v4.0 or the most recent version except for the following: 
o nausea, vomiting, or diarrhea lasting ≤ 72 hr 
o Grade 3 fatigue lasting ≤ 7 days 
o hypersensitivity reactions lasting ≤ 72 hrs   
o Grade 3 hyperglycemia lasting ≤ 72 hr with standard anti-diabetic therapy 
o Grade 3 increases in liver transaminases in patients with liver metastases. (Note: 
Grade 4 increases in LFTs in any patient will be considered a DLT) 
o clinical laboratory abnormalities that are reversible to ≤ Grade 1 or baseline status 
within 72 hr with outpatient care and/or monitoring, or that are considered not 
clinically significant by the Principal Investigator 
 
Hematologic DLT: 
 Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/L]  
 Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 38.3ºC) 
 Grade 4 thrombocytopenia (< 25.0 x 109/L) lasting > 4 days or that requires platelet 
transfusion 
 Grade ≥ 3 thrombocytopenia associated with Grade ≥ 3 bleeding 
 Any hematologic toxicity resulting in death (i.e. Grade 5) 
 
In addition, any other AE that is felt to be treatment-limiting in the medical opinions of the 
Principal Investigator and the Sponsor’s Medical Monitor may be considered a DLT. These 
include, but are not limited to the following: 
 Any toxicity leading to more than one missed dose of either GX-188E or pembrolizumab 
during the DLT-evaluation period 
 Any toxicity leading to > 2 weeks delay in initiation of the 2nd cycle of pembrolizumab 
 
No additional patients will be enrolled until all patients in Part A have completed the DLT 
window and the investigational treatment regimen has been deemed safe. If ≤ 1 patient of 6 
enrolled patients experiences DLT, enrollment into Part B will be initiated. If 2 patients 
experience a DLT, an additional 3 patients will be enrolled and evaluated for DLTs. If 3 or more 
patients in the first 6 or 9 patients experience a DLT, the combination at the current treatment 
schedule will be considered too acutely toxic and enrollment will begin at a reduced frequency 
treatment schedule (see Study Treatment Regimen, Treatment Reduction Plan). Depending on 
the occurrence rate of DLT, all patients without DLT, who receive the recommended Phase 2 
treatment regimen, and who are considered evaluable for efficacy from Part A will be included 
in the first stage of Part B. 
 
Part B. Exploratory Efficacy Evaluation in Advanced Cervical Cancer Patient (Simon Two-
Stage Design) 
In Part B, patients will receive the treatment schedule for GX188E + P that was determined from 
Part A to be well-tolerated. In the first stage of Part B, 15 patients with advanced HPV 16 or 18 
positive cervical cancer will be treated. If at least 3 patients experience an objective response 
(i.e. partial response or better) by RECIST v1.1 in the first 24 weeks of treatment, an additional 
13 patients will be enrolled for a total of 28 patients in Part B. If 2 or fewer patients in the first 
stage experience an objective response, enrollment into Part B will be discontinued for futility. 
Study has passed the first stage of Simon-Two stage design. 
 


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Part C. Efficacy Evaluation in Larger Number of Patients 
If at least 8 of the 28 subjects enrolled in Part B, experience an objective response who are 
considered evaluable for efficacy, it will be considered that ORR satisfies the criteria for study 
expansion and additional 17 subjects (at least) will be enrolled in Part C to evaluate efficacy 
further in larger patient population (N=60). If only 7 or fewer subjects in Part B experience an 
objective response, enrollment to Part C will not open. 
STUDY TREATMENT REGIMEN 
GX-188E will be administered intramuscularly using electroporation (EP) to alternating 
injection sites at deltoid and lateralis muscles during the study period, on Week 1 Day 1 and 
again at Weeks 2, 4, 7, 13, 19, and 46(Optional).  Patients will also receive pembrolizumab, 
administered intravenously per standard prescribing practices. Patients will be radiographically 
assessed for response (by both RECIST v1.1 and iRECIST) approximately every 9 weeks, or 
more frequently as clinically indicated. The full Schedule of Events is outlined in Appendix 1. 
 
Starting Schedule 
Agent 
Treatment Days 
Dosage 
GX-188E  
Week 1 Day 1, Week 2, Week 4, Week 
7 and Week 13, Week 19 and Week 46 
(Optional)  
Two IM injections (1 mg to each  
deltoid or lateralis muscle; total 
of 2 mg per vaccination day) with 
colocalized EP 
Pembrolizumab 
(P) 
Day 1 q 3 weeks (e.g. Day 1 of Weeks 
1, 4, 7, 10, 13, etc.) 
200 mg IV 
 
Treatment Reduction Plan 
In the event that the starting treatment schedule is determined to be too toxic according to the 
DLT rules in Part A, the following treatment-reduction plan will be implemented: 
 
Treatment 
Schedule 
GX-188E  
 
Pembrolizumab 
(P) 
Starting 
Schedule 
Week 1 Day 1, Week 2 Day 1, Week 4, 
Week 7, Week 13, Week 19, and Week 
46(Optional) 
Day 1 q 3 weeks 
Reduction 
Level 1 
Week 1 Day 1, Week 4, Week 7, Week 
13, Week 19, and Week 46 (Optional) 
(remove Week 2) 
Day 1 q 3 weeks 
(unchanged) 
Note: In the event of a protocol-defined DLT, only a reduction in the frequency of GX-188E will 
be made. There will be no reduction in the dose level of GX-188E and no modifications made to 
P 
 
If 3 in either 6 or 9 patients in Reduction Level 1 experience a DLT, then the combination will 
be considered too toxic and enrollment into the study will be discontinued. 
 
SAFETY MONITORING PLAN 
Safety Monitoring Board. The Safety Monitoring Committee (SMC) will be responsible for 
evaluating patients’ safety data and determining the overall safety and tolerability profile of the 
investigational treatment regimen. The SMC will be comprised of the Sponsor Medical Monitor, 
and the Principal Investigator from each participating site.  
 


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In Part A, the SMC will convene after the first 6 subjects have completed the DLT observation 
period, to discuss safety observations and determine (1) whether any AE meets the criteria for a 
DLT and (2) whether Part B may be initiated.  
During Part B and C, the SMC will continue to convene at least once quarterly to discuss the 
treatment safety profile. 
INCLUSION CRITERIA 
1. Patients must be female and age ≥ 18 years on day of signing of informed consent; 19 years 
for patients treated in Korea 
2. Patients with histologically or cytologically confirmed advanced or metastatic HPV-positive 
(HPV-16 or HPV-18) cervical cancer, who have disease progression after treatment with all 
available therapies for metastatic disease that are known to confer clinical benefit, or are 
intolerant to treatment, or refuse standard treatment. 
Note: there is no limit to the number of prior treatment regimens. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
4. Life Expectancy of at least 6 months 
5. Patients must agree to provide either an archival tumor tissue sample or fresh biopsy sample 
for baseline biomarker tissue analyses, including staining for PD-L1. If archival tissue is not 
available and the patient does not have biopsy-accessible tumor lesions, the patient will be 
excluded. 
6. Patients must have  adequate organ function as defined in the following table (Table 1). 
Specimens must be collected within 28 days prior to the start of study treatment. 
Table 1: Organ Function Requirements for Eligibility 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/L1 
Renal 
 
Creatinine OR 
Measured or calculated2 creatinine clearance 
GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN (except in patients with 
Gilbert’s Syndrome who must have a total 
bilirubin < 3x ULN and ALT < 3x ULN) 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 


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Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use 
of anticoagulants 
ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) =aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
1 Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 4 weeks.  
2 
Creatinine clearance (CrCl) should be calculated using the Cockroft-Gault equation. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies. 
7. Patients must have RECIST 1.1 measurable disease, defined as: 
o Tumor lesion ≥ 1 cm in longest diameter (LD) on an axial CT or MRI image (≤5 mm 
reconstruction interval)  
-OR- 
o Lymph node ≥1.5 cm in the short axis on CT (≤5 mm reconstruction interval) 
8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy 
test within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
9. WOCBP must be willing to use an adequate dual method of contraception during the course 
of the study through 120 days after the last dose of study medication. Post-menopausal 
females (> 45 years old and without menses for > 1 year) and surgically sterilized females 
are exempt from these requirements.  Note: Abstinence is acceptable if this is the usual 
lifestyle and preferred contraception for the subject. 
10. Be willing and able to provide written informed consent for the trial in accordance with 
federal, local, and Institutional guidelines. 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
1. Patient has disease that is suitable for local therapy administered with curative intent. 
2. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (e.g., breast carcinoma) that have undergone potentially curative 
therapy are not excluded. 
3. Patient is expected to require any other form of antineoplastic therapy while on study; 
including systemic chemotherapy, radiation therapy (except for palliative purposes) 
biological therapy, or immunotherapy not specified in this protocol. 


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4. Patient has a history of active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, 
CD137)  and was discontinued from that treatment due to a Grade 3 or higher immune-
related Adverse Event (irAE).  
6. Patients with active autoimmune disease requiring systemic immunosuppressive treatment 
within the past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment and is allowed.  
7. Has had an allogeneic solid organ or allogeneic bone marrow transplant  
8. Patient has had a prior, non-PD-1/PD-L1/PD-L2, anti-cancer monoclonal antibody (mAb) 
(e.g., bevacizumab, cetuximab, etc.) within 4 weeks prior to the first dose of study 
medication or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
9. Has received prior systemic anti-cancer therapy, including investigational agents within 4 
weeks, or within 2 weeks for targeted small molecule therapies with a half-life of < 48 hrs 
prior to the first dose of study medication 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤ Grade 2 neuropathy and/or ≤Grade 2 anemia may be eligible. 
Note: If patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
10. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must 
have recovered from all radiation-related toxicities.  
11. Patient has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to the first dose of study medication. 
12. Patients with bilateral hydronephrosis that cannot be alleviated with ureteral stents or 
percutaneous nephrostomy. 
13. Has severe hypersensitivity (≥Grade 3) pembrolizumab and/or any of its excipients. 
14. Patient has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.  
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug. 
16. Patient has risk factors for bowel obstruction or bowel perforation (examples include but not 
limited to a history of acute diverticulitis, intra-abdominal abscess, and abdominal 
carcinomatosis). 
17. Patient who is currently participating in or has participated in a study of an investigational 
agent or used an investigational device within 4 weeks of the first dose of study medication. 


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Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been > 4 weeks after the last dose of the previous investigational 
agent. 
18. Unstable/inadequate cardiac function: 
 Symptomatic ischemia 
 Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics are excluded); 1st degree AV block or asymptomatic 
LAFB/RBBB are eligible 
 Myocardial infarction in the previous six months 
 Congestive heart failure (New York Heart Association class III to IV) 
19. Has an active infection requiring systemic therapy. 
20. Participants with known human immunodeficiency virus (HIV) and/or history of Hepatitis 
B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus 
(HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known 
positive Hep C Ab result and known quantitative HCV RNA results greater than the lower 
limits of detection of the assay.  
21. Patient has a known history of active TB (Bacillus Tuberculosis) 
22. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study 
intervention. Note: Administration of killed vaccine are allowed. 
23. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study. 
24. Patient who received an implantable electronic medical device (e.g., pace maker) 
25. A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
26. Patients who are pregnant or lactating. 
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the participant's participation for the 
full duration of the study, or is not in the best interest of the participant to participate, in the 
opinion of the treating investigator. 
 
BIOPSIES AND PERIPHERAL BLOOD SAMPLES 
All patients are required to submit either an archival or fresh biopsy sample of their tumor for 
molecular and histological analysis at Screening/Baseline. In addition, patients with accessible 
lesions will be requested to submit a tumor biopsy for correlative studies at Week 10. Details for 
tissue sample requirements can be found in Section 23.1 and the Protocol Laboratory Manual. 
 
All patients will be required to submit peripheral blood samples for exploratory immunological 
evaluation throughout their participation on the study. Peripheral blood samples will be obtained 
at Screening, Week 1, Week 4, Week 7, Week 10, Week 16, Week 22, Week 49 and 
approximately every 27 weeks thereafter until study discontinuation. 


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DURATION OF PARTICIPATION 
Patients may continue treatment for as long as they continue to benefit, for up to 2 years or until 
confirmed disease progression; intercurrent illness that prevents further administration of the 
investigational treatment; unacceptable adverse event(s); patient decision to withdraw from the 
study; significant patient non-compliance with the protocol; or general or specific changes in the 
patients’ condition that, in the opinion of the investigator, render the patient unacceptable for 
further study participation. Unless a patient withdraws consent or dies during the treatment 
period of the study, she will be followed for up to 1 year after study treatment discontinuation 
for survival data. 
 
STATISTICAL METHODS 
Maximum 60 patients are planned for enrollment into this clinical trial.  
 
Safety Analysis. All patients who receive at least one dose of the investigational treatment will 
be included in the safety population.  All safety analyses will be performed on the safety 
population.  Adverse Events (AE) will be coded according to the MedDRA adverse event 
dictionary.  The results will be tabulated to examine their frequency, organ systems affected, 
and relationship to study treatment.  The results of laboratory tests will be evaluated similarly.   
 
Efficacy Analysis. Efficacy results, including but not limited to ORR24, BORR, DOR, DCR, 
TTR, PFS, and OS for patients enrolled into Part A will be provided using descriptive statistics. 
Objective responses will be evaluated according to both RECIST v1.1 and Response Evaluation 
Criteria In Solid Tumors for Immunotherapeutics (iRECIST).  
Note: Confirmatory scans are required for all determinations of objective response (PR or CR), 
Stable disease(SD) and disease progression (PD). Confirmatory scans must be performed at 
least 4 weeks later. 
 
Part B follows a Simon Two-Stage mini-max design.  The sample size for the first stage of Part 
B is 15 patients; the sample size for the second stage is 13 patients, for a total of 28 patients.  
Patients from Part A without a DLT, who receive the recommended Phase 2 treatment regimen 
and who are considered evaluable for efficacy will be included in the analysis for Part B Stage 
1. For a null hypothesis ORR24 of 0.15 and an alternative hypothesis ORR24 of 0.35, the sample 
size of 28 subjects will provide a one-sided significance level of 5% and a power of 80%.  For 
Stage 1, a minimum of three patients must demonstrate a response (PR or better) to proceed to 
the second stage. Study has passed the first stage of Simon-Two stage design. If Stages 1 and 2 
are completed, a minimum of 8 patients must demonstrate a response (PR or better) to reject the 
null hypothesis. If a patient’s responses could not be confirmed, that patient will not be included 
in the primary efficacy population for ORR24.  
 
Part C is to evaluate efficacy in larger patient population.  
In Keynote-158 study (pembrolizumab monotherapy in patients who have progressed with 
standard of care systemic therapy), ORR in total patients (i.e. regardless of PD-L1 status) and 
with CPS ≥ 1  were 12.2% and 14.6%, respectively.  
Given this, null hypothesis for ORR24 was set at P0 = 12.2%. With an alternative hypothesis for 
ORR24 of Pa = 37%, the sample size of 60 subjects was calculated considering two-sided 
significance level of 0.05, 97% power, and 25% dropout rate.  
The confidence interval (CI) for ORR24 will be estimated using exact Clopper-Pearson method, 
and if the lower bound of the two-sided 95% CI for ORR24 exceeds 12.2%, it will be proven to 


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satisfy the primary efficacy. And it will be analyzed using two-sided exact binomial test for a 
null hypothesis for ORR24 of P0 = 12.2%  with a significance level of P < 0.05. 
 


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Introduction 
 
Background on HPV-16 and 18 Positive Cervical Cancer 
Human Papillomaviruses (HPVs) are DNA viruses, which can infect squamous and mucosal 
epithelium and drive the pathogenesis of a variety of cancers. It is estimated that HPVs, 
especially serotypes 16 (HPV 16) and 18 (HPV 18), cause approximately 70% of all cervical 
cancers. Although the rates of cervical cancer have been declining over the past 40 years, 
largely due to effective screening and increased use of the Papanicolaou test, and the 
development of preventive HPV vaccinations (e.g., Gardasil, Gardasil 9, Cervarix), the 
American Cancer Society estimates that in 2016, approximately 13,000 new cases of invasive 
cervical cancer will be diagnosed and over 4,000 women will die from this disease in the United 
States alone. Rates of cervical cancer are significantly higher in less developed countries, 
making it the second most common cancer in women worldwide1-3. 
 
HPV-driven tumors have developed a variety of mechanisms to subvert immune surveillance. 
The tumor and tumor microenvironment is characterized by (1) the downregulation of MHC 
Class I expression and impaired antigen processing and presentation, (2) resistance to immune-
mediated, cytotoxic T-lymphocyte (CTL) cytotoxicity, (3) expression of immunosuppressive 
cytokines (e.g., TGF-β and IL-10) and immune-checkpoint molecules (e.g. PD-L1) and (4) the 
presence of immune cells with immunosuppressive properties (e.g., regulatory T cells, 
myeloid-derived suppressor cells)4-7. It follows that therapies aimed at promoting tumor-
specific immunity and reversing the immunosuppressive tumor microenvironment may be an 
effective treatment strategy in these cancers.     
  
This clinical trial will evaluate the safety and efficacy of a treatment combination that seeks to 
promote the anti-tumor immune response against HPV-16 and 18 positive cervical cancer by 
(1) promoting a tumor-specific, CD8+ immune response against the HPV E6 and E7 oncogenic 
epitopes through vaccination (GX-188E), and (2) preventing CD8+ T-cell exhaustion within 
the tumor microenvironment through blockade of the PD1 immune checkpoint 
(pembrolizumab).  


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Background on the Compounds 
 
GX-188E: Promoting HPV-16 and 18-Specific Anti-Tumor Immunity 
The first step to inducing cell-mediated immunity is the presentation of antigen by “professional” 
immunostimulatory antigen presenting cells (APCs), such as dendritic cells. GX-188E is a 6085 
base pair DNA vaccine containing HPV E6/E7 genes fused to Flt3 ligand. GX-188E was 
designed to induce a specific immune response against the E6 and E7 oncoproteins associated 
with the “high-risk” HPV serotypes, HPV-16 and 18. The GX-188E construct is a fusion gene 
encoding both E6 and E7 antigens as well as the extracellular domain of Flt3L to target and 
activate dendritic cells. In addition, the GX-188E-encoded sequence contains the secretion 
signal sequence derived from tissue plasminogen activator (tpa) to promote protein product 
secretion of the GX-188E-encoded antigenic fusion protein (Figure 1). The final expressed 
protein product is an 85 kDa antigenic (E6/E7) fusion protein with Flt3L-mediated 
immunostimulatory activity. In clinical trials, GX-188E has demonstrated (1) the ability to 
induce a tumor-specific CD8+ immune response and (2) functional activity to eliminate target 
cells against high-grade cervical intra-epithelial neoplasms (CIN3, carcinoma in-situ)8. 
 
 
 


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Figure 1. pGX27-E6E7 plasmid DNA map 
 
 
 
8.2.1.1 
Electroporation: Methodology for Cell Transfection 
Transfection of cells with naked plasmid DNA, such as GX-188E, requires a mechanism such 
as electroporation (EP). Although the exact mechanism by which EP facilitates transfection 
has not been established, the method has been used effectively for more than 3 decades by 


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molecular biologists to induce the expression of transfected genes. EP, which uses controlled 
electrical pulses, is thought to temporarily increase permeability of cell membrane and thereby 
increasing the cellular uptake of DNA plasmid. Recently, EP delivery of DNA has shown to 
increase antigen expression >10-fold higher and resulted in longer lasting immune response 
compared to conventional intramuscular injection in preclinical and early stage of clinical 
trials9. Pre-clinical study conducted by Ichor (EP provider) demonstrated that intramuscular EP 
enhanced transfection efficiency of DNA into muscle cells (myocytes) far more than 10 folds 
in an analysis using reporter gene expression (Figure 2). This enhanced expression of antigens 
resulted in increased T cell responses as well as survival rate against tumor challenge21. Clinical 
applications of EP have been tested, especially in cancer treatment and gene therapy10-12. 
Despite what may be lower gene delivery efficiency and shorter duration of gene expression 
compared to viral vectors, electroporation of DNA is not associated with the production of 
untoward anti-viral cell-mediated immune responses or the production of neutralizing anti-viral 
antibodies.  
Figure 2. GFP expression in muscle cross sections with or without EP (Ichor) 
 
Currently, a variety of EP devices using similar principles are under development. The 
intramuscular TriGridTM Delivery System (TDS-IM) by Ichor was used for GX-188E delivery 
in a Phase 1 trial in high-grade cervical intraepithelial neoplasia (CIN), and is currently 
employed in an ongoing Phase 2 multinational trial8, 13. At this time, EP-mediated gene transfer 
remains investigational and is not licensed by the FDA or EMEA except for clinical use. 


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8.2.1.2 
GX-188E Dose and Regimen Rationale 
In Phase 1, patients with high-grade CIN were treated with GX-188E at a dose of 1 mg, 2 mg 
and 4 mg per vaccination. Immunological responses, histological improvement and reduction 
in viral copy were observed at all doses, and there was no clear evidence for a dose-immune 
response relationship.  Furthermore, all three patients in the 1 mg dose cohort had normal 
histology, no evidence of intraepithelial lesions, and were negative by PCR for HPV at 36 
weeks after GX-188E initial administraion8. In addition, since utilizing multiple sites rather 
than a single site enhanced immune responses19, the number of inoculation sites will be 
increased to two sites. Therefore, the decision was made to move forward in cervical cancer at 
the 1 mg/site x 2 anatomic sites for a total 2 mg per vaccination day dosage. 
The vaccination schedule employed in the Phase 1 and Phase 2 trials in high-grade CIN includes 
only 3 GX-188E vaccinations, administered on the first day of treatment, at Week 4 and Week 
12. Although this vaccination schedule has demonstrated efficacy in a pre-malignant condition, 
a more aggressive schedule may be required for the treatment of advanced cervical cancer. This 
trial will involve more frequent vaccinations, with the goal of inducing a more robust, rapid and 
sustained immune response against HPV infected cells.  Patients will receive GX-188E 
vaccinations at Week 1 Day 1, Week 2, Week 4, Week 7, Week 13, Week 19. An optional GX-
188E administration may be given at week 46 if it is in the best interests of the patient, as 
determined by the investigator, once the patient has completed 37 weeks of treatment.  
Additional GX-188E administration(s) may be given to the subject after discussion with the 
sponsor. In this case of multiple injections, since repeated inoculation at the same site interferes 
with efficient transgene expression20, alternating inoculation between deltoid and lateralis 
muscles will be applied to overcome the interference. 
 
Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 
2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a 


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number of indications.  For more details on specific indications refer to the Investigator 
Brochure. 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 
Pembrolizumab contains the S228P stabilizing mutation and has no antibody-dependent cell-
mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity. 
Pembrolizumab modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-
α), interferon gamma (IFN-γ), and other cytokines. The antibody potentiates existing immune 
responses only in the presence of antigen and does not nonspecifically activate T cells. 
Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer patients, and primates. In T cell stimulation assays using 
human donor blood cells, the EC50 was in the range of 0.1 to 0.3 nM (see pembrolizumab 
Investigator Brochure). 
8.2.2.1 
Pembrolizumab Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades22 . Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma.23-24  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)25-26.  


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The structure of murine PD-1 has been resolved.42 PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains  tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-
cell signaling cascade26-29 . The mechanism by which PD-1 down-modulates T-cell responses 
is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins30-32 . As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in advanced cervical cancer. 
8.2.2.1.1 
Pre-Clinical and Clinical Trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities32-39  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma.36,39-42 In such studies, tumor infiltration by 
CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were observed, 
indicating that the mechanism underlying the antitumor activity of PD-1 checkpoint inhibition 
involved local infiltration and activation of effector T cell function in vivo39. Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see the Investigator’s 
Brochure [IB]). 
8.2.2.1.2 
Justification for Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by: 


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 Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
 Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses 
to the highest doses studied. Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 


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complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols. 
 
Hypothesis and Study Objectives 
 
Hypothesis 
This study is separated into three Parts, Part A, B and C. Part A will establish the recommended 
Phase 2 regimen for the investigational treatment; thus, Part A is not hypothesis-driven.  
Part B of this study will evaluate the exploratory efficacy of the investigational treatment 
regimen at the schedule established as safe and well-tolerated in Part A (i.e. recommended 
Phase 2 treament regimen).  Part B follows a Simon Two-Stage minimax design. It is 
hypothesized that the investigational treatment regimen will improve the ORR24  from 15% 
(Hnull) to 35% (Halt). The null hypothesis assumes an 15% ORR24 for this patient population 
receiving single-agent pembrolizumab14. In Part C, the null hypothesis assumes an 12.2% 
ORR24 for patient population receiving single-agent pembrolizumab44, regardless of PD-L1 
status. For additional details, please refer to Section 24. 
 
Study Objectives 
The primary objective of Part A is to establish the safety and tolerability of the investigational 
treatment regimen, and to determine the recommended treatment schedule for Part B. 
Secondary objectives of Part A include clinical efficacy and include, but are not limited to, 
objective response rate (ORR) by both RECIST v1.1 criteria17 (see Appendix 5) and Response 
Evaluation Criteria In Solid Tumors for Immunotherapeutics (iRECIST)18 (see Appendix 6), 
time-to-best response (TTR), duration of response (DOR), progression-free survival (PFS) and 
overall survival (OS). 
The primary objective of Part B and C is to evaluate the efficacy of the investigational study 
treatment, as determined by ORR24 by RECIST v1.1 criteria. Secondary objectives include, but 
are not limited to, BORR by RECIST v1.1 and iRECIST, TTR, DOR, OS, PFS, and DCR. In 
addition, the safety and tolerability of the investigational treatment regimen will also continue 
to be evaluated.  
Exploratory objectives of this study are to generate key biomarker data to understand the 
biological, and specifically, immunological mechanisms associated with and effects of the 
investigational treatment regimen. Peripheral blood will be collected to evaluate for the ability 
of GX-188E to induce a systemic HPV-16 and HPV-18-specific T-cell response that may 


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include, but is not limited to, expansion of CD4+ and CD8+ T-cells that recognize E6 or E7 
peptide epitopes. Tumor tissue will be obtained to determine whether the GX-188E vaccination 
promotes a Th1-polarized anti-tumor immune response. For further details on planned 
biomarker evaluations, please refer to Section 23.  
 
 
Study Design 
 
Description and Rationale for Study Design  
Compared to previous trials of GX-188E, this clinical trial employs a new GX-188E vaccination 
schedule, includes concurrent administration of pembrolizumab (P) and will enroll patients with 
advanced cervical cancer. Therefore, this necessitates a study that is designed to (1) evaluate 
the safety and tolerability of the GX-188E plus pembrolizumab (P) regimen, (2) establish a 
recommended Phase 2 treatment schedule, and (3) evaluate the clinical and biological efficacy 
of the investigational treatment regimen.    
Protocol GX-188E-005 is a Phase Ib/II multi-national, multi-center, open-label trial of GX-
188E plus pembrolizumab (P),  (GX-188E + P). Part A will be principally focused on safety 
and tolerability, and will establish the recommended Phase 2 treatment schedule for the 
investigational regimen. In Part B and C, the anti-tumor efficacy of the investigational regimen 
will be explored. 
 
 
Part A: Evaluation of Safety and Tolerability 
Part A follows a standard 6 + 3 design and will establish the recommended Phase 2 treatment 
schedule for the investigational combination. 
A minimum of 6 patients will be enrolled and treated at the Starting Schedule (see Table 3 in 
Section 12). If none or only 1 of the first 6 patients experiences a dose-limiting toxicity (DLT) 
(for protocol defined DLTs, please refer to Section 21), the study will move into Part B. If two 
patients experience a DLT, an additional 3 patients will be enrolled and evaluated for DLTs. If 
no additional patients experience a DLT (i.e. only 2 out of 9 patients have DLTs), enrollment 
into Part B will be initiated. If 3 patients in 6 or 9 have a DLT, the Starting Schedule will be 
considered to be too toxic and enrollment into Reduction Level 1 (see Table 3 in Section 12) 
will be initiated. If one of the first 6 patients, or no more than 2 patients in a total of 9, 
experiences a DLT at Reduction Level 1, then this regimen will be moved into Part B of the 
study. If 3 patients in 6 or 9 receiving Reduction Level 1 experience a DLT, then the 


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investigational regimen will be considered to be too toxic and no additional patients will be 
enrolled into the trial. Only one reduction in the treatment schedule is planned.  
Patients without DLT who are treated with the recommended Phase 2 regimen and who are 
considered to be evaluable for efficacy will be included in the efficacy analysis for the first 
stage of Part B. 
 
Part B: Exploratory Efficacy Evaluation of GX-188E + P  
Part B of this study employs a Simon Two-Stage design to evaluate the anti-tumor efficacy of 
the investigational combination at the recommended Phase 2 schedule established as tolerable 
in Part A. In the first stage (Stage 1) of Part B, 15 patients will be treated. These may include 
any patients from Part A (1) who do not experience a DLT, (2) receive the recommended Phase 
2 treatment regimen, and (3) who are considered evaluable for efficacy. If at least 3 efficacy 
evaluable patients from Part B Stage 1 (see Section 24.4) have objective responses by RECIST 
v1.1 criteria (partial response or better) within the first 24 weeks of treatment, an additional 13 
patients will be enrolled, for a total of 28 efficacy evaluable patients. If 2 or fewer efficacy 
evaluable patients in Part B Stage 1 have an objective response, enrollment into the study will 
be discontinued for futility. Study has passed the first stage of Simon-Two stage design. 
 
Part C: Efficacy Evaluation in Larger Number of Patients 
If at least 8 of the 28 subjects enrolled in Part B, experience an objective response who are 
considered evaluable for efficacy, it will be considered that ORR satisfies the criteria for study 
expansion and additional subjects will be enrolled in Part C to evaluate efficacy further in larger 
population. If only 7 or fewer subjects in Part B experience an objective response, enrollment 
to Part C will not open. 
 
Number of Patients 
Maximum 60 patients are planned for recruitment to both Parts A, B and C of this study. As 
previously described in Section 10.2 above, minimum of 6 patients will be enrolled into Part 
A. The maximum number of safety evaluable patients to be enrolled into Part A is 18.  
Part B of this study employs a Simon-Two Stage Design. A minimum of 15 efficacy evaluable 
patients (see Section 24.4), which may include some patients from Part A, will be included in 
the analysis for Stage 1. If 3 or more patients in Stage 1 experience objective responses (i.e., 
Partial Response or better), the study will move into Part B Stage 2 and an additional 13 patients 


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will be treated, for a total of 28 efficacy evaluable patients. Study has passed the first stage of 
Simon-Two stage design. 
If at least 8 of the 28 subjects enrolled in Part B, experience an objective response who are 
considered evaluable for efficacy, it will be considered that ORR satisfies the criteria for study 
expansion and additional 17 subjects (at least) will be enrolled in Part C to evaluate efficacy 
further in larger population (N=45~60). Refer to the Section 24.3 Sample Size and Power for 
detailed assumptions for sample size estimation. 
 
Number of Study Centers 
The study will be performed at least 8 investigational sites in the the Republic of Korea. 
Additional sites may be added as necessary for patient enrollment. 
 
Selection of Study Population 
All patients must participate in the consent process.  During the consent process, the person 
obtaining consent must inform the patient of all elements of informed consent.  No protocol-
specific procedures, including screening procedures, are to be performed until the patient has 
signed and dated an institutional review board (IRB)/independent ethics committee (IEC)-
approved informed consent form.  For each patient, study participation begins with the signing 
and dating of the informed consent form.  Patients must also meet the inclusion and exclusion 
criteria to be enrolled in the study. 
 
Inclusion Criteria 
1. Patients must be female and age ≥ 18 years on day of signing of informed consent; 19 
years for patients treated in Korea 
2. Patients with histologically confirmed advanced or metastatic HPV-positive (HPV-16 
or HPV-18) cervical cancer, who have disease progression after treatment with all 
available therapies for metastatic disease that are known to confer clinical benefit, or 
are intolerant to treatment, or refuse standard treatment. 
Note: there is no limit to the number of prior treatment regimens. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
4. Life Expectancy of at least 6 months 
5. Patients must agree to provide either an archival tumor tissue sample or fresh biopsy 
sample for baseline biomarker tissue analyses, including staining for PD-L1. If archival 


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tissue is not available and the patient does not have biopsy-accessible tumor lesions, the 
patient will be excluded. 
6. Patients must have must have adequate organ function as defined in the following table 
(Table 1). Specimens must be collected within 28 days prior to the start of study 
treatment. 
Table 1: Organ Function Requirements for Eligibility 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/L1 
Renal 
 
Creatinine OR 
Measured or calculated2 creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN (except in patients with 
Gilbert’s Syndrome who must have a total 
bilirubin < 3x ULN and ALT < 3x ULN) 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use 
of anticoagulants 
ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) =aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
1 Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 4 weeks.  
2 Creatinine clearance (CrCl) should be calculated using the Cockroft-Gault equation. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies. 
7. Patients must have RECIST measurable disease, defined as: 


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o Tumor lesion ≥ 1 cm in longest diameter (LD) on an axial CT or MRI image (≤5 
mm reconstruction interval)  
-OR- 
o Lymph node ≥1.5 cm in the short axis on CT (≤5 mm reconstruction interval) 
8. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required 
9. WOCBP must be willing to use an adequate dual method of contraception during the 
course of the study through 120 days after the last dose of study medication. Post-
menopausal females (> 45 years old and without menses for > 1 year) and surgically 
sterilized females are exempt from these requirements.  Note: Abstinence is acceptable 
if this is the usual lifestyle and preferred contraception for the subject.  
10. Be willing and able to written informed consent for the trial in accordance with federal, 
local, and Institutional guidelines. 
 
 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Patient has disease that is suitable for local therapy administered with curative intent 
2. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (e.g., breast carcinoma) that have undergone potentially 
curative therapy are not excluded.  
3. Patient is expected to require any other form of antineoplastic therapy while on study; 
including systemic chemotherapy, radiation therapy (except for palliative purposes) 
biological therapy, or immunotherapy not specified in this protocol. 
4. Patient has a history of active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, 
OX 40, CD137)  and was discontinued from that treatment due to a Grade 3 or higher 
immune-related Adverse Event (irAE).  
6. Patients with active autoimmune disease requiring systemic immunosuppressive 
treatment within the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment and is allowed.  


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7. Has had an allogeneic solid organ or allogeneic bone marrow transplant  
8. Patient has had a prior, non-PD-1/PD-L1/PD-L2, anti-cancer monoclonal antibody 
(mAb) (e.g., bevacizumab, cetuximab, etc) within 4 weeks prior to the first dose of 
study medication or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
9. Has received prior systemic anti-cancer therapy, including investigational agents within 
4 weeks, or within 2 weeks for targeted small molecule therapies with a half-life of <48 
hrs prior to the first dose of study medication 
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy and/or ≤Grade 2 anemia  
may be eligible. 
Note: If patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
10. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants 
must have recovered from all radiation-related toxicities 
11. Patient has received transfusion of blood products (including platelets or red blood cells) 
or administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoietin) within 4 weeks prior to the first dose of study medication. 
12. Patients with bilateral hydronephrosis that cannot be alleviated with ureteral stents or 
percutaneous nephrostomy 
13. Has severe hypersensitivity (≥Grade 3) pembrolizumab and/or any of its excipients. 
14. Patient has a history of (non-infectious) pneumonitis that required steroids or has 
current pneumonitis. 
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.. 
16. Patient has risk factors for bowel obstruction or bowel perforation (examples include 
but not limited to a history of acute diverticulitis, intra-abdominal abscess, and 
abdominal carcinomatosis). 
17. Patient who is currently participating in or has participated in a study of an 
investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of study medication 
Note: Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been > 4 weeks after the last dose of the previous 
investigational agent. 
18. Unstable/inadequate cardiac function: 
 Symptomatic ischemia 


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 Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics are excluded); 1st degree AV block or 
asymptomatic LAFB/RBBB are eligible 
 Myocardial infarction in the previous six months 
 Congestive heart failure (New York Heart Association class III to IV) 
19. Has an active infection requiring systemic therapy. 
20. Participants with known human immunodeficiency virus (HIV) and/or history of 
Hepatitis B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ 
Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is 
defined by a known positive Hep C Ab result and known quantitative HCV RNA results 
greater than the lower limits of detection of the assay.. 
21. Patient has a known history of active TB (Bacillus Tuberculosis) 
22. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study drug. Note: Administration of killed vaccines are allowed. 
23. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study. 
24. Patient who received an implantable electronic device (e.g., pace maker) 
25. A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to 
treatment.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required 
26. Patients who are pregnant or lactating. 
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator. 
 
Duration of Patient Participation 
All patients will be permitted to remain on study to receive the investigational combination 
treatment as long as it is well tolerated and both the Investigator and Sponsor agree that the 
patient may be clinically benefitting from treatment, for up to 2 years.  Reasons for treatment 
discontinuation include, but are not limited to, the following: 
 Unacceptable or Dose-Limiting Toxicity 
 Disease Relapse or Progression 
 Death 
 Voluntary withdrawal of consent 
 Non-compliance to study procedures and requirements 
 Investigator decision 


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 Sponsor decision to terminate the study 
Unless a patient withdraws consent or dies during the treatment period of the study, she will be 
followed for up to 1 year after study treatment discontinuation for survival data. 
 
Duration of Study 
The duration of the study will depend on the recruitment rate and the duration of treatment for 
those patients enrolled.  
 
Investigational Treatments-Product Information 
The investigational treatment for this study consists of intramuscular vaccination with GX-
188E, delivered with electroporation and intravenous administration of pembrolizumab. 
Table 2. Investigational Treatment Product Details 
Product 
Active Ingredient 
Inactive Ingredient(s) 
GX-188E 
2 mg/mL* 
pGX27-E6E7 
Potassium Chloride (USP) 
Sodium Phosphate Dibasic, Anhydrous  (USP) 
Potassium Phosphate Monobasic, Anhydrous, Crystals (NF) 
Sodium Chloride (USP) 
Water for Injection (USP) 
Pembrolizumab 
pembrolizumab 
 L-histidine, polysorbate 80, and sucrose. May contain 
hydrochloric acid/sodium hydroxide, or water for injection 
*Target concentration of the DNA plasmid 
 
GX-188E Product Information 
As previously described, GX-188E, is a DNA plasmid that encodes a fusion protein containing 
the E6 and E7 proteins of HPV16 and 18, and human Fms-like tyrosine kinase 3 ligand (hFLT-
3L). GX-188E will be provided by Genexine Inc. or its designee. 
The GX-188E vials will be shipped directly from the manufacturer or its designee to regional 
depot which to be shipped to each individual study site. Each vial will be labeled with a single 
panel label. Vials will only be handled by designated personnel (e.g. pharmacist) at each site.  
 


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Storage and Handling of GX-188E 
Genexine, Inc. will be responsible for assuring that the quality of the GX-188E investigational 
product is adequate for the duration of the trial. Unless otherwise specified, GX-188E will be 
shipped at -20oC with a temperature monitoring device. If the temperature monitoring device 
denotes temperatures outside the pre-specified range, the Sponsor, or its designee should be 
contacted immediately.  
 
GX-188E should be stored in a secure area according to local regulations, and should be 
transferred from the shipping container to the appropriate storage conditions (refrigerated at -
20ºC) upon arrival. The recommended storage condition for GX-188E is -20°C. The Sponsor 
should be notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be recorded 
and monitored regularly. 
 
 
Dispensing of GX-188E 
It is the responsibility of the Investigator to ensure that GX-188E is only dispensed to study 
participants. GX-188E must be dispensed only from official study sites by authorized personnel 
according to local regulations. GX-188E will be provided to the investigational pharmacy in 
vial form directly from the manufacturing facility or designee.  
The designated site staff member will be responsible for dispensing the appropriate volumes 
(one 0.5 ml volume) of GX-188E according to the instructions provided in the study Pharmacy 
Manual.  In brief, a single injection syringe containing 1 mg of GX-188E will be prepared and 
loaded into the Cartridge of the Integrated Applicator (Figure 3). A qualified investigator or 
designee will deliver GX-188E by pressing a single button in the Integrated Applicator, which 
will deliver all its content at once, into the patient’s deltoid or lateralis muscle. 


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Figure 3. TDS-IM ® Cartridge and Integrated Applicator 
 
 
 
Records of GX-188E Disposition at Investigational Site(s) 
It is the responsibility of the Investigator to ensure that a current record of GX-188E disposition 
is maintained at the study. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 Amount received and placed in storage area; 
 Amount currently in storage area; 
 Label ID number or batch number and use date or expiry date; 
 Dates and initials of the person responsible for each investigational product inventory 
entry/movement; 
 Amount dispensed to each patient, including unique patient identifiers; 
 Amount transferred to another area/site for dispensing or storage; 
 Non-study disposition; 
 Amount returned to Sponsor; 
 Amount destroyed at study site, if applicable. 
 
Integrated Applicator 
Application Cartridge 
(and syringe) 
Pulse Stimulator 


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Return and Destruction of GX-188E 
Upon completion or termination of the study, all unused and/or partially used GX-188E product 
must be returned to Genexine, Inc., or its designee, if not authorized by Genexine, Inc. to be 
destroyed at the site. GX-188E product that is returned to Genexine Inc., or its designee, must 
be accompanied by the appropriate documentation. Returned supplies should be in the original 
containers. Empty containers should not be returned to Genexine Inc. It is the Investigator’s 
responsibility to ensure proper disposal for all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of unused investigational product(s) should be arranged by the responsible Site 
Monitor. 
If GX-188E products are to be destroyed on site, it is the Investigator’s responsibility to ensure 
that arrangements have been made for the proper disposal, and written authorization has been 
granted by Genexine, Inc. or its designee. It is the Investigator’s responsibility to ensure that 
procedures for proper disposal have been established according to applicable regulation and 
guidelines and institutional procedures, and appropriate records of the disposal have been 
documented. The unused investigational products can only be destroyed after being inspected 
and reconciled by Genexine Inc. or responsible party designated Site Monitor. 
 
 
TDS-IM ®  Electroporation Device Use and Accountability 
Detailed instructions for use of the TDS-IM® device are located in the TDS-IM® Operations 
Manual. Each clinical site will receive training for the use of the TDS-IM® device.  
The GX-188E vaccination and electroporation procedure must be performed by qualified 
personnel who have been trained to participate in this clinical trial. Any individual designated 
to perform the procedure should be permitted by the relevant local authorities to administer 
vaccinations to patients (e.g. MD, DO, PA, NP, RN) in addition to receiving device training 
from sponsor personnel.  
Each clinical site is responsible for maintaining investigational device accountability. This 
includes recording the TDS-IM ® serial number, applicator serial number, and array lot number 
used for vaccination + EP of each subject. 


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Pembrolizumab Product Information 
As previously described, Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) 
monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 
(PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) 
and programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD 1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda™ (pembrolizumab) 
is indicated for the treatment of patients across a number of indications.  For more details on 
specific indications refer to the Investigator brochure. 
Pembrolizumab is provided as a solution for infusion, in 100 mg/vial dose strength. Clinical 
supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  Receipt and dispensing of trial medication must be recorded by an 
authorized person at the trial site. Clinical supplies may not be used for any purpose other than 
that stated in the protocol. 
 
 
Investigational Treatment Plan-Route and Regimen 
The investigational treatment regimen of GX-188E + pembrolizumab (P) will be administered 
according to the schedules described in this section. The investigational treatment regimen will 
be offered to each patient as long as both the patient and Investigator agree that it continues to 
be well tolerated, and there has been no evidence of clinical or radiographic disease progression. 
 
Part A: Establishing Recommended Phase 2 Treatment Schedule 
The full investigational treatment plan is described in Table 3. 
 
Starting Treatment Schedule 
The following treatment schedule will be the initial regimen to be explored in this study. If this 
regimen is considered to be well-tolerated, in accordance with the rules of the “6 + 3” study 
design and the protocol-defined dose-limiting toxicities (DLTs) (Section 21), the study will 
move into Part B (Simon Two-Stage) and will employ this treatment schedule. If 3 patients 
in the first 6 or 9 experience DLTs, then the Reduction Level 1 treatment schedule described 
in Section 12.1.1.3 will be explored. 


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12.1.1.1 
GX-188E Administration 
GX-188E will be injected intramuscularly (IM), to either deltoid (D) or lateralis (L) muscles, 
followed immediately by co-localized electroporation (EP) at each scheduled vaccination day. 
Each muscle will receive 1 mg of GX-188E, for a total of 2 mg per vaccination day. 
Vaccination sites should alternate between deltoid and lateralis muscles according to the 
following schedule: Week 1 Day 1 (both right and left D), Week 2 Day 1 (both right and left 
L), Week 4 Day 1 (both right and left D),  Week 7 Day 1 (both right and left L), Week 13 Day 
1 (both right and left D), Week 19 Day 1 (both right and left L).An optional GX-188E 
administration may be given at week 46 if it is in the best interests of the patient, as determined 
by the investigator, once the patient has completed 37 weeks of treatment.  Additional GX-
188E administration(s) may be given to the subject after discussion with the sponsor. For GX-
188E administrations at Week 46 Day 1, a 2-week window period is permitted in this protocol 
because this vaccination is considered to be “booster” and a large window period is not 
expected to alter the biological effects. Vaccination sites of GX-188E can be alternated to either 
deltoid or lateralis muscles, if GX-188E is not administered correctly at the vaccincation site. 
In this cases, altered vaccination sites must be recorded on the CRF. 
12.1.1.2 
Pembrolizumab (P) Administration 
Pembrolizumab will be administered according to standard clinical and institutional practices. 
In brief, Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week 
treatment cycle after all procedures and assessments have been completed. For the purposes of 
this study, pembrolizumab should be administered after the GX-188E vaccination on all days 
in which patients are scheduled to receive both. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
12.1.1.3 
Timing of Dose Administration 
Trial treatment of pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each pembrolizumab cycle due to administrative reasons 


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Reduction Level 1 Treatment Schedule 
If the starting treatment schedule described in Section 12.1.1 is not considered tolerable based 
on the incidence of dose-limiting toxicities (DLTs) (Section 20), the safety of the following 
treatment schedule (“Reduction Level 1”) will be explored. If Reduction Level 1 is considered 
to be well-tolerated, in accordance with the rules of the “6 + 3” study design and the protocol-
defined DLTs, the study will move into Part B (Simon Two-Stage) and will employ this 
treatment schedule. If 3 patients in 6 or 9 experience a DLT, then the investigational regimen 
will be considered too toxic and enrollment into the study will be discontinued.   
12.1.2.1 
Reduction Level 1 GX-188E 
The modification to GX-188E administration at Reduction Level 1 involves removal of the 
GX-188E vaccination at Week 2 Day 1. At Reduction Level 1, GX-188E will be administered 
Week 1 Day 1, Week 4 Day 1, Week 7 Day 1, Week 13 Day 1, Week 19 Day 1 and Week 46 
Day 1(Optional).  
12.1.2.2 
Reduction Level of Pembrolizumab 
The dosage and frequency for pembrolizumab will not be modified. Patients will receive the 
regimen for pembrolizumab as described in Section 12.1.1.2 
 
Table 3. Investigational Treatment Schedules 
Treatment 
Schedule 
GX-188E 
Pembrolizumab 
(P) 
Starting Schedule 
Week 1 Day 1, Week 2, Week 4, Week 7, Week 
13, Week 19 and Week 46 (Optional)  
200 mg Day 1 q 3 
weeks 
Reduction Level 1 Week 1 Day 1, Week 4, Week 7, Week 13, Week 
19, and Week 46 (Optional) 
(remove Week 2) 
200 mg Day 1 q 3 
weeks 
(unchanged) 
 
 
General Dosing Adjustments and Delays and Supportive Care Instructions 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. 


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Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included 
as part of the evaluation. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 4. 


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Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab. 
General instructions: 
1. For Severe and life-threatening irAEs, should be treated with IV corticosteroid should be initiated first 
corticosteroids followed by oral steroidsteroids. Other immunosuppressive treatment should be initiatedbegin if 
the irAEs cannot beare not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE v4.0 or 
the most recent 
version) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 Add prophylactic 
antibiotics for 
opportunistic 
infections 
 Monitor participants 
for signs and symptoms 
of pneumonitis 
 Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment 
Recurrent  
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
 Monitor participants 
for signs and symptoms 
of enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation 
(ie, peritoneal signs and 
ileus). 
 Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis.  
 Participants with 
diarrhea/colitis 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. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
 Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
 Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 


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prednisone or 
equivalent) 
followed by taper 
enzyme value returned 
to baseline or is stable 
Grade 3 b or 4 c  
Permanently 
discontinue 
 Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
New onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
 Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated. 
 Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue d  
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
 Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue  
 Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
 Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold  
 Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper. 
 Monitor changes of 
renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
 Based on severity 
of AE administer 
corticosteroids 
 Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
All Other immune-
related AEs 
Persistent Grade 2 
Withhold 
 Based on severity 
of AE administer 
corticosteroids  
 Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event e 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 


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a. AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0   5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5   3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b. AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0   20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0   10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c. AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d. The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e. Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 


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  Requirements for treatment discontinuation are not strict and individual situations will 
be evaluated on a case-by-case basis. Treatment discontinuation for both non-hematological 
and hematological toxicities will be based on the Principal Investigator’s judgment following 
discussion with the Sponsor’s Medical Monitor. 
 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 5. 
 
 


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Table 5. Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
 
Stop Infusion. 
 
Additional appropriate medical therapy may include 
but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDs 
 
Acetaminophen 
 
Narcotics 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100 mL/hr. to 50 
mL/hr.). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Participant 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
study interventionwith: 
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 
500-1000 
mg po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
 
 
Stop Infusion. 
 
Additional appropriate medical therapy may include 
but is not limited to: 
 
Epinephrine** 
 
IV fluids 
 
Antihistamines 
 
NSAIDs 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 or the most recent 
version (CTCAE) at http://ctep.cancer.gov 


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Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks or 21 days of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for interruption is to be documented in the patient's 
study record. 
 
Supportive Care Guidelines for Events of Clinical Interest and Immune-
related Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
of potential irAEs.  An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE. Patients who 
develop a Grade 2 or higher irAE should be discussed immediately with the Sponsor.   
 
Prior Treatment 
Patients should have disease that is relapsed or refractory to standard-of-care treatment 
regimens.  Patients should not be candidates for other approved, standard-of-care therapies.  
Patients with newly-diagnosed disease that is not amenable to definitive surgery and who 
refuse treatment with standard regimens are permitted with clear Investigator documentation.  
In addition, the determination that there are “no available therapies that will confer clinical 
benefit” for the patient will be based on the medical opinion of the Principal Investigator.  
 
Reasonable efforts will be made to determine all relevant prior treatments received by the 
patient during the Screening period.  All previous cancer treatments, including systemic 


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therapies, radiation and/or surgical procedures, should be recorded on the patients’ case report 
forms (CRF). 
 
Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting. 
 
Concomitant Treatments 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medications must be recorded on the CRF, including all 
prescription, over-the-counter (OTC), herbal and vitamin supplements, and IV medications 
and fluids. The reason for treatment, name of the drug, dosage, route, and start and stop dates 
of administration for each concomitant medication will also be reported on the CRF.  All 
changes (e.g., changes in dose, discontinuation, etc.) in concomitant treatments that occur 
during the trial period should also be reported. 
All concomitant medications received to the subject within 28 days prior to the first dose  
through the end of the subject’s study participation should be recorded. (However, during the 
follow-up period after the end of the clinical trial, only the data about the antineoplastic 
therapy (surgical therapy, chemotherapy, radiation therapy, etc.) treated after the end of the 
subject’s study participation is recorded.).Concomitant medications administered 30 days 
after the last dose of study treatment should be recorded for SAEs and events of clinical 
interest (ECIs) as defined in Section 20.8 
 
Acceptable Concomitant Medications 
With the exception of medications specifically prohibited in Exclusion Criteria 3 and 6, and 
during the treatment period of this study (see Section 15.2), patients are permitted to receive 
any supportive medications and treatments to manage ongoing medical conditions or 
AEs. .Patients may receive red blood cell and platelet transfusions, or other hematopoietic 
support (i.e. growth factors) as needed during study participation after eligibility has been 
determined and the patient has been enrolled into the trial.   


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Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from study intervention or vaccination 
may be required.  The investigator is to discuss prohibited medication/vaccination with the 
Sponsor’s Clinical Director.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant's primary physician.  However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor and the participant. 
Listed below are specific restrictions for concomitant therapy or vaccination during the course 
of the study: (Note: There are no prohibited therapies during the post-treatment long-term 
follow-up period).  
 Anti-cancer systemic chemotherapy or biological therapy other than those specified in 
the protocol (GX-188E, pembrolizumab) 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol  
 Investigational agents other than Use of investigational therapeutic agents than those 
specified in the protocol (i.e., investigational regimen; GX-188E, pembrolizumab).  
 Radiation therapy   
o Note:  Radiation therapy to a symptomatic solitary lesion, to the brain, or for 
palliative purposes may be allowed after consultation with Sponsor Medical 
Monitor.   
 Live or live attenuated vaccines within 30 days prior to the first dose of trial treatment 
and while participating in the trial.  
Note: Administration of killed vaccines are allowed.  
Note: Any licensed COVID-19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines.  These vaccines will be treated just as any other concomitant 
therapy. Investigational vaccines (i.e., those not licensed or approved for Emergency 
Use) are not allowed. 
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor Medical 
Monitor. Topical and inhaled steroids are permitted. 


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 Red blood cell or platelet transfusion, and hematopoietic growth factors are not 
permitted within 4 weeks prior to the first dose of study medication. However, once a 
patient has met all eligibility criteria and has enrolled into the trial, hematopoietic 
support treatments are permitted.    
Patients who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Patients 
may receive other medications that the Investigator deems to be medically necessary.  
 
STUDY PROCEDURES AND OBSERVATIONS 
All procedures for Part A,B and C are identical. These procedures are described in table format 
in the Schedule of Events (Appendix 1) 
 
Screening Evaluation 
The following Screening assessments must be performed within 28 days before administration 
of any component of the investigational treatment regimen. Procedures listed below that are 
performed as part of the normal standard of care (SOC) and within 28  days prior to Week 1 
Day 1 may be used for screening purposes.If there are clinically significant abnormal 
laboratory test results or suspicious laboratory results, at the discretion of investigator (1) one 
time re-test for subjects with screening purposes is allowed (2) For screen-fail subjects with 
same reason above, one time re-screen is allowed. 
 : 
1. Sign and date an IRB/IEC-approved informed consent form before any study-specific 
(i.e., non-SOC) screening procedures are performed. 
2. Demographic information including date of birth, gender, and ethnic origin  
3. Medical history, including review of prior cancer treatments and documentation of 
HPV 16 or 18 positive cervical cancer. HPV-16 or HPV-18 positivity will be 
determined according to the patients’ previous medical records or in situ PCR method 
using the patients’ archival tissue sample or new biopsy tissue sample.  
4. Review of concomitant medications 
5. ECOG performance evaluation 


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6. Moore criteria evaluation (APPENDIX 3). Determine whether the patient is classified 
as low risk, mid risk, or high risk based upon Moore criteria15, 16 
7. Complete physical examination including weight (kg) and height (cm) 
8. Vital signs [sitting blood pressure, pulse rate, respiratory rate, and temperature] 
9. Chest X-ray, ECG and Clinical laboratory evaluation (hematology, coagulation, serum 
chemistry, serology, urinalysis), including blood CEA/TA4 levels and thyroid function 
tests; see Appendix 4. 
10. Serum or urine pregnancy test.  This is only required for females of child-bearing 
potential and must be negative within 3 days prior to Week 1 Day 1. 
11. Research blood collection. (including blood sample for Flt-3L level monitoring) 
12.  Pre-treatment tumor biopsy. All patients must submit either an archival tumor tissue 
sample or fresh biopsy sample at Screening.  Coagulation tests must be performed and 
evaluated within 24 hr prior to all biopsy procedures. 
13. Radiographic evaluation of tumor burden. Scans performed within 28 days of Week 1 
Day 1 will be accepted and do not need to be repeated unless a clinically significant 
difference is suspected.  See Appendices 5 and 6. 
 
A patient who meets all of the inclusion criteria may enter the study.  Screen failures will be 
reported into the Screen Failures Log. 
 
Week 1 Day 1 
At the Week 1 Day 1 visit, patients will return to the clinic for the first administration of GX-
188E and P.  
Patients will undergo the following procedures on Week 1 Day 1: 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 


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5. Clinical laboratory evaluation (hematology, serum chemistry, urinalysis). The 
laboratory tests may not be performed repately if the screening tests were performed 
within 7 days of Week 1 Day 1 and the clinically significant changes for the results 
were not suspected. 
6. Research blood collection. This sample must be obtained prior to the first dose of GX-
188E and pembrolizumab. 
7. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
8. Administration of GX-188E at both right and left deltoid muscles 
9. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both.  
 
Week 2 Day 1 (± 3 days) 
At Week 2 Day 1, patients will return to the clinic for administration of GX-188E (without 
pembrolizumab) and undergo the following procedures: 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. Clinical laboratory evaluation (hematology and serum chemistry).  
6. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
7. Administration of GX-188E at both right and left lateralis muscles 
 


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Week 3 Day 1 (±3 days) 
Only safety evaluations will occur at the Week 3 Day 1 visit; no study drugs will be 
administered.  Patients will undergo the following procedures on Week 3 Day 1: 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. Clinical laboratory evaluation (hematology and serum chemistry).  
 
Week 4 Day 1 (± 3 days) 
At Week 4 Day 1, patients will return to the clinic for administration of GX-188E + P and 
undergo the following procedures: 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology and serum chemistry).  
7. Research blood collection.  
8. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
9. Administration of GX-188E at both right and left deltoid muscles (or, lateralis muscles 
for Reduction Level 1) 
10. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both.  
 


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Week 7 Day 1 (±3Days) 
At Week 7 Day 1, patients will return to the clinic for administration of GX-188E + P and 
undergo the following procedures:  
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology, serum chemistry, and both blood CEA/TA4 
levels and thyroid function tests).  
7. Research blood collection.  
8. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
9. Administration of GX-188E at both right and left lateralis muscles (or, deltoid muscles 
for Reduction Level 1) 
10. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both.  
 
 
Week 10 Day 1 (± 3 days) 
At Week 10 Day 1, patients will return to the clinic to receive pembrolizumab and undergo the 
following procedures:  
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 


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5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology, serum chemistry, urinalysis, coagulation). 
7. Research blood collection. (including blood sample for Flt-3L level monitoring) 
8. Optional post-baseline tumor biopsy.  Coagulation tests must be performed and 
evaluated within 24 hr prior to all biopsy procedures. 
9. Radiographic evaluation of tumor burden and determination of response by RECIST 
v1.1 and iRECIST.  See Appendices 5 and 6.  
10. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both.  
 
 
Week 13 Day 1 (± 3 days) 
At Week 13 Day 1, patients will return to the clinic for administration of GX-188E + P and 
undergo the following procedures:  
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology, serum chemistry, and both blood CEA/TA4 
levels and thyroid function tests).  
7. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
8. Administration of GX-188E at both right and left deltoid muscles (or, lateralis muscles 
for Reduction Level 1) 


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9. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both. 
 
 
Week 16 Day 1 (± 3 days) 
Patients will return to the clinic to receive pembrolizumab. Standard-of-care safety procedures 
are required only as clinically indicated and per institutional standards of care in association 
with usual pembrolizumab administration. Only clinically significant abnormalities will be 
reported into the database and noted as adverse events. 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight  
4. Symptom-directed physical exam  
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology and serum chemistry).  
7. Research blood collection 
8. Pembrolizumab administration. For the purposes of this study, pembrolizumab should 
be administered after the GX-188E vaccination on all days in which patients are 
scheduled to receive both. 
 Week 19 Day 1 (±3 days) 
At Week 19 Day 1, patients will return to the clinic for administration of GX-188E + P and 
undergo the following procedures 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 


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6. Clinical laboratory evaluation (hematology, serum chemistry, and both blood CEA/TA4 
levels and thyroid function tests).  
7. Radiographic evaluation of tumor burden and determination of response by RECIST 
v1.1 and irRECIST.  See Appendices 5 and 6. 
8. Pain Assessment. Within 30 minutes before and 5 minutes (± 2 minutes) after GX-
188E administration, pain score in association with the electroporation (EP) procedure 
should be reported.  
9. Administration of GX-188E at both right and left lateralis muscles (or, deltoid muscles 
for Reduction Level 1) 
10. Administration of pembrolizumab. For the purposes of this study, pembrolizumab 
should be administered after the GX-188E vaccination on all days in which patients 
are scheduled to receive both. 
 Other Schedules Subsequent to Week 19 Day 1 
After Week 19 Day 1, GX-188E vaccination will occur only one additional time, at Week 46 
Day 1. In case that, an optional GX-188E administration may be given at week 46 if it is in the 
best interests of the patient, as determined by the investigator, once the patient has completed 
37 weeks of treatment. Additional GX-188E administration(s) may be given to the subject after 
discussion with the sponsor. 
Pembrolizumab will continue to be administered once every 3 weeks.  
Blood CEA/TA4 levels and thyroid function tests will be performed approximately every 6 
weeks for the duration of study participation. 
Research blood will be collected further at Week 22, Week 49, and every 27 weeks thereafter. 
(Including blood sample for Flt-3L level monitoring). Research blood collections are not 
performed on Day 1 of Week 103 visit but at the EOS visit. 
 
Every 3 Weeks (after Week 19 Day 1)(± 3 days) 
After Week 19 Day 1, patients will return to the clinic to receive pembrolizumab. Standard-of-
care safety procedures are required only as clinically indicated and per institutional standards 


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of care in association with usual pembrolizumab administration. Only clinically significant 
abnormalities will be reported into the database and noted as adverse events. The last dose of 
Pembrolizumab would be administered on Week 103 Day 1 and patients will undergo the 
following procedures. 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight  
4. Symptom-directed physical  
5. Clinical laboratory evaluation (as indicated; only clinically significant findings will be 
reported).  
6. Pembrolizumab administration  
 
Every 9 Weeks (after Week 19 Day 1) (± 1 week) 
Approximately every 9 weeks after Week 19 Day 1, patients will return to the clinic to undergo 
the following procedures: 
1. AE monitoring 
2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology, serum chemistry).  
7. Radiographic evaluation of tumor burden and determination of response by RECIST 
v1.1 and iRECIST.  See Appendices 5 and 6. 
In accordance with the standard administration schedule (i.e. every 3 weeks), pembrolizumab 
will also be administered at these visits as appropriate.  
 
Week 46 Day 1 (± 1 week, GX-188E optional administration) 
At Week 46 Day 1, patients will return to the clinic to receive undergo the following procedures: 
1. AE monitoring  


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2. Recording of concomitant medications  
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. ECOG Performance Status 
6. Clinical laboratory evaluation (hematology, serum chemistry).  
7. An optional GX-188E administration may be given at week 46 if it is in the best 
interests of the patient, as determined by the investigator, once the patient has 
completed 37 weeks of treatment. Additional GX-188E administration(s) may be given 
to the subject after discussion with the sponsor. (Optional) Pain Assessment. Within 30 
minutes before and 5 minutes (± 2 minutes) after GX-188E administration, pain score 
in association with the electroporation (EP) procedure should be reported.  
8. (Optional) Administration of GX-188E at both right and left deltoid muscles (or, 
lateralis muscles for Reduction Level 1) 
In accordance with the standard administration schedule (i.e. every 3 weeks), pembrolizumab 
will also be administered as appropriate. For the purposes of this study, pembrolizumab should 
be administered after the GX-188E vaccination on all days in which patients are scheduled to 
receive both.  
 
 End of Study (EOS) 
The End of Study (EOS) visit must occur within 28 days of treatment discontinuation / 
completion (Week 103 Day 1) and prior to initiation of any new anti-cancer therapy/regimen.  
All patients discontinuing study treatment for any reason should undergo the following EOS 
procedures: 
1. AE monitoring 
2. Recording of concomitant medications 
3. Vital signs and weight 
4. Complete physical examination  
5. ECOG performance status evaluation 


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6. Clinical laboratory values (hematology, coagulation, chemistry, urinalysis, and both 
blood CEA/TA4 levels and thyroid function tests) 
7. Serum or urine pregnancy test for women of child-bearing potential 
8. Research blood collection 
9. Optional post-baseline tumor biopsy (only requested for patients with biopsy-
accessible lesions and who discontinue from study prior to Week 10).  Coagulation 
tests must be performed and evaluated within 24 hr prior to all biopsy procedures. 
11. Radiographic evaluation of tumor burden and determination of response by RECIST 
v1.1 and iRECIST.  See Appendices 5 and 6. Note: This is not required if confirmed 
PD is the reason for study discontinuation. 
 Long-Term Follow-Up 
Patients will enter into the long-term follow-up phase of the study after the EOS visit to obtain 
survival data. Survival data may be obtained either by clinic visit or by remote communication 
(e.g., telephone call or email) or hospital medical records. Sites must follow up with patients 
approximately every 4 months for up to 1 year to obtain the following data: 
 Survival status: Is the patient still living? (Yes or No) 
o If “No”, what was the approximate date of death? 
 Has the patient received any subsequent active anti-cancer treatment (this does not 
include palliative measures)? (Yes or No) 
o If “Yes”, what treatments has the patient received? 
Family 
members, 
primary 
care 
giver, 
public 
records, 
or 
primary 
treating 
oncologist/oncologist’s office may confirm a patient’s death. 
 
Patient Identification and Tracking 
Each patient will be assigned a unique number and will keep this number for the duration of 
the study.  Patient numbers will not be reassigned or reused for any reason.  Patients should be 
identified to the Sponsor only by their assigned number, initials, date of birth, and sex.  The 
Investigator must maintain a patient master log. 
 


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Screen Failures 
Patients who sign an informed consent form but who do not meet all inclusion and exclusion 
criteria and who do not receive any part of the investigational treatment regimen, are defined 
as Screen Failures. For all screen failures, the Investigator (or designee) will record the 
screening number, patient initials, and reason(s) for screen failure into the Screen Fail Log. 
These data will be retained in the Investigator’s study files, reviewed for completeness and 
collected at the end of the study.  
 
 
Discontinuation/Withdrawal criteria 
 
Discontinuation of Study Treatment  
Discontinuation of study treatment does not represent withdrawal from the study. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
 Recurrent Grade 2 pneumonitis 
 Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 pembrolizumab 
cycles (at least 24 weeks), including 2 doses of pembrolizumab beyond the date 
when the initial CR was declared.  
 Completion of 35 treatments (approximately 2 years) with pembrolizumab.  Note: The 
number of treatments is calculated starting with the first dose of pembrolizumab.  
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, adverse events, disease progression, patient request, Investigator decision, protocol 
violation, patient noncompliance, and study termination by the Sponsor.  
When a patient discontinues or is withdrawn, the Investigator will notify the Sponsor (or 
designee) and should perform the procedures indicated in the EOS column in the Schedule of 
Events (Appendix 1) within 28 days after discontinuation of study drug and prior to initiation 
of any therapy.   
 
SAFETY REPORTING AND DOCUMENTATION OF CLINICAL RESULTS 
 
Safety Evaluations  
For safety information on GX-188E, refer to the most recent version of the Investigator’s 
Brochure. For safety information on pembrolizumab, please refer to the package inserts. 


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Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results.  
More frequent safety evaluations than required by this protocol may be performed if clinically 
indicated and at the discretion of the Investigator. All adverse events (AEs) will be recorded 
from the time the patient receives the first dose of the investigational treatment regimen to 28 
days after the last dose. 
 
Physical Examination 
Complete physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner) at Screening and End of Treatment. Symptom-directed physical 
exam are required at each clinical visit and as clinically indicated. Please refer to the Schedule 
of Events (Appendix 1). 
 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be obtained in 
the sitting position. All patients should be sitting for 3-5 min prior to obtaining vital signs. 
Please refer to the Schedule of Events (Appendix 1). 
 
Safety Laboratory Determinations 
Laboratory evaluations, including complete blood count with differential, comprehensive 
chemistry panel, coagulation tests, thyroid function tests, and urinalysis, will be performed as 
noted in the Schedule of Events (Appendix 1). 
 
 
Pain Assessment 
On each GX-188E vaccination day, Pain Assessment Monitoring will be performed within 30 
minutes before and 5 minutes (± 2 minutes) after the vaccination procedure using a 0-10 
numeric pain rating scale (Figure 4). 


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Figure 4. Numeric Pain Rating Scale 
 
 
 
Adverse Events (AE) 
The Investigator will evaluate all adverse events (AEs) according to the NCI Common 
Terminology Criteria for Adverse Events Version 4.0 or the most recent version. An adverse 
event (AE) is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a test article in 
a clinical study. The event does not need to be causally related to the investigational treatment. 
An AE includes, but is not limited to, the following: 
 Any clinically significant worsening of a preexisting condition 
 An AE occurring from overdose (i.e., a dose higher than that indicated in the 
protocol) of a test article, whether accidental or intentional 
 An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article 
 An AE that has been associated with the discontinuation of the use of a test article 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis on 
the adverse event page in the CRF: 
 Accompanied by clinical symptoms 
 Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 


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 Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
Clear progression of the patient’s primary malignancy should not be reported as an AE, 
unless it results in hospitalization or death. Findings that are clearly consistent with the 
expected progression of the underlying cancer should not be reported as an adverse event, and 
hospitalizations due to the progression of cancer do not necessarily qualify for an AE. If there 
is any uncertainty about a finding being due solely to progression of primary malignancy, the 
finding should be reported as an AE as appropriate. 
AEs should be considered treatment-related, unless they fulfill the following criteria: 
 Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or 
 The AE has no plausible temporal relationship to administration of the investigational 
product (e.g., a new cancer diagnosed 2 days after first dose of study drug). 
Relatedness to study medication will be graded as either,“probably”, “possibly”, “unlikely”, 
or “unrelated” as follows: 
Probably Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Abates upon discontinuation of the drug 
 Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state 
Possibly Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Could have been produced by the patient’s clinical state or by other modes of therapy 
administered to the patient 
Unlikely Related - The adverse event 
 Does not follow a reasonable sequence from drug administration 
 Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 


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Unrelated – The adverse event 
 Does not follow a reasonable sequence from drug administration 
 Is readily explained by and considered by the Principal Investigator to be an expected 
complication of the patient’s primary malignancy, clinical state, concurrent medical 
conditions, or by other modes of therapy administered to the patient 
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the investigational treatment, but is considered by the Investigator and/or the Sponsor’s 
Medical Monitor (or designee) to be related to the research conditions, i.e., related to the fact 
that a patient is participating in the study. For example, a protocol-related AE may be an 
untoward event related to a medical procedure required by the protocol (e.g. bleeding from a 
protocol-required biopsy). 
 
Serious Adverse Event (SAE) 
All AEs will be evaluated for seriousness. A serious adverse event (SAE) is an AE that meets 
at least one of the following criteria: 
 Results in death (NOTE: death is an outcome, not an event) 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of an existing hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect 
 Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Life-threatening, in the context of an SAE, refers to immediate risk of death as the event 
occurred per the reporter. A life-threatening experience does not include an experience, had it 
occurred in a more severe form, which might have caused death, but as it actually occurred, 


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did not create an immediate risk of death. For example, hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though hepatitis of a more 
severe nature can be fatal. Similarly, an allergic reaction resulting in angioedema of the face 
would not be life-threatening, even though angioedema of the larynx, allergic bronchospasm, 
or anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital. Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered 
a serious adverse event (SAE). In the absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE. This is the case in the following situations: 
 The hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol. Day or night survey visits for biopsy or surgery required by 
the protocol are not considered serious. 
 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery). This should be recorded in 
the study file. 
 Emergency room visit less than 24hrs or other department visits that do not result in 
hospitalization (if the case is not considered as important medical or life-threatening 
event) is not included as SAE. 
 Hospitalization for survey visits or annual physicals falls into the same category. 
In addition, hospitalizations planned before the start of the study, for a preexisting condition 
that has not worsened, do not constitute an SAE.  
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 


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Other Reportable Information 
Certain information, although not considered an SAE, must be recorded, reported, and 
followed up as indicated for an SAE. This includes:  
 A case involving a pregnancy exposure to the investigational therapy. Please refer to 
Section 20.4.1 for further details and requirements. Pregnancies occurring up to 6 
months after completion of the study treatment must also be reported to the Investigator.  
 Overdose (e.g., a dose higher than that indicated in the protocol) with or without an AE. 
If an adverse event(s) is associated with or results from an overdose of one or more of 
the investigational agents, the event must be reported as an SAE, even if no other 
criteria for SAE are met. Any overdoses of pembrolizumab must be reported to the 
Sponsor and to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-
1220) within 24 hours. 
 Abuse (e.g., use for nonclinical reasons) with or without an AE 
 Inadvertent or accidental exposure with or without an AE 
 
Contraception and Pregnancy 
GX-188E and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of sperm.   
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (from the day of study medication initiation, or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 120  days after the 
last dose of study medication. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the study. 


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20.4.1.1 
Acceptable Methods of Contraception 
Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% 
per year) when used consistently and correctly. Below is a list of highly effective methods of 
contraception: 
 Intrauterine device (IUD) 
 Hormonal (birth control pill, injections, implants, patch) 
 Tubal ligation 
 Partner's vasectomy 
Additional effective methods (barriers) are noted below: 
 Male condom with spermicidal agent 
 Diaphragm or cervical cap with spermicidal agent 
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.  The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical  trial and the preferred and usual lifestyle of the subject. Periodic abstinence (eg., 
calendar,  or post-ovulation symptothermal methods) and withdrawal are NOT acceptable 
methods alone and must be supplemented with one of the methods considered highly 
effective, listed above 
 
Pregnancy 
.If a participant inadvertently becomes pregnant while on study, the participant will be 
immediately discontinued from study treatment. The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. 


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Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment. 
 
Unexpected AE and SAE 
An AE is considered unexpected if it is not listed in the investigator brochure or package insert 
for GX-188E or pembrolizumab, is not listed at the specificity or severity that has been 
observed, or, is not consistent with the risk information described.  
“Unexpected,” as used in this definition, also refers to adverse events that are mentioned in the 
investigator brochure or package inserts as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are not 
considered unexpected if the event is clearly due to disease progression. 
 
Reporting and Follow-Up Requirements for Adverse Events, Serious Adverse 
Events and Other Reportable Safety Events 
 
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
 All AE’s or ECI’s = from the time of treatment through 30 days following cessation of 
study treatment 
 All SAE’s =90 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier 
 All pregnancies and exposure during breastfeeding, from the time of treatment through 
120 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy 
 Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related. 


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The Investigator must follow-up on all treatment-related AEs, SAEs, and other reportable 
events until the events have subsided, returned to baseline, the patient has initiated any other 
anti-cancer treatment, or in case of permanent impairment, until the condition stabilizes. 
All AEs and SAEs must be recorded on source documents and collected in EDC. 
Although AEs should be based on the signs or symptoms detected during the physical 
examination and on clinical evaluation of the patient, a specific diagnosis should be reported 
as the AE whenever feasible. In addition to the information obtained from those sources, the 
patient should be asked the following nonspecific question: “How have you been feeling since 
your last visit?” Signs and symptoms should be recorded using standard medical terminology. 
Any unanticipated risks to the patients must be reported promptly to the IRB/IEC. 
 
Serious Adverse Event (SAE)-Specific and Expedited Reporting 
All SAEs, other reportable information, and SAE follow-up information must be reported 
within 24 hr of learning of the event by completing the Adverse Event eCRF in the Medidata 
database. Genexine, Inc (or designee) will process and evaluate all SAEs as soon as the reports 
are received. For each SAE received, Genexine, Inc. (or designee) will make a determination 
as to whether the criteria for expedited reporting have been met. 
Genexine, Inc. (or designee) is responsible for reporting relevant SAEs to the relevant 
regulatory authorities and participating Investigators, in accordance with FDA regulations 21 
CFR 312.32, ICH Guidelines, European Clinical Trials Directive (Directive 2001/20/EC), 
and/or local regulatory requirements. To meet this requirement, Genexine, Inc. (or designee) 
may request additional information from the sites, including but not limited to, hospitalization 
records. Any requests for such information should be addressed in a timely manner.  
Reporting of SAEs by the Investigator to the Institutional Review Board (IRB) or Ethics 
Committee (EC) will be done in accordance with the standard operation procedures and 
policies of the IRB/EC. Adequate documentation must be maintained showing that the IRB/EC 
was properly notified. 


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Adverse Events that are considered related to the investigational treatment, unexpected and 
serious will be reported as an IND Safety Report to the FDA in accordance with the standards 
set in the Code of Federal Regulations [21 CFR 312.32 (c)(1), 21 CFR 312.32(c)(2), 21 CFR 
312.32(d)(2)]. 
 
Events of Clinical Interest (ECI) 
Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECI) and 
must be recorded as such on the Adverse Event electronic case report forms and reported within 
24 hours to the Sponsor. 
ECIs for this trial include: 
 An overdose of investigational product that is not associated with clinical symptoms or 
abnormal laboratory results.  
 
 an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing*. 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The trial site guidance for 
assessment and follow up of these criteria can be made available. It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to 
proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial. 
ECIs that occur in any patient from the date of first dose through 30 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not 
related to the investigational product, must be reported within 24 hours to the Sponsor.  
 
Treatment of Pembrolizumab Overdose 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or ≥5 
times the indicated dose.  


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No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
 
Dose-Limiting Toxicities (DLTs) 
All toxicities will be graded using NCI-CTCAE Version 4.0 or the most recent version based 
on the investigator assessment.   
The DLT window of observation will be during Cycle 1 of pembrolizumab (ie., the first 3 
weeks of treatment prior to Week 4 Day 1 visit ). A DLT is defined as any AE that is not clearly 
due to progression of the patient’s primary malignancy, occurs within the DLT window of 
observation period, and that meets at least one of the criteria below:  
Non-Hematologic Dose Limiting Toxicities: 
 Any CTCAE (v4.0 or the most recent version) Adverse Event of ≥ Grade 3 treatment-
related non-hematological toxicity except the following: 
o nausea, vomiting, or diarrhea lasting ≤ 72 hr 
o Grade 3 fatigue lasting ≤ 7 days 
o hypersensitivity reactions lasting ≤ 72 hrs  
o Grade 3 hyperglycemia lasting ≤ 72 hr with standard anti-diabetic therapy 
o Grade 3 increases in liver transaminases in patients with liver metastases. (Note: 
Grade 4 increases in LFTs in any patient will be considered a DLT) 
o clinical laboratory abnormalities that are reversible to ≤ Grade 1 or baseline status 
within 72 hr with outpatient care and/or monitoring, or that are considered not 
clinically significant by the Principal Investigator 
 
Hematologic Dose Limiting Toxicities: 
 Grade 4 neutropenia (ANC < 0.5 x109/L) 
 Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with temperature ≥ 38.3°C) 
 Grade 4 thrombocytopenia (platelet count < 25.0 x 109/L) lasting > 4 days or that 
requires platelet transfusion 
 Grade ≥ 3 thrombocytopenia (platelet count < 50.0 x 109/L) associated with Grade ≥ 3 
bleeding 


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 Any hematologic toxicity resulting in death (i.e. Grade 5) 
In addition, any other AE that is felt to be treatment-limiting in the medical opinions of the 
Principal Investigator and the Sponsor’s Medical Monitor may be considered a DLT. These 
include, but are not limited to the following: 
 Any toxicity leading to more than one missed dose of either GX-188E or 
pembrolizumab during the DLT-evaluation period 
 Any toxicity leading to > 2 weeks delay in initiation of the 2nd cycle of pembrolizumab 
 
 
Evaluation and Reporting of Efficacy Data 
 
Tumor Imaging and Assessment of Disease 
For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. MRI is the strongly preferred modality for imaging the brain. The same imaging 
technique regarding modality, ideally the same scanner, and the use of contrast should be 
used in a participant throughout the study to optimize the reproducibility of the assessment of 
existing and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. 
 
Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
treatment initiation. The site study team must review screening images to confirm the 
participant has measurable disease per RECIST 1.1. 
The screening images must be submitted to the central imaging vendor for confirmation of 
measurable disease per RECIST 1.1 for eligibility prior to treatment initiation.  
 
Tumor Imaging During the Study 
The first on-study imaging assessment should be performed approximately 9 weeks (±3 days]) 
from the date of treatment initation. Subsequent tumor imaging should be performed every 9 
weeks (±3 days at Week 19, ±7 days for subsequent timepoints) or more frequently if clinically 
indicated. Imaging timing should follow calendar days and should not be adjusted for delays 


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in cycle starts. Imaging should continue to be performed until disease progression is identified 
by the investigator (unless the investigator elects to continue treatment and follow iRECIST), 
the start of new anticancer treatment, withdrawal of consent, or death, whichever occurs first. 
All supplemental imaging must be submitted to the central imaging vendor.  
Objective response and stable disease should be confirmed by a repeat imaging assessment. 
Tumor imaging to confirm SD, PR or CR should be performed at least 4 weeks after the first 
indication of a response is observed. Participants will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point. Note:  Response does not typically need to be verified in real 
time by the central imaging vendor. 
Per iRECIST (Appendix 6 and Section 22.3), disease progression should be confirmed by the 
site 4 to 8 weeks after site-assessed first radiologic evidence of PD in clinically stable 
participants. Participants, who have unconfirmed disease progression may continue on 
treatment at the discretion of the investigator until progression is confirmed by the site, 
provided they have met the conditions detailed in Section 22.3. Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable. Participants, who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study treatment. Exceptions are detailed in 
Section 22.3. 
 
End of Treatment and Follow-Up Tumor Imaging 
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory. For participants who discontinue study treatment due to documented disease 
progression, this is the final required tumor imaging if the investigator elects not to implement 
iRECIST. 


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For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks) until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
 
RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used by the blinded, independent central reviewers (BICR) as the 
primary measure for assessment of tumor response, date of disease progression, and as a 
basis for all protocol guidelines related to disease status (e.g., discontinuation of study 
treatment).   
All efficacy endpoints, including the primary response endpoint of Part 2, overall response rate 
within the first 24 weeks of treatment (ORR24), will be evaluated and categorized using the 
new international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee, version 1.1.17  
RECIST v1.1 response definitions are briefly described below; for detailed instructions on 
RECIST v1.1, please refer to Appendix 5.  
RECIST v1.1 Response Definitions for the 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. 
Partial Response (PR) 
At least a 30% decrease in the sum of 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of 
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. (Note: the appearance of one or more 
new lesions is also considered progression). 


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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. 
 
RECIST v1.1 Response Definitions for the Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target 
lesion(s) or/and 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* 
*Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression 
status should be confirmed later on by the review panel (or study chair) 
 
RECIST v1.1 Definitions for the Evaluation of Overall Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
ORR is defined as the proportion of efficacy evaluable patients (see Section 24.3) with a tumor 
size reduction that meets the RECIST v1.1 Overall Response definition of a Partial Response 
(PR) or Complete Response (CR). If a CR has been confirmed for a patient, the sponsor will 


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discuss with the patient’s investigator whether the study treatments need to be continued or 
not. 
If a patient’s responses could not be confirmed, that patient will not be included in the primary 
efficacy population for ORR24.  
In addition, efficacy endpoints will also be determined using the immune-related RECIST 
(iRECIST)18 (please refer to Appendix 6). 
 
iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the Investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the Investigator, working with 
local radiology, according to the rules outlined in Appendix 6. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some participants 
can have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response. This data will be captured in the clinical database. 
Clinical stability is defined as the following:  
 Absence of symptoms and signs indicating clinically significant progression of 
disease 
 No decline in ECOG performance status  
 No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR.  


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If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 6, study 
treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in the Schedule of Events 
(Appendix 1) and submitted to the central imaging vendor.  
A description of the adaptations and iRECIST process is provided in Appendix 6, with 
additional details in the iRECIST publication43. A summary of imaging and treatment 
requirements after first radiologic evidence of progression is provided in Table 6 and illustrated 
as a flowchart in Figure 5. 
 


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Table 6. Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST 1.1 [For those 
studies in which PFS 
is the primary 
endpoint, add the 
following: that has 
been verified by 
BICR] 
Repeat imaging at 4 
to 8 weeks to confirm 
PD. 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 4 
to 8 weeks to confirm 
PD per Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) 
by iRECIST per 
Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
Investigator 
assessment 
Repeat imaging at 4 
to 8 weeks to confirm 
PD.  May occur at 
next regularly 
scheduled imaging 
visit. 
Continue study treatment 
at the Investigator’s 
discretion. 
Repeat imaging at 4 
to 8 weeks to confirm 
PD per Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
Investigator 
assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study treatment 
at the Investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study treatment 
if condition has improved 
and/or clinically stable per 
Investigator’s discretion.  
Next tumor imaging should 
occur according to the 
regular imaging schedule. 


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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
BICR = Blinded Independent Central Review; iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1.; VOP=verification of progression 
[For studies, in which PFS is the primary endpoint, add the following: Note:  If progression has been centrally verified, further management is by the site, based on iRECIST.  
Any further imaging should still be submitted to the central imaging vendor, but no rapid review will occur. If RECIST 1.1 disease progression has not been centrally verified, 
ideally the site should continue treatment. Whether or not treatment continues, imaging should be collected and submitted to the central imaging vendor with VOP request until 
RECIST 1.1 progression is verified by BICR.]  
 


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Figure 5: Imaging and Treatment for Clinically Stable Participants Treated with 
pembrolizumab after First Radiologic Evidence of PD Assessed by the Investigator 
 
 
 
 


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Correlative studies and biomarker evaluations  
Establishing proof-of-biological concept is a key objective of this study. As previously 
described, the goal of GX-188E + P treatment is to induce a tumor-specific anti-tumor 
immunological response that does not become halted at the PD1 immune checkpoint. To 
explore the biological mechanisms and pharmacodynamic effects of the investigational 
treatment regimen, paired tumor biopsies and peripheral blood samples will be obtained from 
all study participants.  
 
Tumor Tissue for Biomarker Analyses 
A key exploratory objective of the study is to evaluate the additional immunological treatment 
effects of GX-188E + P on the tumor microenvironment depending on the PD-L1 expression 
at baseline. Tumor biopsy samples will be evaluated for molecular and histological changes, 
particularly as these changes pertain to the inflammatory mechanisms. This will be assessed by 
comparing paired biopsies whenever feasible, one obtained at baseline (archival or fresh 
sample) prior to study treatment initiation, and one obtained at approximately 10 weeks on 
study. The changes in the intratumoral inflammatory infiltrate and PD-L1 expression at 
baseline will be analyzed by immunohistochemical(IHC) staining and the tumor evaluation 
will be conducted by a central laboratory. 
All patients must submit either an archival tumor tissue sample, or a fresh biopsy sample for 
biomarker testing, including staining for PD-L1. For this study, it is expected that archival 
tumor tissues will be the principal source for baseline tumor biomarker analysis. Patients who 
do not have either archival tumor tissues available or biopsy-accessible lesions for a fresh 
biopsy will be excluded from the study. 
Ideally, archival samples should have been obtained within 30 days of study enrollment and 
without administration of other anti-cancer treatment(s) in the interim period. In cases where 
archival samples were obtained >30 days from study enrollment or other cancer treatments 
were administered in the interim, the biopsy date and interim cancer treatments should be 
documented.  
For patients without archival tissue samples but who have biopsy-accessible lesions and agree 
to undergo a biopsy procedure, the baseline sample must be obtained prior to administration of 
the first dose of either GX-188E or pembrolizumab.   


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For patients with biopsy-accessible lesions, a second biopsy will be requested optionallyat 
approximately 10 weeks following study treatment initiation in order to evaluate the effects of 
the investigational treatment regimen on the tumor microenvironment. For patients who 
discontinue from study prior to Week 10 and with accessible lesions, every effort should be 
made to obtain an optional post-baseline biopsy. For detailed instructions on biopsy sample 
processing, please refer to the study Laboratory Manual.  
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks is preferred; if 
submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory otherwise a new specimen may be requested. For additional details on tissue sample 
submission, please refer to the study Laboratory Manual. 
 
Planned Peripheral Blood Biomarker Analyses 
All study participants are required to provide peripheral blood samples for exploratory 
immunological evaluation throughout their study participation according to the schedule 
described in the Schedule of Events (Appendix 1). In brief, peripheral blood samples will be 
obtained at Screening, Week 1, Week 4, Week 7, Week 10, Week 16, Week 22, Week 49,  and 
approximately every 27 weeks thereafter. For detailed instructions on peripheral blood research 
sample processing, please refer to the study Laboratory Manual. 
Peripheral blood samples will be evaluated for molecular markers of an antigen-specific 
cellular and humoral immune response. For example, paired pre- and post-baseline PMBC-
derived T cells may be assessed for (1) increased HPV-specific T-cell responses by ELISPOT 
analysis; (2) modulation of T-cell receptor diversity; (3) epitope-spreading to non-HPV 
epitopes, including mutation-derived neoantigens; (4) multiparametric flow cytometry to 
assess additional leukocyte populations of immunologic interest.  
 
Statistical Analysis 
 
Statistical Plan Summary 
Study Design Overview 
This is a Phase Ib/II multicenter, open-label study in patients with advanced, non-
resectable HPV 16 or 18-positive cervical cancer. The study consists of two different 
parts. Part A employs a standard 6 + 3 design to evaluate the safety of the 
investigational study regimen. Part B uses a Simon Two-Stage design to explore the 
efficacy of the investigational study regimen at the treatment schedule established as 
safe in Part A. Additional subjects will be enrolled in Part C to evaluate efficacy in 
larger population.  


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Analysis Populations 
Safety Population: All patients who receive at least 1 dose of 1 agent in the 
investigational treatment regimen (i.e. either GX-188E or P) will be included in the 
analysis of safety, regardless of the duration of treatment. 
DLT-evaluable Population. Part A patients who receive all of the planned 
administrations of both agents (GX-188E and P) within the DLT-evaluation period 
(the first three weeks of treatment prior to Week 4 Day 1 visit), unless doses are missed 
within the first two weeks of treatment (i.e., Week 1 Day -1 to Week 2 Day 7) due to 
DLT(s). 
Efficacy Evaluable Population.  
 
All patients who discontinue the study treatment regimen early due to 
treatment-related toxicity  
 
Patients who discontinue study due to disease-related death, unequivocal 
tumor progression or with at least 1 post-baseline tumor assessment AND 
who received at least 45 days of treatment  
 
Patients from Part A, who receive the recommended Phase 2 regimen and 
who meet the aforementioned criteria  
Primary Endpoint(s) 
Part A: Safety: Incidence of Dose-limiting toxicities (DLTs) 
Part B&C: Objective Response Rate within 24 weeks (ORR24) by RECIST 1.1. 
Response determinations from the BICR will be used for the primary endpoint 
Secondary Endpoints 
 
Incidence, nature and severity of adverse events and serious adverse events 
 
Best Overall Response Rate (BORR), Time-to-Best Response (TTR), 
Duration of Response (DOR), Disease Control Rate (DCR), median 
Progression-Free Survival (mPFS) and 6 month PFS rate and Median 
Overall Survival(mOS) 
 
Response endpoints by iRECIST 
Statistical Methods for 
Efficacy & Immunogenicity/  
Analyses 
  
Efficacy Analyses.  Descriptive statistics will be employed to analyze the efficacy 
data. It also provides subject plots for individual patients. Summary statistics for 
continuous variables will include the mean, standard deviation, median, interquartile 
range, and range (minimum/maximum). Categorical variables will be presented as 
frequency counts and percentages, and time-to-event variables will be summarized 
with number of non-missing observations, median survival time, and survival 
probability using Kaplan-Meier method if applicable. Kaplan Meier plot will also be 
provided.  
 
Immunogenicity Analyses. 
Immunogenicity will be described to explore humoral and cellular immune 
responses to GX-188E and P (e.g., antibodies to E6 and E7 and the number of 
antigen-specific IFN-γ secreting T lymphocytes in samples of PBMC) in blood 
samples obtained from study subjects  
Treatment Assignment 
All participants will be allocated GX-188E + pembrolizumab 
Statistical Methods for Safety 
Analyses 
Summary statistics will be provided for the safety endpoints as appropriate.  
Interim Analyses 
An interim analysis will be performed with safety and efficacy data in case of at 
least 22 patients in efficacy evaluable population, after obtaining week 10 tumor 
assessment results (either by investigator/BICR). 
Final Analysis 
The final analysis will be performed to report a primary CSR based on a data cut off 
after all 60 patients in the planned efficacy evaluable population have completed 
tumor assessment within 24 weeks by the investigator per RECIST v1.1 
Since patient will be treated until they met one of the discontinuation criteria, some 
patients may still be ongoing at the time of final analysis. Therefore, a long-term 
follow-up study can be performed after final analysis with all available data (no cut-
off date applied). 
Multiplicity 
No multiplicity adjustment is planned in this trial. 
Sample Size and Power  
Part A Safety Evaluation: For Part A, the goal is to determine a treatment schedule 
for which the rate of DLTs is less than 33% in 6 or 9 patients. A minimum of 6 patients 


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are planned with a maximum of 18 DLT-evaluable patients for the Starting Treatment 
Schedule and Reduction Level 1 
Part B: Part B follows a 1-sided Simon 2-Stage design; 15 patients, will be included 
in the first stage analysis. If ≥ 3 objective responses (PR or better) are observed in 
the first stage, another 13 patients will be enrolled into the second stage, for a total 
of 28 patients. For a null hypothesis ORR24 of 0.15 and an alternative hypothesis 
ORR24 of 0.35, the sample size of 28 patients will provide a one-sided significance 
level of approximately 5% and a power of 80%.  
 
Part C: Part C is to evaluate efficacy in larger patient population.  
In Keynote-158 study (pembrolizumab monotherapy in patients who have 
progressed with standard of care systemic therapy), ORR in total patients (i.e. 
regardless of PD-L1 status) and with CPS ≥ 1 were 12.2% and 14.6%, respectively. 
Given this, null hypothesis for ORR24 was set at P0 = 12.2%. With an alternative 
hypothesis for ORR24 of Pa = 37%, the sample size of 60 subjects was calculated 
considering two-sided significance level of 0.05, 97% power, and 25% dropout rate.  
The confidence interval (CI) for ORR24 will be estimated using exact Clopper-
Pearson method, and if the lower bound of the two-sided 95% CI for ORR24 exceeds 
12.2%, it will be proven to satisfy the primary efficacy. And it will be analyzed 
using two-sided exact binomial test for a null hypothesis for ORR24 of P0 = 12.2%  
with a significance level of P < 0.05.  
 
 
General Statistical Considerations 
This is a Phase Ib/II multicenter, open-label study in patients with advanced, non-resectable 
HPV 16 or 18-positive cervical cancer. The study consists of two different parts. Part A 
employs a standard 6 + 3 design to evaluate the safety of the investigational study regimen. 
Part B uses a Simon Two-Stage design to explore the efficacy of the investigational study 
regimen at the treatment schedule established as safe in Part A.  
Since this is an open-label clinical trial, in general, descriptive statistics will be employed to 
analyze the data. Summary statistics for continuous variables will include the mean, standard 
deviation, median, interquartile range and range (minimum/maximum). Categorical variables 
will be presented as frequency counts and percentages, and time-to-event variables will be 
summarized with number of non-missing observations, median survival time, and survival 
probability using Kaplan-Meier method if applicable. Kaplan Meier plot will also be provided. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy, and 
safety measures. The efficacy analysis will be conducted on the Efficacy Evaluable Population, 
and the safety analysis will be performed on the Safety Population.  
All confidence intervals will be constructed at the 95% confidence level. Data listings will be 
created to support each table and to present all data collected.  


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In Part C, the significance level of 5% will be used for two-sided exact binomial test for a null 
hypothesis for ORR24 of P0 = 12.2%. 
 
Sample Size and Power 
Part A Safety Evaluation: For the traditional 6+3 design of Part A, the goal is to determine a 
treatment schedule for which the rate of DLTs is less than 33% in 6 or 9 patients. A minimum 
of 6 patients are planned for Part A, with a maximum of 18 DLT-evaluable patients for the 
Starting Treatment Schedule and Reduction Level 1. If 3 in 6 or 9 patients at Reduction Level 
1 have DLTs, then the investigational treatment regimen will be considered too toxic and 
enrollment into the study will be discontinued. 
Part B: Part B follows a 1-sided Simon 2-Stage design; 15 patients, including all patients from 
Part A without a DLT, who receive the recommended Phase 2 regimen and who meet the 
criteria for the Efficacy Evaluable Population (see Section 24.4), with HPV 16 or 18 positive 
advanced cervical cancer will be included in the first stage analysis. If 3 or more objective 
responses (PR or better) are observed in the first stage, another 13 patients will be enrolled into 
the second stage, for a total of 28 patients in Part B. Study has passed the first stage of Simon-
Two stage design. For a null hypothesis ORR24 of 0.15 and an alternative hypothesis ORR24 of 
0.35, the sample size of 28 patients will provide a one-sided significance level of approximately 
5% and a power of 80%. If Stages 1 and 2 are completed, a minimum of 8 patients must 
demonstrate a response (PR or better) to reject the null hypothesis.  
Part C: Part C is to evaluate efficacy in larger patient population.In Keynote-158 study 
(pembrolizumab monotherapy in patients who have progressed with standard of care systemic 
therapy), ORR in total patients (i.e. regardless of PD-L1 status) and with CPS ≥ 1  were 12.2% 
and 14.6%, respectively.   
Given this, null hypothesis for ORR24 was set at P0 = 12.2%. With an alternative hypothesis 
for ORR24 of Pa = 37%, the sample size of 60 subjects was calculated considering two-sided 
significance level of 0.05, 97% power, and 25% dropout rate.  
The confidence interval (CI) for ORR24 will be estimated using exact Clopper-Pearson method, 
and if the lower bound of the two-sided 95% CI for ORR24 exceeds 12.2%, it will be proven to 
satisfy the primary efficacy.  
 


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Analysis Populations 
Safety Population. All patients who receive at least 1 dose of 1 agent in the investigational 
treatment regimen (i.e. either GX-188E or P) will be included in the analysis of safety, 
regardless of the duration of treatment. 
DLT-evaluable. Unless doses are missed within the first two weeks of treatment (i.e., Week 1 
Day -1 to Week 2 Day 7) due to DLT(s), a patient must receive all of the planned 
administrations of both agents (GX-188E and P) within the DLT-evaluation period to be 
considered evaluable for DLT. If a patient misses any treatment within the first two weeks of 
the study for reasons other than a DLT, the patient will be considered non-evaluable for DLT 
and replaced.  
Efficacy Evaluable Population. All patients who discontinue the study treatment regimen early 
due to treatment-related toxicity will be considered evaluable for efficacy. Patients who 
discontinue study due to disease-related death, unequivocal tumor progression or with at least 
1 post-baseline tumor assessment must have received at least 45 days of treatment to be 
considered evaluable for efficacy. Patients in Part B and C who do not meet the aforementioned 
requirements will be considered non-evaluable for response and may be replaced. Patients from 
Part A, who receive the recommended Phase 2 regimen and who meet the aforementioned 
criteria for the Efficacy Evaluable Population will be included in the analysis for Part B and C. 
The following table provides further, more specific details. 
 
 


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Table 7. Determination of Patients to be Included in Efficacy Evaluable. 
Patient Cohort 
Reason for Discontinuation 
Number of Days 
on Protocol 
Treatment 
Include in Efficacy 
Evaluable 
Population 
(Yes/No)? 
Part A receiving 
RP2 regimen* 
Protocol-Defined Dose 
Limiting Toxicity (DLT), 
or other toxicity 
Not applicable 
Yes, included in 
Efficacy Evaluable 
Population 
Part A receiving 
RP2 regimen* 
Disease-related death, 
unequivocal tumor 
progression or at least 1 
post-baseline tumor 
assessment 
< 45 days 
No 
Part A receiving 
RP2 regimen* 
Disease-related death, 
unequivocal tumor 
progression or at least 1 
post-baseline tumor 
assessment 
≥ 45 days 
Yes, included in 
Efficacy Evaluable 
Population 
Part A, receiving 
dose > RP2 
regimen* 
Any 
Not applicable 
No 
Part B and C 
Disease-related death, 
unequivocal tumor 
progression, or at least 1 
post-baseline tumor 
assessment 
< 45 days 
No, patient may be 
replaced 
Part B and C 
Disease-related death, 
unequivocal tumor 
progression, or at least 1 
post-baseline tumor 
assessment  
≥ 45 days 
Yes, included in 
Efficacy Evaluable 
Population 
Part B and C 
Toxicity 
Not applicable 
Yes, included in 
Efficacy Evaluable 
Population 
*RP2 regimen = Recommended Phase 2 regimen of GX-188E 
 
Efficacy Analysis 
Response to treatment will be evaluated using both RECIST v1.1 (Appendix 5) and iRECIST 
(Appendix 6). For each patient with objectively measurable disease and who meet the criteria 
for inclusion in the Efficacy Evaluable population (Section 24.44), response to therapy (overall 


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response within 24 weeks and best overall response), time-to-best-response, duration of 
response (DOR), progression-free survival (PFS), and overall survival (OS) will be calculated. 
Responses for patients who do not meet the criteria for inclusion into the Efficacy Evaluable 
population may also be described.  
Definitions for response and survival outcomes are provided below: 
Efficacy Endpoints for Individual Patients 
Endpoint 
Definition 
Overall Response within 24 
weeks (OR24) 
The best objective response achieved within the first 24 
weeks of treatment initiation 
Best Overall Response (BOR) 
The best objective response achieved prior to study 
discontinuation 
Time-to-Best Response (TTR) 
Time from treatment initiation to the best objective 
response achieved. This endpoint is only determined for 
patients who have a PR or CR. 
Duration of Response (DOR) 
Time from documentation of objective tumor response 
(PR or CR) to disease progression. This endpoint is only 
determined for patients who have a PR or CR. 
Progression-Free Survival (PFS) 
Time from treatment initiation until documented disease 
progression or death 
Overall Survival (OS) 
Time from treatment initiation until death from any cause 
 
The Kaplan-Meier method will be used to estimate the median Duration of Response (DOR), 
median Progression-Free Survival (PFS), and median Overall Survival (OS).  
Endpoints for the Efficacy Evaluable Study Population 
Population efficacy endpoints will only include those patients who meet the criteria for 
inclusion in the Efficacy Evaluable population (Section 24.4). The definition of statistics 
calculated by the endpoints is as follows. 
Statistics 
Definition 
Overall Response Rate within 24 
weeks (ORR24) 
The proportion of efficacy evaluable patients who 
achieve an objective response (PR or CR) within the first 
24 weeks of treatment initiation 
Best Overall Response Rate 
(BORR) 
The proportion of efficacy evaluable patients who 
achieve an objective response (PR or CR) prior to study 
discontinuation 
Median Progression-Free 
Survival time (mPFS) 
Timepoint at which the probability of progression-free 
survival equlas to 50% in the efficacy evaluable 
population 


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6-month PFS rate 
Probability that the progression has not occurred by 6 
months 
Median Overall Survival time 
(mOS) 
Timepoint at which the probatility of survival equlas 50% 
in the efficacy evaluable population 
Disease Control Rate (DCR) 
The proportion of efficacy evaluable patients who had a 
CR, PR or Stable Disease 
Median Duration of Response 
(mDOR) 
Timepoint at which the probability of disease progression 
equals 50% after documented objective  tumor response 
(PR or CR). This endpoint only includes patients who 
have achieved an objective response. Kaplan-Meier 
method will be used to estimate mDOR. 
Median Time to Best Response 
(mTTR) 
Timepoint from treatment initiation to the best objective 
response achieved (i.e., PR or CR whichever occurs 
earlier) in 50% of patients. Median TTR will be 
calculated using descriptive statistics in the population 
restricted to subjects with the best objective response 
In addition, relationships between antitumor activity and exploratory biomarkers of immune 
system changes may be explored. 
 
Safety Analysis 
Safety variables to be analyzed are AEs, laboratory test results (e.g., hematology, coagulation, 
serum chemistry, thyroid function tests, and urinalysis), and vital signs. Clinically significant 
changes from baseline will be summarized using descriptive statistics.  
Adverse event severity will be graded according to the CTCAE v4.0 or the most recent version 
and terms recorded on the CRFs will be mapped to preferred terms using the most recent 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA®). All AEs will 
be summarized according to the system organ class and preferred term within the organ class. 
Adverse events will be tallied for overall frequency (number and percentage of patients), worst 
reported severity, and relationship to the investigational study drugs for each preferred term 
per patient. Serious adverse events will be similarly summarized. Listings of deaths, SAEs, and 
AEs leading to early termination of study treatment or premature withdrawal from study will 
also be provided.  
 
Interim Analysis  
An interim analysis will be performed with safety and efficacy data in case of at least 22 
patients in efficacy evaluable population, after obtaining week 10 tumor assessment results 
(either by investigator/BICR).  
 


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Final Analysis  
The final analysis will be performed to report a primary CSR based on a data cut off after all 
60 patients in the planned efficacy evaluation population have completed tumor assessment 
within 24 weeks by the investigator per RECIST v1.1 
Since patient will be treated until they met one of the discontinuation criteria, some patients 
may still be ongoing at the time of final analysis. Therefore, a long-term follow-up study can 
be performed after final analysis with all available data (no cut-off date applied).  
 
 
GENERAL STUDY MANAGEMENT INFORMATION 
 
Informed Consent 
The Investigator will provide for the protection of the patients by following all applicable 
regulations. These regulations are available upon request from the Sponsor. The Informed 
Consent Form used during the informed consent process must be reviewed by the Sponsor and 
approved by the IRB/IEC. 
Before any procedures specified in the protocol are performed, a patient must: 
 Be informed of all pertinent aspects of the study and all elements of informed consent 
 Be given time to ask questions and time to consider the decision to participate 
 Voluntarily agree to participate in the study 
 Sign and date an IRB/IEC approved Informed Consent Form 
 
Institutional Review Board and Institutional Biosafety Committee Approvals 
An Institutional Review Board (IRB), which is operating in accordance with Title 21 of the 
Code of Federal Regulations Part 56, must approve the clinical protocol and corresponding 
informed consent form and agree to monitor the conduct of the trial and review its progress at 
regular intervals. Before the Sponsor or its designate will make investigational product 
available, and before the trial begins, the investigator will provide to the Sponsor documented 
evidence of IRB approval, demonstrating review and approval of this clinical protocol, and 
informed consent form. 
 
 
An Institutional Biosafety Committee (IBC), which is duly registered with the NIH Office of 
Biotechnology Activity (NIH/OBA) in accordance with NIH Guidelines, must approve the 


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clinical protocol. The investigator will provide to the Sponsor documented evidence of IBC 
approval prior to initiation of the clinical trial. 
  
 
Pre-Study Documentation 
The Investigator must provide the Sponsor with the following documents BEFORE enrolling 
any patients: 
 Completed and signed form 1572 
 All applicable country-specific regulatory forms 
 Current, dated curricula vitae for the Investigator, Subinvestigators, and other 
individuals having significant investigator responsibility who are listed on the Form 
1572 or equivalent, or the clinical study information form. 
 Copy of the IBC approval letter 
 Copy of the IRB/IEC approval letter for the protocol and informed consent. All 
advertising, recruitment, and other written information provided to the patient must be 
approved by the IRB/IEC. Written assurance of continuing approval (at least annually) 
as well as a copy of the annual progress report submitted to the IRB/IEC must also be 
provided to the Sponsor.  
 Copy of the IRB/IEC-approved Informed Consent Form to be used 
 Where applicable, a list of the IRB/IEC members or a FWA/DHHS number 
 Copy of the protocol sign-off page signed by the Investigator 
 Copy of the current medical license (online verification is also acceptable) of the 
Principal Investigator, any Subinvestigators and any other individuals having 
significant responsibility as listed in the 1572 
 Fully executed Clinical Trial Agreement (CTA) 
 Where applicable, a financial disclosure form for the Principal Investigator and any 
other persons listed in the 1572 
 A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other 
facilities conducting tests. This document should be returned along with the 1572. The 


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Sponsor must be notified if the laboratory is changed or if any additional laboratory is 
to be used. 
 List of normal laboratory values and units of measure for all laboratory tests required 
by the protocol. This is required for each laboratory to be used during the study. The 
Sponsor must be notified if normal values or units of measurement change. 
 
Protocol Amendments 
Any significant change in the study requires a protocol amendment. An Investigator must not 
make any changes to the study without IRB/IEC and Sponsor approval. All protocol 
amendments must be reviewed and approved following the same process as the original 
protocol. 
 
Direct Access, Data Handling, and Record Keeping 
 
Confidentiality 
All study-related laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using anonymous 
identifiers. Linkage to patients’ study data is only possible after accessing a password-protected 
database. Access to the database is only available to individuals directly involved in the study.  
Patient personal health information that is accessed for this study will not be reused or disclosed 
to any other person or entity, or for other research. 
 
Case Report Forms (CRFs) 
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All study-related information will be recorded on source documents. All required data will be 
recorded in the CRFs. All CRF data must be submitted to the Sponsor throughout and at the 
end of the study.  
The Clinical Research Coordinator (CRC), or other properly trained site personnel, will 
complete the CRFs as soon as possible upon completion of the study visit; the Investigator will 
review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by site 


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personnel. All source documentation should be kept in separate research folders for each 
patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation will be available for review/monitoring by the Sponsor (or designee) 
and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data. 
At study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
25.5.2.1 
Records Retention 
The Investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the longer 
of: (i) 3 years after the last marketing authorization for the study drug has been approved or 3 
years after study completion  or (ii) such longer period as required by applicable global 
regulatory requirements. At the end of such period, the Investigator shall notify the Sponsor in 
writing of its intent to destroy all such material. The Sponsor shall have 30 days to respond to 
the Investigator’s notice, and the Sponsor shall have a further opportunity to retain such 
materials at the Sponsor’s expense.  
 
Oversight and Monitoring 
The Sponsor (or designee) will be the monitoring entity for this study. The data will be checked 
for completeness and correctness in real-time online and during scheduled site monitoring 
visits. 
Discrepancy reports will be generated and transferred to the study center for resolution by the 
Investigator or his/her designee. 
The Sponsor (or designee), in collaboration with all participating Investigators, will routinely 
review all adverse events and suspected adverse reactions considered “serious”. The Sponsor 


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(or designee) will audit study-related activities to ensure that the study is conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP). Significant findings will be communicated to the site Investigator and, 
as applicable, the local IRB. For additional information, please refer to the Clinical Monitoring 
Plan and Safety Monitoring Plan. 
 
Study Suspension, Termination, and Completion 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason. If the Investigator suspends or terminates the study, the Investigator must promptly 
inform the Sponsor and the IRB/IEC and provide a detailed written explanation. The 
Investigator will also return all study-specific investigational treatment agents (i.e. GX-188E, 
pembrolizumab), study-specific equipment (e.g., TDS-IM ®  Electroporation Device), 
containers, and other study materials to the Sponsor or designee, unless specific permissions 
and instructions have been provided for on-site destruction of the materials. Upon study 
completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with 
final reports and summaries as required by regulations. 
 
Protection of Human Patients 
 
Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all patients involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits.  
 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be 
asked to sign the HIPAA form and informed consent documents. The original signed document 
will become part of the patient’s medical records, and each patient will receive a copy of the 


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signed document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 
 


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APPENDIX 1: SCHEDULE OF EVENTS (SCREENING -WEEK 10) 
 
Screening 
(-28 to 0) 
Treatment Week 
Week 1 Day 1 
Week 2 Day 1 (± 
3 days) 
Week 3Day 1 
(± 3 days) 
Week 4 Day 1 
(± 3 days) 
Week 7 Day 1 
(± 3 days) 
Week 10  Day 1 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
Physical Exam2 and Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
Performance Status (ECOG) 
X 
 
 
 
X 
X 
X 
Moore Criteria Risk Categorization4 
X 
 
 
 
 
 
 
Adverse Events5 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications6 
X 
X 
X 
X 
X 
X 
X 
CBC (w/diff, platelet count)7 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry8 
X 
X 
X 
X 
X 
X 
X 
Serology9, Chest X-ray, ECG 
X 
 
 
 
 
 
 
Thyroid Function Tests and CEA/TA410 
X 
 
 
 
 
X 
 
Urinalysis11 
X 
X 
 
 
 
 
X 
Coagulation Assessment12 
X 
 
 
 
 
 
X 
Pregnancy Test13 
X 
 
 
 
 
 
 
Research Blood Collection 14 
X 
X 
 
 
X 
X 
X 
GX-188E Vaccinationn (i.m.)  
 
X 
X13 
 
X13 
X 
 
Pain Assessment15 
 
X 
X 
 
X 
X 
 
Pembrolizumab (i.v.) 
 
X 
 
 
X 
X 
X 
Tumor Biopsy Sample16 
X 
 
 
 
 
 
X 
Radiographic 
Evaluation 
of 
Tumor 
Burden17 
X 
 
 
 
 
 
X 
 


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1. Medical history includes any significant comorbid conditions requiring active treatment as well as surgeries and therapies related to the treatment of malignancies, including 
cervical cancer. Cervical cancer history includes review of prior treatments and documentation of HPV-16 or -18 positivity. Medical records and/or local laboratory results 
will be considered adequate documentation HPV-16 or -18 positivity 
2. Screening and End of Study require a complete physical exam. For all other study, physical exams should be symptom-directed and clinically significant findings reported 
as adverse events. 
3. Vitals to include heart rate, respiratory rate, temperature, blood pressure (systolic and diastolic) weight, and height. Height only required at screening 
4. Determine whether the patient has low risk, mid risk or high risk disease based upon Moore criteria (See Appendix 3). 
5. Adverse event monitoring begins once a patient receives the first dose of study treatment and continues until 28 days after the last administration of study treatment, or until 
the initiation of a new anti-cancer therapy, whichever occurs first. For Serious Adverse Events (SAEs), follow up will continue for 90 days.  
6. Concomitant medication is defined as any prescription or over-the-counter preparation, including vitamins and supplements. All concomitant medications from 28 days 
before Day 1 through the end of the subject’s study participation must be recorded. (During the follow-up period after the end of the clinical trial, only the data about the 
antineoplastic therapy (surgical therapy, chemotherapy, radiation therapy, etc.) treated after the end of the subject’s study participation is recorded.) 
7. CBC w/differential to include: Hemoglobin, Platelets, Red Blood Cells, White Blood Cells, Basophils (%)), Eosinophils (%)), Lymphocytes (%)), Monocytes (%), 
Neutrophils (Abs) and Hematocrit. 
8. Serum Chemistry at Screening to include: Sodium, Potassium, CO2 or bicarbonate, Chloride, Albumin, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Blood Urea 
Nitrogen, Calcium, Creatinine, Glucose, Magnesium, Phosporus, Total Protein, LDH, and Cockcroft-Gault calculated Creatinine Clearance. At all other time points, only a 
basic metabolic panel (Na, K, CO2 or bicarbonate, Cl, Ca, BUN, creatinine & glucose) plus AST and ALT are required. Other tests may be ordered as clinically indicated. 
However, if subjects had the result of serum chemistry tests at the screening which met the all in/exclusion criteria and the investigators judged that the result of same tests 
at W1D1 were no clinical significance, they can be enrolled. 
9. Serology at Screening to include: HIV Ag/Ab, HAV Ab (IgM), HBV Ab, HBV sAg, HCV Ab, HCV RNA (HCV real time PCR) 
10. Includes thyroid-stimulating hormone (TSH), free thyroxine (FT4), and T3. Thyroid function tests and CEA/TA4 levels will be performed approximately every 6 weeks. 
11. Urinalysis is only required at Screening, Week 1 Day 1, Week 10 Day 1, and End of Study. Urinalysis should be ordered as clinically indicated at any other timpoint. 
12. Coagulation assessment includes: prothrombin time, partial thromboplastin time, and international normalized ratio (PT/PTT/INR). Coagulation assessments are only 
required at Screening and End of Study. On-treatment coagulation assessments (e.g., Week 10) are only required if a biopsy is planned and must be evaluated within 24 
hours prior to biopsy collection on the same day.  
13. All females of child-bearing potential must have a negative serum or urine pregnancy test within 3 days prior to the first dose of study treatment. 
14. Blood collection. Samples will include serum for immune response Flt-3L(Screening, Week10, Week22, Week49 then after every 27 weeks) and whole blood for PBMC T 
cell responses(Screening, Week1, Week4, Week7, Week10, Week16, Week22, Week49 then after every 27 weeks). Samples obtained at all time points associated with 
study treatment administration, except for Screening, should be obtained prior to administration of either/both agents. Blood sample for Flt-3L will be collected at screening 
visit, week 10, week 22, week 49 and every 27 weeks thereafter. 
15. Pain assessment using a 0-10 numeric pain rating scale will be administered prior to and 5 minutes (+ 2 minutes) following each GX-188E electroporation procedure 
16. All patients must submit either an archival tumor tissue sample OR fresh biopsy sample at Screening. Biopsies will be evaluated for bio-markers using immunohistochemistry 
but not limited to it.Patients with biopsy-accessible lesions will be asked to provide an optional biopsy sample at approximately Week 10 (or End of Study if the patient 
discontinues prior to Week 10) for paired biopsy analysis. 


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17. Radiographic evaluations of tumor burden by RECIST v1.1 will be performed by a blinded independent central reviewer at Screening, approximately every 9 weeks during 
the treatment period, or more frequently as clinically indicated, and at End of Study if the reason for discontinuation is other than for confirmed radiologic disease progression. 
Scans obtained within 28 days prior to Week 1 Day 1 will be accepted for Screening and do not need to be repeated unless a clinically significant difference is suspected. 
Confirmatory scans are required approximately 4 weeks after any scan that indicates either an objective response, stable disease or disease progression, 
 
 


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SCHEDULE OF EVENTS (SUBSEQUENT TO WEEK 10) 
 
 
 
Treatment Week 
Week 13 Day 1 
(± 3 days) 
Week 16 Day 1 
 (± 3 days) 
Week 19 Day 1 
(± 3 days) 
Every 3 Weeks 
after Week 19 
Day 1 
(± 3 days) 
Approx. every 9 
Weeks 
after 
Week 19 Day 1 
(± 1 week) 
Week 46 Day 1 
(± 1 week)  
End of Study17 
Follow-Up 
Physical Exam1 and Vital Signs2 X 
X 
X 
X 
X 
X 
X 
Performance Status (ECOG) 
X 
X 
X 
 
X 
X 
X 
Adverse Events3 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications4 
X 
X 
X 
X 
X 
X 
X 
CBC (w/diff, platelet count) 5 
X 
X 
X 
 
X 
X 
X 
Serum Chemistry6  
X 
X 
X 
 
X 
X 
X 
Thyroid Function Tests and 
CEA/TA47 
X 
 
X 
X 
 
 
X 
Urinalysis8 
 
 
 
 
 
 
X 
Coagulation Assessment9 
 
 
 
 
 
 
X 
Pregnancy Test10 
 
 
 
 
 
 
X 
Research Blood Collection  11 
 
X 
(X + 3 wk)11 
 
 
(X + 3 wk)11 
X 
GX-188E Vaccination (i.m.) 
X 
 
X 
 
 
(X)16 
 
Pain Assessment12 
X 
 
X 
 
 
X 
 
Pembrolizumab (i.v.)13 
X 
X 
X 
X 
 
X 
 
Tumor Biopsy14 (optional) 
 
 
 
 
 
 
X 
Radiographic 
Evaluation 
of 
Tumor Burden15 
 
 
X 
 
X 
 
X 
 
 


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1. Screening and End of Study require a complete physical exam. For all other study, physical exams should be symptom-directed and clinically significant findings reported 
as adverse events. 
2. Vitals to include heart rate, respiratory rate, temperature, blood pressure (systolic and diastolic) weight, and height. Height only needs to be obtained at screening. 
3. Adverse event monitoring begins once a patient receives the first dose of either agent of the investigational study regimen and continues until 28 days after the last 
administration of study treatment, or until the initiation of a new anti-cancer therapy, whichever occurs first. For Serious Adverse Events (SAEs), follow up will continue 
for 90 days. 
4. Concomitant medication is defined as any prescription or over-the-counter preparation, including vitamins and supplements. All concomitant medications from 28 days 
before Day 1 through the end of the subject’s study participation must be recorded. (During the follow-up period after the end of the clinical trial, only the data about the 
antineoplastic therapy (surgical therapy, chemotherapy, radiation therapy, etc.) treated after the end of the subject’s study participation is recorded.) 
5. CBC w/differential to include: Hemoglobin, Platelets, Red Blood Cells, White Blood Cells, Basophils (%), Eosinophils (%), Lymphocytes (%), Monocytes (%), Neutrophils 
(Abs) and Hematocrit. 
6. At all timepoints, (except for Screening), only a basic metabolic panel (Na, K, CO2 or bicarbonate, Cl, Ca, BUN, creatinine & glucose) plus AST and ALT are required. 
Other tests may be ordered as clinically indicated.  
7. Includes thyroid-stimulating hormone (TSH), free thyroxine (FT4), and T3. Thyroid function tests and CEA/TA4 levels will be evaluated approximately every 6 weeks for 
the duration of study participation (i.e., Screening/Baseline, Week 7, Week 13, Week 19, Week 25, etc). 
8. Urinalysis is only required at Screening, Week 1 Day 1, Week 10 Day 1, and End of Study. Urinalysis should be ordered as clinically indicated at any other timpoint. 
9. Coagulation assessment includes: prothrombin time, partial thromboplastin time, and international normalized ratio (PT/PTT/INR). Coagulation assessments are only 
required at Screening and End of Study. On-treatment coagulation assessments (e.g., Week 10) are only required if a biopsy is planned and must be evaluated within 24 
hours prior to biopsy collection on the same day.  
10. All females of child-bearing potential must have serum or urine pregnancy test at End of Study. 
11. Blood collection.Samples will include serum for immune response Flt-3L(Screening, Week10, Week22, Week49 then after every 27 weeks) and whole blood for PBMC T 
cell responses(Screening, Week1, Week4, Week7, Week10, Week16, Week22, Week49 then after every 27 weeks). Samples obtained at all time points associated with 
study treatment administration, except for Screening, should be obtained prior to administration of either/both agents.  
12. Pain assessment using a 0-10 numeric pain rating scale will be administered prior to and 5 minutes (+ 2 minutes) following each GX-188E electroporation procedure  
13. Pembrolizumab will be administered every 3 weeks for the duration of study participation 
14. Patients with biopsy-accessible lesions will be asked to provide an optional biopsy sample at approximately Week 10 (or End of Study if the patient discontinues prior to 
Week 10) for paired biopsy analysis.  Biopsies will be evaluated for bio-markers using immunohistochemistry but not limited to it. 
15. Radiographic evaluations of tumor burden by RECIST v1.1 will be performed by a blinded independent central reviewer approximately every 9 weeks, or more frequently 
as clinically indicated, and at End of Study if the reason for discontinuation is other than for confirmed radiologic disease progression. Confirmatory scans are required 
approximately 4 weeks after any scan that indicates either an objective response, stable disease or disease progression. 
16. An optional GX-188E administration may be given at week 46 if it is in the best interests of the patient, as determined by the investigator, once the patient has completed 
37 weeks of treatment. Additional GX-188E administration(s) may be given to the subject after discussion with the sponsor.  
17. The End of Study (EOS) visit must occur within 28 days of treatment discontinuation/completion (Week 103 Day 1) and prior to initiation of any new anti-cancer 
thepapy/regimen. 
 


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Schematic Flow Chart 
   
 


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APPENDIX 2: LIST OF LIVE VACCINES. 
Source: 
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/us-
vaccines.pdf 
Patients who received any of the live vaccines listed below within 30 days of Screening are 
excluded from the study and cannot be enrolled. 
Vaccine 
Trade Name 
Manufacturer 
Type / Route 
Adenovirus 
Adenovirus Type 4 & 
Type 7 
Barr Labs Inc. 
Live Viral / Oral (tablets) 
Herpes Zoster (Shingles) 
Zostavax 
Merck 
Live Attenuated Viral / SC 
Influenza 
FluMist® 
Medimmune 
Live Attenuated Viral / Intranasal 
(spray) 
Measles, Mumps, Rubella 
M-M-R®  II 
Merck 
Live Attenuated Viral / SC 
Measles, Mumps, Rubella, 
Varicella 
ProQuad® 
Merck 
Live Attenuated Viral / SC 
 
Rotavirus 
RotaTeq® 
Merck 
Live Viral / Oral (liquid) 
Rotarix® 
GlaxoSmithKline 
Live Viral / Oral (liquid) 
Typhoid 
Vivotif® 
PaxVax 
Live Attenuated Bacterial / Oral 
(capsules) 
Varicella 
Varivax® 
Merck 
Live Attenuated Viral / SC 
Varicella 
Suduvax® 
Green Cross 
Live Attenuated Viral / SC 
Vaccinia (Smallpox) 
ACAM2000® 
sanofi 
Live 
Attenuated 
Viral 
/ 
Percutaneous 
Yellow Fever 
YF-Vax® 
sanofi 
Live Attenuated Viral / SC 
BCG for Tuberculosis 
 
[multiple 
manufacturers] 
Live attenuated / SC 
 
  
 
 


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APPENDIX 3: MOORE’S CRITERIA FOR DETERMINING PROGNOSIS IN 
CERVICAL CANCER 
Source: Moore DH et al., 2010 
All study participants should be categorized as low-risk, mid-risk or high-risk based upon the 
criteria and instructions below. 
Criterion 
Risk Factor 
1 point each 
0 points each 
Race 
Black 
Non-Black 
GOG 
Performance 
Status* 
1 or 2 
0 
Site of Disease 
Pelvis 
Non-pelvis 
Prior Platinum Agent as 
a Radiosensitizer?  
Yes 
No 
1st Recurrence within 1 
year since diagnosis? 
Yes 
No 
Add number of risk factors, or points, to obtain the Total Risk Score 
Total Score 
Risk Category 
0-1 
Low-Risk 
2-3 
Mid-Risk 
4-5 
High-Risk 
 
*GOG Performace Status 
GOG Score 
Activity Level 
0 
Fully active, unrestricted activities of daily living 
1 
Ambulatory, but restricted in strenuous activity 
2 
Ambulatory, and capable of self care. Unable to work. Out of bed for greater 
than 50% of waking hours 
3 
Limited self care, or confined to bed or chair 50% of waking hours. Needs 
special assistance 
4 
Completely disabled, and no self care 
5 
Dead 
 
 


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APPENDIX 4. CLINICAL LABORATORY TESTS 
CLINICAL LABORATORY TESTS RESULTS WITHIN 4 WEEKS (8 WEEKS FOR SEROLOGY) PRIOR TO THE START OF STUDY 
TREATMENT  WILL BE CONSIDERED AS ELIGIBLE TEST RESULTS FOR SCREENING PROCEDURES. 
Hematology (Peripheral Blood Sample) 
 Hemoglobin and hematocrit 
 RBC count 
 White blood cell count with differential 
 Platelet count 
Coagulation Tests 
 PT, aPTT and INR 
Serum Chemistry-Comprehensive Metabolic Panel (Peripheral Blood Sample)  
 Sodium 
 Potassium 
 Chloride 
 CO2  
 Calcium 
 Magnesium 
 Phosphorus 
 Glucose1 
 Blood urea nitrogen 
 Creatinine 
 Total protein 
 Albumin 
 Total and direct bilirubin2 
 Aspartate aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase (AP) 
1 
Fasting glucose is not required. Values considered abnormal must be interpreted in the context of a non-
fasting state as clinically appropriate 
2 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
 
Serology 
 HIV Ag/Ab 
 HAV Ab (IgM) 
 HBV Ab 
 HBV sAg 
 HCV Ab 
 HCV RNA (HCV realtime PCR) 
 
Urinalysis 
 Protein 
 Glucose 
 Ketones 
 Bilirubin 
 Hemoglobin/myoglobin 
 Nitrite 
 
 Leukocyte esterase 
 pH 
 Specific gravity 
 Urobilinogen 
 Microscopic evaluation (only when protein, 
esterase or hemoglobin dipstick is positive)  


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APPENDIX 5: RECIST CRITERIA VERSION 1.1 
 
Source: Eisenhauer et al., 2009 
Sponsor’s Note: Confirmatory scans are required approximately 4 weeks after any scan that 
indicates either an objective response or disease progression 
 
MEASURABILITY OF TUMOR AT BASELINE 
Definitions 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows. 
Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm by caliper measurement (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. See also section below on ‘Baseline documentation of target 
and non-target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment:  
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions.  


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 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.  
 Blastic bone lesions are non-measurable.  
Cystic lesions: 
 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. 
Lesions with prior local treatment:  
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  
SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
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 
should always be done rather than 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 
and  10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 


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If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the subject at baseline and follow-up, should 
be guided by the tumor type under investigation and the anatomic location of the disease. For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be 
optimized to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. 
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. 
*A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of 
the surrounding tissue on the attenuation corrected image. 
 
TUMOR RESPONSE EVALUATION 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients 
with measurable disease at baseline will be enrolled into this study.  
Measurable disease is defined by the presence of at least one measurable lesion.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means in instances where patients have only one or two organ sites involved a maximum 
of two (one site) and four lesions (two sites), respectively, will be recorded. Other lesions in 
that organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by 
CT scan). 


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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. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagital or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a short 
axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should 
be recorded as the node measurement. All other pathological nodes (those with short axis  10 
mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 
mm are considered non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, 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.  
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).  
RESPONSE CRITERIA 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
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. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.  
 Progressive Disease (PD): At least a 20% increase in the sum of 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 


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also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 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.  
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis < 10 mm. For PR, SD, and PD, the actual short axis measurement of 
the nodes is to be included in the sum of target lesions.  
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’. When this occurs it is important that a value be recorded on the case report form: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned and BML (below measurable limit) should be ticked (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well 
and BML should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 


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obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.  
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
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): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).  
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows:  
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the face of SD or PR 
of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore the increase must be substantial. 


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New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which 
it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
Time point response 
It is assumed that at each protocol specified time point (i.e., radiographic evaluation of tumor 
burden), a response assessment occurs. Table A provides a summary of the timepoint response 
status calculation at each time point for patients who have measurable disease at baseline.  
Table A: Time Point Response: Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response  
[at time point] 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 


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change the assigned time point response. This would be most likely to happen in the case of 
PD.  
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, or could 
not be assessed because of poor image quality or obstructed view, the Response for Target 
Lesions should be “Unable to Assess” since the patient is not evaluable. Similarly, if one or 
more non-target lesions are indicated as ‘not assessed’, the response for non-target lesions 
should be “Unable to Assess” (except where there is clear progression). Overall response would 
be “Unable to Assess” if either the target response or the non-target response is “Unable to 
Assess” (except where this is clear evidence of progression) as this equates with the case being 
not evaluable at that time point. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it 
be based on increase in size of the nodes. As noted earlier, this means that patients with CR 
may not have a total sum of ‘zero’ on the case report form (CRF).  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease.  
Conditions that define ‘early progression, early death, and non-evaluability are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity).  
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status 
of complete response. 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. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 


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assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
disease, will also take into consideration the appearance of new lesions and will depend upon 
confirmatory scans. For this study, determinations of either CR, PR or PD require a 
confirmatory scan at least 4 weeks later. This is described further in Table B below. 
 
Table B.Best Overall Response 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this Category Also 
Requires 
CR 
CR 
No 
CR 
≥4 weeks confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
≥4 weeks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
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 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression 


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APPENDIX 6: DESCRIPTION OF THE iRECIST PROCESS FOR ASSESSMENT OF 
DISEASE STATUS AND DISEASE PROGRESSION  
iRECIST Assessment of Disease 
Source: Seymour L et al. 2017 
The RECIST Working Group recently published iRECIST to provide a standard approach to 
the evaluation of solid tumors with measurements and assessment of the disease burden in trials 
that incorporate one or more immunotherapies. iRECIST follows similar recommendations 
provided by RECIST 1.1 in terms of methods of lesion measurement and size criteria, and the 
methodology of determining response is also comparable. However, there are some key 
differences between iRECIST and RECIST v1.1 that are highlighted in the table below. These 
differences take into account tumor shrinkage or disappearance following an initial RECIST 
v1.1. progression. Disease progression by iRECIST requires confirmation at a subsequent 
assessment, 4-8 weeks after the initial RECIST v1.1. PD determination. Additionally, iRECIST 
categorizes new lesions as Target or Non-Target. Importantly, the time point response and best 
overall response by iRECIST may be different from RECIST v1.1 and should be recorded 
separately.  
The 
following 
table 
was 
modified 
from 
EORTC 
iRECIST 
Training 
slides: 
http://recist.eortc.org/irecist/  
 
iRECIST 
Definitions of measurable, non-
measureable diseases 
Same as RECIST v1.1 
Definitions of Target and Non-Target 
lesions 
Same as RECIST v1.1 
Measurement and management of 
nodal disease 
Same as RECIST v1.1 
Calculation of the sum-of-
measurement (SOM) 
Same as RECIST v1.1 
Definitions of CR, PR, and SD, and 
their duration 
Same as RECIST v1.1 
Confirmation of CR and PR 
Same as RECIST v1.1 
Definition of progression in Target 
and Non-Target lesions 
First RECIST v1.1 PD is considered unconfirmed for 
iRECIST, termed 
i-Unconfirmed Progression (iUPD) 
Management of new lesions 
Assessed using RECIST 1.1 principles: 
 Classified as measurable or non-measurable 


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 Up to 5 (2 per site) measured (but not included 
in the SOM of target lesions identified at 
baseline) and recorded as new lesions target 
(NL-T) with an i-sum of measurements (iSOM) 
 Other new lesions (measurable/non-measurable) 
are recorded as new lesions non-target (NL-NT) 
 New lesions do not have to resolve for 
subsequent iSD or iPR providing that the next 
assessment did not confirm progression 
Time point response after RECIST 
1.1 progression 
There can be iSD, iPR or iCR after RECIST 1.1 PD 
 First RECIST 1.1 PD is “unconfirmed” for iRECIST 
– termed iUPD  
 iUPD must be confirmed at the next assessment (4-8 
weeks)  
 If confirmed, termed iCPD 
Time point response is dynamic and based on 
 Change from baseline (for iCR, iPR, iSD) or change 
from nadir (for PD) 
 The last i-response 
Confirmation of progression required 
First RECIST 1.1 PD is “unconfirmed” for iRECIST; 
disease progression must be confirmed at the next 
assessment (4-8 weeks later  
Treatment past RECIST 1.1 PD is permitted if patient 
clinically stable 
 No worsening of performance status 
 No clinically relevant ↑in disease related symptoms 
 No requirement for intensified management of 
disease related symptoms (analgesics, radiation, 
palliative care) 
Collection of reason why progression 
cannot be confirmed 
Record the reason iUPD not confirmed 
 Not stable 
 Treatment stopped but patient not 
reassessed/imaging not performed  
 iCPD never occurs 
 Patient has died 
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a participant on study treatment 


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until repeat imaging is obtained (using iRECIST for participant management (see Table 6 and 
Figure 5). This decision by the Investigator should be based on the participant’s overall clinical 
condition. 
Clinical stability is defined as the following:  
 Absence of symptoms and signs indicating clinically significant progression 
of disease 
 No decline in ECOG performance status  
 No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
 Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
o Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
 Unequivocal progression of non-target lesion(s) identified at baseline 
 Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up 
to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline.  All other new lesions will be followed qualitatively as New Lesions 
– Non-target. 
Assessment at the Confirmatory Imaging 


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On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
 Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 None of the progression-confirming factors identified above occurs AND 
 The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 None of the progression-confirming factors identified above occurs, AND 
 The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 


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In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the intervals 
as outlined in the Schedule of Events (Appendix 1) and submitted to the central imaging vendor. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
 Target lesions 
o Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
 Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD. 
o If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of non-target lesions, taken as a whole. 
 New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging 


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the burden of new lesions has increased from its smallest value (for new target lesions, the sum 
of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It 
will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or 
iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication. 
 

SAP_001.pdf: 
 
Analysis Plan  
  
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Page 1  of 48 
 
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Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL NO. GX-188E-005 
A MULTI-CENTER, OPEN-LABEL PHASE IB-II TRIAL OF THE COMBINATION OF GX-
188E VACCINATION AND PEMBROLIZUMAB IN PATIENTS WITH ADVANCED, NON-
RESECTABLE HPV TYPE 16 AND/OR 18 POSITIVE CERVICAL CANCER 
 
 
 
 
AUTHOR: XIN WANG 
VERSION NUMBER AND DATE: FINAL V 1.1, 05SEP2022 
 
 


 
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Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.1 (Dated 05Sep2022) for Protocol v4.0 dated 29Aug2022. 
 
Name 
Signature 
Date 
Author: 
Xin Wang 
 
 
 
Position: 
Biostatistician  
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis 
Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Yoon-Jeong Choi 
 
 
 
Position: 
Project Lead 
 
Company: 
Genexine, Inc. 
 
Approved By: 
Minkyu Heo 
 
 
 
Position: 
Head of Clinical Development Dept. 
 
Company: 
Genexine, Inc. 
 
 


 
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Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
MODIFICATION HISTORY 
Unique 
Identifier 
for 
this Version 
Date 
of 
the 
Document 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
1.0 
14Jul2022 
Xin Wang 
Not Applicable – First Version 
1.1 
05Sep2022 
Xin Wang 
Protocol final v4.0 is released on 
29Aug2022. 
SAP 
is 
updated 
accordingly. 
 
 


 
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Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................ 9 
2. 
STUDY OBJECTIVES ..................................................................................................................... 9 
2.1. 
Primary Objectives ......................................................................................................................................9 
2.2. 
Secondary Objectives ..................................................................................................................................9 
2.3. 
Exploratory Objectives .............................................................................................................................. 10 
3. 
STUDY DESIGN ........................................................................................................................... 11 
3.1. 
General Description ................................................................................................................................... 11 
3.2. 
Schedule of Events..................................................................................................................................... 13 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 13 
4. 
PLANNED ANALYSES ................................................................................................................ 13 
4.1. 
Safety Monitoring Committee (SMC) ......................................................................................................... 14 
4.2. 
Interim Analysis ......................................................................................................................................... 14 
4.3. 
Final Analysis ............................................................................................................................................. 14 
5. 
ANALYSIS POPULATIONS ....................................................................................................... 14 
5.1. 
All Patients Screened Population ............................................................................................................... 14 
5.2. 
Safety Population ...................................................................................................................................... 15 
5.3. 
DLT Evaluable Population .......................................................................................................................... 15 


 
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                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
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5.4. 
Efficacy Evaluable Population .................................................................................................................... 15 
6. 
GENERAL CONSIDERATIONS ................................................................................................. 17 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 17 
6.2. 
Baseline ..................................................................................................................................................... 17 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 17 
6.4. 
Statistical Tests .......................................................................................................................................... 18 
6.5. 
Common Calculations ................................................................................................................................ 18 
6.6. 
Software Version ....................................................................................................................................... 18 
7. 
STATISTICAL CONSIDERATIONS .......................................................................................... 18 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 18 
7.2. 
Multicenter Studies ................................................................................................................................... 18 
7.3. 
Missing data .............................................................................................................................................. 19 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 19 
7.5. 
Examination of Subgroups ......................................................................................................................... 19 
8. 
OUTPUT PRESENTATIONS ..................................................................................................... 20 
9. 
DISPOSITION AND WITHDRAWALS .................................................................................... 21 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 21 
10.1. 
Derivations ............................................................................................................................................ 22 


 
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11. 
MEDICAL HISTORY ................................................................................................................... 22 
12. 
MEDICATIONS AND PROCEDURES....................................................................................... 23 
12.1. 
Prior and Concomitant Medications and Non-Drug Treatment .............................................................. 23 
12.2. 
Prior Anti-cancer Therapies ................................................................................................................... 24 
12.3. 
Subsequent Anti-Cancer Therapies ........................................................................................................ 24 
13. 
STUDY MEDICATION EXPOSURE .......................................................................................... 24 
13.1. 
Derivations ............................................................................................................................................ 25 
14. 
STUDY MEDICATION COMPLIANCE ..................................................................................... 26 
14.1. 
Derivations ............................................................................................................................................ 26 
15. 
EFFICACY OUTCOMES .............................................................................................................. 27 
15.1. 
Primary Efficacy Endpoints .................................................................................................................... 28 
15.2. 
Secondary Efficacy Endpoints ................................................................................................................ 30 
15.3. 
Exploratory Efficacy Endpoints ............................................................................................................... 34 
16. 
SAFETY OUTCOMES .................................................................................................................. 34 
16.1. 
Adverse Events ...................................................................................................................................... 34 
16.1.1. 
All Treatment Emergent Adverse Events ..................................................................................................34 
16.1.1.1. 
Severity .............................................................................................................................................35 
16.1.1.2. 
Relationship ......................................................................................................................................35 
16.1.2. 
Treatment Related Adverse Events (TRAE)...............................................................................................35 


 
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16.1.3. 
TEAEs Leading to Discontinuation or Interruption of Study Medication ..................................................35 
16.1.4. 
AEs Leading to Study Discontinuation ......................................................................................................36 
16.1.5. 
AEs Leading to Death ................................................................................................................................36 
16.1.6. 
Serious Adverse Events .............................................................................................................................36 
16.1.7. 
Dose Limiting Toxicity (DLT) ......................................................................................................................37 
16.1.8. 
Adverse Events of Clinical Interest ...........................................................................................................38 
16.1.9. 
Immune-related Adverse Events (irAEs) ...................................................................................................38 
16.2. 
Deaths ................................................................................................................................................... 39 
16.3. 
Laboratory Evaluations .......................................................................................................................... 39 
16.4. 
Electrocardiogram (ECG) Evaluations ..................................................................................................... 40 
16.5. 
Vital Signs .............................................................................................................................................. 40 
16.6. 
Physical Examination ............................................................................................................................. 41 
16.7. 
Other Examinations ............................................................................................................................... 41 
17. 
REFERENCES ............................................................................................................................... 42 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS OUTPUT CONVENTIONS
 .................................................................................................................................................................... 43 
Dates & Times ....................................................................................................................................................... 43 
Significant Digits of Summary Statistics ................................................................................................................ 43 
Spelling Format ..................................................................................................................................................... 44 
Presentation of Study Phase ................................................................................................................................. 44 
Presentation of Visits ............................................................................................................................................ 44 


 
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Listings .................................................................................................................................................................. 45 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................................. 46 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 46 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 48 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis 
of efficacy and safety data for Protocol GX-188E-005. It describes the data to be summarized 
and analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version V4.0, dated 29Aug2022. The 
exploratory objectives of this study (described in SAP section 2.3) are not in IQVIA Biostatistics 
work scope and analysis methods for exploratory objectives are not included in this SAP. 
2. STUDY OBJECTIVES 
This study is separated into Parts A, B and C. Part A is the evaluation of safety and tolerability 
of GX-188E + Pembrolizumab (P) in patients with HPV 16+ and/or 18+ Advanced Cervical 
Cancer and will establish the recommended Phase 2 regimen for the investigational treatment. 
Part B is using Simon Two-Stage Design to evaluate the exploratory efficacy of Recommended 
Phase 2 GX-188E + P Regimen in patients with HPV 16+ and/or 18+ Advanced Cervical Cancer. 
Part C is the efficacy evaluation in larger number of patients. 
2.1. 
PRIMARY OBJECTIVES 
The primary objectives are: 
• 
Part A: To establish the safety and tolerability of GX-188E +P and to identify the 
recommended Phase 2 treatment regimen. 
• 
Part B: To evaluate Objective Response Rate within 24 weeks (ORR24) by Response 
Evaluation Criteria in Solid Tumor (RECIST) 1.1. Response determinations from the 
blinded, independent central reviewers (BICR) will be used for the primary endpoint. 
• 
Part C: To evaluate ORR24 by RECIST 1.1. Response determinations from the BICR 
will be used for the primary endpoint. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of Part A are to evaluate: 


 
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• 
Objective Response Rate within 24 weeks (ORR24) by RECIST 1.1 and Response 
Evaluation Criteria in Solid Tumors for Immunotherapeutics (iRECIST). 
• 
Best Overall Response Rate (BORR), Time-to-Best Response, Duration of Response 
(DOR), Progression-Free Survival (PFS) and Overall Survival (OS). 
The secondary objectives of Parts B and C are to evaluate: 
• 
Safety and tolerability. 
• 
BORR by RECIST v1.1 and iRECIST. 
• 
Progression-Free Survival (PFS): 6-month PFS rate (Probability that the progression 
has not occurred by 6 months), median PFS time  
• 
Overall Survival (OS): 6-month OS rate (Probability of being alive just before 6 months), 
Median OS time 
• 
Disease Control Rate (DCR) 
• 
Duration of Response (DOR) 
• 
Time-to-Best Response (TTR) 
2.3. 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
• 
To evaluate the ability of GX-188E to induce a systemic HPV-16 and HPV-18-specific 
T-cell response that includes, but is not limited to, expansion of CD4+ and CD8+ T-cells 
that recognize E6 or E7 peptide epitopes. 
• 
To investigate whether GX-188E vaccination promotes a Th1-polarized anti-tumor 
immune response. 
• 
To assess whether GX-188E vaccination increases tumor immunogenicity (e.g. 
increased expression of antigen presentation and processing machinery, increased 
TILs). 
• 
Identification of biomarkers that has possibility to implicate clinical response and safety 
and/or mechanism of action of GX-188E and pembrolizumab. 


 
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3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This is a Phase Ib/II open-label trial to evaluate the safety and efficacy of GX-188E plus 
pembrolizumab, (GX-188E + P) in patients with advanced HPV-16+ or HPV-18+ cervical cancer. 
This study is separated into three Parts, A, B and C.  
Part A. Initial Safety Evaluation  
The study will begin with Part A, a safety run-in, employing a “6+3 design”, to ensure that the study 
treatment is not associated with unacceptable acute toxicities. 
The starting dose in Part A for GX-188E will be 2 mg (1 mg/site x 2 vaccination sites). Six (6) 
vaccination days are planned. (week 1, week 2, week 4, week 7, week 13 and week 19). An 
optional GX-188E administration may be given at week 46 if it is in the best interests of the patient, 
as determined by the investigator, once the patient has completed 37 weeks of treatment.  
Additional GX-188E administration(s) may be given to the patient after discussion with the sponsor. 
GX-188E will be administered on Day 1 of the following schedule: 
• 
Weeks 1, 2, 4, 7, 13, 19 and 46 (Optional) 
The standard dose of pembrolizumab (200 mg every 3 weeks) will be administered. No dose 
escalation of either agent is planned.  
The first 6 patients will be enrolled and evaluated for the first 3 weeks (prior to week 4 Day 1 visit) 
for dose-limiting toxicities (DLTs). A DLT is defined as any adverse event (AE) that is not clearly 
due to progression of the patient’s malignancy, that occurs within the first 3 weeks (prior to week 
4 Day 1 visit) of treatment initiation, and that meets at least one of the non-hematologic or 
hematologic criteria. 
In addition, any other AE that is felt to be treatment-limiting in the medical opinions of the principal 
Investigator and the Sponsor’s Medical Monitor may be considered a DLT. 
No additional patients will be enrolled until all patients in Part A have completed the DLT window 
and the investigational treatment regimen has been deemed safe. If ≤ 1 patient of 6 enrolled 
patients experiences DLT, enrolment into Part B will be initiated. If 2 patients experience a DLT, 
an additional 3 patients will be enrolled and evaluated for DLTs. If 3 or more patients in the first 6 
or 9 patients experience a DLT, the combination at the current treatment schedule will be 
considered too acutely toxic and enrolment will begin at a reduced frequency treatment schedule. 


 
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Depending on the occurrence rate of DLT, all patients without DLT, who receive the recommended 
Phase 2 treatment regimen, and who are considered evaluable for efficacy from Part A will be 
included in the first stage of Part B.  
Sample Size for Part A Safety Evaluation: For the traditional 6+3 design of Part A, the goal is to 
determine a treatment schedule for which the rate of DLTs is less than 33% in 6 or 9 patients. A 
minimum of 6 patients are planned for Part A, with a maximum of 18 DLT-evaluable patients for 
the Starting Treatment Schedule and Reduction Level 1. If ≥ 3 in 6 or 9 patients at Reduction Level 
1 have DLTs, then the investigational treatment regimen will be considered too toxic and 
enrolment into the study will be discontinued. 
Part B. Exploratory Efficacy Evaluation in Advanced Cervical Cancer Patient (Simon Two-Stage 
Design) 
In Part B, patients will receive the treatment schedule for GX188E + P that was determined from 
Part A to be well-tolerated. In the first stage of Part B, 15 patients with advanced HPV 16 or 18 
positive cervical cancer will be treated. If at least 3 patients experience an objective response (i.e. 
partial response or better) by RECIST v1.1 in the first 24 weeks of treatment, an additional 13 
patients will be enrolled for a total of 28 patients in Part B. If 2 or fewer patients in the first stage 
experience an objective response, enrollment into Part B will be discontinued for futility. Study has 
passed the first stage of Simon-Two stage design. 
Sample Size for Part B: Part B follows a 1-sided Simon 2-Stage minimax design; 15 patients, 
including all patients from Part A without a DLT, who receive the recommended Phase 2 regimen 
and who meet the criteria for the Efficacy Evaluable Population with HPV 16 or 18 positive 
advanced cervical cancer will be included in the first stage analysis. If 3 or more objective 
responses (Partial response or better) are observed in the first stage, another 13 patients will be 
enrolled into the second stage, for a total of 28 patients in Part B. Study has passed the first stage 
of Simon-Two stage design. For a null hypothesis ORR24 of 0.15 and an alternative hypothesis 
ORR24 of 0.35, the sample size of 28 patients will provide a one-sided significance level of 
approximately 5% and a power of 80%. If Stages 1 and 2 are completed, a minimum of 8 patients 
must demonstrate a response (partial response or better) to reject the null hypothesis. If a patient’s 
response could not be confirmed, that patient will not be included in the primary efficacy analysis 
for ORR24.  
Part C. Efficacy Evaluation in Larger Number of Patients 
If at least 8 of the 28 patients enrolled in Part B, experience an objective response who are 
considered evaluable for efficacy, it will be considered that objective response rate (ORR) satisfies 
the criteria for study expansion and additional 17 patients (at least) will be enrolled in Part C to 


 
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evaluate efficacy further in larger patient population (N=60). If only 7 or fewer patients in Part B 
experience an objective response, enrollment to Part C will not open.  
Sample Size for Part C: Part C is to evaluate efficacy in larger patient population. In Keynote-158 
study (pembrolizumab monotherapy in patients who have progressed with standard of care 
systemic therapy), ORR in total patients (i.e. regardless of PD-L1 status) and with CPS ≥ 1 were 
12.2% and 14.6%, respectively.  
Given this, null hypothesis for ORR24 was set at P0 = 12.2%. With an alternative hypothesis for 
ORR24 of Pa = 37%, the sample size of 60 subjects was calculated considering two-sided 
significance level of 0.05, 97% power, and 25% dropout rate.  
The confidence interval (CI) for ORR24 will be estimated using exact Clopper-Pearson method, 
and if the lower bound of the two-sided 95% CI for ORR24 exceeds 12.2%, it will be proven to 
satisfy the primary efficacy. And it will be analyzed using two-sided exact binomial test for a null 
hypothesis for ORR24 of P0 = 12.2% with a significance level of 0.05.  
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in appendix 1 of the protocol. The End of Study (EOS) visit 
must occur within 28 days of treatment discontinuation/completion and prior to initiation of any 
new anti-cancer therapy/regimen. 
3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
No immunogenicity analyses are planned for the Exploratory/Biomarker objectives while the 
protocol mentioned. 
For the efficacy endpoint overall survival, it was decided to present 6-month OS rate with median 
OS time. 
4. PLANNED ANALYSES 
One interim analysis and one final analysis will be performed for this study. 


 
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4.1. 
SAFETY MONITORING COMMITTEE (SMC)  
The Safety Monitoring Committee (SMC) will be responsible for evaluating patients’ safety data 
and determining the overall safety and tolerability profile of the investigational treatment regimen. 
The SMC will be comprised of the Sponsor Medical Monitor, and the Principal Investigator from 
each participating site. 
Analysis for SMC review is not in IQVIA Biostatistics work scope and the relevant analysis 
methods for SMC review are not included in this SAP. 
4.2. 
INTERIM ANALYSIS  
An interim analysis will be performed with safety and efficacy data in case of at least 22 patients 
in efficacy evaluation population, after obtaining week 10 tumor assessment results (by 
investigator/BICR). 
4.3. 
FINAL ANALYSIS  
The final analysis will be performed to report a primary CSR based on a data cut off after all 60 
patients in the planned efficacy evaluation population have completed tumor assessment within 
24 weeks by the investigator per RECIST v1.1 
Since patient will be treated until they met one of the discontinuation criteria, some patients may 
still be ongoing at the time of final analysis. Therefore, a long-term follow-up study can be 
performed after final analysis with all available data (no cut-off date applied). 
5. ANALYSIS POPULATIONS 
Agreement and authorization of patients included/ excluded from each analysis population will 
be conducted prior to Database Lock.  
5.1. 
ALL PATIENTS SCREENED POPULATION  
The all patients screened population will contain all patients who provide informed consent for 
this study. 


 
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5.2. 
SAFETY POPULATION  
The patients who receive at least 1 dose of 1 agent in the investigational treatment regimen (i.e. 
either GX-188E or P) will be included in the analysis of safety, regardless of the duration of 
treatment. 
5.3. 
DLT EVALUABLE POPULATION  
Part A patients who receive all of the planned administrations of both agents (GX-188E and P) 
within the DLT-evaluation period (the first three weeks of treatment prior to Week 4 Day 1 visit), 
unless doses are missed within the first two weeks of treatment (i.e., Week 1 Day 1 to Week 2 
Day 7) due to DLT(s). 
5.4. 
EFFICACY EVALUABLE POPULATION  
All patients who complete the study will be included into the efficacy evaluable population. These 
patients will be identified by using the “Subject's status?” with answer “Completed trial” from end 
of study page of CRF.   
All patients who discontinue the study treatment regimen early due to treatment-related toxicity 
will be considered evaluable for efficacy. These patients will be identified as those with DLT. 
Patients who discontinue study due to disease-related death, unequivocal tumor progression or 
with at least 1 post-baseline tumor assessment must have received at least 45 days on protocol 
treatment to be considered evaluable for efficacy. Patients who discontinue study due to 
disease-related death will be identified by using the “Primary reason for premature 
discontinuation from study” with answer “Death” from end of study page of CRF and the “Was 
death disease related” with answer “Yes” from death details page of CRF. Patients who 
discontinue study due to unequivocal tumor progression will be identified by using “Primary 
reason for premature discontinuation from study” with answer “Disease Relapse or Progression” 
from end of study page of CRF. Patients who discontinue study with at least 1 post-baseline 
tumor assessment will be identified as those with at least one RECIST/iRECIST Overall 
Response data on RECIST/iRECIST Overall Response page of CRF after screening visit. 
Patients in Part B and Part C who do not meet the aforementioned requirements will be 
considered non-evaluable for response and may be replaced. Patients from Part A, who receive 
the recommended Phase 2 regimen and who meet the aforementioned criteria for the Efficacy 
Evaluable Population will be included in the analysis for Part B and Part C. The following table 
provides further, more specific details. 


 
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Table 1. Determination of Patients to be Included in Efficacy Evaluable Population 
Patient Cohort 
Reason for Discontinuation 
Number of Days 
on Protocol 
Treatment 
Include in Efficacy 
Evaluable Population 
(Yes/No)? 
Part A receiving RP2 
regimen* 
Protocol-Defined DLT, or 
other toxicity^ 
Not applicable 
Yes, included in 
Efficacy Evaluable 
Population 
Part A receiving RP2 
regimen* 
Disease-related death, 
unequivocal tumor 
progression or at least 1 post-
baseline tumor assessment 
< 45 days 
No 
Part A receiving RP2 
regimen* 
Disease-related death, 
unequivocal tumor 
progression or at least 1 post-
baseline tumor assessment 
≥ 45 days 
Yes, included in 
Efficacy Evaluable 
Population 
Part A, receiving 
dose > RP2 regimen* 
Any 
Not applicable 
No 
Part B and Part C 
Disease-related death, 
unequivocal tumor 
progression, or at least 1 
post-baseline tumor 
assessment 
< 45 days 
No, patient may be 
replaced 
Part B and Part C 
Disease-related death, 
unequivocal tumor 
progression, or at least 1 
post-baseline tumor 
assessment  
≥ 45 days 
Yes, included in 
Efficacy Evaluable 
Population 
Part B and Part C 
Toxicity^ 
Not applicable 
Yes, included in 
Efficacy Evaluable 
Population 
*RP2 regimen = Recommended Phase 2 regimen of GX-188E 
^ Toxicity = Any dose limiting toxicity (DLT). 


 
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6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/ stop 
day of assessments and events.  
Reference start date is defined as the day of the first dose of study medication (either GX-188E 
or P, whichever occurred first), Day 1 is the day of the first dose of study medication and will 
appear in every listing where an assessment date or event date appears.  
• 
If the date of the event is on or after the reference date, then:  
Study Day = (date of event – reference date) + 1. 
• 
If the date of the event is prior to the reference date, then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, study day, and any corresponding 
durations will appear partial or missing in the listings. 
6.2. 
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement (including 
unscheduled assessments) taken prior to reference start date and time. Reference start date 
and time is defined as the date and time of the first dose of study medication (either GX-188E 
or P, whichever occurred first). In the case where the time is unknow and last non-missing 
measurement and the reference start date coincide, that measurement will be considered pre-
baseline, but AEs and medications commencing on the reference start date will be considered 
post-baseline.  
6.3. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries but will contribute to the 
best/worst case value where required (e.g. shift table).  


 
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In the case of a retest (same visit number assigned), the latest available measurement for that 
visit will be used for by-visit summaries.  
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. 
STATISTICAL TESTS 
The default significance level will be 5% 2-sided; confidence intervals will be 95% (2-sided), 
unless otherwise specified in the description of the analyses. 
6.5. 
COMMON CALCULATIONS 
For quantitative measurements, the following formulates will be used if applicable: 
 
• 
Change from baseline =Test Value at Visit X – Baseline Value 
• 
Percentage change from Baseline (%) = (Test Value at Visit X – Baseline Value) / 
Baseline Value × 100 
6.6. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
7. STATISTICAL CONSIDERATIONS 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
No adjustment for covariates and factors will be used in the analyses. 
7.2. 
MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centres. Because a small 


 
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number of patients are expected at each center, data from all centers will be pooled and no 
center effect will be investigated. 
7.3. 
MISSING DATA 
Generally, missing data will not be imputed. 
For death date, if year and month of death date are known but the day of date is unknown, day 
will be imputed as 1. For example, if a patient is reported to die on Dec 2016, the death date will 
be imputed as 01Dec 2016.  
Imputed dates will NOT be presented in the listings. 
Partial dates of adverse events and prior/concomitant medication will be handled as described 
in Appendix 2.  
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
No multiple comparisons and multiplicity adjustment will be performed. 
7.5. 
EXAMINATION OF SUBGROUPS 
(1)  In Part C, ORR24, BORR and DCR will be assessed and described in the following 
subgroups: 
 
• 
Age 
o Less than 50 years 
o ≥50 to < 65 
o Equal to or more than 65 years 
 
• 
HPV type 
o HPV-16 
o HPV-18 or both 
 
• 
Histology type 
o Squamous cell carcinoma 
o Adenocarcinoma 


 
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• 
Prior bevacizumab 
o Yes 
o No  
 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status at baseline 
o 0 
o 1  
 
• 
PD-L1 status at baseline 
o Positive (≥1 CPS) 
o Negative (<1 CPS) 
 
In Part C, DOR, TTR, PFS and OS by PD-L1 status, HPV type, and Histologic type 
subgroups will be summarized. Kaplan-Meier curve of BICR/investigator-assessed PFS 
according to RECIST v1.1 stratified by PD-L1 result, or HPV type, or Histologic type will 
be displayed. Kaplan-Meier curve of overall survival stratified by PD-L1 result or HPV type, 
or Histologic type will also be displayed. 
(2) Using pain killer or local anaesthetic as a premedication to control the pain may affect 
Pain assessments. A subset of the safety population (who used pain killer or local 
anaesthetic to control the pain before GX-188E administration using electroporator) will 
be used for sensitivity analysis. The following summaries will be made based on the 
subset of safety population.  
• 
Pain Assessments Summary  
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The mock up TFLs shell provided with this SAP describe the presentations for this study and 
therefore the format and content of the summary tables, figures, and listings to be provided by 
IQVIA Biostatistics. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
interquartile range, and range (minimum/maximum). Categorical variables will be presented as 
frequency counts and percentages, and time-to-event variables will be summarized with number 


 
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of non-missing observations, median time, and survival probability using Kaplan-Meier method if 
applicable. Kaplan Meier plot will also be provided. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy, and safety 
results. The efficacy analysis will be conducted on the Efficacy Evaluable Population, and the 
safety analysis will be performed on the Safety Population.  
Data listings will be created to support each table and to present all data collected. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study. Patient disposition 
and withdrawals will be presented for all patients enrolled population. Patient disposition and 
withdrawals include information about patients enrolled, patients who received study medication, 
patients who completed/withdrew from study medication/study, reason for study medication 
withdrawal and study early termination. The breakdown of patients into the analysis sets will be 
presented. 
A listing of inclusion/exclusion criteria deviations and reason for screen failure will be provided 
for screen failure patients.  
Additionally, IQVIA clinical trial management system (CTMS) protocol deviation (PD) will be 
used. Any protocol deviations identified during the course of the study will be listed and the 
number and percentage of patients in each type of protocol deviations will be summarized for 
the SAF. 
Follow-up time (months) is the time between a specified event (death, end of the study, follow-
up date or completion/ last contact date, whichever occurred later) and the date of first dose. 
• 
Follow-up time (months) = (the date of event-the date of first dose +1)/30.4375 
Follow-up time will be summarized for safety population. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the DLT evaluable 
population, safety population and efficacy evaluable population. 
Descriptive statistics will be used for summarizing the patients’ characteristics. No statistical 
testing will be carried out for demographic or other baseline characteristics. 


 
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The following demographic and other baseline characteristics will be summarized for this study. 
Individual data will also be listed. 
• 
Age (years) - calculated relative to date of consent 
• 
Childbearing potential 
• 
Race  
• 
Ethnicity 
• 
Weight (kg) 
• 
BMI (kg/m2) 
• 
ECOG Performance Status 
• 
Moore’s criteria for determining prognosis in cervical cancer 
• 
PD-L1 test result 
10.1. 
DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Age (years) = Year of informed consent (IC) – Year of birth, if month of IC is later than 
month of birth, or if month of IC is equal to month of birth but day of informed consent is 
later than or equal to day of birth; 
Age (years) = Year of informed consent – Year of birth – 1, otherwise. 
In this case, if one patient is more than 45 years old but less than 46 years old, then this 
patient will be presented as age 45.  
11. MEDICAL HISTORY 
Medical History information will be presented for the safety population.  
General Medical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), Version 21.1 or higher. Data captured on the “Medical History – General” form of the 
Case Report Form (CRF) will be presented in frequency table by System Organ Class (SOC) and 
Preferred Term (PT) in descending order of total frequency. For SOCs or PTs with the same total 
frequency, categories will be sorted alphabetically.  


 
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Medical History data captured on the “Medical History – Cancer and HPV” will be presented. 
The following information will be summarized: 
• 
Medical History Term by SOC and PT (HPV and Advanced inoperable or metastatic 
cervical cancer) 
• 
Histologic Type at diagnosis 
• 
Stage of disease at diagnosis 
• 
Stage of disease at enrolment 
• 
HPV Variant (HPV 16+/ HPV 18+/ Other)   
• 
Type of anti-cancer therapy (Prior oncologic drugs and biologics / Prior oncologic surgery 
and procedures / Prior oncologic radiation) 
• 
Target Lesion(s) at time of screening (Uterus, Lymph node, Liver, Lung, Spleen, Bone, 
Adrenal Gland, Tubes, Ovaries, Vagina, Bladder, Urethra, Rectum, Others) 
• 
Non-Target Lesion(s) at time of screening (Uterus, Lymph node, Liver, Lung, Spleen, 
Bone, Adrenal Gland, Tubes, Ovaries, Vagina, Bladder, Urethra, Rectum, Others) 
Medical history data will be listed. 
12. MEDICATIONS AND PROCEDURES 
12.1. 
PRIOR AND CONCOMITANT MEDICATIONS AND NON-DRUG 
TREATMENT 
All concomitant medications received by the patient within 28 days prior to the first dose through 
the end of the patient’s study participation should be recorded on the “Prior and Concomitant 
Medications” page of CRF. Prior medications are those medications that were stopped prior to 
first study treatment. Concomitant medications are medications taken at least once after first study 
treatment. Medications stopped on the same day as first study treatment will be considered as 
prior medication only. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. The PT will be used for tabulation. The summary tables will show the number and 
percentage of patients by PT, for each part and overall. Pre and concomitant medications will be 
summarized separately. The descriptive summaries for pre and concomitant medications will be 


 
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presented for the safety population. Missing or partial dates for medications will be handled 
according to Appendix 2 of this analysis plan. In the case where it is not possible to define a 
medication as prior or concomitant, the medication will be classified by the worst case; i.e. 
concomitant. For the summaries of concomitant medications, patients who take the same 
medication (in terms of the PT), more than once will only be counted once for that medication. The 
detailed information of prior and concomitant medication use including medication name, 
indication, dose, start date, end date, ongoing or not, frequency and route of administration, etc. 
will be listed.  
Non-Drug treatment will be collected on the “Prior and Concomitant Non-Drug Treatment” form of 
CRF including procedure name, indication, start date, end date and ongoing or not. Non-Drug 
treatment name will be coded using MedDRA Version 21.1 or higher version. Non-Drug treatment 
information will be summarized by SOC and PT. Non-Drug treatment will be listed for safety 
population. 
12.2. 
PRIOR ANTI-CANCER THERAPIES 
Information collected on the “Prior Oncologic Drugs and Biologics”, “Prior Oncologic Surgery and 
Procedure”, and “Prior Oncologic Radiation” pages of CRF will be summarized descriptively.  
12.3. 
SUBSEQUENT ANTI-CANCER THERAPIES 
Subsequent new anti-cancer therapy after the end of the study will be listed.  
13. STUDY MEDICATION EXPOSURE 
Exposure data will be presented for the safety population. 
The date of first study medication administration will be taken from the CRF “Exposure – GX-
188E” and “Exposure – Pembrolizumab” form. The date of last study medication will be taken 
from the “Date of last administration” on “End of Treatment” page of CRF for GX-188E and 
Pembrolizumab.  
The variables relevant to the extent of exposure listed as below will be summarized for safety 
population. Individual exposure data recorded in “Exposure – GX-188E” and “Exposure – 
Pembrolizumab” as well as the derived variables will also be listed. 
• 
Duration of exposure of GX-188E 


 
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• 
Number of Doses of GX-188E  
• 
Percentage of Patients with GX-188E interruption 
• 
Duration of exposure of Pembrolizumab 
• 
Number of Doses of Pembrolizumab  
• 
Percentage of Patients with Pembrolizumab interruption 
The information of the overdose, abuse and accidental exposure of GX-188E and 
Pembrolizumab will be collected in “Overdose, Abuse, Accidental Exposure – GX-188E” and 
“Overdose, Abuse, Accidental Exposure – Pembrolizumab” form in CRF. The overdose, abuse 
and accidental exposure data will be listed for safety population. 
13.1. 
DERIVATIONS 
• 
Duration of exposure to GX-188E (weeks)= (Last dose date of GX-188E – First dose 
date of GX-188E +1) / 7 
When the start or stop date is missing, then the exposure will be treated as missing. 
Interruptions, compliance, and dose changes are not taken into account for duration of 
exposure. 
• 
Number of Doses of GX-188E (times) = Count total numbers from “Exposure – GX-188E 
Vaccination” CRF page with response of “Yes” to the question “Was GX-188E 
administered at this visit?”  
• 
Duration of exposure to Pembrolizumab (weeks)= (Last dose date of Pembrolizumab – 
First dose date of Pembrolizumab +1) / 7 
When the start or stop date is missing, then the exposure will be treated as missing. 
Interruptions, compliance, and dose changes are not taken into account for duration of 
exposure. 
• 
Number of Doses of Pembrolizumab (times) = Count total numbers from “Exposure – 
Pembrolizumab” CRF page with response of “Yes” to the question “Was Pembrolizumab 
administered at this visit? “  


 
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14. STUDY MEDICATION COMPLIANCE  
Compliance with study medication—based on the drug exposure data—will be calculated as the 
amount taken divided by the prescribed amount expressed as a percentage. “Per Visit” 
Compliance to GX-188E, Overall Compliance to GX-188E, “Per Visit” Compliance to 
Pembrolizumab and Overall Compliance to Pembrolizumab will be calculated.  
The compliance will also be summarized by categories as below: 
• 
< 80% 
• 
80 – 120% 
• 
> 120% 
The variables relevant to compliance to study medication will be presented in summary table for 
the safety population. Individual data will be listed. 
14.1. 
DERIVATIONS 
• 
“Per Visit” Compliance to GX-188E (%) = (Dose in mg administrated at location 1+Dose 
in mg administrated at location 2)/Planned dose in mg per day*100, presented to 1 
decimal place. 
Planned dose per day is total of 2 mg per vaccination day.  
• 
Overall Compliance to GX-188E (%) = Actual Number of Doses of GX-188E / Planned 
Number of Doses of GX-188E Injection 
Planned number of doses of GX-188E (times) = 6 
• 
“Per Visit” Compliance to Pembrolizumab (%) =Dose in mg per administration /Planned 
dose in mg per administration *100, presented to 1 decimal place. 
• 
Overall Compliance to Pembrolizumab (%) = Actual Number of Doses of Pembrolizumab 
/ Planned number of doses of Pembrolizumab 
Planned number of doses of Pembrolizumab (times) = 35 


 
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15. EFFICACY OUTCOMES  
Tumor response to treatment will be evaluated using both RECIST v1.1 and iRECIST. For each 
patient with objectively measurable disease and who meet the criteria for inclusion in the Efficacy 
Evaluable population, response to therapy will be calculated. The analysis of ORR24, BORR and 
DCR per RECIST v1.1 will also be performed in safety population as sensitivity analysis. 
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(e.g., discontinuation of study treatment).  All efficacy endpoints will be evaluated and categorized 
using RECIST 1.1. Confirmatory scans are required for all determinations of objective response 
[Partial response (PR) or Complete response (CR)], Stable disease (SD) and disease progression 
(PD). Confirmatory scans must be performed at least 4 weeks later. 
Investigator assessment of tumor response based upon RECIST v1.1 will be analyzed in the same 
way as the corresponding BICR-assessed endpoints (except Kaplan-Meier curves which will only 
be presented for BICR assessment). Concordance between BICR and Investigator assessments 
will be summarized at a patient level for BOR. 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor response 
and progression and make treatment decisions. When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local radiology, 
according to the rules outlined in Appendix 6 of protocol. This allowance to continue treatment 
despite initial radiologic PD takes into account the observation that some participants can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. This data will be captured in the clinical database. 
Efficacy endpoints are as follows. 
• 
Objective Response Rate within 24 weeks (ORR24) 
• 
Best Overall Response Rate (BORR) 
• 
Progression-Free Survival including 6-month PFS rate and median PFS time 
• 
Overall Survival including 6-month OS rate and median OS time 
• 
Disease Control Rate   
• 
Duration of Response  
• 
Time to Best Response 


 
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15.1. 
PRIMARY EFFICACY ENDPOINTS 
The primary efficacy variable is BICR-assessed ORR24 by RECIST 1.1 in Part B and C. 
Best overall response within 24 weeks (BOR24) is the best objective response achieved within 
the first 24 weeks of treatment prior to study discontinuation. All available response designations 
will contribute to the BOR24 determination.  If a patient’s BOR24 could not be confirmed, that 
patient will not be included in the primary efficacy population for ORR24. Additional patients will 
be enrolled to meet the study hypothesis. Any CR or PR must be confirmed by a sequential 
assessment that is at least 4 weeks apart. The confirmation rule is defined in Table 2 (please 
refer to RECIST 1.1 [1]). The confirmed response will be determined before analysis. The 
number and percentage of patients in each category of best overall response CR, PR, SD, PD 
or Not Evaluable (NE) will be provided.  
ORR24 is the proportion of efficacy evaluable patients who achieve an objective response (PR 
or CR) within 24 weeks prior to study discontinuation. The number and percentage of patients 
who achieve best overall response of PR or CR will be summarized. 
 
If the first responses can be confirmed by the second response within 24 weeks of treatment, 
they will be included as responses for ORR24. Also, If the first response within 24 weeks is 
confirmed by the second response after 24 weeks of treatment, the first response should be 
included as response for ORR24. 
Table 2. Best overall response when confirmation of CR and PR is required per RECIST 1.1 
Guideline 
Overall response  
First time point 
Overall response 
Subsequent time 
point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
PR, or SD provided at least 28 days’ duration, 
otherwise PDa 
CR 
SD 
SD provided at least 28 days’ duration, 
otherwise PD 


 
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CR 
PD 
SD provided at least 28 days’ duration, 
otherwise PD 
CR 
NE 
SD provided at least 28 days’ duration, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided at least 28 days’ duration, 
Otherwise PD 
PR 
NE 
SD provided at least 28 days’ duration, 
Otherwise NE 
NE 
NE 
NE 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
not evaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
In the case of best response equal to SD, the minimum duration for SD should be met. In other 
words, there will be at least once overall response being SD or CR or PR after 28 days from the 
first dose of study medication. For example, if the first overall response is CR evaluated less 
than 28 days from the first dose, with subsequent overall response as PD, then the best overall 
response should be PD. If the first overall response is CR evaluated on or more than 28 days 
from the first dose, with subsequent overall response as PD, then the best overall response 
should be SD.  
In the case of only one tumor assessment post dosing, if PD reported, the best overall response 
will be PD. Otherwise, if less than 28 days from the first dose, the best overall response should 


 
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be NE. If the only post dosing tumour assessment is 28 or more days from the first dose and 
overall response equal to CR or PR or SD, the best overall response will be SD, otherwise NE. 
BICR-assessed ORR24 by RECIST v1.1 will be displayed for Part B and Part C.  
In Part C, BICR-assessed ORR24 by RECIST v1.1 will be calculated for patients overall. 95% 
confidence interval for ORR24 will be estimated using exact Clopper-Pearson method. In Part C, 
it will be analyzed using two-sided exact binomial test for a null hypothesis for ORR24 of P0 = 
12.2% with a significance level of 0.05.  
15.2. 
SECONDARY EFFICACY ENDPOINTS 
• 
BORR 
BORR in Parts A, B and C is one of the secondary efficacy endpoints. Both BICR-assessed 
BORR and Investigator-assessed BORR by RECIST 1.1 or iRECIST in Parts A, B and C will be 
calculated. 
BICR-assessed BORR by iRECIST and investigator-assessed BORR by RECIST 1.1 or 
iRECIST in Parts B and C will be calculated. 
Overall responses evaluated according to iRECIST will be used for analysis. iRECIST defines 
i-Unconfirmed Progression (iUPD) on the basis of RECIST 1.1 principles; however, iUPD 
requires confirmation, which is done on the basis of observing either a further increase in size 
(or in the number of new lesions) in the lesion category in which progression was first identified 
in (ie, target or non-target disease), or progression (defined by RECIST 1.1) in lesion categories 
that had not previously met RECIST 1.1 progression criteria. However, if progression is not 
confirmed, but instead tumour shrinkage occurs (compared with baseline), which meets the 
criteria of iCR, iPR, or iSD, then the bar is reset so that iUPD needs to occur again (compared 
with nadir values) and then be confirmed (by further growth) at the next assessment for i-
Confirmed Progression (iCPD) to be assigned. If no change in tumour size or extent from iUPD 
occurs, then the timepoint response would again be iUPD. This approach allows atypical 
responses, such as delayed responses that occur after pseudo progression, to be identified, 
further understood, and better characterised. The iBOR is the best time-point response recorded 
from the start of the study treatment until death or lost to follow up before the end of the study, 
whichever occurs first, taking into account any requirement for confirmation. Confirmation of iCR 
and iPR is the same as that in Table 2 per RECIST v1.1. Confirmation of progression is also 
required per iRECIST.  
BORR will be summarized by number of patients and percentages. The BORR and its 95% 
confidence interval will be presented. The 95% (exact) confidence interval will be calculated 


 
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based on the Clopper-Pearson method. PROC FREQ procedure of SAS will be used to calculate 
95% (exact) confidence interval by the Clopper-Pearson method. 
• 
ORR24  
24 weeks ORR in Part A is one of the secondary efficacy endpoints. Both BICR-assessed ORR24 
and Investigator-assessed ORR24 by RECIST 1.1 or iRECIST in Part A will be calculated.  
ORR24 will be summarized by number of patients and percentages. The ORR24 and its 95% 
confidence interval will be presented. The 95% (exact) confidence interval will be calculated 
based on the Clopper-Pearson method.  
• 
DCR 
DCR is defined as the percentage of patients who had a CR, PR or Stable Disease. 95% 
confidence interval of DCR will be calculated using the Clopper-Pearson method. 
DCR in Parts A, B and C is one of the secondary efficacy endpoints. Both BICR-assessed DCR 
and Investigator-assessed DCR by RECIST 1.1 or iRECIST in Parts A, B and C will be 
calculated.  
• 
DOR 
Duration of response only applies to the subgroup of patients in efficacy evaluation population 
whose best overall response is CR or PR according to RECIST v1.1. Median DOR time is the 
timepoint at which the probability of disease progression equals 50% after documented objective  
tumor response (PR or CR).  
Subject continuing without disease progression or death will be censored and the censoring 
date will be the date of the last evaluable tumor assessment prior to data cut-off/start of 
subsequent anti-cancer therapy. In case of progression or death after two or more consecutive 
missed tumor assessments, censoring will be done at last evaluable tumor assessment date 
prior to the missed tumor assessments. Reason of censoring will be summarized. 
The Kaplan-Meier method will be used to estimate the median DOR time, and 2-sided 95% CI 
for the median will be provided. BICR-assessed DOR and investigator-assessed DOR by 
RECIST v1.1 will be displayed for Part A, Part B and Part C. Kaplan-Meier curve for BICR-
assessed DOR will be presented.  
• 
TTR 
TTR is time from treatment initiation to the best objective response achieved (i.e., PR or CR 
whichever occurs earlier). This endpoint is only determined for patients who have a PR or CR 
by RECIST v1.1. Median TTR is the timepoint from treatment initiation to the best objective 
response achieved in 50% of patients. Median TTR will be calculated using descriptive statistics 


 
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in efficacy evaluation population restricted to patients with the best objective response. BICR-
assessed TTR and investigator-assessed TTR by RECIST v1.1 will be displayed for Part A, Part 
B and Part C.  
• 
PFS 
PFS is defined as the time from treatment initiation until documented disease progression or 
death from any cause. If the patient progresses or dies after two or more consecutive missed 
tumor assessment visits, the patient will be censored at the time of the latest evaluable RECIST 
v1.1 assessment. Two consecutive missed/non-evaluable tumor assessment visits is defined as 
no evaluable tumor assessment within 126 days (2*9 weeks) of first dose or the previous 
evaluable RECIST 1.1 measurement. If the patient has no evaluable tumor assessment visits 
after first dose or does not have evaluable baseline tumor assessment data, the patient will be 
censored on the date of first dose. Table 3 defines the censoring rules for PFS.  
Table 3. Censoring Rules for Analysis of Progression-Free Survival 
Description 
Event/Cen
sor 
Date of Event/Censor 
Documented progression before two 
consecutive missed tumor 
assessment visits 
Event 
Date of documented disease 
progression 
Death (without progression) before 
two consecutive missed tumor 
assessment  
Event 
Date of death 
Death or progression after two or 
more consecutive missed tumor 
assessments 
Censor 
Date of last evaluable tumor 
assessment prior to the 
consecutive missed tumor 
assessment visits  
Progression or death after 
subsequent anti-cancer therapy 
Censor 
Date of the last evaluable tumor 
assessment prior to start of 
subsequent anti-cancer therapy 
No evaluable baseline or post-
baseline tumor assessment  
Censor 
Date of first dosing of study 
medication 


 
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No progression and no death before 
end of study or data cut-off 
Censor 
Date of last evaluable tumor 
assessment 
Median PFS time (months) is the timepoint at which the probability of progression-free survival 
equals 50% in the efficacy evaluable population. 
6-month PFS rate is the proportion of efficacy evaluable patients without evidence of disease 
progression and who are alive 6 months after treatment initiation. 
Kaplan-Meier method will be used to estimate median PFS and the corresponding 95% CI. 
Kaplan-Meier curves will be constructed to provide a visual presentation of the BICR assessed 
PFS rate change with time. The PFS rate and 95% CI at 6 months will also be summarized.   
BICR-assessed PFS and investigator-assessed PFS by RECIST v1.1 will be displayed for Part 
A, Part B and Part C. 
• 
OS 
Overall survival is defined as the time from treatment initiation until death from any cause. 
Median OS time (months)l is the timepoint at which the probability of survival equals 50% in the 
efficacy evaluable population. Patients developing no event will be censored on the last known 
survival date. Patients providing no follow-up information will be censored on the day of first 
dosing. Kaplan-Meier method will be used to estimate median OS and the corresponding 95% 
CI. Kaplan-Meier curves will be constructed to provide a visual presentation of the OS rate 
change with time. 
6-month OS rate is the proportion of efficacy evaluable patients who are alive 6 months after 
treatment initiation. The OS rate and 95% CI at 6 months will also be summarized.   
OS will be displayed for Part A, Part B and Part C. 
• 
Waterfall, Spider, Swim-lane and forest Plots 
A waterfall plot will be prepared to visually present the best percentage change from baseline in 
sum of diameters in target lesions for each patient grouped by PD-L1 status, HPV type, and 
histologic type. 
A Spider Plot will be used to visualize changes in sum of diameters in target lesions with best 
overall response by BICR according to RECIST 1.1. With a Spider Plot, post-baseline 
measurements are compared to the baseline. Thus, the data plotted is the percent change from 
baseline over the period of patient evaluation. Each leg of the “spider” represents a unique 
patient.  
Swim-lane Plot for Tumor Response will be presented to show tumor assessment by at each 


 
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visit. Specifically, the Swim-lane plot will show total time to tumor response, whether the 
response was complete or partial, when the response started/ended and censoring information 
of the patient grouped by PD-L1 status, HPV type, and Histologic type.  
These plots will be displayed only for Part C. 
In Part C, a forest plot will be used to display BICR Assessed BORR according to RECIST v1.1 
across subgroups. 
15.3. 
EXPLORATORY EFFICACY ENDPOINTS 
Not Applicable. 
16. SAFETY OUTCOMES 
Safety variables to be analyzed are AEs, laboratory test results (e.g., hematology, coagulation, 
serum chemistry, thyroid function tests, and urinalysis), vital signs and others.  
All outputs for safety outcomes will be based on the safety population. The results will be 
presented for Part A, Part B Part C and overall except for DLT.  
16.1. 
ADVERSE EVENTS 
An adverse event is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article in a clinical study. AEs will be coded using MedDRA 21.1 or higher.  
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to define 
an AE as treatment emergent or not, the AE will be classified by the worst case; i.e. treatment 
emergent.  
An overall summary of number and percentage of patients and number of adverse events within 
each of the categories described in the section below except for DLT, will be provided.  
Listings will include both TEAEs and Non-TEAEs. Tables will include TEAEs. 
16.1.1. ALL TREATMENT EMERGENT ADVERSE EVENTS 
Treatment emergent adverse events are defined as AEs that started or worsened on or after the 


 
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first dose of study medication. In the case where it is not possible to define an AE as treatment 
emergent or not, the AE will be classified by the worst case; i.e. treatment emergent. 
Incidence of TEAEs will be presented by SOC and PT and also broken down further as shown 
in the following sections. 
16.1.1.1. Severity 
The severity of all TEAEs shall be graded according to 5 grades (Grade 1 to Grade 5) in 
accordance with the national cancer institute common terminology criteria for adverse event (NCI 
CTCAE) V4.0 or the most recent version. 
If a patient reports a TEAE more than once within that SOC/ PT, the AE with the worst-case 
severity will be used in the corresponding severity summaries.  
16.1.1.2. Relationship 
Relationship to study medications, as indicated by the Investigator, is classed as” Probably 
related”, “Possibly related”, “Unlikely related” and “Unrelated” (decreasing in severity of 
relationship). 
If a patient reports the same AE more than once within that SOC/ PT, the AE with the worst-
case relationship to study medications will be used in the corresponding relationship summaries. 
16.1.2. TREATMENT RELATED ADVERSE EVENTS (TRAE) 
TRAE is defined as an AE with relationship to study medications as “Probably related” or 
“Possibly related” to GX-188E and/or Pembrolizumab. TRAEs with a missing relationship to 
study medication will be regarded as “Probably related” to study medication.  
Summary tables for all TRAEs will be tabulated together. TRAEs with Relationship to GX-188E 
and TRAEs with Relationship to Pembrolizumab will be also summarized separately.  
16.1.3. TEAES LEADING TO DISCONTINUATION OR INTERRUPTION OF STUDY MEDICATION 
TEAEs leading to drug interruption of GX-188E will be identified by using the “Action Taken with 
GX-188E” with answer “Drug Interrupted” from the AE page of the CRF. TEAEs leading to drug 
interruption of pembrolizumab will be identified by using the “Action Taken with pembrolizumab” 
with answer “Drug Interrupted” from the AE page of the CRF. 
TEAEs leading to permanent discontinuation of GX-188E will be identified by using the “Action 
Taken with GX-188E” with answer “Drug withdrawn” from the AE page of the CRF. TEAEs 
leading to permanent discontinuation of pembrolizumab will be identified by using the “Action 


 
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Taken with pembrolizumab” with answer “Drug withdrawn” from the AE page of the CRF.  
For TEAEs leading to discontinuation or interruption of study medication, summaries of 
incidence rates (frequencies and percentages) by SOC and PT will be prepared. 
16.1.4. AES LEADING TO STUDY DISCONTINUATION 
TEAEs leading to study discontinuation will be identified by using the “Did this event lead to 
withdrawal from the study?” with answer “Yes” from the AE page of the CRF.  
For TEAEs leading to study discontinuation, summaries of the number and percentage of 
patients by SOC and PT will be prepared. For TRAEs leading to study discontinuation will be 
summarized in the same way. 
16.1.5. AES LEADING TO DEATH 
TEAEs leading to death are those events which are recorded as “Fatal” on the Adverse Events 
page of the CRF.  
A summary of TEAEs and TRAEs leading to death by SOC and PT will be prepared. 
16.1.6. SERIOUS ADVERSE EVENTS 
All AEs will be evaluated for seriousness. A serious adverse event (SAE) is an AE that meets at 
least one of the following criteria: 
• 
Results in death (NOTE: death is an outcome, not an event) 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in a persistent or significant disability or incapacity  
• 
Results in a congenital anomaly or birth defect  
• 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
SAEs will be identified as those events recorded as “Serious” on the Adverse Events page of 


 
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the CRF.  
Summaries of all SAEs and SAEs Related to study medications by SOC, PT and Maximum 
CTCAE Grade will be prepared.  
16.1.7. DOSE LIMITING TOXICITY (DLT) 
A DLT is defined as any AE that is not clearly due to progression of the patient’s primary 
malignancy, occurs within the DLT window of observation period, and that meets at least one of 
the criteria below: 
• 
Non-Hematologic Dose Limiting Toxicities: 
Any CTCAE (v4 or the most recent version) AE of ≥ Grade 3 treatment-related non-
hematological toxicity except for the following: 
o nausea, vomiting, or diarrhea lasting ≤ 72 hr 
o Grade 3 fatigue lasting ≤ 7 days 
o hypersensitivity reactions lasting ≤ 72 hrs 
o Grade 3 hyperglycemia lasting ≤ 72 hr with standard anti-diabetic therapy 
o Grade 3 increases in liver transaminases in patients with liver metastases. (Note: Grade 4 
increases in LFTs in any patient will be considered a DLT) 
o clinical laboratory abnormalities that are reversible to ≤ Grade 1 or baseline status within 72 
hr with outpatient care and/or monitoring, or that are considered not clinically significant by the 
Principal Investigator 
• 
Hematologic Dose Limiting Toxicities: 
o Grade 4 neutropenia (ANC < 0.5 x109/L) 
o Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with temperature ≥ 38.3°C) 
o Grade 4 thrombocytopenia (platelet count < 25.0 x 109/L) lasting > 4 days or that requires 
platelet transfusion 
o Grade ≥ 3 thrombocytopenia (platelet count < 50.0 x 109/L) associated with Grade ≥ 3 bleeding 
o Any hematologic toxicity resulting in death (i.e. Grade 5) 
In addition, any other AE that is felt to be treatment-limiting in the medical opinions of the 
Principal Investigator and the Sponsor’s Medical Monitor may be considered a DLT. These 
include, but are not limited to the following: 


 
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o Any toxicity leading to more than one missed dose of either GX-188E or pembrolizumab during 
the DLT-evaluation period 
o Any toxicity leading to > 2 weeks delay in initiation of the 2nd cycle of pembrolizumab. 
The DLT window of observation will be during Cycle 1 of pembrolizumab (ie., the first 3 weeks 
of treatment prior to week 4 Day 1 visit). 
A DLT will be identified on “Adverse Events” form of CRF with the response of “Yes” to the 
question “Is this AE considered as a DLT (Dose-Limiting Toxicities)?”. 
Summaries of DLTs by DLT Category, SOC, PT and Maximum CTC Grade will be prepared for 
DLT evaluable population in Part A. 
16.1.8. ADVERSE EVENTS OF CLINICAL INTEREST  
Adverse Events of Clinical Interest (AECI) for this trial include: 
• 
An overdose of investigational product that is not associated with clinical symptoms or 
abnormal laboratory results.  
• 
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing 
or unscheduled laboratory testing. 
Adverse Events of Clinical Interest are those events recorded as “Yes” for the question of “Is 
this an AE of Clinical Interest?” on the Adverse Events page of the CRF. AECI categories based 
on AE page of CRF are as follows: overdose, abuse, accidental exposure and elevated liver 
enzymes. A summary of AECIs by AECIs category and by SOC and PT will be prepared.  
16.1.9. IMMUNE-RELATED ADVERSE EVENTS (IRAES) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action. Special attention should be paid to AEs that may be suggestive 
of potential irAEs. An irAE can occur shortly after the first dose or several months after the last 
dose of treatment. 
irAEs will be identified as those events which are recorded as “Yes” for the question of “Is this 
an immune-related AE?” on the Adverse Events page of the CRF. A summary of irAE by SOC 


 
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and PT will be prepared. 
16.2. 
DEATHS 
If any patients die during the study as recorded on the “death details” page of the CRF, the 
information will be presented in a summary table and a data listing. 
16.3. 
LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for Hematology, 
Coagulation, Blood Chemistry, Urinalysis, Thyroid function tests, TA4 and CEA.  
Presentations will use SI Units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted 
to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” 
or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Incidence of abnormal values according to normal range criteria 
• 
Incidence of abnormal values according to clinical judgement. 
• 
Shift from baseline according to clinical judgement 
• 
Listing of individual laboratory data  
16.3.1. 
LABORATORY REFERENCE RANGES  
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
16.3.2. 
CTCAE GRADING FOR LABORATORY DATA 
Laboratory measurements will be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) grading system as defined in the following link: 


 
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https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Laboratory CTCAE Grade by Scheduled Visit will be summarized. Shift from baseline to worst 
CTCAE grade according to CTC grading system for parameters whose CTCAE scale is 
available will be provided.  
16.4. 
ELECTROCARDIOGRAM (ECG) EVALUATIONS 
ECG will be measured at screening visit only. Results from the 12-Lead ECG will be listed.  
16.5. 
VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Heart Rate (bpm) 
• 
Respiratory Rate (resp/min) 
• 
Body Temperature (⁰C) 
• 
Weight (kg) 
The following summaries will be provided for vital signs data: 
• 
Actual and change from baseline by visit  
• 
Incidence of markedly abnormal values  
• 
Shift from baseline to worst post baseline according to markedly abnormal criteria 
• 
Listing of individual vital sign data 
16.5.1. 
VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with 
the following predefined markedly abnormal criteria: 


 
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Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND  
change from baseline 
≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline 
≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 105 mmHg AND 
change from baseline 
≥ 15 mmHg 
Heart rate 
Bpm 
≤ 50 bpm AND 
change from baseline ≤ -15 
bpm 
≥ 120 bpm AND 
change from baseline 
≥ 15 bpm 
Body 
temperatur
e 
˚C 
NA 
≥ 38.3 ˚C AND 
change from baseline ≥ 1.1 
˚C 
Weight 
Kg 
percentage change from 
baseline ≤ -7.0 % 
percentage change from 
baseline ≥ 7.0 % 
16.6. 
PHYSICAL EXAMINATION  
Physical examination results will be listed. 
16.7. 
OTHER EXAMINATIONS 
ECOG of Performance Status will be reported for the study. The following summaries will be 
provided for the ECOG data. 
• 
Worst post-baseline result 
• 
Baseline and post-baseline by visit summary table 


 
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• 
Shift from baseline to worst post-baseline table 
Individual ECOG data will be listed. 
Device malfunction information collected on “Device Malfunction” page of CRF will be listed.  
Tumor Biopsy Sample collected on “Tumor Biopsy Sample” page of CRF will be listed. 
Pregnancy test information will be listed.  
Serology results will be listed.  
Pain assessment information will be summarized and listed.  
A listing will be provided for patients whose trial participation are impacted by COVID-19, 
including patient number and site number together with a description of the impact. These 
protocol deviations are documented in IQVIA clinical trial management system, 
Research blood collection will be listed.  
17. REFERENCES 
 1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer. 2009;45(2):228–247. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS OUTPUT 
CONVENTIONS 
Outputs will be presented according to the following IQVIA’ general guidelines and template for 
outputs conventions.  
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYYYThh:mm. 
SIGNIFICANT DIGITS OF SUMMARY STATISTICS 
1 Summary statistics are displayed with the following digits. 
Description 
Characteristic 
Number of decimal places 
Count 
n 
0 
Count corresponding to the 
number of patients for a cohort 
N 
0 
Mean 
Mean 
As in source + 1 
Standard Deviation 
SD 
As in source + 1 
Confidence Interval 
CI 
As in source + 1 
Minimum 
Min  
As in source 
Median 
Median 
As in source + 1 
Maximum 
Max 
As in source 
Percentage 
% 
1 * 


 
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Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
*   Number of decimal places can be two, if necessary. 
2 If the source has more than 5 significant digits, the above would be replaced with the 
corresponding number of significant digits. 
SPELLING FORMAT 
English US  
PRESENTATION OF STUDY PHASE 
For outputs, groups will be represented as follows and in that order: 
Group 
For Tables and Graphs 
For Listings (include if different 
to tables) 
Part A  
Part A  
Part A  
Part B 
Part B 
Part B 
Part C 
Part C 
Part C 
PRESENTATION OF VISITS 
For outputs, visits in listings will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening 
Screening 
Week 1 Day 1 
W1D1 
… 
… 
End of Treatment 
EOT 


 
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Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Long Name (default) 
Short Name  
End of Study  
EOS 
CRF visits will be displayed in the listings. Analysis baseline defined in SAP will be flagged and 
will be identified in the listings as needed. Analysis visits will be displayed in the tables.  
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Study part  
• 
Patient ID 
• 
Visit Number or Date (where applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that 
it cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 


 
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Page 47  of 48 
 
Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
START DATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if 
day and month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if 
day and month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
 
 
 


 
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Document : \\ieedc-vnac01\Biosdata\Genexine\GX-188E\GYA02599\Biostatistics\Documentation\SAP 
Author: Xin Wang                                                                                                           Version Number: 1.1 
 
                                                                                                                                  Version Date: 05Sep2022 
Template No:  CS_TP_BS016 Revision 6                                                                      Reference:  CS_WI_BS005     
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START 
DATE 
STOP 
DATE 
ACTION 
Known/ 
Partial/ 
Missing 
Known 
If stop date <= study med start date, assign as prior  
If stop date >study med start date, assign as concomitant  
 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If stop date <=study med start date, assign as prior 
If stop date >study med start date, assign as concomitant 
 
 
Missing 
If stop date is missing could never be assumed a prior 
medication, assign as concomitant