Clinical trial NCT05311176
Conditions: Gastric Cancer Cancer of Stomach Gastric Adenocarcinoma Stomach Cancer Stomach Adenocarcinoma Gastroesophageal Junction Adenocarcinoma
Keywords: HER2 Immunotherapy
Sponsor: Imugene Limited
Start date: 2022-08-17; Completion date: 2024-04-04
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, signal generating, open-label, 2-Arm, non-randomized study, in patients with metastatic HER2/neu over-expressing gastric cancer or gastroesophageal adenocarcinomas.

Detailed description:
It is hypothesized that the introduction of HER-Vaxx after 1L treatment in patients that have progressed under trastuzumab may overcome potential resistance against trastuzumab in combination with chemotherapy and can be continued after chemotherapy is terminated. Based on pre-clinical data HER-Vaxx may also synergize with pembrolizumab and therefore serve as a potentially better tolerated and chemotherapy-free treatment opportunity in metastatic patients that progressed under their previous therapy.

The study is designed to generate safety data and efficacy signals to support further development of HER-Vaxx in ≥2L mGC/GEJ cancer after progression with trastuzumab.

The study includes two treatment arms that will be analyzed independently using a 2-Stage design:

* Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab plus paclitaxel)
* Arm 2: HER-Vaxx in combination with pembrolizumab.

All patients must have received trastuzumab and progressed after 1L to be eligible for enrolment. Patients who have received an immune checkpoint inhibitor (ICI) previously will exclusively be enrolled in Arm 1 (HER-Vaxx + chemotherapy). Patients who are naïve to ICI treatment will exclusively be enrolled into Arm 2 (HER-Vaxx + pembrolizumab).

Arms: arm 1: Patients who have received an immune checkpoint inhibitor (ICI) previously will exclusively be enrolled in Arm 1 treated with HER-Vaxx (IM) in combination with chemotherapy (ramucirumab plus paclitaxel) arm 2: Arm 2 will investigate the combination of HER-Vaxx plus pembrolizumab in patients who are naïve to ICI treatment including patients who have had chemotherapy only treatment after progression on trastuzumab. As the combination treatment has not been investigated, Arm 2 is planned to initiate with a safety run-in phase.
Interventions: intervention 1: IMU-131 intervention 2: Ramucirumab plus Paclitaxel intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: IMU-131 will be administered intramuscularly into the deltoid region of the arm on Day 1, 15, 29 and 57 and then every 63 days until disease progression or treatment discontinuation. intervention 2: Chemotherapy to be administered every 3 weeks (Q3W) starting on Day 1. intervention 3: Pembrolizumab will be administered every 3 weeks (Q3W) starting on Day 1 until disease progression or treatment discontinuation.

Protocol documents:
Prot_000.pdf: 
NCT #: NCT05311176


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
IMUGENE LIMITED 
Page 2 
CONFIDENTIAL 
PROTOCOL ACCEPTANCE FORM 
nextHERIZON: AN OPEN-LABEL, SIGNAL GENERATING, PHASE 2 STUDY OF 
HER-VAXX IN COMBINATION WITH CHEMOTHERAPY OR PEMBROLIZUMAB 
IN PATIENTS WITH METASTATIC HER2/NEU OVER-EXPRESSING GASTRIC OR 
GASTROESOPHAGEAL JUNCTION (GEJ) ADENOCARCINOMAS WHO HAVE 
PREVIOUSLY RECEIVED TRASTUZUMAB AND PROGRESSED ON 
THIS TREATMENT 
Compound:  
IMU-131 
Compound Name: 
HER-Vaxx 
Protocol Number: 
IMU.131.203 
IND Number: 
27918 
Sponsor: 
Imugene Limited 
 Suite 12.01, Level 12 
4-6 Bligh Street
SYDNEY NSW 2000
Australia 
Amendment: 
4 
I agree to conduct the study in accordance with the current protocol. 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
Please keep the signed original form in your investigator site file, and return a copy to your 
local study monitor.  


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 3 
CONFIDENTIAL 
DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original protocol 
15 October 2021 
N/A 
Amendment 1 
01 December 2021 
- clarify prior treatment requirement for 
enrollment into Arms  
- add 15-day interval between enrollment 
of first 3 patients into Arm 2 
Amendment 2 
02 March 2022 
Table 1: SoA updated 
 
S2.1.3/S2.2.4: Exploratory objectives and 
endpoints updated 
 
S3.5: Clarify maximum pembrolizumab 
treatment duration 
 
S4.3: Update exclusion criteria #4, #18 & 
#19 
 
S5.4/Figure 2: Update treatment plan 
with additional blood sample collection.  
 
S6 and subsections: Move screening 
exploratory endpoint blood sample to 
Baseline/Day1, add biomarker blood 
sample collection to Days 1, 22, 43 and 
64, allow for 72-hour collection window 
prior to Day 1. Add ECOG at Day 64. 
  
S6.4.10: Clarify intra-tumor analysis. 
 
S7.1.4: Clarify SAE follow-up period for 
pembrolizumab.  
S7.1.9: Clarify follow-up period for 
pregnancy.  
S8.4: Confirm expansion of either Arm if 
≥ 4 of 15 patients have an objective 
response. 
Various typographical, administrative, 
and formatting changes and clarifications 
to wording to improve readability. 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 4 
CONFIDENTIAL 
Document 
Version Date 
Summary of Changes 
Amendment 3 
11 July 2022 
Table 1: SoA updated to align with 
modified schedules for Arm 1 
Table 2: SoA updated to align with 
modified schedules for Arm 2 
S1.6.2: Modified continuation treatment 
for Arm 1 and Arm 2 
S2/Synopsis (Objectives & Endpoints): 
Modify chemotherapy for Arm 1 
S3/ Synopsis (Study Design):  
- 
Modify chemotherapy for Arm 1 
- 
Add safety run-in for Arm 1 
- 
Modified dosing schedule for 
Arm 1 and Arm 2 
S4.2/Synopsis (Exclusion Criteria)/: 
Modify Exclusion #16  
S5/Synopsis (Duration of Patients 
Participation and Duration of Study):  
- 
Modify chemotherapy for Arm 1 
- 
Add safety run-in for Arm 1 
- 
Modified dosing schedule for 
Arm 1 and Arm 2 
S6/Synopsis (Study Treatment (s) Dose 
and Route of Administration): Modify 
HER-Vaxx dose. Modify chemotherapy. 
Additional biomarker blood sample 
collection.  
S7: Investigational Plan updated to align 
with dosing schedule modifications 
S8.2.5: Updated Safety Contact 
Information 
Various typographical, administrative, 
and formatting changes and clarifications 
to wording to improve readability. 
Amendment 4 
8 August 2023 
Updated Safety contact information.  
Modified contraception and pregnancy 
timelines.  
Updated eligibility to allow prior Enhertu 
treatment in Arm 1. 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 5 
CONFIDENTIAL 
Document 
Version Date 
Summary of Changes 
Updated eligibility such that confirmation 
of HER2 status after trastuzumab failure 
only required for Arm 2 and for minimal 
number of patients for Arm 1. 
Clarified wording related to eligibility for 
Arm 1 +/- prior immune checkpoint 
inhibitors.  
Revised exclusion criteria related to 
Immune Checkpoint Inhibitors.  
Updated sponsor address 
Added additional ctDNA blood draws 
and updated Schedule of Activities.  
Updated schema per changes above and 
added dosing schema. 
Modified dosing for Arm 2 to align more 
closely with Arm 1. 
Added statement regarding future use of 
unused central laboratory samples. 
Other formatting and administrative 
changes 
 
 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 6 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................10 
LIST OF FIGURES .................................................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
CLINICAL PROTOCOL SYNOPSIS .....................................................................................16 
SCHEDULE OF ACTIVITIES ................................................................................................29 
1. 
INTRODUCTION ..........................................................................................................34 
1.1 
HER-Vaxx (IMU-131) and Pembrolizumab ........................................................34 
1.2 
Background and Rationale ....................................................................................34 
1.3 
Clinical Rationale for HER-Vaxx (IMU-131, HER2/neu Peptide Vaccine) ........35 
1.4 
Pembrolizumab Pharmaceutical and Therapeutic Background ............................37 
1.5 
Pre-clinical and Clinical Trials for Pembrolizumab .............................................38 
1.6 
Risks and Benefits for nextHERIZON .................................................................39 
1.6.1. 
Vaccination-specific Potential Risks Include the Following .................39 
1.6.2. 
Management of Risks .............................................................................40 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................41 
2.1 
Objectives .............................................................................................................41 
2.1.1. 
Primary Safety Objective .......................................................................41 
2.1.2. 
Primary Efficacy Objective ....................................................................41 
2.1.3. 
Secondary Objective ..............................................................................41 
2.1.4. 
Exploratory Objectives ...........................................................................41 
2.2 
Endpoints ..............................................................................................................41 
2.2.1. 
Primary Safety Endpoints .......................................................................41 
2.2.2. 
Primary Efficacy Endpoint .....................................................................41 
2.2.3. 
Secondary Efficacy Endpoints ...............................................................42 
2.2.4. 
Exploratory Endpoints ............................................................................42 
3. 
STUDY DESIGN ...........................................................................................................43 
3.1 
Overall Study Design ............................................................................................43 
3.1.1. 
Safety and HER2 Antibody Consideration ............................................44 
3.1.2. 
Safety Evaluation for Combination in Arm 1 and Arm 2 ......................45 
3.2 
Safety Review Committee ....................................................................................46 
3.3 
Measures to Minimize Bias ..................................................................................47 
3.4 
Duration of Patient Participation ..........................................................................47 
4. 
STUDY PATIENT POPULATION ...............................................................................48 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 7 
CONFIDENTIAL 
4.1 
Inclusion Criteria ..................................................................................................48 
4.2 
Exclusion Criteria .................................................................................................49 
4.3 
Contraception Guidelines .....................................................................................51 
4.3.1. 
Use in Nursing Women ..........................................................................51 
5. 
TREATMENT, PATIENT, STUDY AND SITE DISCONTINUATION .....................52 
5.1 
Study Treatment Discontinuation .........................................................................52 
5.2 
Patient Discontinuation from the Study ................................................................53 
5.3 
Study Discontinuation ..........................................................................................53 
5.4 
Site Discontinuation ..............................................................................................55 
6. 
STUDY TREATMENT .................................................................................................56 
6.1 
Manufacturing and Labelling ...............................................................................56 
6.1.1. 
Vaccine Supply ......................................................................................56 
6.2 
Preparation and Dispensing ..................................................................................56 
6.3 
Dose Selection ......................................................................................................56 
6.3.1. 
Dose Selection HER-Vaxx .....................................................................56 
6.3.2. 
Dose Selection Chemotherapy ...............................................................57 
6.3.3. 
Dose Selection Pembrolizumab .............................................................57 
6.3.4. 
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab ....................................................58 
6.3.5. 
Dose Modification and Toxicity Management of Infusion-reactions 
Related to Pembrolizumab .....................................................................62 
6.3.6. 
Other Allowed Dose Interruption for Pembrolizumab ...........................63 
6.3.7. 
Dose Interruption for HER-Vaxx ...........................................................64 
6.3.8. 
Dose Interruption for Chemotherapy .....................................................64 
6.4 
Administration ......................................................................................................64 
6.5 
Compliance ...........................................................................................................65 
6.6 
Treatment of Overdose Arm 2 ..............................................................................65 
6.7 
Meals and Dietary Restrictions .............................................................................66 
6.8 
Drug Storage and Drug Accountability ................................................................66 
6.9 
Concomitant Medications .....................................................................................66 
6.9.1. 
Permitted Medications ............................................................................66 
6.9.2. 
Prohibited Medications ..........................................................................67 
6.10 Method of Assigning Patients to Treatment .........................................................68 
6.11 Patient Enrollment ................................................................................................68 
6.12 End of Study .........................................................................................................68 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 8 
CONFIDENTIAL 
7. 
INVESTIGATIONAL PLAN ........................................................................................69 
7.1 
Screening ..............................................................................................................69 
7.2 
Re-Screening .........................................................................................................69 
7.3 
Screen Failures and Replacement of Patients .......................................................69 
7.4 
End of Treatment ..................................................................................................70 
7.5 
Survival Follow-Up ..............................................................................................70 
7.6 
Unscheduled Visit .................................................................................................70 
7.6.1. 
Assessments via Telemedicine ...............................................................71 
7.6.2. 
Demographic Data and Medical History ................................................71 
7.6.3. 
Physical Examination .............................................................................71 
7.6.4. 
Height, Weight & Vital Signs ................................................................71 
7.6.5. 
Radiographic Assessment ......................................................................71 
7.6.6. 
Cardiac Assessment ................................................................................72 
7.6.7. 
Laboratory Assessments .........................................................................72 
7.6.8. 
HER2/neu Overexpression .....................................................................74 
7.6.9. 
ECOG Performance Status .....................................................................74 
7.6.10. Pregnancy Test .......................................................................................74 
7.6.11. Tumor Biopsy .........................................................................................74 
8. 
ADVERSE EVENT REPORTING ................................................................................75 
8.1 
Definition ..............................................................................................................75 
8.1.1. 
Adverse Event ........................................................................................75 
8.1.2. 
Abnormal Test Findings .........................................................................76 
8.1.3. 
Treatment-Emergent Adverse Event (TEAE) ........................................76 
8.1.4. 
Serious Adverse Event (SAE) ................................................................77 
8.1.5. 
Adverse Events of Clinical Interest ........................................................77 
8.1.6. 
Suspected Adverse Reactions (SAR) .....................................................79 
8.1.7. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................79 
8.1.8. 
Toxic Death ............................................................................................79 
8.1.9. 
Pregnancy ...............................................................................................79 
8.1.10. Withdrawal Due to Adverse Events .......................................................80 
8.2 
Monitoring, Reporting, and Documentation of SAEs/AEs ..................................80 
8.2.1. 
Monitoring of AEs .................................................................................80 
8.2.2. 
Documentation of AEs ...........................................................................81 
8.2.3. 
Adverse Event Severity Assessment ......................................................81 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 9 
CONFIDENTIAL 
8.2.4. 
Causality Assessment to Treatment .......................................................83 
8.2.5. 
Reporting of SAEs .................................................................................83 
8.2.6. 
SUSARs .................................................................................................85 
8.2.7. 
Sponsor Reporting Requirements to Regulatory Authorities .................85 
9. 
STATISTICAL METHODS ..........................................................................................86 
9.1 
Statistical Analysis Plan .......................................................................................86 
9.2 
Data Sets to be Analyzed ......................................................................................86 
9.3 
Statistical Evaluation ............................................................................................86 
9.3.1. 
Efficacy Analysis ...................................................................................87 
9.3.2. 
Safety Analysis .......................................................................................87 
9.3.3. 
Immunogenicity Analysis ......................................................................88 
9.4 
Sample Size Determination ..................................................................................88 
9.5 
Disposition, Demographic and Other Baseline Characteristics ............................88 
9.6 
Exposure ...............................................................................................................88 
9.7 
Interim Analysis ....................................................................................................89 
10. 
DATA HANDLING AND RECORD KEEPING ..........................................................90 
10.1 Data Collection .....................................................................................................90 
10.2 Monitoring ............................................................................................................90 
10.3 Documentation and Material Supply ....................................................................91 
10.4 Record Retention ..................................................................................................91 
10.5 Medical Coding ....................................................................................................91 
10.6 Health Economics Data Collection .......................................................................91 
11. 
ADMINISTRATIVE ASPECTS ....................................................................................92 
11.1 Quality Assurance Audit .......................................................................................92 
11.2 Investigator Site File .............................................................................................92 
11.3 Protocol Deviations ..............................................................................................92 
11.4 Clinical Study Report ...........................................................................................93 
12. 
ETHICAL AND LEGAL CONSIDERATIONS ...........................................................94 
12.1 Institutional Review Boards / Independent Ethics Committees ...........................94 
12.2 Patient Informed Consent .....................................................................................94 
12.3 Study Discontinuation and Closure ......................................................................95 
12.4 Confidentiality ......................................................................................................95 
12.5 Protocol and Investigator Brochure ......................................................................95 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 10 
CONFIDENTIAL 
12.6 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
 ..............................................................................................................................95 
12.7 Compensation for Medicine-induced Injury .........................................................96 
12.8 Publication Policy and Protection of Trade Secrets .............................................96 
12.9 Conflict of Interest Policy .....................................................................................97 
13. 
REFERENCE LIST ........................................................................................................98 
14. 
APPENDICES ..............................................................................................................101 
14.1 Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scoring (Oken et al, 1982) .......................................................................101 
14.2 Appendix B: Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 ...........................................................................................................102 
 
LIST OF TABLES 
Table 1. 
Schedule of Activities Arm 1 (HER-Vaxx + Chemotherapy) ..............................29 
Table 2. 
Schedule of Activities Arm 2 (HER-Vaxx + Pembrolizumab) ............................32 
Table 3. 
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab .......................................................59 
Table 4. 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .............................................................................................................62 
Table 5. 
List of Interventions Arm 2 ..................................................................................65 
Table 6. 
Grading of Local Adverse Event Intensity ...........................................................82 
 
 
LIST OF FIGURES 
Figure 1. 
Study Schema .......................................................................................................44 
 
 
 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 11 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
°C 
degree Celsius 
µg 
microgram 
1L 
first line 
5-FU 
5-fluorouracil 
ADCC 
Antibody-dependent cellular cytotoxicity 
ADR 
Adverse drug reaction  
ADC 
Antibody-Drug Conjugate 
AE(s) 
Adverse event(s) 
AESI 
Adverse events of special interest 
AGC 
Advanced Gastric Cancer  
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APAP 
N-acetyl-para-aminophenol 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
B cell 
B lymphocyte 
BDISH 
Brightfield double in situ hybridization  
BHCG 
Beta-human chorionic gonadotrophin 
BSA 
Body Surface Area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CBER 
Center for Biologics Evaluation and Research 
CD28 
Cluster of differentiation 28 
CD3ζ 
Cluster of differentiation 3 zeta 
CDC 
Complement-dependent cytotoxicity 
CEA 
Carcinoembryonic antigen 
CI 
Confidence interval 
CISH 
Chromogenic in situ hybridization 
CNS 
Central nervous system 
CrCl 
Creatinine clearance 
CSA 
Clinical Study Agreement 
ctDNA 
circulating tumor cell DNA 
CTLA4 
Cytotoxic T-lymphocyte-associated protein 4 
CONSORT 
Consolidated Standards of Reporting Trials 
CPS 
combined positive score 
CR 
Complete Response  
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Contract research organization 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 12 
CONFIDENTIAL 
CRP 
C-reactive protein 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
National Cancer Institute’s Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating Tumor DNA 
DILI 
Drug-induced Liver Injury 
DLT 
Dose-limiting toxicity 
DoR 
Duration of Response 
DRESS 
Drug Rash with Eosinophilia and System Symptom 
DSUR 
Development safety update report  
EAS 
Evaluable analysis set 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGF 
epithelial growth factor  
EGFR 
Epidermal growth factor receptor 
EoT 
End of treatment  
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FISH 
Fluorescent in situ hybridization 
FU 
Follow Up 
G 
Gauge 
GC 
Gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal junction 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transpeptidase 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HER2/neu 
Human epidermal growth factor receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 13 
CONFIDENTIAL 
ICH 
International Conference on Harmonization 
ICI 
Immune checkpoint inhibitor  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Commitee 
IFNγ 
Interferon gamma 
IgG 
Immunoglobulin G 
IgG4 
Immunoglobulin G4 
Ig-V type 
Ig-variable–type 
IHC 
Immunohistochemistry 
IM 
Intramuscular(ly) 
IMP 
Investigational Medicinal Product 
IMU 
Imugene Limited, Australia 
IMU-131 
Investigational product consisting of P467-CRM in Montanide adjuvant 
IND 
Investigational New Drug 
INDSR 
Investigational New Drug Safety Report 
IO 
Immuno-oncology 
irAE 
Immune related AE 
IRB/IEC 
Institutional review board/independent ethics committee 
ISF 
Investigational Site File  
ITT 
Intent-to-Treat   
IUD 
intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
LFT 
liver function test 
LLN 
Lower limit of normal 
LVEF 
Left ventricular ejection fraction 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mGC 
Metastatic Gastric Cancer 
mL 
milliliter 
mm 
millimeter 
MSS 
Microsatellite stable status 
MUGA 
Multiple gated acquisition (scan) 
N 
number 
NCCN 
National Comprehensive Cancer Network® 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing  
NSAID 
Nonsteroidal anti-inflammatory drugs 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 14 
CONFIDENTIAL 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBPK 
Physiologically-based PK 
PBMC 
Peripheral blood mononuclear cell 
PBS 
Phosphate-buffered saline 
PD 
Progressive Disease  
PD-1 
Programmed cell death 1 
PD-L1 
Programmed death-ligand 1 
PD-L2 
Programmed death-ligand 2 
PEV6C 
First generation formulation of IMU-131 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PKCθ 
Protein kinase C theta 
PPAS 
Per-protocol analysis set 
PR 
Partial Response  
pRBC 
Packed red blood cell 
PT 
Preferred term 
PVG 
Pharmacovigilance 
Q2W 
Once every 2 weeks 
Q3W 
Once every 3 weeks 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RoW 
Rest of World 
SAE(s) 
Serious adverse event(s) 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SAR 
Serious Adverse Reaction  
SD 
Stable Disease 
SJS 
Stevens-Johnson Syndrome 
SmPC 
Summary of Product Characteristics 
SoC 
Standard of Care  
SOC 
System organ class 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 Diabetes Mellitus 
T cell 
T lymphocyte  
TEAEs 
Treatment-emergent Adverse Events 
TEN 
Toxic Epidermal Necrolysis 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 15 
CONFIDENTIAL 
TMB 
Tumor mutational burden 
TMDD 
Target-mediated drug disposition  
TME 
Tumor microenvironment  
ToGA 
Trastuzumab for Gastric Cancer 
T-regs 
Regulatory T-cells 
TTP 
Time to Progression 
ULN 
Upper limit of normal 
USPI 
United States Prescribing Information 
VEGFR  
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WHO 
World Health Organization  
WOCBP 
Women of childbearing potential 
ZAP70 
Zeta-chain-associated protein kinase 
 
 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 16 
CONFIDENTIAL 
CLINICAL PROTOCOL SYNOPSIS 
Study Number 
and Title 
IMU.131.203 
nextHERIZON: An open-label, signal generating, phase 2 study of HER-
Vaxx in combination with chemotherapy or pembrolizumab in patients with 
metastatic HER2/neu over-expressing gastric or gastroesophageal junction 
(GEJ) adenocarcinomas who have previously received trastuzumab and 
progressed on this treatment  
Sponsor 
Imugene Limited  
IND Number  
027918 
Clinical Phase 
Phase 2 
Indication / 
Target 
population  
Human epidermal growth factor receptor 2 (HER2/neu) overexpressing advanced 
or metastatic adenocarcinoma of the stomach or gastroesophageal junction. 
The intended population is: 
• Patients who have progressed on or after trastuzumab and other HER2 
targeted treatments for their advanced or metastatic disease  
• Arm 1 only: Patients with documented HER-2 positivity at diagnosis.  
A post-progression biopsy either fresh or archival tissue, or pathology 
report should be provided.  
• Arm 2 only: Patients who have confirmed HER2/neu overexpression 
since progression on or after trastuzumab by tumor biopsy (post-
progression fresh or archival tissue, or post-progression pathology 
report).  
• Sponsor may approve use of liquid (blood-based) biopsy where tumor 
biopsy is not clinically indicated 
Number of Sites 
Approximately 15 sites globally  
Number of 
Patients 
A total of approximately 30 evaluable patients (15 in each Arm). 
Rationale 
Gastric cancer (GC) is one of the most common cancers worldwide and the 
third leading cause for cancer death. About 10 to 20% of GC are HER2/neu 
over-expressing (IARC, 2021).  Gastric cancer is often diagnosed at an 
advanced stage, defined as unresectable locoregional or metastatic disease, 
which has extremely poor prognosis with 5-year survival not exceeding 5 to 
20% (ACS, 2021). Despite significant progress in the treatment of metastatic 
GC, most patients with metastatic disease succumb to the disease. Therefore, 
improving the treatment options and effectiveness is critical in changing the 
outcomes for patients with advanced and metastatic gastric cancer.  
For patients with advanced and metastatic, HER2/neu over-expressing GC or 
GEJ adenocarcinoma, the addition of trastuzumab to standard cisplatin/ 


Investigational Product: 
IMU-131 (HER-Vaxx) 
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fluoropyrimidine chemotherapy improved overall survival (OS) significantly 
with a Hazard Ratio (HR) of 0.65 (Bang, 2010).  
Ramucirumab is a human IgG1 monoclonal antibody receptor antagonist 
designed to bind to the extracellular domain of VEGFR-2. The phase III 
RAINBOW trial evaluated the efficacy and safety of ramucirumab plus 
paclitaxel vs placebo plus paclitaxel in patients with locally advanced or 
metastatic gastric or GEJ adenocarcinoma who have progressed after first-line 
chemotherapy (Wilke, 2014). OS was significantly longer in the ramucirumab 
plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 
months [95% CI: 8·5,10·8] vs 7·4 months [95% CI: 6·3,8·4], hazard ratio 
0·807 [95% CI: 0·678, 0·962]; p=0·017). PFS was significantly increased in 
the treatment group compared to the control group (4.4 months [95% CI: 4.2, 
5.3] vs 2.9 months [95% CI: 2.8,3.0], hazard ratio 0·64 [95% CI: 0·54, 0·75]; 
p<0·001). Confirmed objective response rate (ORR) was 28% (95% CI: 23, 
33) in the ramucirumab plus paclitaxel Arm compared with 16% (95% CI: 13, 
20) for those receiving placebo plus paclitaxel. Ramucirumab plus paclitaxel 
is now approved as a second-line treatment option for patients with metastatic 
gastric cancer, who failed first-line treatment with platinum- and 
fluoropyrimidine-based combinations or trastuzumab in combination with 
cisplatin and 5-fluorouracil/cisplatin and capecitabine. 
Most recently there have been two Food and Drug Administration (FDA) 
approvals that will change the treatment landscape for metastatic GC 
(mGC)/GEJ. 
On January 15th, 2020, the FDA granted approval for Enhertu® (trastuzumab 
deruxtecan), as treatment in HER2/neu over-expressing GC patients who have 
received a prior trastuzumab based therapy.  
On May 5th, 2021, the FDA granted accelerated approval to Keytruda® 
(pembrolizumab) in combination with trastuzumab, fluoropyrimidine- and 
platinum-containing chemotherapy for the 1L treatment of patients with 
locally advanced unresectable or metastatic HER2/neu positive gastric or GEJ 
adenocarcinoma. The approval was based on the prespecified interim analysis 
of the first 264 patients of the ongoing KEYNOTE-811 (NCT03615326) 
study, a multicenter, randomized, double blind, placebo-controlled study in 
patients with HER2/neu positive- advanced gastric or GEJ adenocarcinoma 
who had not previously received systemic therapy for metastatic disease.   
Despite the recent advances for the treatment in HER2/neu overexpressing 
GC/GEJ cancer, there remains an unmet need for treatments that are well 
tolerated and may include alternative treatment to chemotherapy or to 
treatment with trastuzumab-deruxtecan.  
The safety and immunogenicity of the HER-Vaxx (IMU-131) have been 
shown in a Phase 1b dose finding and an ongoing randomized controlled 
Phase 2 HERIZON study (IMU.ACS.001), treating patients with advanced 
and metastatic GC and GEJ with HER-Vaxx + chemotherapy. The study 
showed an OS benefit with a HR of 0.558 (2-sided 80% CI: 0.349 0.895) at 
updated final analysis. Safety was shown to be similar between the treatment 
Arms, with no significant vaccination related toxicity (Maglakelidze, 2023).  


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
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To overcome resistance to immunotherapy within GI cancer, one promising 
strategy is to increase the number of cytotoxic immune cells within the tumor 
microenvironment (TME) via the use of polyclonal vaccines such as HER-
Vaxx. Active immunization with HER-Vaxx has induced high and long-
lasting antibody levels and expanded lymphocytes’ subpopulations, such as 
interferon gamma (IFNγ) producing CD4 and CD8 T cells (Tobias, 2017).  
Therefore, the introduction of HER-Vaxx in patients that have progressed on 
or after trastuzumab or other HER-2 targeted treatments may overcome 
potential HER-2 resistance. Based on pre-clinical synergy HER-Vaxx may 
also synergize with pembrolizumab and therefore serve as a potentially better 
tolerated and chemotherapy-free treatment opportunity in metastatic patients 
that progressed under their previous therapy.  
Study 
Treatment(s) 
IMU-131  
The investigational product, IMU-131, will be supplied as drug substance 
P467-CRM197 (aqueous phase vaccine) and Montanide ISA 51 VG 
(adjuvant). P467-CRM197 is composed of 3 individual B-cell epitopes (P467) 
selected from the HER2/neu structure and conjugated to CRM197. P467-
CRM197 emulsified with Montanide ISA 51 VG forms IMU-131 (HER-
Vaxx). 
Chemotherapy (Arm 1) 
Chemotherapy will be ramucirumab plus paclitaxel. Chemotherapy 
(ramucirumab and paclitaxel) will be sourced or reimbursed by the Sponsor 
as required by local health authority regulations.   
Pembrolizumab (Arm 2) 
Pembrolizumab is a 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). 
Pembrolizumab will be sourced or reimbursed by the Sponsor where required 
by local health authority regulations. 
Study Design 
This study will evaluate safety and efficacy of HER-Vaxx in combination with 
chemotherapy or pembrolizumab in patients with mGC/GEJ cancer who have 
progressed on or after trastuzumab treatment. 
   
The study includes two treatment Arms that will be analyzed independently 
using a 2-Stage design: 
• Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab 
plus paclitaxel)  
• Arm 2: HER-Vaxx in combination with pembrolizumab. 
Eligibility for Arm 1 requires patients with mGC/GEJ adenocarcinoma 
overexpressing HER-2/neu who have progressed on or after trastuzumab in 
combination with chemotherapy as first line therapy; patients that 


Investigational Product: 
IMU-131 (HER-Vaxx) 
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subsequently progressed on or after trastuzumab deruxtecan or another anti-
HER2 treatment are eligible  for enrolment in Arm 1. Arm 1 eligibility does 
not depend on prior treatment with immune checkpoint inhibitors (ICIs).  
Eligibility for Arm 2 requires that patients be naïve to immune checkpoint 
inhibitors and have progressed on or after first line treatment with a HER-2 
targeted therapy including trastuzumab in combination with standard of care 
chemotherapy.  
For each Arm, after 8 evaluable patients are enrolled (Stage 1), if 1 or more 
patients respond (i.e., experience complete response [CR] or partial response 
[PR]), an additional 7 evaluable patients will be enrolled in that Arm (Stage 2). 
If there are no responses in Stage 1, then preliminary anti-tumor activity in the 
group will not have been identified and no further patients will be enrolled in 
that Arm. If the Arm continues to Stage 2, a total of 15 evaluable patients will 
be studied for that Arm. The Arm will be considered successful if ≥ 4 treated 
patients respond, and the Arm may be expanded to enroll 25 patients. This 
design is applied to each Arm separately. 
Arm 1 requires that a minimum of 5 of 8 patients in Stage 1 and additional 
5 patients  (i.e. 10 of the total 15 patients enrolled) in Stage 2 must have 
HER2/neu overexpression as assessed by the central lab or post-progression 
pathology report.  
Arm 2 requires that all patients enrolled must have post-progression HER2/neu 
overexpression confirmed locally for eligibility and subsequently assessed by the 
central lab or post-progression pathology report. 
Stage 1 of each Arm will include a safety run-in phase with staggered 
enrolment with the first 3 patients receiving their first treatment dose at least 
15 days apart. After 3 patients are treated with the combination and are 
considered evaluable for the safety run-in period as defined below, a Safety 
Review Committee (SRC) consisting of study investigators and Sponsor 
medical monitor will assess the combination to ensure it is safe before 
enrolling the remaining patients. 
Safety evaluation for combination in Arm 1 and Arm 2 
Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab 
plus paclitaxel)  
This combination safety evaluation will be based on three evaluable patients 
at a single dose level of HER-Vaxx plus chemotherapy (ramucirumab plus 
paclitaxel). An initial 3 patients will be treated and observed for the occurrence 
of dose-limiting toxicities (DLTs) for a period of 29 days (including 3 doses 
of HER-Vaxx and at least 1 cycle of chemotherapy).  Safety data will be 
reviewed by the SRC before further patients are enrolled. 
Arm 2: HER-Vaxx in combination with pembrolizumab. 
This combination safety evaluation will be based on three evaluable patients 
at a single dose level of HER-Vaxx plus pembrolizumab. An initial 3 patients 
will be treated and observed for the occurrence of DLTs for a period of 29 days 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
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(including 3 doses of HER-Vaxx and at least 1 dose of pembrolizumab).  
Safety data will be reviewed by the SRC before further patients are enrolled. 
Evaluation of DLTs and enrolment decisions for each: 
• If less than one-third of evaluable patients experience a DLT 
(i.e., 0 out of 3, or 1 out of 6), recruitment into the Arm may proceed. 
• If 1 out of the first 3 patients experiences a DLT, 3 more patients will 
be entered into the Arm. If 0 of these 3 additional patients experience 
a DLT, recruitment into the Arm may proceed. 
• If a DLT is observed in one-third or more patients (i.e., 2 or more of 
6 patients) recruitment into the Arm will be stopped. 
The occurrence of any DLT will be assessed during the first 29 days. 
DLTs will be graded according to National Cancer Institute [NCI]-Common 
Terminology Criteria for Adverse Events [CTCAE] version 5.0. 
 
nextHERIZON study design: 
 
ORR = objective response rate; OS = overall survival; PFS= progression free survival; DoR 
= duration of response   
Objectives 
Primary Safety Objective: 
• To evaluate the safety and tolerability of HER-Vaxx in combination 
with chemotherapy (ramucirumab plus paclitaxel) or pembrolizumab. 
Primary Efficacy Objective: 
• To evaluate the ORR of HER-Vaxx in combination with chemotherapy 
or pembrolizumab according to RECIST 1.1.  
Secondary Objectives: 
• 
To evaluate additional efficacy and survival measures (OS, PFS, DoR) 
of HER-Vaxx in each Arm.  


Investigational Product: 
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Exploratory Objectives: 
• To evaluate humoral and cellular immunogenicity data of HER-Vaxx 
plus chemotherapy (ramucirumab plus paclitaxel) or pembrolizumab.  
• To evaluate  immunogenicity and biochemical markers of tumor 
progression to clinical outcomes of ORR, OS, PFS, and DoR.  
• To evaluate Arm-specific associations between clinical outcome and 
HER2/neu expression, PD-L1 expression and tumor mutational burden 
(TMB). 
Endpoints 
 
Primary Safety Endpoints: 
• Frequency and severity of AEs graded by Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. 
• Frequency and severity of immune-related AEs. 
• Frequency of patients discontinuing study treatment due to AEs. 
• Changes and shifts from baseline in clinical laboratory, vital signs, 
echocardiogram or multiple gated acquisition (MUGA) scan and 
electrocardiogram (ECG) parameters. 
Primary Efficacy Endpoint: 
• ORR measured from baseline as the proportion of patients achieving a 
confirmed best overall response of CR or PR according to RECIST 
v1.1 based on local review. 
Secondary Efficacy Endpoints: 
• DoR measured from earliest CR or PR until first documentation of PD 
based on RECIST v1.1, or death due to any cause. 
• PFS defined as the time from first dose of study drug to first 
documentation of progressive disease (PD) based on RECIST v1.1, or 
to death from any cause. 
• OS defined as the time from first dose of study drug to death from any 
cause. 
Exploratory Endpoints: 
• 
Values and changes from baseline in humoral and cellular 
immunogenicity including P467-specific antibodies, HER2-specific 
antibodies, vaccine-specific cytokine levels and regulatory and effector 
T and B cells. 
• Evaluation and Arm-specific associations of serum and biochemical 
markers of tumor progression and immunogenicity, including humoral 
and cellular responses, with measures of clinical response including 
ORR, DoR, PFS, and OS. 
• 
Analysis of HER2/neu expression, PD-L1 expression and TMB in pre- 
and post-treatment tumor biopsies / liquid biopsies (ctDNA/NGS). 


Investigational Product: 
IMU-131 (HER-Vaxx) 
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Duration of 
Patients 
Participation and 
Duration of 
Study 
Study treatment will continue until disease progression (i.e., if in the opinion 
of investigator there is no clinical benefit of further treatment after 
radiographic progression), unacceptable toxicities, withdrawal from study 
treatment for other reasons, or death.  
The end of treatment (EoT) visit will be completed at least 30 days after last 
study treatment. 
All patients will be followed for survival every 12 weeks from date of EoT for 
up to 3 years.   
Inclusion 
Criteria 
Patients must meet all the following inclusion criteria to be eligible for 
enrolment into the study: 
1. Informed of the investigational nature of this study and provided written 
informed consent for the study in accordance with institutional, local, and 
national guidelines; 
2. Age ≥18 years of age on day of signing informed consent; 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1; 
4. Life expectance of a minimum of 3 months; 
5. Confirmed diagnosis of advanced or metastatic HER2/neu overexpressing 
gastric or GEJ adenocarcinoma;  
6. Progressed on or after trastuzumab therapy in combination with standard 
of care chemotherapy as first line therapy: 
a. Arm 1 only: Patients who subsequently progressed on or after 
trastuzumab deruxtecan or another anti-HER2 treatment are eligible.  
Prior therapy with ICIs is allowed, however eligibility does not depend 
on prior treatment with ICIs.  
b. Arm 2 only: Patients must be naïve to ICIs. 
7. At least one measurable lesion as defined by RECIST 1.1 criteria and 
assessed by the local investigator; 
8. Arm 1 only: Patients with documented HER-2 positivity at diagnosis.  A 
post-progression tumor biopsy (post-progression fresh or archival tissue) 
or post-progression pathology report should be provided for a minimum 
of 5 of 8 patients in Stage 1 and 10 of total 15 after completion of Stage 2 
are required;  Arm 2 only: HER2/neu overexpression (3+ by 
immunohistochemistry [IHC] or if IHC 2+ confirmed by fluorescent in 
situ hybridization [FISH], brightfield double in situ hybridization 
[BDISH] or chromogenic in situ hybridization [CISH]) using post-
progression fresh or archival tissue, or post-progression pathology report.  
Sponsor may approve use of liquid (blood-based) biopsy where tumor 
biopsy is not clinically indicated; 
9. Adequate left ventricular ejection function at baseline, defined as left 
ventricular ejection fraction (LVEF) > 50% by echocardiogram or MUGA 
scan; 


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10. Adequate hematologic function:  
a. ANC ≥ 1500/µL 
b. Platelet count ≥ 100 000/µL 
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
• 
Note: Criteria must be met without packed red blood cell 
(pRBC) transfusion within the prior 2 weeks. Patients can 
be on stable dose of erythropoietin (≥ approximately 
3 months); 
11. Adequate hepatic function: 
a. Total bilirubin ≤ 1.5 x upper limit of normal [ULN] OR direct bilirubin 
≤ ULN for patients with total bilirubin levels > 1.5 ULN; 
b. Alanine aminotransferase (ALT) and aspartate transaminase (AST) 
≤ 2.5 x ULN if no liver involvement or ALT and AST ≤ 5 x ULN with 
liver involvement; 
12. Adequate renal function: creatinine ≤ 1.5 x ULN OR measured or 
calculated creatine clearance (glomerular filtration rate [GFR] can also be 
used in place of creatinine or creatinine clearance [CrCl] as calculated by 
institutional standards) ≥30 mL/min for patients with creatinine levels 
>1.5 × institutional ULN; 
13. Male patients must agree not to donate sperm and to use a highly effective 
method of contraception throughout the study and for at least 180 days 
after the last dose of assigned treatment; Female patients of childbearing 
potential must agree to use a highly effective method of contraception 
throughout the study and for at least 180 days after the final dose of HER-
Vaxx, at least 92 days after the final dose of ramucirumab, at least 
120 days after the final dose of pembrolizumab, and for 180 days after the 
final dose of paclitaxel. A patient is of childbearing potential if, in the 
opinion of the Investigator, she is biologically capable of having children 
and is sexually active. 
14. A female patient is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP);  
b. A WOCBP who agrees to use highly effective method of contraception 
during the treatment period and for at least 180 days after the final dose 
of HER-Vaxx, at least 92 days after the final dose of ramucirumab, at 
least 120 days after the final dose of pembrolizumab, and for 180 days 
after the final dose of paclitaxel; 
15. Willing and able to comply with all aspects of the protocol. 


Investigational Product: 
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Exclusion 
Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Prior non-investigational therapy for advanced Gastric Cancer within 14 
days or major surgery within 28 days  prior to Day 1  
a. Patients must have recovered from all adverse events (AEs) due to 
previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 
2 neuropathy may be eligible. Patients with endocrine-related AEs 
Grade ≤ 2 requiring treatment or hormone replacement may be 
eligible; 
b. If participant has received major surgery, they must have recovered 
adequately from the procedure and/or complications from the surgery 
prior to starting study treatment; 
2. Has received prior radiotherapy within 2 weeks of start of study treatment 
or have had a history of radiation pneumonitis;  
Note: Participants must have recovered from all radiation-related 
toxicities. Three months of clinical stability is required post radiotherapy 
for CNS disease. A 1-week washout is permitted for palliative radiation 
(≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease; 
3. Arm 2 only: Has received prior therapy with immune checkpoint inhibitors 
(e.g. anti-PD-1, anti-PD-L1, or anti-PD-L2); 
4. Previous malignant disease (other than primary malignancy) within the 
last 5 years, except basal or squamous cell carcinoma of the skin or 
cervical carcinoma in situ; 
5. Concurrent active malignancy except for adequately controlled limited 
basal cell carcinoma of the skin; 
6. Clinically significant cardiovascular disease, or other diseases that in the 
Investigator’s opinion may influence the patient’s tolerance to study 
treatment; 
7. Pleural effusion or ascites requiring more than weekly drainage; 
8. Known allergy to any of the study medications, their analogues, or 
excipients; 
9. Prior organ transplantation, including allogenic stem-cell transplantation; 
10. Chronic immunosuppressive therapy including, but not exclusively, 
steroids (a maximum of 10 mg prednisone a day or equivalent is permitted) 
or any other form of immunosuppressive therapy within 7 days prior the 
first dose of study drug; 
11. Active, known, or suspected autoimmune disease. Participants with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll; 


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12. Has a history of (non-infectious) pneumonitis / interstitial lung disease that 
required steroids or has current pneumonitis / interstitial lung disease; 
13. Serious medical or psychiatric illness that could, in the Investigator’s 
opinion, potentially interfere with the completion of the treatment 
according to the protocol. Patients with known alcohol or drug abuse are 
not eligible;  
14. Known history of human immunodeficiency virus (HIV) infection or 
Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or 
known active Hepatitis C virus (defined as HCV Ribonucleic acid (RNA) 
[qualitative] is detected) infection;  
Note: No testing for HIV, Hepatitis B and Hepatitis C is required unless 
mandated by a local health authority;  
15. Current participation or has participated in a study of an investigational 
agent or has used an investigational device within 3 weeks prior to the first 
dose of study treatment; 
Note: Patients who have entered the follow-up phase of an investigational 
study may participate as long as it has been 3 weeks after the last dose of 
the previous investigational agent; 
16. Any vaccination within 14 days prior to starting study treatment; Arm 2 
only: Planned live or live attenuated vaccinations. 
17. Pregnant or lactating females; 
18. Documented hypersensitivity to any component of study treatment or 
excipients. 
Study 
Treatment(s) 
Dose and Route 
of 
Administration 
The dose of HER-Vaxx to be used in combination with chemotherapy or 
pembrolizumab will be 100 µg.  
HER-Vaxx will be administered Intramuscular(ly) (IM) into the deltoid region 
of the upper arm with a 25-38 mm (1-1.5 inches), 21-23G needle as per the 
Schedule of Activities until treatment discontinuation criterion is met.  HER-
Vaxx will be administered at least 48 hours prior to initiation of chemotherapy 
or administered at least 30-60 minutes prior to the administration of 
pembrolizumab depending on assigned Arm (when scheduled on the same day).  
Arm 1: 
Patients will receive HER-Vaxx on Days 1 and 15 of Cycle 1, Day 1 of Cycles 
2 and 3, then Day 1 of every second cycle from Cycle 3 onwards (Cycle 3 Day 
1, Cycle 5 Day 1, etc.). Patients will also receive intravenous (IV) 
administration of chemotherapy (ramucirumab 8 mg/kg IV on Days 8 and 22 
of a 28-day cycle + paclitaxel 80 mg/m2 IV on Days 8, 15, and 22 of a 28-day 
cycle), at least 48 hours following the IM administration of HER-Vaxx (when 
scheduled on the same day) and continue to receive chemotherapy treatment for 
as long as clinically indicated. HER-Vaxx may continue independently of 
chemotherapy until treatment discontinuation criterion is met. Similarly, if HER-


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
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Vaxx has been discontinued, chemotherapy may continue independently until 
treatment discontinuation criterion is met. 
Arm 2: 
Patients will receive HER-Vaxx on Days 1 and 15 of Cycle 1, Day 1 of Cycles 
2 and 3, then Day 1 of every 3rd cycle from Cycle 3 onward (Cycle 3 Day 1, 
Cycle 6 Day 1, etc.). Cycle 1 is a 28-day cycle and all subsequent cycles are 
21-day cycles. Patients will also receive IV pembrolizumab (200 mg Q3W 
starting on Cycle 1, Day 8 and continuing on Day 1 of every cycle from Cycle 
2 onward) at least 30--60 min following the IM administration of HER-Vaxx 
(when scheduled on the same day) and will continue treatment until treatment 
discontinuation criterion is met. HER-Vaxx may continue independently until 
treatment discontinuation criterion is met if pembrolizumab has been 
discontinued. Similarly, if HER-Vaxx has been discontinued, pembrolizumab 
may continue independently until treatment discontinuation criterion is met for 
a maximum of 35 cycles (approximately 2 years). 
Concomitant 
Medications 
Permitted medications include, but are not limited to: 
1. Anti-emetics or anti-diarrheal agents as required 
2. N-acetyl-para-aminophenol drugs (APAP, 
[paracetamol/acetaminophen]) 
3. Nonsteroidal anti-inflammatory drugs (NSAIDs) 
The use of APAP and NSAIDs should be assessed on a per-patient basis. 
Guidelines for the use of paracetamol (acetaminophen) and NSAIDs are as 
follows:  
Paracetamol 
• Paracetamol may be used for the treatment and first signs of flu-like signs 
and symptoms, that may be associated with HER-Vaxx vaccination.  
• Dosing of paracetamol: The recommended dose is 500 or 1000 mg every 6 
to 8 hours. The MAXIMUM daily (24-hour) dose must NOT exceed 
3000mg and requires adequate hepatic function.  
NSAIDs 
• The decision to use oral NSAIDs should be made for each individual patient, 
with attention to the patient's renal and hydration status at the time of HER-
Vaxx administration or the time of imaging scans with contrast. 
• Dosing of NSAIDs (e.g., oral ibuprofen, other NSAIDs permitted): The 
recommended dose is 400 or 600 mg ibuprofen (or an equivalent dose for 
other NSAIDs) every 8 hours. The MAXIMUM daily (24-hour) dose must 
NOT exceed 1800 mg ibuprofen (or an equivalent dose for other NSAIDs) 
and 
for 
a 
total 
of 
two 
days 
only.  
 


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The following medications/treatments are prohibited during the study:  
• Other investigational drug. 
• Continuous systemic treatment with either corticosteroids or other 
immunosuppressive or immuno-modulatory medications unless required 
to treat an immune adverse event.  
o Note: inhaled or topical steroids and physiological replacement 
doses of up to 10 mg daily prednisone equivalents are permitted. 
• Total doses greater than 24 mg dexamethasone equivalent of oral 
corticosteroids per chemotherapy cycle.  
• Both treatment Arms: Any vaccination within 14 days prior to any study 
treatment and during first treatment cycle.  
• Arm 2 only: Live or live attenuated vaccines while participating in the 
study are not allowed. Note: Inactivated vaccines are allowed after the 
first treatment cycle. 
• Other anti-cancer therapy (i.e., chemotherapy; hormonal therapy; 
extensive, 
non-palliative 
radiation 
therapy, 
or 
standard 
or 
investigational agents). 
Statistical 
Analysis 
Summary statistics for continuous variables will include the number of patients 
(n), mean, standard deviation, median, minimum, and maximum.  
Summary statistics for categorical variables will include the frequency and 
percentage of patients in each category.  
Summary statistics for time to event data will include the number of patients, 
estimated median and its 95% CI, 25th percentile, 75th percentile, minimum, and 
maximum times to event, number of events (total and censored).   
Results will be summarized by Arm.  All data will be listed. Baseline is assumed 
to be the last observation prior to first dose of study drug. 
The safety analysis set (SAF) consists of all patients who receive at least one 
dose of study treatment. All safety and tolerability evaluations will be based on 
this analysis set.  
The full analysis set (FAS), which includes all enrolled participants who receive 
at least 1 administration of study treatment, will be used for analyses of OS and 
may be used for additional analyses of selected efficacy endpoints. 
The evaluable analysis set (EAS), which includes all participants who receive at 
least 1 administration of study treatment and have an evaluable baseline tumor 
assessment and who have at least one evaluable post-baseline tumor response 
assessment as per RECIST v1.1 or were discontinued due to toxicity, will be the 
primary analysis set for analyses of response-based anti-tumor activity 
endpoints. 
The ORR along with the associated 95% CI based on the Clopper-Pearson exact 
method, will be reported. The Kaplan-Meier method will be used to summarize 


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OS, PFS and DoR.  The EAS will be the primary analysis set for analysis of 
ORR, PFS, and DoR.  The FAS will be the primary analysis set for analysis of 
OS. 
All safety analyses will be conducted in the SAF. 
Adverse events (AEs) will be coded according to the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). The severity of AEs 
will be graded according to NCI CTCAE, v5.0. 
Treatment-emergent adverse events (TEAEs) are defined as any AE with onset 
or worsening of a pre-existing condition after the first dose of study drug through 
30 days for AEs and 90 days for SAEs/irAEs following the last dose of study 
drug. Events including TEAEs, AEs leading to dose reduction/interruption, AEs 
related to study drug, serious adverse events (SAEs), AEs leading to study drug 
discontinuation, and fatal AEs will be summarized by system organ class (SOC) 
and preferred term (PT). A summary of AEs of NCI CTCAE Grade 3 or higher, 
as well as the most frequent AEs (by preferred term), and AEs by relationship to 
study treatment, will be provided. 
A listing of DLTs will be reported for the safety run-in phase of both Arms.  
Values and changes from baseline in clinical laboratory results will be 
summarized by visit. Clinical laboratory values will be graded according to the 
NCI CTCAE, for applicable tests. Shifts in toxicity grades from baseline grade 
will be summarized. Shifts from baseline in ECOG performance status also will 
be summarized.  
Sample Size  
For each Arm, after 8 evaluable patients are enrolled (Stage 1), an additional 7 
evaluable patients will be enrolled in that Arm (Stage 2) if 1 or more patients 
respond (i.e., experience CR or PR). If there are no responses in Stage 1, then 
preliminary anti-tumor activity in the group will not have been identified and no 
further patients will be enrolled in that Arm. If the Arm continues to Stage 2, a 
total of 15 evaluable patients will be studied for that Arm. The Arm will be 
considered successful if ≥ 4 treated patients respond, and the Arm may be 
expanded to enroll 25 patients. This design is applied to each Arm separately 
and is based on a 2-Stage Simon Minimax design for a total of 15 evaluable 
patients (null hypothesis that ORR ≤ 11% versus the alternative hypothesis that 
ORR ≥ 40% with alpha=0.07268 and power=90.463%). 
 
 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED                                                                                      CONFIDENTIAL 
Page 29 
 
  SCHEDULE OF ACTIVITIES 
The Schedule of Activities tables provide an overview of the protocol visits and procedures for each Arm. Refer to Study Procedures (Section 7) for detailed 
information on each procedure and assessment required for compliance with the protocol.  
Table 1. 
Schedule of Activities Arm 1 (HER-Vaxx + Chemotherapy) 
Cycle 
Screening (S) 
Cycle 1(T) 
Cycle 2(T) 
Cycle 3 Onwards(T) 
End of 
Treatment(E) 
Survival  
Follow Up (U) 
Day 
D-21 to D-1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
  
  
Cumulative Day 
D-21 to D-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
 
 
Visit window 
 - 
- 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 7d) 
(+/- 7d) 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
X 
X(A) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy (B) 
X 
  
  
  
  
X 
  
  
  
  
X 
  
Demographics  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical 
Exam (C) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(C) 
X 
X 
X 
X 
  
Weight & Vital 
Signs(D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(D) 
X 
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Radiographic 
Assessment(F)  
  
X 
X(F) 
  
  
Cardiac 
Assessment(G) 
X 
  
  
  
  
  
  
  
  
C4D1(G) 
  
  
  
X 
  
Pregnancy 
Test (H) 
X 
X 
  
  
  
X 
  
  
  
X(H) 
  
  
X 
  
HIV, Hepatitis 
B/C (I) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology, 
Chemistry(J) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(J) 
X 
X 
X 
X 
  
Thyroid 
Function Tests(K) 
X 
X 
  
  
  
  
  
  
  
X(K) 
  
  
  
X 
  
Exploratory 
Biomarker (L) 
  
X 
X 
  
X 
  
  
X 
  
X(L) 
  
  
  
X 
  


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED                                                                                      CONFIDENTIAL 
Page 30 
 
Cycle 
Screening (S) 
Cycle 1(T) 
Cycle 2(T) 
Cycle 3 Onwards(T) 
End of 
Treatment(E) 
Survival  
Follow Up (U) 
Day 
D-21 to D-1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
  
  
Cumulative Day 
D-21 to D-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
 
 
Visit window 
 - 
- 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 7d) 
(+/- 7d) 
Immunology – 
humoral (M) 
   
X 
X 
  
X 
  
  
X 
  
X 
  
  
  
X 
X  
Immunology –
cellular (N) 
X 
X 
X 
  
X 
  
  
X 
  
X(N) 
  
  
  
X 
  
ctDNA (O) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HER-Vaxx (P) 
  
X 
  
X 
  
X 
  
  
  
X(P) 
  
  
  
  
  
Ramucirumab(Q) 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
Paclitaxel(Q) 
  
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
  
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse 
Events(R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(R) 
Survival/ 
anti-cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Table 1 Footnotes 
A. If screening assessments (Hematology, Blood Chemistry, Thyroid Function Test, Eastern Cooperative Oncology Group [ECOG], Cellular Immunology & Pregnancy Test) are performed 
within 72 hours of the first study treatment administration, the assessments do not have to be repeated on Cycle 1, Day 1.   
B. Documentation of HER-2 positivity at diagnosis is required. A screening visit or archival tumor biopsy (either fresh or archival tissue) or post-progression pathology report should be 
provided. Cycle 2 and End of Treatment tumor biopsies are optional. The Cycle 2 optional tumor biopsy can be taken on any day during Cycle 2. 
C. A limited, symptom-directed physical examination may be performed post Cycle 1, Day 1. Physical exam to be performed at each HER-Vaxx and chemotherapy treatment visit. In HER-
Vaxx treatment cycles (C3 C5, C7..), physical exam to be performed at each visit in the cycle (while chemotherapy continues). In non-HER-Vaxx treatment cycles (C4, C6 C8 ..), physical 
exam not required at D1, but required at D8, D15, D22 (while chemotherapy continues). 
D. Weight and Vital Signs (blood pressure, respiratory rate, heart rate and temperature) to be recorded prior to receiving study treatment. In addition, record temperature 30 min (±10 mins) 
after each HER-Vaxx vaccination. For Arm 1, weight to be used for body surface area (BSA) calculation as per institutional practice. Weight & vital signs must be performed at each 
HER-Vaxx and chemotherapy treatment visit. In HER-Vaxx treatment cycles (C3 C5, C7..), weight & vital signs to be performed at each visit in the cycle (while chemotherapy continues). 
In non-HER-Vaxx treatment cycles (C4, C6 C8 ..), weight & vital signs not required at D1, but required at D8, D15, D22 (while chemotherapy continues).  
E. The end of treatment (EoT) visit will be completed at least 30 days after last study treatment.  
F. Radiographic assessments: Cycle 1 assessment can be performed up to 14 days prior to Cycle 1 Day 1 and then every 6 weeks from Cycle 1, Day 1 within a +/- 3 day window until disease 
progression, or withdrawal for any other reason. Radiographic assessment is according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria. Upon PD, a scan 
will be scheduled 4 to 6 weeks after initial PD scan to confirm progression. After discontinuation from the study for any reason other than disease progression, radiographic change will be 
collected every 12 weeks until determination of progressive disease.  


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED                                                                                      CONFIDENTIAL 
Page 31 
 
G. Cardiac assessment includes 12-lead ECG and echocardiography or multiple gated acquisition (MUGA) scan. Assessment to be performed at Screening, Cycle 4, Day 1 and then Day 1 
every 3 cycles and EoT.  Significant abnormal cardiac assessments should be evaluated by a cardiologist.   
H. Highly sensitive urine pregnancy test (sensitivity of at least 25 mIU/mL) for all female patients of childbearing potential will be collected once each cycle prior to study treatment and/or 
chemotherapy: 
• on Day 1 of each odd-numbered cycle, starting Cycle 3. 
• on Day 8 of each even-numbered cycle, starting Cycle 4. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Treatment may be delayed until negative beta-human chorionic gonadotrophin 
(BHCG) blood test is received.  
I. 
Testing for human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C is not required unless mandated by a local health authority. 
J. 
Local hematology and chemistry laboratory testing to be collected prior to receiving any study treatment. Local labs can be drawn up to 72 hours before any on-study clinic visit. Local 
labs to be taken at each HER-Vaxx and chemotherapy treatment visit. In HER-Vaxx treatment cycles (C3, C5, C7, etc.), safety labs are to be taken at each visit in the cycle (while 
chemotherapy continues). In non-HER-Vaxx treatment cycles (C4, C6, C8, etc.), safety labs are not required at D1, but are required at D8, D15, D22 (while chemotherapy continues). 
K. Thyroid function test to be performed prior to receiving study treatment. Thyroid function test is performed on Day 1 every 2nd cycle from Cycle 3 onward.  
L. Whole blood for exploratory biomarkers (all exploratory biomarkers except ctDNA which is captured separately per footnote O) to be collected prior to administration of study treatment. 
Exploratory biomarkers to be collected on Day 1 every 2nd cycle from Cycle 3 onward. 
M. Whole blood for humoral immunity samples to be collected prior to administration of study treatment. Blood samples for humoral immunity to be collected on Day 1 of every cycle from 
Cycle 3 onward and every 12 weeks for up to 1 year during Survival Follow Up.  
N. Whole blood for cellular immunity peripheral blood mononuclear cell (PBMC) samples to be collected prior to administration of study treatment. Cellular immunity samples to be 
collected on day 1 of every 2nd cycle from Cycle 3 onward. 
O. Whole blood for ctDNA HER-2 genotyping will be collected prior to administration of study treatment on Day 1 of every cycle. 
P. HER-Vaxx to be administered as indicated for Cycles 1 through 3 and on Day 1 of every 2nd cycle from Cycle 3 (i.e. Cycles 3, 5, 7, …) onward until treatment discontinuation criterion is 
met. Patients to be observed for 30 minutes post HER-Vaxx administration. Note: Please ensure that HER-Vaxx is administered at least 48 hours before starting paclitaxel (when 
scheduled on the same day). 
Q. Ramucirumab 8 mg/kg IV on Days 8 and 22 of a 28-day cycle + paclitaxel 80 mg/m2 on Days 8, 15, and 22 of a 28-day cycle, for as long as clinically indicated. Paclitaxel to be 
administered at least 48 hours after administration of HER-Vaxx (when scheduled on the same day). 
R. During Survival Follow-Up serious adverse events (SAEs) considered related to study treatment are to be reported 90 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first.  
S. Screening can occur across multiple clinic visits within the 21-day screening period.  
T. Each cycle is 28 days. 
U. After study discontinuation and completion of the End of Treatment visit, patients will be followed for survival every 12 weeks (± 7 days) for up to 3 years. 
 
 
 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED                                                                                      CONFIDENTIAL 
Page 32 
 
Table 2. 
Schedule of Activities Arm 2 (HER-Vaxx + Pembrolizumab) 
Cycle 
Screening (T) 
Cycle 1(U) 
Cycle 2(U) 
Cycle 3(U) 
Cycle 4 
Onwards(U) 
End of 
Treatment(F) 
Survival Follow 
Up (V) 
Day 
D -21 to D -1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 1 
  
  
Cumulative Day 
D-21 to D-1 
1 
8 
15 
22 
29 
43 
50 
71 
 
 
Visit window 
 - 
- 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 7d) 
(+/- 7d) 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
Eligibility 
X 
X(A) 
  
  
  
  
  
  
  
  
  
HER2+ Assessment(B)  
X 
  
  
  
  
  
  
  
  
  
  
Tumor biopsy (C) 
X 
  
  
  
  
X 
  
  
X 
  
Demographics  
X 
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
  
  
  
  
  
  
  
  
  
  
Physical Exam (D) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Weight and vital signs (E) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
ECOG 
X 
X 
  
  
  
  
  
  
  
X 
  
Radiographic Assessment(G) 
  
X 
X(G) 
  
  
Cardiac Assessment(H) 
X 
  
  
  
  
  
  
  
X(H) 
X 
  
Pregnancy Test (I) 
X 
X 
  
  
  
X 
  
X 
X 
X 
  
HIV, Hepatitis B/C (J) 
X 
  
  
  
  
  
  
  
  
  
  
Hematology, Chemistry(K) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Thyroid Function Tests(L) 
X 
X 
  
  
  
  
X 
  
X(L) 
X 
  
Exploratory Biomarker (M) 
  
X 
X 
  
X 
  
X 
  
X(M) 
X 
  
Immunology – humoral (N) 
  
X 
X 
  
X 
  
X 
  
X 
X 
X  
Immunology – cellular (O) 
X 
X 
X 
  
X 
  
X 
  
X(O) 
X 
  
ctDNA (P) 
 
X 
 
 
 
X 
 
X 
X 
X 
 
HER-Vaxx (Q) 
  
X 
  
X 
  
X 
  
 X(Q) 
 
X  
  
Pembrolizumab(R) 
  
  
X 
  
  
X 
  
X 
X 
  
  
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Events(S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(S) 
Survival/anti-cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
X 
 
Table 2 Footnotes 
A. If screening assessments (Hematology, Blood Chemistry, Thyroid Function Test, Eastern Cooperative Oncology Group [ECOG], Cellular Immunology, & Pregnancy Test) are 
performed within 72 hours of the first study treatment administration, the assessments do not have to be repeated on Cycle 1, Day 1.  
B. Human epidermal growth factor receptor 2 (HER2/neu+) assessment prior to enrollment. Confirmed HER2/neu overexpression (3+ by immunohistochemistry (IHC) or if IHC 2+ 
confirmed by fluorescent in situ hybridization [FISH], brightfield double in situ hybridization [BDISH] or chromogenic in situ hybridization [CISH]) using post-progression fresh or 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED                                                                                      CONFIDENTIAL 
Page 33 
 
archival tissue, or post-progression pathology report. Sponsor may approve inclusion based on liquid (blood based) biopsy to assess patients’ HER2/neu positivity where tumor biopsy 
is not clinically indicated. 
C. A post-progression fresh or archival tumor biopsy sample or post-progression pathology report will be obtained for all patients to confirm eligibility. Cycle 2 and End of Treatment 
tumor biopsies are optional.  The optional tumor biopsy can be taken on any day during Cycle 2. 
D. A limited, symptom-directed physical examination may be performed post Cycle 1, Day 1. The physical exam must be performed prior to receiving any study treatment.  
E. Weight and Vital Signs (blood pressure, respiratory rate, heart rate and temperature) to be recorded prior to receiving study treatment. In addition, record temperature 30 min (±10 mins) 
after each HER-Vaxx vaccination.  
F. The end of treatment (EoT) visit will be completed at least 30 days after last study treatment. 
G. Radiographic assessments: Cycle 1 assessment can be performed up to 14 days prior to Cycle 1, Day 1 within a +/- 3 day window and then every 6 weeks from Cycle 1, Day 1 until 
disease progression, or withdrawal for any other reason. Radiographic assessment is according to response evaluation criteria in solid tumors (RECIST) version 1.1 response criteria. 
Upon PD, a scan will be scheduled 4 to 6 weeks after initial PD scan to confirm progression. After discontinuation from the study for any reason other than disease progression, 
radiographic change will be collected every 12 weeks until determination of progressive disease.  
H. Cardiac assessment includes 12-lead ECG and echocardiography or multiple gated acquisition (MUGA) scan. Assessments to be performed at Screening, Cycle 4 Day 1, then every 4 
cycles and at EoT.  Significant abnormal cardiac assessments should be evaluated by a cardiologist.           
I. 
Highly sensitive urine pregnancy test (sensitivity of at least 25 mIU/mL) for all female patients of childbearing potential will be collected once each cycle prior to study drug 
treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Treatment may be delayed until negative beta-human chorionic 
gonadotrophin (BHCG) blood test is received.  
J. 
Testing for Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C is not required unless mandated by a local health authority. 
K. Local hematology and chemistry laboratory testing to be collected at each study treatment visit prior to receiving any study treatment. Local labs can be drawn up to 72 hours before 
any on-study clinic visit.  
L. Thyroid function test to be performed prior to receiving study treatment. Thyroid function test to be performed on day 1 every 2nd cycle from Cycle 4 onward (i.e., cycles 4, 6, 8, 
10…).  
M. Whole blood for exploratory biomarkers (all exploratory biomarkers except ctDNA which is captured separately per footnote O) to be collected prior to receiving study treatment.  
Exploratory biomarker samples to be collected every 3rd cycle from Cycle 4 onward (i.e., cycles 4, 7, 10…).  
N. Humoral samples to be collected prior to receiving study treatment. Blood samples for humoral immunity to be collected on Day 1 of every cycle from Cycle 4 onward and every 12 
weeks for up to 1 year during Survival Follow Up. 
O. Cellular immunity peripheral blood mononuclear cell (PBMC) to be collected prior to receiving study treatment. Cellular immunity samples to be collected every 3rd cycle from Cycle 
4 onwards. 
P. Whole blood for ctDNA HER-2 genotyping will be collected prior to administration of study treatment on Day 1 of every cycle. 
Q. HER-Vaxx to be administered as indicated for Cycles 1 through 3 and on day 1 of every 3rd cycle from Cycle 3 onward (i.e., cycles 3 6, 9, 12…)  until treatment discontinuation 
criterion is met. Patients to be observed for 30 minutes post HER-Vaxx administration. Note: Please ensure that HER-Vaxx is administered at least 30-60 minutes before starting 
pembrolizumab (when scheduled on the same day). 
R. Pembrolizumab 200 mg administered until treatment discontinuation criterion met for a maximum of 35 cycles. Pembrolizumab to be administered at least 30-60 minutes following 
administration of HER-Vaxx (when scheduled on the same day). 
S. During Survival Follow-Up Serious adverse events (SAEs) considered related to study treatment are to be reported 90 days after the final dose of study treatment or until initiation of 
new systemic anti-cancer therapy, whichever occurs first.  
T. Screening can occur across multiple clinic visits within the 21-day screening period.  
U. Cycle 1 is 28 days. Cycles from Cycle 2 onwards are 21 days.  
V. After study discontinuation and completion of the End of Treatment visit, patients will be followed every 12 weeks (± 7 days) for up to 3 years. 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 34 
CONFIDENTIAL 
1. 
INTRODUCTION 
1.1 
HER-Vaxx (IMU-131) and Pembrolizumab  
The investigational product, IMU-131, will be supplied as drug substance P467-CRM197, 
which is composed of 3 individual B-cell epitopes (P467) selected from Human epidermal 
growth factor receptor 2 (HER2/neu) structure and conjugated to CRM197, which becomes 
HER-Vaxx when emulsified with excipient Montanide (ISA 51 VG Sterile). IMU- 131 induces 
the patient’s own B cells to produce endogenous anti-HER2/neu antibodies.  
HER-Vaxx (IMU-131) is being developed for the treatment of patients with HER2/neu 
overexpressing metastatic or advanced adenocarcinoma of the stomach or GEJ (referred to as 
advanced gastric cancer [AGC]). Refer to Investigator’s Brochure (IB) for detailed background 
information on HER-Vaxx (IMU-131).  
Pembrolizumab is a potent humanized Immunoglobulin G4 (IgG4) monoclonal Antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD1) 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 PD1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an 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 and for detailed background 
information refer to the Summary of Product Characteristics (SmPC). 
1.2 
Background and Rationale 
HER-Vaxx is being developed for the treatment of patients with HER2/neu overexpressing 
metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction, referred 
to as AGC. 
The transmembrane tyrosine kinase receptor HER2/neu is also known as Neu, Erb-2, CD340, 
or p185 is a member of the epidermal growth factor receptor (EGFR/ErbB) family. HER2/neu 
is weakly detectable in epithelial cells of normal tissues but is overexpressed in 15% to 25% 
of several cancers (Zhang, 2009). In patients with gastric cancer, the receptor has been found 
to be overexpressed in 15% to 25% of patients (Hofmann, 2008; Park, 2006; Yano, 2006) 
where it is associated with a poor prognosis, more aggressive disease, and shorter survival. 
Where it is overexpressed, HER2/neu is typically the primary driver of proliferation for the 
malignant cells. The overexpression seems to be stable and homogenous in primary tumors as 
well as their metastases. These findings suggest HER-2/neu may be an attractive target of 
cancer immunotherapy. 
AGC occurs primarily in an inoperable state with metastatic spread to distant lymph nodes or 
to inner organs and – if operable – tends to recur frequently. The 5-year survival rate of patients 
with Stage IIIc and IV gastric cancer is only 9% and 4%, respectively (Wagner, 2007) For 
initial systemic treatment for metastatic and locally advanced HER2-positive AGC, 
trastuzumab, an HER2/neu inhibitory mAb, is administered in combination with chemotherapy 
doublets (Roy, 2009). Addition of trastuzumab to the chemotherapy regimen, significantly 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
IMUGENE LIMITED 
Page 35 
CONFIDENTIAL 
improved median overall survival (OS): 13.5 vs 11.1 months (p=0.0048). Based on these data, 
the combination of trastuzumab plus 5- Fluorouracil (5-FU) and cisplatin chemotherapy has 
become registered as the standard therapeutic option in first line (1L) setting. However, 
trastuzumab has been associated with a serious decline in heart function for some patients, and 
other potentially serious side effects include infusion reactions, pulmonary edema, and 
respiratory distress.  
The elucidation of various molecular pathways involved in the development of AGC has led 
to a multitude of studies of targeted therapies. Following the success of the ToGA trial, agents 
such as those targeting the vascular endothelial growth factor (VEGF) angiogenesis pathway 
have been investigated. Ramucirumab is a human IgG1 monoclonal antibody receptor 
antagonist designed to bind to the extracellular domain of VEGFR-2. The phase III RAINBOW 
trial evaluated the efficacy and safety of ramucirumab plus paclitaxel vs placebo plus paclitaxel 
in patients with locally advanced or metastatic gastric or GEJ adenocarcinoma who have 
progressed after first-line chemotherapy (Wilke, 2014). OS was significantly longer in the 
ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 
months [95% CI: 8·5,10·8] vs 7·4 months [95% CI: 6·3,8·4], hazard ratio 0·807 [95% CI: 
0·678, 0·962]; p=0·017). PFS was significantly increased in the treatment group compared to 
the control group (4.4 months [95% CI: 4.2, 5.3] vs 2.9 months [95% CI: 2.8,3.0], hazard ratio 
0·64 [95% CI: 0·54, 0·75]; p<0·001). Confirmed ORR was 28% (95% CI: 23, 33) in the 
ramucirumab plus paclitaxel Arm compared with 16% (95% CI: 13, 20) for those receiving 
placebo plus paclitaxel. Ramucirumab plus paclitaxel is now approved as a second-line 
treatment option for patients with metastatic gastric cancer, who failed first-line treatment with 
platinum- and fluoropyrimidine-based combinations or trastuzumab in combination with 
cisplatin and 5-fluorouracil/cisplatin and capecitabine. 
Despite the recent advances for the treatment in HER2/neu overexpressing gastric cancer 
(GC)/GEJ cancer and the approvals for Enhertu® and Keytruda® as > 1L treatment options, 
there remains an unmet need for treatments that are well tolerated and induce durable 
responses.  
To overcome resistance to immunotherapy within AGC, one promising strategy is to increase 
the number of cytotoxic immune cells directly within the tumor microenvironment (TME) via 
the use of polyclonal vaccines such as HER-Vaxx. Active immunization with HER-Vaxx has 
induced high and long-lasting antibody levels and expanded lymphocytes’ subpopulations, 
such as interferon gamma (IFNγ) producing CD4 and CD8 T cells (Weir, 2011; Alanji, 2006; 
Matsushita, 2013). Therefore, the introduction of HER-Vaxx after 1L treatment in patients that 
have progressed on trastuzumab may overcome potential resistance against trastuzumab in 
combination with chemotherapy. It may also synergize with pembrolizumab and therefore 
serve as a potentially better tolerated and chemotherapy-free treatment opportunity in 
metastatic patients that progressed under their previous therapy.  
1.3 
Clinical Rationale for HER-Vaxx (IMU-131, HER2/neu Peptide Vaccine) 
Polyclonal antibodies generated against IMU-131 peptides bind three separate regions of the 
HER2 receptor in domains III and IV thereby inhibiting intracellular signaling as well as 
inducing antibody dependent cellular cytotoxicity (ADCC) and complement-dependent 
cytotoxicity (CDC).  


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In vitro and in vivo animal experiments with an earlier formulation of IMU-131, PEV6C, have 
corroborated this approach and have shown the ability to generate an effective antibody 
response by human B-cells (Wiedermann, 2010). These antibodies were able to induce ADCC 
and CDC and to inhibit the proliferation of HER2/neu overexpressing tumor cells in vitro. 
PEV6C was also able to effectively inhibit the emergence of HER2/neu overexpressing breast 
tumors in a transgenic mouse model (Wiedermann, 2010).  
IMU-131 is a HER2/neu antigen peptide – adjuvant emulsion (P467-CRM197 – Montanide 
emulsion) which is injected intramuscularly (IM) into the patient to stimulate innate immunity 
in response and is processed by antigen presenting cells. The immune system then generates 
specific adaptive immunity to the HER2/neu antigen peptides. This ultimately leads to the 
development of B cells that secrete endogenous HER2/neu-specific antibodies that block 
binding HER2 signaling. Blocking HER2 signaling inhibits proliferation and results in 
apoptosis in HER2/neu overexpressing tumor cells. Antibody binding to HER2/neu positive 
cells also signals for additional immunologic clearance through ADCC and CDC. 
Immunization with this multi-epitope vaccine performed in a c-neu transgenic mouse model 
demonstrated that the vaccine led to delayed onset of tumor growth and reduced tumor 
progression in vivo (Wiedermann, 2021), providing the rationale to move into human clinical 
testing.  
Several strategies of combining cancer vaccines with chemotherapy have been tested. These 
studies have revealed that immune-stimulatory cancer vaccines can be safely used in 
combination with immunosuppressive chemotherapies to condition the immune system and to 
create an environment where cancer vaccines have a better chance of success. Among the 
chemotherapies tested to enhance immune responses from vaccines, the underlying mechanism 
of supporting the immune response of vaccines are favorably described for 5-FU- and cisplatin-
based regimens and provide a rationale for the combination of both chemotherapies with an 
immune-stimulatory vaccine (Weir, 2011). Gastric cancer patients have been successfully 
immunized with G17DT immunogen resulting in anti-gastrin titers while receiving 
simultaneous cisplatin and 5-FU chemotherapy (Weidermann, 2021). Matsushita et al (2013) 
in a Phase 1 study treated patients with AGC using a vaccine containing a mixture of synthetic 
peptides and oral tegafur/uracil leucovorin. Among the 10 treated patients the responses were 
1 partial response (PR) and 7 patients with stable disease (SD).  
In the Phase 1 clinical trial of IMU-131 predecessor, PEV6C which was studied in combination 
with docetaxel in breast cancer patients without HER2/neu overexpression, eight of 10 patients 
exhibited an increase in HER2/neu-specific antibody titers directed against vaccine peptides as 
well as native HER2/neu protein. A marked increase in cellular immune responses was 
observed in the majority of vaccinated patients. In addition, the number of 
CD4+CD25+Foxp3+ T regulatory cells was markedly reduced following vaccination, 
suggesting the vaccine was effective in overcoming immunological tolerance to HER2/neu. 
These data support that the 3 peptide sequences contained in IMU-131 are effective in 
generating antibodies against HER2/neu as well as inducing additional immunologic changes 
that increase the activity of cellular immunity and reduce immunologic tolerance to HER2/neu 
expressing cells (Weidermann, 2021).  
Between 08-May-2017 to 08-Feb-2023, 61 patients (14 in Phase 1b and 36 in Phase 2 and 11 
in the Phase 2 Extension) diagnosed with metastatic or advanced, HER-2/neu overexpressing, 
gastric or GEJ adenocarcinoma were enrolled in the IMU-131 clinical development program 


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(HERIZON [IMU.ACS.001]), of which 47 patients (14 in Phase 1b, 19 in Phase 2, 11 Phase 2 
Extension) were dosed with IMU-131. The preliminary immunology and clinical response data 
from Phase 2 reveal that the addition of HER-Vaxx to chemotherapy significantly prolonged 
survival. Safety data to date indicate that IMU-131 is well tolerated with no significant local 
or systemic reactions, and no need for pretreatment or for modification to the dose or treatment 
schedule due to safety (Weidermann, 2021, Maglakelidze, 2023). The updated final analysis 
showed an OS benefit with a HR of 0.558 (2-sided 80% CI: 0.349,0.895). Safety, in terms of 
hematological and non-hematological adverse events, was shown to be similar between the 
treatment Arms, with no significant vaccination-related toxicity (Maglakelidze, 2023).  
The safety and immunological data from HERIZON supports a dose of 100 µg peptide P467 
antigen equivalent conjugated to CRM197 in a Montanide emulsion (HER-Vaxx [IMU-131]) 
as a 1.0 mL injection on Days 0, 14, 35 followed by a booster 42 days later and subsequent 
boosters every 63 days. The 100 µg dose induced consistently high P467 Abs and HER2 Ab 
with an observed correlation of titer levels with clinical response.  
The investigation of HER-Vaxx plus pembrolizumab is planned in Arm 2 of this study. 
Nonclinical data demonstrate a synergistic effect of combination HER2 and PD-1 vaccines 
which resulted in almost 90% of tumor growth inhibition in an HER2+ syngeneic mouse model 
(Kaumaya, 2020). Preliminary clinical data documented that treatment of HER-Vaxx can 
induce the upregulation of PD-L1 directly in the tumor tissue, turning a ‘cold’ tumor ‘hot’. 
Within Arm 2, pembrolizumab will be administered in combination with HER-Vaxx 
independent of tumor mutational burden (TMB) / microsatellite stable status (MSS)/ 
programmed death-ligand 1 (PD-L1) status of the tumor. 
The proposed dose regimen for both treatment arms in the nextHERIZON study is based on 
empirical data from the Phase 1b/2 HERIZON study, pre-clinical data demonstrating the 
immunostimulatory effects of HER-Vaxx, and theoretical grounds for priming of the immune 
system 
prior 
to 
administering 
potentially 
immunosuppressive 
chemotherapy 
or 
immunostimulatory therapy with a checkpoint inhibitor. 
The initiation of combination therapy with either standard of care chemotherapy (ramucirumab 
+ paclitaxel) or pembrolizumab, depending on the treatment group, begins one week after the 
first priming dose of HER-Vaxx. Treatment with chemotherapy for Arm 1 begins on study day 
8, with a second dose of HER-Vaxx given on study day 15. This chemotherapy regimen 
continues for each 28-day cycle. Treatment with pembrolizumab for Arm 2 is administered 
every 21 days following the study day 8 dose. A similar staggered, priming approach to 
combination therapy with HER-Vaxx and standard of care chemotherapy using platinum and 
fluoropyrimidine-based chemotherapy regimens was successfully used in the HERIZON study 
with good safety and tolerability and stimulation of anti-HER2neu antibodies by HER-Vaxx 
(refer to the IB). 
1.4 
Pembrolizumab Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis, 2010). 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 


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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 (Dudley, 2005; Hunder, 2008). 
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) (Greenwald, 
2005; Okazaki, 2001). 
The structure of murine PD-1 has been resolved (Zhang, 2004). 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 2 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 cascade (Zhang, 2004; Chemnitz, 2004; Shepard, 2004; Riley, 2009). 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 proteins 
(Parry, 2005; Francisco, 2010) As a consequence, the PD 1/PD-L1 pathway is an attractive 
target for therapeutic intervention in HER2/neu overexpressing metastatic or advanced gastric 
or gastro-esophageal cancer. 
1.5 
Pre-clinical and Clinical Trials for Pembrolizumab 
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 
modalities (Blank, 2004; Weber, 2010; Strome, 2003; Spranger, 2014; Curran, 2010; Pilon-
Thomas, 2010). 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 (Strome, 2003; Curran, 2010; Pilon-Thomas, 
2010; Nomi, 2007).  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 vivo (Pilon-Thomas, 2010; Hirano, 2005). 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. 


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1.6 
Risks and Benefits for nextHERIZON 
It is anticipated that the information gained from this study will contribute to the development 
of a safe and effective anti-HER2/neu peptide vaccine. It is unknown whether patients will 
benefit from participation in this study. The investigational product-related risks to patients in 
this study are associated with the general risk of vaccination, however HER-Vaxx in the 
HERIZON study revealed no systemic or immune related toxicities with only mild local 
injection site reactions. The combination of HER-Vaxx plus chemotherapy showed a similar 
adverse event profile as chemotherapy alone.  
The general risks to patients will arise from their common chemotherapy (Arm 1) or from risks 
associated with pembrolizumab (Arm 2). Serious and potentially fatal specific and general risks 
are associated with ramucirumab plus paclitaxel (Arm 1), that will be administered to patients 
on this study. These treatments are standard care for this disease (NCCN, 2022) and are given 
in a standard fashion that is familiar to all Investigators. All patients are likely to experience 
chemotherapy-associated adverse events (AEs).  
The risks of pembrolizumab administration are detailed in the Summary of Product 
Characteristics (SmPC) and label of the compound (Keytruda® SmPC). Pembrolizumab has 
been documented to cause immune-mediated adverse reactions and infusion-related reactions, 
for which a series of measures including dose modifications are recommended (Keytruda® 
SmPC/label, Section 6.3.4. and 6.3.5).  
1.6.1. Vaccination-specific Potential Risks Include the Following 
Local reactions: An inflammatory reaction as manifested by redness, swelling, and/or 
tenderness may occur at the site of vaccine injection. Local reactions are expected to resolve 
within days to weeks without medical intervention and sequelae.  
Systemic reactions: May include flu-like symptoms with low-grade fever, chills, and malaise. 
Experience to date with other peptide vaccines suggests that if such reactions occur, they 
resolve in days to weeks without therapy or limitation of daily activity. Serum sickness 
reactions due to deposition of antigen-antibody complexes or idiosyncratic immune responses 
not dependent on immune complexes could develop, resulting in damage to organs such as the 
liver or kidney. Such immune-mediated reactions have not been reported to date for HER2/neu 
peptide vaccines. Temporary ascending paralysis, the Guillain-Barré syndrome, may occur 
with any vaccine, although it is very rare. 
The elicitation of polyclonal antibody responses may also elicit antibodies capable of binding 
Fc receptors and fixing complement making serum sickness and serum sickness-like reactions 
due to deposition of antigen-antibody complexes theoretically possible. These reactions 
manifest 5-10 days after treatment and consist of skin rashes, joint pains and fever and have 
been described for exogenously administered antibodies such as snake anti-venom, horse 
anti-thymocyte globulin (ATG), rabies and tetanus anti-serum. In this setting the large amounts 
of antibody can bind to the target antigens and cause immune complex deposition in the tissues. 
Symptoms and signs typically resolve after cessation of the treatment and may require 
treatment with high dose corticosteroids for severe reactions. However, non-clinical data 
indicate HER-Vaxx induces low levels of endogenous antibodies which are not expected to 
produce circulating immune complexes. Idiosyncratic immune responses not dependent on 


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immune complexes could also develop, resulting in damage to organs, such as the liver or 
kidney. 
Allergic reactions and anaphylaxis: Allergic and anaphylactic reactions are also possible. 
No such reactions have been observed to date. 
1.6.2. Management of Risks 
The design of this Phase 2 study supports appropriate medical monitoring of patients. Physical 
monitoring of patients occurs after each vaccination and at regular intervals during each study. 
Safety Review Committee (SRC) meetings during dose combination, as well as site 
teleconferences between the medical monitor, sponsor representatives and investigational site 
staff will occur regularly during the study. 
To minimize the risk to patients and maximize safety, the following factors have been 
incorporated into the study design: 
• Detailed safety and laboratory assessments will be performed.  
• Review of safety data and dose-limiting toxicities (DLTs) by the SRC  
• All clinical observations will be evaluated by the Investigator on an ongoing basis.  
• Each patient must stay on site for at least 30 min after HER-Vaxx administration on 
each treatment day. 
• The study agent(s) must be administered in a clinical setting where emergency 
resuscitative equipment and personnel trained in the management of anaphylaxis are 
immediately available to treat systemic reactions under the direct supervision of a 
physician.  
• To minimize the potential risk of the combination treatment, the first 3 patients in each 
Arm are planned to be treated at least 15 days apart and observed for DLTs over 
29 days. Decisions on the extensions of the safety run-in or the inclusion of the 
remaining patients will be made by the SRC. Dose modifications for pembrolizumab 
are described in Section 6.3.4 and 6.3.5 below. 
 
Complete information for HER-Vaxx (IMU-131) or pembrolizumab is provided in the IB and 
SmPC respectively. 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives  
2.1.1. Primary Safety Objective 
• To evaluate the safety and tolerability of HER-Vaxx in combination with chemotherapy 
(ramucirumab plus paclitaxel) or pembrolizumab. 
 
2.1.2. Primary Efficacy Objective 
• To evaluate the objective response rate (ORR) of HER-Vaxx in combination with 
chemotherapy or pembrolizumab according to RECIST 1.1.  
 
2.1.3. Secondary Objective 
• To evaluate additional efficacy and survival measures (OS, progression free survival 
[PFS], duration of response [DoR]) of HER-Vaxx in each Arm.  
 
2.1.4. Exploratory Objectives 
• To evaluate humoral and cellular immunogenicity data of HER-Vaxx plus 
chemotherapy (ramucirumab plus paclitaxel) or pembrolizumab.  
• To evaluate immunogenicity and serum and biochemical markers of tumor 
progression to clinical outcomes of ORR, PFS and DoR.   
• To evaluate Arm-specific associations between clinical outcome and HER2/neu 
expression, PD-L1 expression, and TMB. 
 
2.2 
Endpoints 
2.2.1. Primary Safety Endpoints  
• Frequency and severity of adverse events (AEs) graded by Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. 
• Frequency and severity of immune-related AEs. 
• Frequency of patients discontinuing study treatment due to AEs. 
• Changes and shifts from baseline in clinical laboratory, vital signs, echocardiogram or 
multiple gated acquisition (MUGA) scan and electrocardiogram (ECG) parameters. 
 
2.2.2. Primary Efficacy Endpoint 
• ORR measured from baseline as the proportion of patients achieving a confirmed best 
overall response of complete response (CR) or partial response (PR) according to 
RECIST v1.1 based on local review. 
 


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2.2.3. Secondary Efficacy Endpoints 
• DoR measured from earliest CR or PR until first documentation of PD based on 
RECIST v1.1 or death due to any cause.  
• PFS defined as the time from first dose of study drug to first documentation of 
progressive disease (PD) based on RECIST v1.1, or to death from any cause. 
• 
OS defined as the time from first dose of study drug to death from any cause. 
 
2.2.4. Exploratory Endpoints 
• Values and changes from baseline in humoral and cellular immunogenicity including 
P467-specific antibodies, HER2-specific antibodies, vaccine-specific cytokine levels 
and regulatory and effector T and B cells. 
• Evaluation and Arm-specific associations of serum and biochemical markers of tumor 
progression and immunogenicity, including humoral and cellular responses, with 
measures of clinical response including ORR, OS, PFS and DoR. 
• Analysis of HER2/neu expression, PD-L1 expression and TMB in pre- and post-
treatment tumor biopsies/liquid biopsies (circulating tumor DNA [ctDNA]/next 
generation sequencing [NGS]). 
 
 


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3. 
STUDY DESIGN  
3.1 
Overall Study Design 
This study will evaluate safety and efficacy of HER-Vaxx in combination with chemotherapy 
(ramucirumab plus paclitaxel) or pembrolizumab in patients with metastatic GC (mGC)/GEJ 
cancer who have progressed on or after trastuzumab treatment. 
For Arm 2, all patients must be re-assessed for their HER2/neu status prior to enrollment into 
the study due to potential HER2/neu loss during their previous treatment with trastuzumab 
(Seo, 2019). Patients must have confirmed HER2/neu overexpression since last progression by 
tumor biopsy (post-progression fresh or archival tissue, or post-progression pathology report). 
Sponsor may approve inclusion based on liquid (blood-based, ctDNA/NGS) biopsy to assess 
patients’ HER2/neu positivity where tumor biopsy is not clinically indicated.  
The study will include 2 treatment Arms that will be independently assessed for their endpoints. 
• Arm 1: HER-Vaxx + chemotherapy (ramucirumab and paclitaxel)  
• Arm 2: HER-Vaxx + pembrolizumab  
 
Eligibility for Arm 1 requires patients with mGC/GEJ adenocarcinoma overexpressing HER-
2/neu who have progressed on or after trastuzumab in combination with chemotherapy as first 
line therapy;  patients that subsequently progressed on or after trastuzumab deruxtecan or 
another anti-HER2 treatment are eligible for enrolment in Arm 1.  Arm 1 eligibility does not 
depend on prior treatment with immune checkpoint inhibitors (ICIs).  
Eligibility for Arm 2 requires that patients be naïve to immune checkpoint inhibitors and have 
progressed on or after first line treatment with a HER-2 targeted therapy including trastuzumab 
in combination with standard of care chemotherapy.  
In both Arms, HER-Vaxx may continue independently of chemotherapy or pembrolizumab until 
treatment discontinuation criterion is met. In Arm 1, chemotherapy may continue independently 
until treatment discontinuation criterion is met if HER-Vaxx has been discontinued.  In Arm 2, 
pembrolizumab may continue independently of HER-Vaxx until treatment discontinuation 
criterion is met, for a maximum of 35 cycles (approximately 2 years). 
For each Arm, after 8 evaluable patients are enrolled (Stage 1), if 1 or more patients respond 
(i.e., experience CR or PR), an additional 7 evaluable patients will be enrolled in that Arm 
(Stage 2). If there are no responses in Stage 1, then preliminary anti-tumor activity in the group 
will not have been identified and no further patients will be enrolled in that Arm. If the arm 
continues to Stage 2, a total of 15 evaluable patients will be studied for that Arm. The Arm will 
be considered successful if ≥ 4 treated patients respond, and the arm may be expanded to enroll 
25 patients. This design is applied to each arm separately.  
Arm 1 requires a minimum of 5 of 8 patients in Stage 1 and additional 5 patients (i.e. 10 of the 
total 15 patients enrolled) in Stage 2 must have HER2/neu overexpression as assessed by the 
central lab or post-progression pathology report. 


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Arm 2 requires that all patients enrolled must have post-progression HER2/neu overexpression 
confirmed locally for eligibility and subsequently assessed by the central lab or post-
progression pathology report. 
Stage 1 of each arm will include a safety run-in phase with staggered enrollment, with the first 
3 patients receiving their first treatment dose at least 15 days apart. After 3 patients are treated 
with the combination and are considered evaluable for the safety run-in period as defined 
below, a SRC consisting of study investigators, , and Sponsor medical monitor will assess the 
combination to ensure an acceptable safety profile has been established before enrolling the 
remaining patients.  
The primary objectives are to evaluate safety as well as ORR independently for each treatment 
arm. Additional anti-tumor activity in terms of OS, PFS and DoR serve as secondary objectives. 
Exploratory objectives include biomarker evaluation and arm-specific associations of 
biomarkers, including humoral and cellular responses, with measures of clinical response 
including ORR, OS, PFS and DoR. 
The nextHERIZON study set up is provided in Figure 1. 
Figure 1. 
Study Schema 
 
Chemotherapy (ramucirumab 8 mg/kg IV on Days 8 and 22 of a 28-day cycle + paclitaxel 80 mg/m2 IV on Days 
8, 15, and 22 of a 28-day cycle). ORR = objective response rate; OS = overall survival; PFS= progression free 
survival; DoR = duration of response.   
3.1.1. Safety and HER2 Antibody Consideration 
Both Arms will include a safety run-in phase with staggered enrollment with the first 3 patients 
receiving their first treatment dose at least 15 days apart. After 3 patients are treated with the 
combination, and are considered evaluable for the safety run-in period as defined below, a SRC 
consisting of study investigators, , and Sponsor medical monitor will assess the combination to 
ensure an acceptable safety profile has been established before enrolling the remaining patients.  


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3.1.2. Safety Evaluation for Combination in Arm 1 and Arm 2  
Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab plus paclitaxel)  
This combination safety evaluation will be based on three evaluable patients at a single dose 
level of HER-Vaxx plus chemotherapy (ramucirumab plus paclitaxel). An initial 3 patients will 
be treated and observed for the occurrence of DLTs for a period of 29 days (including 3 doses 
of HER-Vaxx and at least 1 cycle of chemotherapy).  Safety data will be reviewed by the SRC 
before further patients are enrolled. 
Arm 2: HER-Vaxx in combination with pembrolizumab 
This combination safety evaluation will be based on three evaluable patients at a single dose 
level of HER-Vaxx plus pembrolizumab. An initial 3 patients will be treated and observed for 
the occurrence of DLTs for a period of 29 days (including 3 doses of HER-Vaxx and at least 
1 dose of pembrolizumab). Safety data will be reviewed by the SRC before further patients are 
enrolled. 
3.1.2.1. 
DLT Evaluation for both Arms 
Evaluation of DLTs and enrollment decisions in each Arm: 
• If less than one-third of evaluable patients experience a DLT (i.e., 0 out of 3, or 1 out 
of 6) recruitment into the Arm may proceed. 
• If 1 out of the first 3 patients experiences a DLT, 3 more patients will be entered into 
the Arm. If 0 of these 3 additional patients experience a DLT, recruitment into the Arm 
may proceed. 
• If a DLT is observed in one-third or more patients (i.e., 2 or more of 6 patients) 
recruitment into the Arm will be stopped. 
 
3.1.2.2. 
DLT Definition 
For the study, the occurrence of any of the following toxicities during the first 29 days will be 
considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related 
to study treatment administration: 
• Grade 3 or 4 cardiac toxicity 
• Grade 4 nonhematologic toxicity (not laboratory). 
• Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: 
o Grade 4 thrombocytopenia of any duration 
o Grade 3 thrombocytopenia associated with clinically significant bleeding 
• Any nonhematologic adverse event (AE) ≥ Grade 3 in severity should be considered a 
DLT, with the following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, 
nausea, or vomiting without use of anti-emetics or anti-diarrheals per standard of care; 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of 
care. 


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• Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
o Clinically significant medical intervention is required to treat the patients or 
o The abnormality leads to hospitalization, or 
o The abnormality persists for > 1 week. 
o The abnormality results in a Drug-induced Liver Injury (DILI)  
o Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc. 
• Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a 
single temperature of > 38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥ 38 degrees C (100.4 degrees F) for more than 1 hour 
o Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 
38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour, with life-threatening consequences 
and urgent intervention indicated. 
• Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
• Grade 5 toxicity. 
 
DLTs will be graded according to NCI- CTCAE version 5.0 (Appendix B). 
3.2 
Safety Review Committee  
Safety data from both Arms will be reviewed by the SRC on an ongoing basis for the duration 
of the study. 
The decision to continue enrollment or extend the safety run-in will be taken by the SRC after 
reviewing all available safety data (including DLTs) from the first 3 evaluable patients that are 
part of the safety run-in and have completed the DLT observation period. The safety run-in can 
be extended by another 3 patients, or all additional patients can be enrolled for Stage 1 based 
on the occurrence of DLTs. 
On an on-going basis, the SRC will review the safety data and make recommendations on the 
continuation of the study following the procedures outlined in the SRC charter. 
The SRC is comprised of study investigators and Sponsor medical monitor. All decisions will 
be documented in the form of minutes. 
Based on the review of available data on safety, the SRC will make recommendations regarding 
further conduct and the scientific and ethical integrity of the study. The SRC will provide one 
of the following recommendations: 
• Arm 1 / Arm 2 is to be continued  
• Arm 1 / Arm 2 is to be stopped 


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• Modification of the study to address safety and dosing issues. 
The Sponsor will act upon these recommendations as appropriate, i.e., the final decision will 
rest with the Sponsor. The Sponsor designee will notify the study team of the final decision 
regarding the SRC recommendations, including any actions to be taken. The study team will 
communicate the SRC recommendations and/or final decision of the Sponsor to all 
Investigators, the Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs) 
and the Food and Drug Administration (FDA), if applicable. Refer to SRC charter for details. 
3.3 
Measures to Minimize Bias 
This is an open-label non-randomized study; blinding and randomization are not applicable. 
3.4 
Duration of Patient Participation 
Study treatment will continue until disease progression (i.e., if in the opinion of investigator 
there is no clinical benefit of further treatment after radiographic progression), unacceptable 
toxicities, withdrawal from study treatment for other reasons, or death.  
The end of treatment (EoT) visit will be completed at least 30 (± 7) days after last study 
treatment. 
All patients will be followed for survival from date of End of Treatment (EoT) every 12 weeks 
(± 7 days) for up to 3 years. 


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4. 
STUDY PATIENT POPULATION 
4.1 
Inclusion Criteria 
Patients must meet all the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Informed of the investigational nature of this study and provided written informed 
consent for the study in accordance with institutional, local, and national guidelines; 
2. Age ≥ 18 years of age on day of signing informed consent; 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 
4. Life expectance of a minimum of 3 months; 
5. Confirmed diagnosis of advanced or metastatic HER2/neu overexpressing gastric or 
GEJ adenocarcinoma;  
6. Progressed on or after trastuzumab therapy in combination with standard of care 
chemotherapy as first line therapy:   
a. Arm 1 only: Patients who subsequently progressed on or after trastuzumab 
deruxtecan or another anti-HER2 treatment are eligible. Prior therapy with ICIs 
is allowed, however eligibility does not depend on prior treatment with ICIs.  
b. Arm 2 only: Patients must be naïve to ICIs. 
7. At least one measurable lesion as defined by RECIST v1.1 criteria and assessed by the 
local investigator; 
8. Arm 1 only: Patients with documented HER-2 positivity at diagnosis. A post-
progression tumor biopsy (post-progression fresh or archival tissue) or post-progression 
pathology report should be provided for a minimum of 5 of 8 patients in Stage 1 and 10 
of total 15 after completion of Stage 2 are required;  Arm 2 only: HER2/neu 
overexpression (3+ by immunohistochemistry [IHC] or if IHC 2+ confirmed by 
fluorescent in situ hybridization [FISH], brightfield double in situ hybridization 
[BDISH] or chromogenic in situ hybridization [CISH]) using post-progression fresh or 
archival tissue, or post-progression pathology report. Sponsor may approve use of 
liquid (blood-based) biopsy where tumor biopsy is not clinically indicated; 
9. Adequate left ventricular ejection function at baseline, defined as left ventricular 
ejection fraction (LVEF) > 50% by echocardiogram or MUGA scan; 
10. Adequate hematologic function:  
a. Absolute neutrophil count (ANC) ≥ 1500/µL 
b. Platelet count ≥ 100 000/µL 
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
Note: Criteria must be met without packed red blood cell (pRBC) transfusion 
within the prior 2 weeks. Patients can be on stable dose of erythropoietin 
(≥ approximately 3 months); 
11. Adequate hepatic function: 
a. Total bilirubin ≤ 1.5 x upper limit of normal [ULN] OR direct bilirubin ≤ ULN 
for patients with total bilirubin levels > 1.5 ULN; 


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b. Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN 
if no liver involvement or ALT and AST ≤ 5 x ULN with liver involvement; 
12. Adequate renal function: creatinine ≤ 1.5 x ULN OR measured or calculated creatine 
clearance (GFR can also be used in place of creatinine or creatinine clearance (CrCl) as 
calculated by institutional standards) ≥ 30 mL/min for patients with creatinine levels 
> 1.5 × institutional ULN; 
13. Male patients must agree not to donate sperm and to use a highly effective method of 
contraception throughout the study and for at least 180 days after the last dose of 
assigned treatment. Females (childbearing potential) must agree to use a highly 
effective method of contraception throughout the study and for at least 180 days after 
the final dose of HER-Vaxx, at least 92 days after the final dose of ramucirumab, at 
least 120 days after the final dose of pembrolizumab, and for 180 days after the final 
dose of paclitaxel. A patient is of childbearing potential if, in the opinion of the 
Investigator, she is biologically capable of having children and is sexually active. 
14. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP)  
b. A WOCBP who agrees to use highly effective method of contraception during 
the treatment period and for at least 180 days after the final dose of HER-Vaxx, 
at least 92 days after the final dose of ramucirumab, at least 120 days after the 
final dose of pembrolizumab, and for 180 days after the final dose of paclitaxel; 
 
15. Willing and able to comply with all aspects of the protocol. 
 
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. 
Prior therapy for advanced Gastric Cancer within 14 days or major surgery within 
28 days prior to Day 1;  
a. Patients must have recovered from all adverse events (AEs) due to previous 
therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy 
may be eligible. Patients with endocrine-related AEs Grade ≤ 2 requiring 
treatment or hormone replacement may be eligible; 
b. If participant has received major surgery, they must have recovered adequately 
from the procedure and/or complications from the surgery prior to starting 
study treatment;  
2. 
Has received prior radiotherapy within 2 weeks of start of study treatment or have had 
a history of radiation pneumonitis;  
Note: Participants must have recovered from all radiation-related toxicities. Three 
months of clinical stability is required post radiotherapy for CNS disease. 
A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) 
to non-central nervous system (CNS) disease; 


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3. 
Arm 2 only:  Has received prior therapy with Immune Checkpoint Inhibitors (e.g. anti-
PD-1, anti-PD-L1, anti-PD-L2); 
4. 
Previous malignant disease (other than primary malignancy) within the last 5 years, 
except basal or squamous cell carcinoma of the skin or cervical carcinoma in situ; 
5. 
Concurrent active malignancy except for adequately controlled limited basal cell 
carcinoma of the skin; 
6. 
Clinically significant cardiovascular disease, or other diseases that in the Investigator’s 
opinion may influence the patient’s tolerance to study treatment; 
7. 
Pleural effusion or ascites requiring more than weekly drainage; 
8. 
Known allergy to any of the study medications, their analogues, or excipients; 
9. 
Prior organ transplantation, including allogenic stem-cell transplantation; 
10. Chronic immunosuppressive therapy including, but not exclusively, steroids 
(a maximum of 10 mg prednisone a day or equivalent is permitted) or any other form 
of immunosuppressive therapy within 7 days prior the first dose of study drug; 
11. Active, known, or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll; 
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease; 
13. Serious medical or psychiatric illness that could, in the Investigator’s opinion, 
potentially interfere with the completion of the treatment according to the protocol. 
Patients with known alcohol or drug abuse are not eligible;  
14. Known history of human immunodeficiency virus (HIV) infection or Hepatitis B 
(defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis 
C virus (defined as HCV Ribonucleic acid (RNA) [qualitative] is detected) infection;  
Note: No testing for HIV, Hepatitis B and Hepatitis C is required unless mandated 
by a local health authority.  
15. Current participation or has participated in a study of an investigational agent or has 
used an investigational device within 3 weeks prior to the first dose of study treatment; 
Note: Patients who have entered the follow-up phase of an investigational study may 
participate as long as it has been 3 weeks after the last dose of the previous 
investigational agent. 
16. Any vaccination within 14 days prior to starting study treatment; Arm 2 only: Planned 
live or attenuated vaccinations. 
17. Pregnant or lactating females; 
18. Documented hypersensitivity to any component of study treatment or excipients. 
 


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4.3 
Contraception Guidelines  
All male and female patients who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and for 
at least 180 days after the final dose of HER-Vaxx, at least 92 days after the final dose of 
ramucirumab, at least 120 days after the final dose of pembrolizumab, and for 180 days after 
the final dose of paclitaxel.  The investigator, in consultation with the patient, will select the 
most appropriate method of contraception for the individual patient from the permitted list of 
contraception methods, and instruct the patient in its consistent and correct use.  The 
investigator, at each study visit, will confirm and document consistent and correct use.  In 
addition, the investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.   
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and 
include (refer to 2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf):  
1. Established use of oral, injected or implanted hormonal (combined estrogen and 
progestogen containing or progestogen-only) methods of contraception. 
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS). 
3.  Male sterilization with appropriately confirmed absence of sperm in the post-
vasectomy ejaculate. 
4. Bilateral tubal occlusion 
5. Sexual abstinence. 
4.3.1. Use in Nursing Women 
It is unknown whether pembrolizumab or HER-Vaxx 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, patients who are breastfeeding are not eligible for enrollment. 


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5. 
TREATMENT, PATIENT, STUDY AND SITE DISCONTINUATION  
5.1 
Study Treatment Discontinuation 
Patients may be permanently discontinued from study treatment if they experience any of the 
following: 
• Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
• Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
• Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• Use of another non-protocol anti-cancer therapy 
• Pregnancy 
• Loss of clinical benefit as determined by the investigator after an integrated assessment 
of radiographic and biochemical data, local biopsy results (if available), and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease)  
Note: Patients may discontinue study treatment and be withdrawn from the study 
based on symptomatic clinical disease progression without documented radiographic 
evidence after discussion with the Sponsor / Medical Monitor 
• Radiographic disease progression per RECIST v1.1 or symptomatic deterioration 
attributed to disease progression 
Note: Therapy may continue beyond progression if the treating physician feels that 
the patient is deriving benefit. A repeat early scan will be done 4 weeks after this 
determination to verify the patient’s status.  
• Contraindications to Repeated Administration of HER-Vaxx 
If any of the following AEs arise during the study they constitute contraindications to 
further administration of HER-Vaxx, and patients should discontinue HER-Vaxx 
treatment permanently and be withdrawn from the study immediately, with appropriate 
safety follow-up by the investigator until resolution of the event, as with any AE (see 
Section 8): 
• 
Anaphylactic reaction following the administration of vaccine(s). 
• 
Any clinically relevant immunosuppressive or immuno-deficient condition. 
 
The following events constitute contraindications to administration of HER-Vaxx. If an 
adverse event, the event must be reported and the patient followed as with any adverse event. 


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Withdrawal of patients experiencing the following events is at the discretion of the investigator 
as indicated below: 
• Acute illness at the time of vaccination 
o Acute illness is defined as the presence of a moderate or severe illness with or 
without fever. All vaccines can be administered to persons with a minor illness 
such as diarrhea, mild upper respiratory infection with or without low-grade 
febrile illness, i.e., temperature < 38°C.  
o Withdrawal is at the discretion of the investigator if acute illness will not resolve 
in sufficient time to allow for vaccination schedule to continue. 
• Temperature > 38°C at the time of vaccination 
o Withdrawal is at the discretion of the investigator if raised temperature will not 
resolve in sufficient time to allow for vaccination schedule to continue. 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate electronic case report form (eCRF).   
5.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, the 
following: 
• Patient withdrawal of consent 
• Study termination or site closure 
• Adverse event 
• Loss to follow-up 
 
Every effort should be made to obtain a reason for patient discontinuation from the study.  The 
primary reason for discontinuation from the study should be documented on the appropriate 
eCRF.   
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
5.3 
Study Discontinuation 
The Sponsor has the right to terminate this study or each Arm independently at any time.  
Reasons for terminating the study may include, but are not limited to, the following: 
• A decision by the Sponsor to suspend or discontinue testing, evaluation, or development 
of the product. If the SRC recommends, based on review of the safety or effectiveness 
data, that the risks of study treatment exceed its potential benefit to study patients, the 
Sponsor may decide to terminate all patient treatment in this study. 


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• The decision by the Sponsor to discontinue the study based on the response 
observations associated with the 2-Stage design of this study, for both Arms 
independently (Section 9.4).  
• The SRC may at any moment recommend temporary suspension of enrollment and 
treatment of patients in this study. 
• Occurrence of a second DLT in any Arm during the DLT period will result in study 
stop and safety review by the SRC.  
• Occurrence of a Grade 5 HER-Vaxx (IMU-131) or combination related adverse event. 
• Occurrence of an AE meeting DLT criteria for hematological and non-hematological 
events in more than one-third of enrolled patients or two Grade 4 adverse events and at 
least possibly related to HER-Vaxx or the combination of HER-Vaxx and 
pembrolizumab (as per Section 3.1.2).  
 
Immune related AEs will be monitored throughout the study as per National Comprehensive 
Cancer Network® [NCCN] guideline insights (Thompson, 2020). 
• Immune related AEs: any Grade ≥ 3 event that does not resolve to Grade 1 (or baseline) 
within 7 days from the onset of the event, or any Grade ≥ 3 organ toxicity involving 
major organ systems that persists for greater than 72 hours, or any Grade ≥ 4 event will 
be reviewed and the SRC together with the Sponsor will decide on: 
o Halting patient dosing or study enrollment until the toxicity data can be further 
studied  
o Evaluating additional patients in a particular Arm to make the study more 
sensitive to characterizing adverse events 
o Exclusion of certain patients thought to be more at-risk for a particular adverse 
event. 
 
The identification of a study-stopping for HER-Vaxx criterion in a patient will result in the 
permanent discontinuation of this patient and enrollment into the affected arm will be 
temporarily held until an appropriate evaluation of the cause of toxicity has been determined 
and a corrective action plan is established if needed.  Under the condition, that any DLTs are 
classified as possibly related to HER-Vaxx, the investigators will decide on continuation of the 
study after consultation of the SRC, in mutual agreement with the Sponsor.  
The Sponsor medical monitor should be notified immediately i.e. within 24 hours of learning 
of their occurrence, and the patient should be followed for safety as clinically indicated until 
the toxicity resolves and, in the opinion of the investigator, no further follow-up regarding the 
toxicity is needed (minimum of at least 30 days after last dose of HER-Vaxx). 
The Investigator will be notified by the Sponsor if the study is terminated or placed on hold. 
The relevant IRBs/IECs and FDA will also be informed according to appropriate regulatory 
requirements. 


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If the study is prematurely terminated or suspended for any reason, the Investigator/Institution 
should promptly inform the study patients and should assure appropriate therapy and follow-
up for the patients. 
Enrollment in an Arm will be terminated if no responses are observed in the first 8 evaluable 
patients within an Arm as per Section 9.4 or 9.7. 
5.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may include, 
but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 


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6. 
STUDY TREATMENT 
6.1 
Manufacturing and Labelling  
6.1.1. Vaccine Supply 
The aqueous phase vaccine (P467-CRM197) is manufactured by PiChem Forschungs- und 
Entwicklungs GmbH, Austria. The adjuvant (Montanide ISA 51 VG) is manufactured by 
Elaiapharm, France. 
The Quality Control Standards and Requirements for the aqueous phase vaccine 
(P467-CRM197) and the adjuvant (Montanide ISA 51 VG) are described in separate release 
protocols/Certificate of Analysis and the required approvals have been obtained. 
6.1.1.1. 
Formulation and Packaging 
The investigational product, HER-Vaxx, will be supplied as P467-CRM197 (aqueous phase 
vaccine) and Montanide ISA 51 VG (adjuvant). P467-CRM197 is supplied as a single vial of 
200 μg aqueous phase vaccine in 1 mL PBS buffer. Montanide is supplied as single 3 mL vial 
of Montanide ISA 51 VG. 
Arm 1: Chemotherapy (ramucirumab plus paclitaxel) will be sourced or reimbursed by the 
Sponsor if required by local health authority regulations or institutional policy.  
Arm 2: Pembrolizumab is an investigational medicinal product (IMP) and will be provided or 
reimbursed by the Sponsor as required by local health authority regulations. 
6.2 
Preparation and Dispensing 
Preparation of IMU-131 should be completed by appropriately trained and qualified pharmacy 
or site staff. Training and qualification will be provided by the Sponsor or their delegate and 
documented in the study file.  
Detailed IMU-131 preparation and dispensing instructions can be found in the pharmacy 
manual. A droplet test will be used to confirm IMU-131 has been prepared correctly. 
Chemotherapy (ramucirumab plus paclitaxel) will be administered IV per SOC and 
Investigator assessment.  
Pembrolizumab for injection will be prepared for IV administration as per SmPC/label. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
6.3 
Dose Selection 
6.3.1. Dose Selection HER-Vaxx 
The dose of HER-Vaxx to be used in combination with chemotherapy or pembrolizumab will 
100 µg.  


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A 1.0ml volume of HER-Vaxx will be administered Intramuscular(ly) (IM) as per the Schedule 
of Activities until treatment discontinuation criterion is met. The dose and dosing schedule 
have been selected based on available data from the IMU.ACS.001 study and are designed to 
compare booster dose schedules (ie., doses administered after first 3 doses) on production of 
HER2 specific antibodies.  
6.3.2. Dose Selection Chemotherapy 
Ramucirumab plus paclitaxel is now approved as a second-line treatment option for patients 
with metastatic gastric cancer, who failed first-line treatment with platinum- and 
fluoropyrimidine-based combinations or trastuzumab in combination with cisplatin and 
5-fluorouracil/cisplatin and capecitabine. Patients in Arm 1 will receive intravenous (IV) 
administration of chemotherapy (ramucirumab 8 mg/kg IV+ paclitaxel 80 mg/m2 IV) as per 
the Schedule of Activities.  
6.3.3. Dose Selection Pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W) as per the 
Schedule of Activities.  
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is 
an appropriate dose of pembrolizumab for adults across all indications. As outlined below, this 
dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer 
(NSCLC) indications demonstrating flat dose- and exposure-efficacy relationships 
from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) representing an approximate 5 
to 7.5 fold exposure range  
• Population pharmacokinetic (PK) analysis showing that both fixed dosing and weight-
based dosing provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 
• 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 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 patients 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 


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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 patient 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 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols. 
6.3.4. Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent immunologic etiology. These 
Immune related AEs (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. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 3.  


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Table 3. 
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are 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 V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Pneumonitis  
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
• 
Monitor patients for 
signs and symptoms 
of pneumonitis 
• 
Evaluate patients 
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 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
• 
Monitor patients 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) 
• 
Patients with 
≥Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 


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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
• 
Patients 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 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
0.5 to 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1 to 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 β-cell 
failure 
Withhold d 
• 
Initiate insulin 
replacement 
therapy for 
patients with 
T1DM 
• 
Administer 
antihyperglycemc 
in patients with 
hyperglycemia 
 
• 
Monitor patients 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 
nonselective 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 


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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) 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 to 2 mg/kg or 
equivalent) 
followed by taper 
• 
Monitor changes of 
renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinue 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude other 
causes 
• 
 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology or 
exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
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 
event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 
to 10.0 x ULN if baseline normal; >3.0 to 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: encephalitis and other clinically important 
irAEs (eg. vasculitis and sclerosing cholangitis). 
 


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6.3.5. 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. The 
dose of pembrolizumab will remain constant at 200 mg Q3W. However, dose modification 
(interruption) and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 4. 
Table 4. 
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 patients 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 patients 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 
patients should be 
premedicated for the next 
scheduled dose. 
Patients who develop Grade 2 
toxicity despite adequate 
premedication should be 
Patients may be premedicated 
1.5 h (± 30 minutes) prior to 
infusion of study intervention 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 


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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
permanently discontinued 
from further study drug 
treatment 
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 patients is deemed 
medically stable in the 
opinion of the investigator. 
• 
Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Patients 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 v5.0 (CTCAE) at http://ctep.cancer.gov. 
 
6.3.6. 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.  


Investigational Product: 
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Protocol Identifier: 
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6.3.7. Dose Interruption for HER-Vaxx 
In case of an unexpected immune related Grade 3 and higher AE, the subsequent dose of HER-
Vaxx should be held until the AE has returned to Grade 1 or resolved. HER-Vaxx can be 
restarted with the approval of the Sponsor. Discuss any HER-Vaxx dose interruption due to 
chemotherapy interruptions with Sponsor. 
6.3.8. Dose Interruption for Chemotherapy 
Dose adjustments, delays, and discontinuation based on AEs, patient’s condition, and 
cumulative toxicities are permitted for the clinical care of the patient at the discretion of the 
Investigator. 
6.4 
Administration 
HER-Vaxx will be administered IM into the deltoid region of the upper arm with a 25-38 mm 
(1-1.5 inches), 21-23G needle as per the Schedule of Activities until treatment discontinuation 
criterion is met. HER-Vaxx will be administered at least 48 hours prior to initiation of 
chemotherapy or at least 30-60 minutes prior to the administration of pembrolizumab 
depending on assigned Arm (when scheduled on the same day).  
Arm 1:  
Patients will receive intravenous (IV) administration of chemotherapy (ramucirumab 8 mg/kg 
IV + paclitaxel 80 mg/m2 IV) as per the Schedule of Activities (Table 1). Chemotherapy will 
be administered at least 48 hours after the administration of HER-Vaxx (when scheduled on 
the same day). Premedication and concomitant medications should be administered as per 
institutional standard practice, with a limit of 24 mg dexamethasone (or equivalent) per 
chemotherapy cycle with a maximum of 8 mg/d during chemotherapy administration. Dose 
adjustments and delays, and discontinuation based on AEs, patient’s condition, and cumulative 
toxicities are permitted for the clinical care of the patient at the discretion of the investigator. 
Patients will receive chemotherapy for as long as clinically indicated. HER-Vaxx may continue 
after termination of chemotherapy until discontinuation criteria is met.  
Body weight will be determined prior to the start of treatment. Body surface area ([BSA]: based 
on weight and baseline height) will be calculated prior to starting chemotherapy. Dose 
modification will be required for > 10% change in BSA, unless the investigator considers this 
not appropriate. 
Arm 2:   
Patients will receive 200 mg pembrolizumab IV as per the Schedule of Activities (Table 2) at 
least 30-60 min following the administration of HER-Vaxx (when scheduled on the same day) 
and will continue treatment until treatment discontinuation criterion is met. Dose modifications 
for HER-Vaxx are not planned and need to be agreed by the Sponsor. Dose modifications for 
pembrolizumab are based on immune mediated adverse reactions and/or infusion-related AEs. 
No dose reduction for pembrolizumab is recommended. In general, withhold pembrolizumab 
for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue 
pembrolizumab for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent 
severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive 


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treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating steroids (see Sections 6.3.4 and 6.3.5 above).  
The interventions to be used in Arm 2 of this study are outlined below (Table 5): 
Table 5. 
List of Interventions Arm 2   
Intervention 
Name 
Dosage 
Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Regimen/Treat
ment Period 
Sourcing 
Pembrolizumab  Solution for 
infusion 
100 mg/vial 
200 mg 
Q3W 
IV infusion 
Until end of trial 
or confirmed 
PD, 
unacceptable 
toxicity, death 
or 
discontinuation 
for any other 
reason for a 
maximum of 35 
treatment 
cycles. 
Provided by 
the Sponsor 
or 
reimbursed if 
sourced 
locally 
HER-Vaxx 
Solution for 
injection 
See Section 6.2 
IM  
See Section 6.3 
Provided by 
the Sponsor 
 
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). 
HER-Vaxx may continue independently until treatment discontinuation criterion is met if 
pembrolizumab is discontinued.  
6.5 
Compliance 
Study site staff are responsible for administration of HER-Vaxx and chemotherapy or 
pembrolizumab. To monitor HER-Vaxx compliance, confirmation of successful preparation 
by droplet test will be documented prior to each administration of HER-Vaxx and the exact 
volume and dose administered will be recorded in the CRF. 
6.6 
Treatment of Overdose Arm 2 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.  
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the patients should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 


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6.7 
Meals and Dietary Restrictions 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
6.8 
Drug Storage and Drug Accountability 
The vaccine and adjuvant must be stored in a safe and locked place with no access for 
unauthorized personnel. 
The peptide antigen P467-CRM197 must be kept frozen until use in a freezer at < -15°C. 
The adjuvant Montanide ISA 51 VG must be stored in a refrigerator at + 2 to + 8°C. 
Storage conditions stated in the Investigator Brochure (IB) may be superseded by the label 
storage conditions. Ensure the label is always checked for correct storage conditions.  
Storage of chemotherapy (ramucirumab plus paclitaxel) and pembrolizumab is as per 
SmPC/label for each drug. 
IMP’s will be disposed of at the study site according to the study site’s institutional standard 
operating procedure or returned to the Sponsor (or Sponsor’s delegate) with the appropriate 
documentation. The site’s method of IMP destruction must be agreed upon by the Sponsor. 
Local or institutional regulations may require immediate destruction of used investigational 
medicinal product for safety reasons. The site must obtain written authorization from the 
Sponsor before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.  Further guidance and information for the final disposition of unused study 
treatment is provided in the Pharmacy Manual.  
6.9 
Concomitant Medications 
6.9.1. Permitted Medications 
Participants will follow their oncology care plan. All medications required as part of a 
participant’s normal clinical care for support of their medical conditions are permitted during 
the study, with the exception of prohibited medications listed in Section 6.9.2. All concomitant 
medications must be recorded in the source documentation and in the CRFs for the duration of 
patient participation. 
Treatment with an oral corticosteroid, such as dexamethasone, up to 8 mg daily (24 mg 
maximum) during each chemotherapy cycle is allowed if required but may impact the 
development of HER2/neu antibodies. 
Permitted medications include, but are not limited to: 
1. Anti-emetics or anti-diarrheal agents as required 
2. N-acetyl-para-aminophenol drugs (APAP, [paracetamol/acetaminophen]) 
3. Nonsteroidal anti-inflammatory drugs (NSAIDs) 


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Protocol Identifier: 
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The use of APAP and NSAIDs should be assessed on a per-patient basis. Guidelines for the 
use of paracetamol (acetaminophen) and NSAIDs are as follows:  
• Paracetamol 
o Paracetamol may be used for the treatment and first signs of flu-like signs and 
symptoms, that may be associated with HER-Vaxx vaccination.  
o Dosing of paracetamol: The recommended dose is 500 or 1000 mg every 6 to 
8 hours.  
o The MAXIMUM daily (24-hour) dose must NOT exceed 3000 mg and requires 
adequate hepatic function.  
• NSAIDs 
o The decision to use oral NSAID should be made for each individual patient, 
with attention to the patient’s renal and hydration status at the time of HER-
Vaxx administration or the time of imaging scans with contrast.  
o Dosing of NSAIDs (e.g., oral ibuprofen, other NSAIDs permitted): The 
recommended dose is 400 or 600 mg ibuprofen (or an equivalent dose for 
other NSAIDs) every 8 hours.  
o The MAXIMUM daily (24-hour) dose must NOT exceed 1800 mg ibuprofen 
(or an equivalent dose for other NSAIDs) and for a total of two days only. 
6.9.2. Prohibited Medications 
The following medications/treatments are prohibited during the study:  
• Other investigational drug. 
• Continuous systemic treatment with either corticosteroids or other immunosuppressive 
medications unless required to treat an immune adverse event.  
o Note: inhaled or topical steroids and physiological replacement doses of up to 
10 mg daily prednisone equivalents are permitted. 
• Total doses greater than 24 mg dexamethasone equivalent of oral corticosteroids per 
chemotherapy cycle. 
• Both treatment Arms: Any vaccination within 30 days prior to any study treatment and 
during first treatment cycle.  
• Arm 2 only: Live or live attenuated vaccines while participating in the study are not 
allowed.  
o Note: Inactivated vaccines are allowed after the first treatment cycle. 
 
o 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. 


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Protocol Identifier: 
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o Investigational vaccines (i.e., those not licensed or approved for Emergency Use) 
are not allowed. 
• Other anti-cancer therapy (i.e. chemotherapy; hormonal therapy; extensive, non-palliative 
radiation therapy, or standard or investigational agents). 
• Immunotherapy not specified in this protocol. 
If the investigator determines that a patient requires any of the aforementioned treatments for 
any reason, HER-Vaxx plus chemotherapy or pembrolizumab must be discontinued.   
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. 
6.10 
Method of Assigning Patients to Treatment 
Eligible patients (see Section 4) will receive HER-Vaxx plus chemotherapy (Arm 1) or 
HER-Vaxx plus pembrolizumab (Arm 2) in this study based on their prior treatment as outlined 
in the inclusion and exclusion criteria in Section 4.   
Once patients are assigned to Arm 1 or 2, patients will be assigned to treatment based on order 
of enrolment.  
6.11 
Patient Enrollment  
All patients will sign the informed consent form (ICF), after being properly informed about the 
study, and subsequently undergo the screening assessments. Patients who do not meet all 
inclusion criteria or who meet any of the exclusion criteria are not eligible for study entry 
(screen failures). As soon as a patient is deemed ineligible during screening, all further study 
evaluations will be cancelled for this patient.  
Each patient will receive a unique number, which is assigned by the site during the screening 
visit and will be used throughout the study.  
All patients, including screening failures, are added to the eCRF  by site staff/Sponsor designee. 
6.12 
End of Study 
End of Study in all participating countries is defined as the date the last patient completes the 
Survival Follow-up Visit. 


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7. 
INVESTIGATIONAL PLAN 
Study procedures and their timepoints are summarized in the Schedule of Activities for each 
arm (Table 1 & Table 2).  
It is the investigator’s responsibility to ensure that the Schedule of Activities is strictly 
followed. Every attempt should be made to complete all study visits as outlined in the Schedule 
of Activities. All missed study visits and visits outside the visit window are considered protocol 
deviations. 
7.1 
Screening 
Patients agreeing to participate in the study will sign the informed consent documents. The 
reason for all screen failures will be documented. The screening assessments should occur 
within 21 days prior to starting treatment on Day 1. 
Screening can occur across multiple clinic visits within the 21-day screening period. At the 
first screening visit the patient will be asked to provide consent and the inclusion/exclusion 
criteria will be checked. All other screening procedures can be conducted at subsequent 
screening visits.  
Patient laboratory results that do not meet the eligibility criteria may be repeated within the 
Screening Period. 
7.2 
Re-Screening 
Patients may be re-screened in the following situations:  
• Drug supply not available at site 
• Unable to attend/schedule first dose visit  
• Tests or procedures are not completed in screening period (i.e., patients who miss their 
21-day screening window).   
For any other situation, agreement must be obtained from Imugene Limited before performing 
re-screening. 
A new ICF must be signed before re-screening can commence. Re-screened patients will keep 
the same screening number. Screening procedures and test results/eligibility checks will be 
updated as part of re-screening. 
7.3 
Screen Failures and Replacement of Patients  
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details and eligibility criteria. These data will be entered 
into the CRF. 


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A patient who misses the first administration of HER-Vaxx for reasons other than safety will 
be replaced.  
For the purpose of the primary analysis set for analyses of response-based anti-tumor activity 
endpoints, in Arm 1 and 2, patients who withdraw before at least one evaluable post-baseline 
tumor response assessment as per RECIST 1.1 for reasons other than toxicity will be replaced.  
In Arm 1, a safety run-in patient may be replaced if the patient does not receive all three 
HER-Vaxx injections and at least 1 cycle of chemotherapy, for reasons other than toxicity 
during the DLT observation period. 
In Arm 2, a safety run-in patient may be replaced if the patient does not receive all three 
HER-Vaxx injections and at least 1 dose of pembrolizumab for reasons other than toxicity 
during the DLT observation period. 
No replacement will occur for patients who withdraw later, for both Arms. 
7.4 
End of Treatment 
The End of Treatment (EoT) visit will be completed at least 30 (± 7) days after the last 
administration of any study treatment.  
7.5 
Survival Follow-Up  
After discontinuation of study treatment and completion of the End of Treatment visit, anti-
cancer therapy and survival information will be collected every 12 weeks (± 7 days) for up to 
3 years or until death (follow-up via phone call allowed). A blood sample for humoral 
immunity assessment is planned every 12 weeks for up to 1 year. Anti-cancer therapy and 
survival information may be collected more frequently than every 12 weeks for quality control 
and data cleaning purposes. After discontinuation from the study for any reason other than 
disease progression, radiographic change will be collected every 12 weeks until determination 
of progressive disease. 
All patients will be followed for radiographic change until determination of progressive disease 
and survival information and anti-cancer treatment until death, unless the patient requests to be 
withdrawn from radiographic change assessment and survival follow-up contact. This request 
must be documented in the source documents and signed by the Investigator. 
7.6 
Unscheduled Visit 
Unscheduled visits may be conducted at any time during this study by the Investigator if 
clinically indicated for the care of the patient.  
An unscheduled visit may include any of the protocol required assessments listed in 
Section 7.3. The exact assessments conducted at the unscheduled visit will be specified by the 
investigator and recorded in the CRF. Additional tests and procedures may be performed at the 
unscheduled visit for the clinical care of the patient after discussion with, and agreement of, 
the medical monitor. 


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7.6.1. Assessments via Telemedicine 
Telemedicine uses advanced telecommunication technologies to exchange health information 
and provide health care services across geographic, social, and other barriers. Where 
circumstances allow, and where additional flexibility is required due to restricted patient access 
to the study clinic or personnel, telemedicine technology may be used to collect study data to 
supplement study assessments. For example, visits may be conducted over several days within 
each visit window, with suitable assessments being completed using telemedicine technology 
with the remaining assessments being completed during a physical clinic visit. Examples of 
study assessments which may be completed using telemedicine technology include 
documenting concomitant treatments and adverse events, ECOG performance status, and 
survival follow-up. 
7.6.2. Demographic Data and Medical History 
Medical history, including clinically significant diseases, surgeries, cancer history (including 
prior cancer therapies and procedures), cardiovascular history, reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline. In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to treatment. At the 
time of each follow-up physical examination, an interval medical history should be obtained 
and any changes in medications and allergies should be recorded.  
Demographic data will include age, sex, and self-reported race/ethnicity. 
7.6.3. Physical Examination  
A complete physical examination will include an evaluation of body systems 
(e.g., cardiovascular, gastrointestinal, neurological, head and neck, respiratory, dermatology). 
After Cycle 1, Day 1 a limited, symptom-directed physical examination is allowed at the 
investigator’s discretion. The physical examination should occur prior to study treatment.  
7.6.4. Height, Weight & Vital Signs  
Body height (at screening visit only), weight, and vital signs (blood pressure, respiratory rate, 
heart rate and temperature) will be measured prior to receiving study treatment as per the 
timepoints in the Schedule of Activities. Temperature to also be recorded 30 min (± 10 mins) 
after each HER-Vaxx vaccination. 
7.6.5. Radiographic Assessment 
Computed Tomography (CT) scan of the chest abdomen and pelvis with contrast should be 
performed. MRI of the abdomen and pelvis with contract and non-contrast CT chest may be 
done in patients with iodine contrast dye allergy or if lesions cannot be visualized on CT scan. 
The same radiographic procedure used to assess disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT scans). Assessments should be 
performed by the same evaluator, if possible, to ensure internal consistency across visits. 
For all patients a radiographic assessment will be performed at Baseline (assessment allowed 
up to 14 days before Day 1 Visit), followed by every 6 weeks until disease progression. After 


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discontinuation from the study for any reason other than disease progression, radiographic 
change will be collected every 12 weeks until determination of progressive disease. Tumor 
assessments must be performed independently of changes to the study treatment administration 
schedule (i.e., when treatment is withheld). If a tumor assessment has to be performed early or 
late, subsequent assessments should be conducted according to the original schedule based on 
the date of first study treatment administration on Day 1. Objective response (complete 
response or partial response) must be confirmed by repeat assessment at least 4 weeks after 
initially documented response. Assessment of the tumor will include evaluation according to 
RECIST 1.1. Upon PD, a scan may be scheduled 4 to 6 weeks after initial PD scan to confirm 
progression. If there are clear signs of progression, confirmation scan is not required.  
At screening, patient eligibility will require radiographic documentation of at least one lesion 
that meets the requirements for selection as a target lesion, as defined by RECIST 1.1, prior to 
patient enrollment. All scheduled scans for patients will be assessed locally and submitted to 
the central imaging vendor to confirm local assessment, if required. In addition, a scan that is 
obtained at an unscheduled time point, for any reason (including suspicion of progression or 
other clinical reason), should also be submitted to the central imaging vendor.   
7.6.6. Cardiac Assessment  
Cardiac assessment by the study Investigator will be based on assessment of 12-lead ECG 
results and evaluation of LVEF by echocardiography or MUGA scan as per the Schedule of 
Activities. Significant abnormal cardiac assessments should be evaluated by a cardiologist.   
7.6.7. Laboratory Assessments 
Hematology and serum chemistry analyses will be performed by an accredited local laboratory. 
Serum predication markers of tumor progression and intra-tumor T cell and biomarker analysis 
including NGS will be performed by an accredited central laboratory. Humoral and cellular 
immunological analysis will be performed by an accredited specialist central immunology 
laboratory. Additional details are provided in the study Laboratory Manual. 
Unused blood /serum and/or tissue samples collected during the study from patients who have 
signed an appropriate informed consent form may be stored and used for future research.  The 
coded samples may be used up to 15 years after the clinical study ends. A patient may contact 
the investigator to have their unused samples destroyed at any time during the storage period. 
Results from the future use studies will not be shared with patients. 
7.6.7.1. 
Safety Laboratory Assessments  
Blood samples of approximately 10 mL per visit for the assessment of hematological and serum 
chemistry parameters will be collected and processed in accordance with local laboratory 
procedures and reference ranges. These samples will be collected prior to administration of any 
study treatment. 
Safety laboratory panels are defined as follows: 
Human immunodeficiency virus (HIV 1/2 antibodies), hepatitis B (HBsAg reactive) and 
hepatitis C (HCV ribonucleic acid [RNA] qualitative) assessments are only required at 
screening if mandated by a local health authority. 


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Hematology:  
Local hematology testing to be collected prior to receiving any study treatment as per the 
Schedule of Activities. Local labs can be drawn up to 72 hours before any on-study clinic 
visit.  
Hematology to include complete blood count (CBC), including red blood cell (RBC) count, 
hemoglobin, hematocrit, reticulocyte count, white blood cell (WBC) count with differential 
(neutrophils, bands, eosinophils, basophils, lymphocytes, monocytes, and other cells), platelet 
count, and C-reactive protein (CRP).  
Serum Chemistry:  
Local serum chemistry testing to be collected prior to receiving any study treatment. Local labs 
can be drawn up to 72 hours before any on-study clinic visit.  
Blood urea nitrogen (BUN) or urea, creatinine, sodium, chloride, potassium, magnesium, 
bicarbonate, calcium, phosphorus, total protein, albumin, alkaline phosphatase, glucose, total 
bilirubin, direct and indirect bilirubin, lactate dehydrogenase (LDH), cholesterol, uric acid, 
triglyceride levels, gamma glutamyl transpeptidase (GGT), AST, and ALT.  
Thyroid Function Test:  
Thyroid stimulating hormone (TSH) and free thyroxine (free T4) to be performed as per the 
Schedule of Activities. Additional tests may be requested by the investigator in case of 
abnormal TSH and/or free T4.  
7.6.7.2. 
Exploratory Endpoint Laboratory Assessments  
A 10  mL whole blood sample to assess ctDNA and an additional 10 mL whole blood sample 
to assess NGS (liquid biopsy), vaccine-specific cytokine levels, soluble HER-2,  and in-vitro 
inhibition of tumor cell growth will be collected from each patient as per the Schedule of 
Activities. These samples will be taken prior to administration of any study treatment. 
7.6.7.3. 
Immunologic Assessments 
7.6.7.3.1. Humoral Samples  
A 10 mL whole blood sample for humoral immunity will be collected from each patient as per 
the Schedule of Activities. These samples will be taken prior to administration of any study 
treatment. Additional samples for humoral immunity will be collected every 12 weeks during 
survival follow up for up to 1 year. 
7.6.7.3.2. Cellular Samples  
A 40 mL blood sample will be collected for peripheral blood mononuclear cell (PBMC) 
isolation and analysis of cellular parameters as per the Schedule of Activities. These samples 
will be taken prior to administration of any study treatment. 


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7.6.8. HER2/neu Overexpression  
Arm 1 only: Documented HER-2 positivity at diagnosis is required. A post-progression tumor 
biopsy (post-progression fresh or archival tissue) or post-progression pathology report should 
be provided. A minimum of 5 of 8 patients enrolled in Stage 1 and an additional 5 in Stage 2 
must have HER2/neu overexpression as assessed by the central lab or post-progression 
pathology report.  
Arm 2 only: confirmation of HER2/neu overexpression since progression on or after 
trastuzumab is required for inclusion in this study due to potential HER2+ loss after 
trastuzumab treatment (Seo, 2009; Takashi, 2020). A previous pathology result confirming 
HER2/neu overexpression is acceptable as long it has been taken after progression on 
trastuzumab (Takashi, 2020). If analysis of a tumor biopsy is required for confirmation of 
HER2/neu overexpression, then this may be achieved via analysis of a fresh or archived tissue 
sample. HER2/neu analysis will be conducted at each center’s local pathology laboratory by 
IHC and FISH, BDISH, or CISH if IHC result is equivocal.  
Using the IHC method an unequivocal result of HER2 overexpression is defined as HER2 +++, 
an equivocal result is defined as HER2 ++, and a negative result is defined as HER2 +. If 
equivocal result (IHC HER2 ++) then additional analysis via FISH, BDISH or CISH will be 
conducted for confirmation of HER2 overexpression. The definition of FISH, BDISH or CISH 
positivity in gastric or gastro–esophageal junction cancer is a HER2: chromosome 17 ratio of 
≥2.0. Sponsor may approve inclusion based on liquid (blood based) biopsy to assess patients’ 
HER2/neu positivity where tumor biopsy is not clinically indicated. 
7.6.9. ECOG Performance Status  
The ECOG performance status should be determined using the criteria defined in Appendix A: 
ECOG Performance Status Scale at the time points specified in the Schedule of Activities. 
7.6.10. Pregnancy Test  
A highly sensitive urine pregnancy test (sensitivity of at least 25 mIU/mL) for all female 
patients of childbearing potential will be collected once per cycle prior to study treatment. If 
the urine pregnancy test is positive (or cannot be confirmed as negative), a serum pregnancy 
test will be required. If the serum pregnancy test is negative, then study treatment may resume.  
7.6.11. Tumor Biopsy 
A screening visit tumor biopsy (post-progression fresh or archival) or post-progression 
pathology report should be provided for patients in Arm 1 and must be obtained for all patients 
in Arm 2. Additional optional tumor biopsies may be collected as per the Schedule of Activities 
where a patient has consented to the additional tumor biopsies and it is feasible to perform the 
assessment. All tumor samples will be analyzed for intra-tumor T cells and biochemical 
markers (including PD-L1 detection by combined positive score [CPS] calculation). The 
screening visit biopsy sample may also be used to determine HER2/neu overexpression. 
 


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8. 
ADVERSE EVENT REPORTING 
All AEs in this study will be collected and processed in accordance with ICH - Good Clinical 
Practice (GCP) and national and local laws and regulations. In line with these regulations, the 
Investigator is responsible for reporting Serious adverse events (SAEs) to the Sponsor, within 
the appropriate timelines (see below). The Investigator is also responsible for notifying the 
appropriate IRBs/IECs of all unanticipated problems involving risk to human patients or others 
as per the guidelines of the Institution and in accordance with aforementioned laws and 
regulations. 
All observed or volunteered AEs regardless of treatment Arm or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections. All 
AEs will be collected in response to a general question about the patient’s well-being and any 
possible changes from the baseline or previous visit, but shall not be specifically solicited with 
respect to particular AEs. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Imugene Limited or its designated representative.   
For all AEs, sufficient information should be obtained by the investigator to determine the 
causality of the AE.  The investigator is required to assess causality.  AEs will be followed 
until resolved, stable, or until the patient’s last study visit or lost to follow-up.  If an AE is not 
resolved or stabilized at the patient’s last visit, it is up to the discretion of the investigator and 
the Sponsor’s medical monitor to determine if further monitoring of the event is warranted. 
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.    
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study.   
8.1 
Definition  
8.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical study patient administered 
with a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether 
or not considered related to the IMP used. All AEs reported by the patient or observed by the 
investigator or site staff will be recorded. 
Examples of AEs include but are not limited to:   
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 


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• Hypersensitivity; 
• Drug abuse; 
• Drug dependency. 
 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy; 
• Exposure via breastfeeding; 
• Medication error. 
 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF. Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs. 
8.1.2. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• Test result leads discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.1.3. Treatment-Emergent Adverse Event (TEAE) 
All AEs reported from the start of the study (Day 1) and until 30 days after the last HER-Vaxx 
dose (for Arm 2 also after last pembrolizumab dose) are considered TEAEs. 


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8.1.4. Serious Adverse Event (SAE) 
Any untoward medicinal occurrence or effect that at any dose: 
• Results in death (not due to disease progression);  
• Is life-threatening (the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe);  
• Requires hospitalization or prolongation of existing hospitalization;  
• Results in persistent or significant disability or incapacity;  
• Results in a congenital anomaly or birth defect. 
 
Any event or hospitalization which is unequivocally due to disease progression will not be 
considered an SAE and therefore, does not require reporting as is outlined in this section. These 
events and hospitalizations will still be reported as an AE.   
Hospitalization for elective treatment of a pre-existing condition that has not worsened from 
its original baseline level will not considered an SAE and therefore, does not require reporting 
as is outlined in this section. 
Any event that does not meet the above criteria may also be considered by the Investigator to 
be a SAE, based on appropriate medical and scientific judgment. This includes important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed in the definition above. 
SAEs will continue to be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.     
8.1.5. Adverse Events of Clinical Interest  
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) also referred to as Adverse Events of Special Interest (AESI) and must be reported to the 
Sponsor within 24 hours of awareness.  
LVEF will be measured by either echocardiogram (ECHO) or MUGA scan. All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for monitoring 
cardiac function. 
8.1.5.1. 
Potential Drug-Induced Liver Injury  
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin 
that meet the criteria outlined below in the absence of other causes of liver injury are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and should always be 
considered important medical events.   
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 


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present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
• Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT ≥ 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin ≥ 2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase ≤ 2 X ULN or not available. 
• For patients with pre-existing ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above: 
o For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT ≥ 2 times the baseline values and ≥ 3 X ULN, or ≥ 8 X LLN 
(whichever is smaller). 
• Concurrent with 
o For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or ≥ 3 times the 
lower limit of normal (whichever is smaller). 
 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.   
This evaluation should include laboratory tests, detailed history and physical assessment.  For 
oncology studies, the possibility of hepatic neoplasia (primary or secondary) should be 
considered.  In addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR, and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced patient, surgery, blood transfusion, history of liver or allergic disease, 
and work exposure, should be collected.   
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may 
be warranted.  
All cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs. 
8.1.5.2. 
Immune related Adverse Events 
If patients experience immune related adverse events (irAEs), then treatment and follow-up of 
these events should be according to guidance provided in “NCCN Guidelines Insights: 
Management of Immunotherapy-Related Toxicities, Version 1.2020 (Thompson, 2020) in 
addition to the specific guidance provided for patients treated with pembrolizumab (Sections 


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6.3.4 and 6.3.5).  Grade 3 or higher irAEs must be reported within 24 hours from when the 
investigator becomes aware of the event. 
8.1.6. Suspected Adverse Reactions (SAR) 
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable 
possibility that HER-Vaxx caused the adverse event. For the purposes of IND safety reporting, 
"reasonable possibility" means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
Adverse reactions are also referred to as toxicity. 
8.1.7. Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any serious adverse reaction where the nature or severity is not consistent with the product 
information mentioned in the Reference Safety Information in the IB or study protocol. 
8.1.8. Toxic Death 
Any death to which drug toxicity is thought to have made a contribution should be notified to 
the Sponsor’s designee at once (and maximally within 24 hours). The Sponsor’s designee will 
notify the SRC and Sponsor immediately. 
8.1.9. Pregnancy 
In this study, pregnancies occurring during participation (including pregnancies of partners of 
male patients) are ground for immediate and permanent discontinuation. They are not 
considered as an AE per se, but they must be reported to the Sponsor. 
The sites will notify their IRBs/IECs according to the IRB’s/IEC’s reporting requirements of 
these pregnancies. The FDA will be notified of pregnancies in the development safety update 
report (DSUR) and the CSR and as Investigational New Drug Safety Report (INDSRs) if 
complications or outcomes meet expedited criteria. 
Pregnancies must be followed up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the patient was discontinued from the study. Pregnancy complications, elective 
terminations and spontaneous miscarriages must be reported as SAEs. 
Patients who become pregnant during the study period must not receive further study treatment 
but may continue other study procedures at the discretion of the investigator.  
Patients should be instructed to notify the investigator if they became pregnant either during 
the study or within 180 days following cessation of study treatment.  If the patient begins a new 
anticancer therapy, the patient must notify the investigator of a pregnancy 30 days following 
cessation of study treatment .  
If a pregnancy occurs during the study or within 180 days following cessation of study 
treatment, or if the patient initiates new anticancer therapy, the pregnancy should be followed 
to term, any premature terminations reported, and the health status of the mother and child 


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including date of delivery and the child’s gender and weight should be reported to Imugene 
Limited after delivery. The mother may freely choose to terminate the pregnancy as her own 
decision. Neither the Sponsor nor investigators should influence this decision in any way. 
Similarly, neither the investigators nor Sponsor have the right to intervene or influence this 
decision and any ensuing procedures. If this occurs, the termination of pregnancy should be 
considered an elective surgical procedure and any associated adverse events attributed 
accordingly.  
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
8.1.10. Withdrawal Due to Adverse Events  
Withdrawal due to AEs should be distinguished from withdrawal due to other causes 
(Section 4.3.1), according to the definition of AE noted earlier, and recorded on the appropriate 
AE CRF page.   
When a patient withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined in Section 8.2.5. 
8.2 
Monitoring, Reporting, and Documentation of SAEs/AEs  
8.2.1. Monitoring of AEs 
Patients will be monitored for AEs from the time of ICF signature and at all timepoints 
indicated in Table 1 and Table 2 (Arm 1 and Arm 2). After informed consent has been obtained 
but prior to initiation of study drug(s), only SAEs caused by a protocol-mandated intervention 
(e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  
AEs will be assessed using CTCAE v5.0 (Appendix A), including start and stop dates, severity, 
relationship to study treatment, outcome and action taken.  
At every study visit, patients will be asked whether they have experienced or are experiencing 
any medically related changes in their health. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications/therapies, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition, for all patients with any remaining SAEs at the last follow-up visit after the last 
treatment administration, regardless of its relationship to study medication, AE information 
needs to be collected until:  
• The symptom subsides or stabilizes;  
• Any clinically relevant abnormal laboratory value has returned to baseline;  
• There is a satisfactory explanation other than the study medication for the change(s) 
observed; or 
• Death, in which case an autopsy report should be supplied to the Sponsor’s designee, if 
performed.  


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8.2.2. Documentation of AEs 
All AEs are to be evaluated for duration, intensity, and relationship to (associated with) the 
study treatment or due to other causes including underlying disease.  
All AEs, both those observed by study site personnel and those spontaneously reported by the 
study patients, must be recorded on the AE page in the CRF, as well as in the patient’s medical 
record using standard medical terminology, regardless of causality.  
Each event should be recorded as a single diagnosis. Accompanying signs (including abnormal 
laboratory values, physical examination findings, pulmonary or cardiovascular function tests) 
or symptoms should not be recorded as additional AEs. However, if the diagnosis is 
unknown/uncertain, signs and symptoms must be recorded. As soon as the diagnosis causing 
the signs and symptoms is known, the event terms will be adjusted to the final diagnosis. 
For each AE, a minimum required information should be reported, which includes: 
• The type of AE; 
• An estimate of its severity (using NCI-CTCAE version 5.0, see Appendix A); 
• Date and time of occurrence; 
• Date of resolution; 
• Actions required; 
• An assessment of its causal relationship to study medication provided in the 
Investigator file.  
 
AEs resulting from concomitant illnesses, reactions to concomitant medications, or from 
disease relapse/progression are also to be recorded. Any medical condition that is present at 
the screening visit will be considered as baseline and will not be reported as an AE but as 
medical history. However, if the condition deteriorates at any time during the study, it will be 
recorded as an AE. Investigators should ensure that the event term recorded captures the change 
in the condition (e.g., “worsening of...”). 
8.2.3. Adverse Event Severity Assessment 
8.2.3.1. 
Adverse Event Intensity Grading 
Patients will be evaluated for safety if they have received any treatment. Adverse events and 
other symptoms will be graded according to NCI-CTCAE v5.0. Each AE is to be classified and 
graded according to CTCAE v5.0 criteria (see Appendix A). Dates of onset and resolution, 
including dates at which the grade of an AE changes, are to be recorded in the patient file.  
If no CTCAE grading is available, the severity of an AE is to be graded as follows: 
• Mild (Grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• Moderate (Grade 2): the event causes discomfort that affects normal daily activities. 


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• Severe (Grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• Life-threatening (Grade 4): the patient was at risk of death at the time of the event 
or the event caused death. 
• Death (Grade 5): death related to an AE. 
 
8.2.3.2. 
Local (injection site) Adverse Event Intensity 
Intensity of the following local AEs should be assessed as described in the table (Table 6) 
below adapted from the FDA, Center for Biologics Evaluation and Research (CBER), 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials dated September, 2007. 
Injection site AEs will be part of AE reporting as per Schedule of Activities at each study visit 
and are to be reported if ≥ Grade 1. 
Table 6. 
Grading of Local Adverse Event Intensity   
Local 
Reaction to 
Injectable 
Product 
Absent 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Absent 
Does not 
interfere with 
activity 
Repeated use 
of non-narcotic 
pain reliever 
> 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Absent 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/ 
Redness * 
Absent 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
Swelling** 
Absent 
2.5 – 5 cm 
and does not 
interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 


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8.2.4. Causality Assessment to Treatment 
The investigator should use medical judgment to determine whether there is a reasonable causal 
relationship, including all relevant factors such as temporal course and latency, pattern of the 
reaction, known pharmacological properties of the product, and alternative explanations 
(e.g., other drugs, medical history, and concomitant diseases). By “reasonable causal 
relationship” it is understood that there is evidence or argument to suggest a causal relationship. 
The relationship of an AE to study medication will be recorded on the CRF and defined as 
follows:  
• Not Related: An AE that does not follow a reasonable temporal sequence related to the 
IMP and is likely to have been produced by the patient’s clinical state, other modes of 
therapy or other known ethology. 
• Unlikely Related: An AE that follows such a temporal sequence from administration 
of the study medication that a relationship is not likely, and is likely to be due to a cause 
such as (known characteristics of) the patient’s clinical state or other treatment. 
• Possibly Related: AE that has a reasonable possibility that the event may have been 
caused by the IMP. The AE has a timely relationship to the IMP; however, the pattern 
of response is untypical, and an alternative cause seems more likely or there is 
significant uncertainty about the cause of the event. 
• Probably Related: An AE that has a reasonable possibility that the event is likely to 
have been caused by the IMP. The AE has a timely relationship and follows a known 
pattern of response, but a potential alternative cause may be present. 
• Definitively Related: There is a reasonable possibility that the event may have been 
caused by the IMP. A certain event has a strong temporal relationship and an alternative 
cause is unlikely. 
 
Ultimately, at the time of data analysis, the relationship to the AE will be categorized as either 
“unrelated” (including unlikely or not related) or “related” (including definitely, probably or 
possibly related). 
If the investigator does not know whether the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor (see Section 8.2.7 Reporting Requirements). If the investigator's 
causality assessment is "unknown but not related to investigational product", this should be 
clearly documented on study records.   
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
8.2.5. Reporting of SAEs 
If an SAE or ECI occurs, Imugene Limited, or its delegated representative, is to be notified 
within 24 hours of investigator or designee awareness of the event.  


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In particular, if the SAE is fatal or life-threatening, notification must be made immediately to 
Imugene Limited, or its delegated representative, irrespective of the extent of available AE 
information.   
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE or ECI reports as well as to the initial and follow-up reporting of exposure during 
pregnancy and exposure via breastfeeding cases.   
In the rare event that the investigator does not become aware of the occurrence of an SAE or 
ECI immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
Safety Reporting Contact Information: 
• By encrypted email to the PPD Pharmacovigilance (PVG) safety inbox 
EMEAASIASafetyCentral.SM@ppdi.com 
• In case of unsuccessful email delivery, the site should report the SAE or ECI to the 
Safety hotline numbers below: 
• By telephone: 
- 
North America: 1-800-201-8725 
- 
Asia Pacific: +44 1223 374 240 
- 
Australia: 1800659318 
  
When prompted, enter the 5-digit access code: 72338 
 
• By fax: 
- 
North America: 1-888-488-9697 
- 
Asia Pacific: +44 1223 374 102 
- 
Australia: 1800571893 
 
For all SAEs, the investigator is obligated to pursue and provide information to Imugene 
Limited in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Imugene Limited to obtain specific additional follow-up 
information in an expedited fashion.  This information collected for SAEs is more detailed than 
that captured on the AE CRF.  In general, this will include a description of the AE in sufficient 
detail to allow for a complete medical assessment of the case and independent determination 
of possible causality.  Information on other possible causes of the event, such as concomitant 
medications and illnesses must be provided.  In the case of a patient death, a summary of 
available autopsy findings must be submitted as soon as possible to Imugene Limited or its 
designated representative. 
Serious Adverse Events (SAEs) will be reported from date of first informed consent confirming 
study participation. After informed consent has been obtained but prior to initiation of study 
drug(s), only SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such 
as biopsies, discontinuation of medications) should be reported. After initiation of study drug 
all adverse events will be reported until 30 days after the last dose of study drug or until 
initiation of new systemic anti-cancer therapy, whichever occurs first. Serious adverse events 
and adverse events of special interest will continue to be reported until 90 days after the final 


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dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first.     
8.2.6. SUSARs 
The Sponsor’s designee, on behalf of the Sponsor, is required by law to report to the health 
authorities in a written safety report:  
1) all fatal or life-threatening suspected unexpected serious adverse reactions (SUSARs) within 
seven (7) calendar days of initial notification;  
and  
2) all other SUSARs within fifteen (15) calendar days of initial notification after the Sponsor 
determines that the information qualifies for reporting.  
 
All Investigators in the study will be informed about SUSARs that have occurred by the 
Sponsor’s designee, on behalf of the Sponsor by calendar day fifteen (15) for submission to 
their IRB/IEC. 
8.2.7. Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations. 
 


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9. 
STATISTICAL METHODS 
9.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written in which the details of the statistical methods 
will be described. Any deviations from the originally planned statistical analysis or SAP will 
be described and justified in the clinical study report. Changes known at the time of SAP 
preparation will also be described in the SAP. 
A data review meeting for each Arm separately will be held before database hard lock. Protocol 
deviations will be reviewed during the data review meeting. Furthermore, assignment of 
patients to the analysis sets will be performed. 
Data of patients who did not meet the entry criteria (screening failures) and data of patients 
who received no investigational product (e.g. due to withdrawal) entered in the clinical 
database will only be listed. These data will not be included in any analysis set. 
All data will be recorded electronically by the study site. The Investigator is responsible for 
ensuring the accuracy, completeness, and legibility of the data reported in the CRFs. The 
monitor will check the accuracy, completeness, and legibility of the data reported in the CRFs. 
9.2 
Data Sets to be Analyzed 
The analysis population sets are defined as follows: 
• The safety analysis set (SAF) consists of all patients who receive at least one dose of 
study treatment. All safety and tolerability evaluations will be based on this analysis 
set.  
• The full analysis set (FAS), which includes all enrolled participants who receive at 
least 1 administration of study treatment, will be used for analyses of OS and may be 
used for additional analyses of selected efficacy and exploratory endpoints. 
• The evaluable analysis set (EAS), which includes all participants who receive at least 
1 administration of study treatment and have an evaluable baseline tumor assessment 
and who have at least one evaluable post-baseline tumor response assessment as per 
RECIST v1.1 or were discontinued due to toxicity, will be the primary analysis set for 
analyses of response-based anti-tumor activity endpoints. 
 
9.3 
Statistical Evaluation 
Summary statistics for continuous variables will include the number of patients (n), mean, 
standard deviation, median, minimum, and maximum.  
Summary statistics for categorical variables will include the frequency and percentage of 
patients in each category.  
Summary statistics for time to event data will include the number of patients, estimated median 
and its 95% CI, 25th percentile, 75th percentile, minimum, and maximum times to event, 
number of events (total and censored).   


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Results will be summarized by Arm.  All data will be listed. Baseline is assumed to be the last 
observation prior to first dose of study drug. The effects of noncompliance, time to first dose, 
treatment discontinuations, and premature withdrawal from study will be assessed to determine 
the impact on the general applicability of results from this study. Further details of the analysis, 
including the handling of missing data, transformations and other data handling procedures will 
be provided in the SAP. Exploratory analyses of the data will be conducted as deemed 
appropriate. 
9.3.1. Efficacy Analysis 
The ORR is defined as the proportion of patients achieving a confirmed best overall response 
of CR or PR according to RECIST 1.1 based on local review. The ORR along with the 
associated 95% CI based on the Clopper-Pearson exact method, will be reported per Arm.  
Survival time is defined as the time from first dose of study drug to the date of death due to 
any cause. Patients who do not die will be censored at the last documented date alive.  PFS is 
defined as the time from first dose of study drug to the date of the first documented progressive 
disease (PD; that is confirmed by a follow up scan), according to RECIST 1.1, or to death from 
any cause. Patients who neither progress nor die will be censored at date of last documented 
response assessment. The DoR measured from the earliest CR or PR until documented PD 
(confirmed after follow up scan), according to RECIST 1.1, or death due to any cause. Patients 
with ongoing responses will be censored at last documented response assessment. The Kaplan-
Meier method will be used to summarize OS, PFS and DoR. The EAS will be the primary 
analysis set for analysis of ORR, PFS, and DoR.  The FAS will be the primary analysis set for 
analysis of OS. Each arm will be summarized independently. 
9.3.2. Safety Analysis  
All safety analyses will be conducted in the SAF. 
Adverse events (AEs) will be coded according to the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). The severity of AEs will be graded according to NCI 
CTCAE, v5.0. 
Treatment-emergent adverse events (TEAEs) are defined as any AE with onset or worsening 
of a pre-existing condition after the first dose of study drug through 30 days for AEs and 90 
days for SAEs/irAEs following the last dose of study drug. Events including TEAEs, AEs 
leading to dose reduction/interruption, AEs related to study drug, SAEs, AEs leading to study 
drug discontinuation, and fatal AEs will be summarized by system organ class (SOC) and 
preferred term (PT). A summary of AEs of NCI CTCAE Grade 3 or higher, as well as the most 
frequent AEs (by preferred term), and AEs by relationship to study treatment, will be provided. 
A listing of DLTs will be reported for the safety run-in phase of Arm 1 and 2. 
Values and changes from baseline in clinical laboratory results will be summarized by visit. 
Clinical laboratory values will be graded according to the NCI CTCAE, for applicable tests. 
Shifts in toxicity grades from baseline grade will be summarized. Shifts from baseline in ECOG 
performance status also will be summarized. 


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Vital signs, ECG, LVEF and concomitant medication data will be summarized. Graphical 
displays will be provided where useful to assist in the interpretation of results. 
9.3.3. Immunogenicity Analysis 
This analysis will be performed on the FAS. The level of HER2-specific antibodies and 
immune phenotyping will be assessed in peripheral blood at baseline and at the timepoints as 
per Table 1 & Table 2 while on treatment. 
Values and changes from baseline in immunological data will be summarized by visit. 
Associations between immunologic endpoints with clinical outcomes will be assessed by 
graphical techniques and measures of association as appropriate. 
9.4 
Sample Size Determination 
The study plans to enroll 15 evaluable patients into each Arm of the study, for a total of 
approximately 30 evaluable patients. 
For each Arm, after 8 evaluable patients are enrolled (Stage 1), an additional 7 evaluable 
patients will be enrolled in that group (Stage 2) if 1 or more patients respond (i.e., experience 
CR or PR). If there are no responses in Stage 1, then preliminary anti-tumor activity in the 
group will not have been identified and no further patients will be enrolled in that Arm. If the 
Arm continues to Stage 2, a total of 15 evaluable patients will be studied for that Arm. The 
Arm will be considered successful if ≥ 4 treated patients respond and the Arm may be expanded 
to enroll 25 patients. This design is applied to each Arm separately and is based on a 2-stage 
Simon Minimax design for a total of 15 evaluable patients (null hypothesis that ORR ≤ 11% 
versus the alternative hypothesis that ORR ≥ 40% with alpha=0.07268 and power=90.463%). 
9.5 
Disposition, Demographic and Other Baseline Characteristics  
A patient disposition table will comprise the number of patients included per Arm, exposed to 
study drug (separately for each agent that is part of the combination), and completing or 
withdrawing from study (including reason for withdrawal). The number of patients in each 
analysis set will be included, also per Arm. The patient disposition will be summarized 
separately by Arm and overall. 
Demographic, medical history, baseline disease characteristics, prior treatments for study 
disease and other baseline data will be presented using summary statistics based on the SAF 
overall and by Arm. 
9.6 
Exposure 
The number of doses and cumulative total dose of HER-Vaxx will be summarized with 
descriptive statistics by Arm and overall.  Concomitant chemotherapy (ramucirumab plus 
paclitaxel including use of dexamethasone) and pembrolizumab administered per protocol will 
also be summarized with descriptive statistics. 


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9.7 
Interim Analysis  
Each Arm will be evaluated independently.  
After 8 evaluable patients are enrolled (Stage 1) an additional 7 evaluable patients will be 
enrolled in that Arm (Stage 2) if 1 or more patients respond (i.e., experience CR or PR). If there 
are no responses in Stage 1, then preliminary anti-tumor activity in the group will not have 
been identified and no further patients will be enrolled in that Arm. If the Arm continues to 
Stage 2, a total of 15 evaluable patients will be studied for that Arm. The Arm will be 
considered successful if ≥ 4 treated patients respond, and the Arm may be expanded to enroll 
25 patients. This design is applied to both arms and is based on a 2-Stage Simon Minimax 
design for a total of 15 evaluable patients (null hypothesis that ORR ≤ 11% versus the 
alternative hypothesis that ORR ≥ 40% with alpha=0.07268 and power=90.463%).  
 
 
 


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10. 
DATA HANDLING AND RECORD KEEPING 
10.1 
Data Collection 
This study will use a 21 CFR Part 11 compliant electronic data capture (EDC) system. An 
eCRF will be used for data recording. Any data requested on the eCRF must be entered and a 
reasonable effort should be made to retrieve any missing data.  
The data will be checked for completeness and correctness and discrepancy reports will be 
generated accordingly and transferred to the study center for resolution by the Investigator or 
his/her designee.  
As part of the responsibilities assumed by participating in the study, the Investigator or Sub-
Investigator agrees to maintain adequate case histories for the patients treated as part of the 
research under this protocol. The Investigator or Sub-Investigator agrees to maintain accurate 
eCRF and source documentation as part of the case histories.  
The Investigators or designees must enter all results collected during the clinical study into 
eCRF. There is a 2-part process to review and collect the eCRF data. Study site personnel will 
enter the data from each study visit within the timelines outlined in the Clinical Trial 
Agreement. Investigators are responsible for approval of the entered and/or corrected data. The 
eCRF responsibilities of the study team members will be documented on the site delegation 
log, which will be collected at the closeout visits. Investigators can authorize Sub-Investigators 
to sign and approve the eCRF if they are designated on Form FDA 1572 (where appropriate 
per local requirements) as Sub-Investigators, have been trained on the EDC system, and have 
their own username and password. Investigators or designees must review and approve the data 
before database lock. 
The completed original eCRFs are the sole property of Imugene Limited and should not be 
made available in any form to third parties, except for authorized representatives of Imugene 
Limited or appropriate regulatory authorities, without written permission from Imugene 
Limited. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  In most 
cases, the source documents are the hospital's or the physician's patient chart.  In these cases 
data collected on the CRFs must match the data in those charts.  
10.2 
Monitoring  
The study will be monitored by a contract research organization (CRO). Its representatives will 
be allowed access to all information resulting from this study and Imugene Limited will have 
an unrestricted right to use such information. The study monitor will have access to laboratory 
test reports and other patient records needed to verify the entries on the CRF. The patients’ 
confidentiality will be respected as required by local law. 


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10.3 
Documentation and Material Supply 
All supplies provided to the investigators for the purpose of carrying out the study are supplied 
only for the purpose of the study and must not be used for any other purpose. The principal 
investigator or (a) person(s) delegated by the principal investigator is/are responsible for the 
security and accountability of all supplies. All such supplies, if not used during the course of 
the study and not forming a part of the documentation required to be retained by the 
investigator, must be returned to Imugene Limited at the conclusion of the study. 
10.4 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Imugene Limited, the 
investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence 
(e.g., letters, meeting minutes, telephone calls reports).  The records should be retained by the 
investigator according to ICH, local regulations, or as specified in the Clinical Study 
Agreement (CSA), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Imugene Limited should be prospectively 
notified.  The study records must be transferred to a designee acceptable to Imugene Limited, 
such as another investigator, another institution, or to an independent third party arranged by 
Imugene Limited.  Investigator records must be kept for a minimum of 15 years after 
completion or discontinuation of the study or for longer if required by applicable local 
regulations.   
The investigator must obtain Imugene Limited's written permission before disposing of any 
records, even if retention requirements have been met. 
10.5 
Medical Coding 
Coding of prior and concomitant medications will be performed using World Health 
Organization (WHO) Drug Dictionary. AEs and medical history will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA, version to be specified in the data 
management plan). 
10.6 
Health Economics Data Collection 
Not applicable. 
 


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11. 
ADMINISTRATIVE ASPECTS 
11.1 
Quality Assurance Audit 
This study may be audited by Imugene Limited or its designee to document the authenticity of 
recorded data and protocol adherence. Patients participating in the study should be informed 
that their records might be reviewed for this purpose, and also by government health 
authorities. The patients’ confidentiality will be respected as required by local law. 
11.2 
Investigator Site File  
At study initiation, each investigator will be provided with an investigator site file (ISF) 
containing information as specified in 21CFR312.62 Investigator recordkeeping and record 
retention. It is the Investigator's responsibility to keep the ISF up to date. 
11.3 
Protocol Deviations 
A protocol deviation is any non-compliance with the clinical study protocol, GCP, or 
requirements in other procedures. The non-compliance may be either on the part of the 
participant, the Investigator, or the study site staff. Because of deviations, corrective actions 
are to be developed by the site and implemented promptly. These practices are consistent with 
ICH E6:  
• 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• Quality Assurance and Quality Control, Section 5.1.1  
• 5.20 Non-compliance, Sections 5.20.1 and 5.20.2.  
 
Major protocol deviations are any deviations that might significantly affect the completeness, 
accuracy, and/or reliability of the study data or that might significantly affect a patient's rights, 
safety, or well-being. This includes deviations related to patient eligibility, informed consent, 
IMP dosing errors, or failing to perform assessments required to interpret the primary endpoint. 
Additional categories may be identified as deemed necessary by the Sponsor.  
All protocol deviations will be reported by the clinical research associates (CRAs) or other 
study-involved personnel, such as data manager and statisticians. The protocol deviations will 
be reviewed by the Sponsor medical monitor. The medical monitor determines whether a 
deviation is major or not. Major deviations are reported to the Sponsor as part of the regular 
reporting. Important protocol deviations will be summarized in the clinical study report. In 
accordance with applicable FDA mandates, the Investigator is responsible for reporting 
protocol deviations to the IRB/IEC. 
In case of a deviation, the Investigator enters a comment in the source documents and the 
non-compliance will be documented in a Monitoring Visit Report by the CRA. All non-
compliance will be followed up and reported to FDA and IRBs/IECs as per regulations. In 
parallel, corrective and/or preventive actions will be undertaken and documented, including 
any retraining of the Investigator and site staff. No waivers for inclusion or exclusion criteria 
will be given. 


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11.4 
Clinical Study Report 
A clinical study report according to ICH Guideline "Note for Guidance on Structure and 
Content of Clinical Trial Reports" will be issued. A summary of the study results will be 
provided to the IRBs/IECs and the FDA within one year after end of study. 


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12. 
ETHICAL AND LEGAL CONSIDERATIONS 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 
2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World Medical 
Association 1996, 2008).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
12.1 
Institutional Review Boards / Independent Ethics Committees 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC. All correspondence with the 
IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should be 
forwarded to Imugene Limited, or its agent. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In that 
event, the investigator must notify the IRB/IEC and Imugene Limited in writing immediately 
after the implementation. 
12.2 
Patient Informed Consent 
All parties will ensure protection of patient personal data and will not include patient names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Imugene Limited, or its delegate, in order 
to de-identify the study patient. In case of data transfer, Imugene Limited and its agents will 
maintain high standards of confidentiality and protection of patient personal data. 
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent document used in this study, and any changes made during the course 
of the study, must be prospectively approved by both the IRB/IEC and Imugene Limited, or its 
agent, before use. 
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.   
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific activity 
is performed.  The investigator will retain the original of each patient's signed consent 
document. 


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12.3 
Study Discontinuation and Closure 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Imugene.  In 
addition, Imugene retains the right to discontinue development of HER-Vaxx at any time. 
If the study is prematurely terminated or discontinued, Imugene will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and the 
hospital pharmacy (if applicable) within 7 days.  As directed by Imugene, all study materials 
must be collected and all CRFs completed to the greatest extent possible. 
12.4 
Confidentiality 
Either prior to or during the course of the study, Imugene Limited or their representatives will 
provide the principal investigator and persons delegated by him/her with confidential 
information, for example, but not limited to, the protocol and the IB. The information may not 
be disclosed to anyone else without prior approval from Imugene Limited in writing. This 
obligation of confidentiality shall survive the completion or early termination of the study. 
12.5 
Protocol and Investigator Brochure  
All study personal must be familiar with the protocol to be able to conduct the study in the 
manner specified.  
Imugene Limited has supplied the investigator with an Investigator’s Brochure (IB), which 
describes the vaccine being tested and its known adverse effects. The investigator must be 
familiar with this document before the study commences. Imugene Limited will provide 
additional information requested by the investigator before commencing the study or during its 
conduct.  
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Imugene Limited. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agencies having jurisdiction over the 
conduct of the study. 
12.6 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, Imugene Limited should be informed immediately.   
In addition, the investigator will inform Imugene Limited immediately of any urgent safety 
measures taken by the investigator to protect the study patients against any immediate hazard, 
and of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 


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12.7 
Compensation for Medicine-induced Injury 
According to local regulations Imugene Limited will provide insurance coverage to all patients 
during study period. Imugene Limited assumes liability for and will indemnify all injuries that 
occur to patients whenever a causal relationship can be established between the event and the 
clinical study procedure or the study substance under study if the following can be 
demonstrated: 
• The event resulted from a study substance, provided that the substance was 
administered according to the current protocol and manufacturer’s instructions. 
• The event occurred as a consequence of diagnostic procedures performed according to 
the study protocol. 
• The event resulted from therapeutic or diagnostic measures legitimately required as a 
consequence of unexpected events caused by the study substance, by comparative 
medication, or by diagnostic procedures called for by the study protocol. 
 
Imugene Limited is not liable for events that occur solely as a consequence of the underlying 
illness of the patient, or for events resulting from diagnostic or therapeutic measures not 
specifically required by the protocol, or for events resulting from negligence (including failure 
to act according to accepted medical practice, or to comply strictly with the protocol or the 
terms of this Agreement) of the investigator or any other involved and/or related clinical staff 
and facilities. 
This indemnity provided by Imugene Limited shall further apply as follows: 
• Imugene Limited is to be informed as soon as possible of any complaint, action or suit 
of proceeding giving rise to the right of indemnification, and the investigator agrees to 
co-operate fully with Imugene Limited in the defense or disposition of all such cases. 
• Imugene Limited will be permitted, at its costs and discretion, to handle and control the 
defense or disposition of all such cases. 
 
No case will be settled without the prior written consent of Imugene Limited. 
12.8 
Publication Policy and Protection of Trade Secrets 
In accordance with standard editorial and ethical practice, Imugene Limited will support 
publication of multicenter studies only in their entirety and not as individual center data except 
for data on sub-studies. 
The following rules will apply for determining authorship: 
• Authorship credit will be based on the Vancouver statement by the International 
Committee of Medical Journal Editors, i.e. substantial contribution to the following 
criteria: 
o Conception and design or analysis and interpretation; 
o Drafting article or critically revising it for intellectual content; 


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Protocol Identifier: 
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o Final approval of the version to be published; 
• Additional criteria for authorship include: 
o Contributors who register 20% or more of the evaluable cases on the study; 
o Significant contribution to the Cohort Review Committee. 
 
In an appropriate footnote, or at the end of the article, the following statement will be made: 
“Participating investigators included: (a list of the individuals who have contributed patients 
and their institutions).” 
Investigator agrees to submit all manuscripts or abstracts to Imugene Limited prior to 
submission. This allows Imugene Limited to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the authors 
of the manuscript. Investigator will collaborate with the study statistician for preparation of 
study data analyses intended to be used in the publication(s) of the study. 
Any formal publication of the study in which input of Imugene Limited personnel exceeded 
that of conventional monitoring will be considered as a joint publication by investigator and 
Imugene Limited. 
Moreover, the following points need to be considered: 
• Without investigator’s prior written consent, Imugene Limited may not make reference, 
either directly or indirectly, in a commercial publication, to Investigator’s name or 
institution, or any of its employees in which Investigator performed the present studies, 
connected with the research and its results. 
• Imugene Limited may not use investigator’s name or the name of the Medical 
University Vienna or its employees connected to the research or to the institution in 
which Investigator performed the present study in its commercial publications as 
recommendation of quality and/or of the finished product and/or of the drug and the 
efficacy of its use. 
• Should Imugene Limited decide to publish the research results, it must publish them in 
their entirety and must not quote anything out of context. 
 
Nothing in the aforementioned limitations in clauses will prevent Imugene Limited from 
quoting from articles, provided that the scientific source of data (scientific conventions, 
scientific newspapers) is mentioned. 
12.9 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in 
the study. 


Investigational Product: 
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Protocol Identifier: 
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13. 
REFERENCE LIST  
Alanji AJ, et al. An open-label, multinational, multicenter study of G17DT vaccination 
combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or 
gastroesophageal cancer: the GC4 study. Cancer. 2006;106(9):1908-16. 
American Cancer Society. Cancer Facts & Figures 2021. Atlanta, Ga: American Cancer 
Society; 2021. Available at 
http://www.cancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-survival-rates. 
Accessed 28 September 2021 
Bang Y-J et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone 
for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer ToGA: 
a phase 3 open-label, randomized controlled trial, Lancet 2010; 376:687-97 
Blank, C., et al., PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 
receptor (TCR) transgenic CD8+ T cells. Cancer Res, 2004. 64(3): p. 1140-5. 
Chemnitz, JM., et al. SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based 
Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only 
Receptor Ligation Prevents T Cell Activation. The Journal of Immunology.2004, 173: 945–
954  
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells 
and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad 
Sci U S A, 2010. 107(9): p. 4275-80.  
Disis, Mary L. Immune Regulation of Cancer. Journal of Clinical Oncology.2010; 28 
(29):4531-4538  
Dudley, M E. et al. Adoptive Cell Transfer Therapy Following Non-Myeloablative but 
Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic 
Melanoma. Journal of Clinical Oncology.2005; 0732-183  
Francisco, LM., et al. The PD-1 pathway in tolerance and autoimmunity. Immunological 
Reviews.2010; 0105-2896  
Greenwald, RJ., et al. The B7 Family Revisited. Annual Reviews.2005; 23:515–48  
Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer 
therapeutic immunity. Cancer Res, 2005. 65(3): p. 1089-96.  
Hofmann M, et al. Assessment of a HER2 scoring system for gastric cancer: results from a 
validation study. Histopathology. 2008;52(7):797-805. 
Hunder NN, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against 
NY-ESO-1. N Engl J Med 2008;358(25):2698-703  
IARC cancer fact sheets: stomach cancer. Available at 
https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf. Accessed 17 
September 2021 


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
Global Protocol Amendment 4, 8 August 2023 
 
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Kaumaya PTP, et al. Immunogenicity and antitumor efficacy of a novel human PD-1 B-cell 
vaccine (PD1-Vaxx) and combination immunotherapy with dual trastuzumab/pertuzumab-
like HER-2 B-cell epitope vaccines (B-Vaxx) in a syngeneic mouse 
model. Oncoimmunology. 2020;9(1):1818437. 
Maglakelidze M et al. A Phase 2 study of HER-Vaxx (IMU-131), a HER2 targeting peptide 
vaccine, plus standard of care chemotherapy in patients with HER2 overexpressing metastatic 
or advanced gastric/GEJ adenocarcinoma. Final Overall Survival Analysis.  ASCO GI 2023 
Matsushita N, et al. Phase I clinical trial of a peptide vaccine combined with tegafur-uracil 
plus leucovorin for treatment of advanced or recurrent colorectal cancer. Oncol Rep. 
2013;29(3):951-9. 
NCCN Clinical Practice Guidelines Oncology Gastric Cancer 
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf (4.2022) 
Nomi, T., et al., Clinical significance and therapeutic potential of the programmed death-1 
ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res, 2007. 
13(7): p. 2151-7.  
Okazaki T, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by 
recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. 
Proc Natl Acad Sci U S A 2001;98(24):13866-71.  
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
Park DI, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. 
Dig Dis Sci. 2006;51(8):1371-9. 
Parry, RV. et al. CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct 
Mechanisms. Molecular and Cellular Biology, 2005; 0270-7306 
Pilon-Thomas, S., et al., Blockade of programmed death ligand 1 enhances the therapeutic 
efficacy of combination immunotherapy against melanoma. J Immunol, 2010. 184(7): p. 
3442-9.   
Riley, JL., PD-1 signaling in primary T cells. Immunological Reviews. 2009; 0105-2896   
Roy V, Perez EA. Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-
positive breast cancer. Oncologist. 2009;14(11):1061-9. 
Seo S, et al. Loss of HER2 positivity after anti-HER2 chemotherapy in HER2- positive 
gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 
(GASTHER3) Gastric Cancer (2019) 22:527–535  
Shepard, KA., et al.  PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3 signalosome and downstream signaling to PKC. FEBS Letters. 2004; 0014-5793  
Spranger, S., et al., Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or 
IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly 
within the tumor microenvironment. J Immunother Cancer, 2014. 2: p. 3.  


Investigational Product: 
IMU-131 (HER-Vaxx) 
Protocol Identifier: 
IMU.131.203 
Protocol Version: 
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Strome, S.E., et al., B7-H1 blockade augments adoptive T-cell immunotherapy for squamous 
cell carcinoma. Cancer Res, 2003. 63(19): p. 6501-5.  
Takashi, K. et al. Comparison of HER2 Status Before and After Trastuzumab-based 
Chemotherapy in Patients With Advanced Gastric Cancer. Anticancer Research Jan 2020, 40 
(1) 75-80.  
Thompson, J.A. et al. NCCN Guidelines Insights: Management of Immunotherapy-Related 
Toxicities, Version 1.2020 in: Journal of the National Comprehensive Cancer Network 
Volume 18 Issue 3 (2020) (jnccn.org)  
Tobias J, et al. Enhanced and long term immunogenicity of a Her-2/neu multi-epitope 
vaccine conjugated to the carrier CRM197 in conjunction with the adjuvant Montanide. BMC 
Cancer 2017: 118 (2017)  
Wagner S, et al. Delayed tumor onset and reduced tumor growth progression after 
gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin 
immunization with a Her-2/neu multi-peptide vaccine and IL-12 in c-neu transgenic mice. 
Breast Cancer Res Treat. 2007;106(1):29-38. 
Weber, J., Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol, 2010. 37(5): p. 430-9.   
Weir G, Liwski R, Mansour M. Immune Modulation by Chemotherapy or Immunotherapy to 
Enhance Cancer Vaccines. Cancers 2011;3: 3114-3142  
Wiedermann U, et al. A virosomal formulated Her-2/neu multi-peptide vaccine induces Her 
2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study. 
Breast Cancer Res Treat. 2010;119(3):673-83. 
Wiedermann, U., et al. (2021). Clinical and Immunologic Responses to a B-Cell Epitope 
Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from 
Phase Ib Trial IMU.ACS.001. Clinical Cancer Research 27(13): 3649-3660.  
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, 
Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, 
Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab 
plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced 
gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, 
randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. doi: 10.1016/S1470-
2045(14)70420-6. Epub 2014 Sep 17. PMID: 25240821. 
Yano T, et al. Comparison of HER2 gene amplification assessed by fluorescence in situ 
hybridization and HER2 protein expression assessed by immunohistochemistry in gastric 
cancer. Oncol Rep. 2006;15(1): p. 65-71. 
Zhang PD, et al. Structural and Functional Analysis of the Costimulatory Receptor 
Programmed Death-1. Immunity.2004; 337-347  
Zhang XL, et al. Comparative study on overexpression of HER2/neu and HER3 in gastric 
cancer. World J Surg. 2009;33(10):2112-8.   


Investigational Product: 
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Protocol Identifier: 
IMU.131.203 
Protocol Version: 
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14. 
APPENDICES 
14.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scoring (Oken et al, 1982) 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
 
 
 


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14.2 
Appendix B: Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI-CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
Quick Reference The NCI-CTCAE is a descriptive terminology, which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.  
Components and Organization System Organ Class (SOC), the highest level of the Medical 
Dictionary for Regulatory Activities (MedDRA) hierarchy, is identified by anatomical or 
physiological system, etiology, or purpose (e.g. SOC Investigations for laboratory test results). 
CTCAE terms are grouped by MedDRA Primary SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (Grade).  
CTCAE Terms An AE is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical 
documentation and scientific analyses. Each CTCAE v 5.0 term is a MedDRA Lowest Level 
Term.  
Definitions A brief definition is provided to clarify the meaning of each AE term.  
Grades Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline:  
• Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
• Grade 2 Moderate: minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
• Grade 3 Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily life.  
• Grade 4 Life-threatening consequences: urgent intervention indicated.  
• Grade 5 Death: related to AE. 

SAP_001.pdf: 
Confidential 
Imugene Limited 
IMU.131.203 
nextHERIZON: AN OPEN-LABEL, SIGNAL GENERATING, PHASE 2 
STUDY OF HER-VAXX IN COMBINATION WITH CHEMOTHERAPY 
OR PEMBROLIZUMAB IN PATIENTS WITH METASTATIC HER2/NEU 
OVER-EXPRESSING GASTRIC OR GASTROESOPHAGEAL JUNCTION 
(GEJ) ADENOCARCINOMAS WHO HAVE PREVIOUSLY RECEIVED 
TRASTUZUMAB AND PROGRESSED ON THIS TREATMENT 
08Nov2023 
Final Statistical Analysis Plan 
Version 1.0 
Prepared by: 
 
PPD 
12th Floor, A-Wing Aurobindo Galaxy 
Hyderabad Knowledge City, Hyderabad, India-500081 
NCT #: NCT05311176


Imugene Limited 
 
Final Statistical Analysis Plan, Version 1.0 
 
IMU.131.203 
 
Date Issued: 08Nov2023 
 
  
 
 
 II 
 
Document History – Changes compared to previous version of SAP: 
Version Date Issued 
SAP Section 
Detail of Changes 
1.0 
08Nov2023 
All Sections 
Final Version 
 
 
 
 
 
 


Imugene Limited 
 
Final Statistical Analysis Plan, Version 1.0 
 
IMU.131.203 
 
Date Issued: 08Nov2023 
 
  
 
  III 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 1 
2.1. PRIMARY SAFETY OBJECTIVE ............................................................................................. 1 
2.2. PRIMARY EFFICACY OBJECTIVE ......................................................................................... 1 
2.3. SECONDARY OBJECTIVE ..................................................................................................... 2 
2.4. EXPLORATORY OBJECTIVES ............................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.1.1. 
Safety and HER2 Antibody Consideration ................................................................. 4 
3.1.2. 
Safety Evaluation for Combination in Arm 1 and Arm 2 ........................................... 4 
3.2. STUDY ENDPOINTS ............................................................................................................. 5 
3.2.1. 
Primary Safety Endpoints ........................................................................................... 5 
3.2.2. 
Primary Efficacy Endpoint ......................................................................................... 5 
3.2.3. 
Secondary Efficacy Endpoints .................................................................................... 5 
3.2.4. 
Exploratory Endpoints ................................................................................................ 5 
3.3. TREATMENTS ...................................................................................................................... 6 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 6 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. SAMPLE SIZE ...................................................................................................................... 8 
4.2. RANDOMIZATION AND BLINDING ....................................................................................... 8 
4.3. ANALYSIS SET .................................................................................................................... 8 
4.3.1. 
All Enrolled Set........................................................................................................... 8 
4.3.2. 
Safety Analysis Set ..................................................................................................... 8 
4.3.3. 
Full Analysis Set ......................................................................................................... 8 
4.3.4. 
Evaluable Analysis Set ............................................................................................... 8 
5. 
PATIENT DISPOSITION ............................................................................................... 9 
5.1. DISPOSITION ....................................................................................................................... 9 
5.2. PROTOCOL DEVIATIONS ..................................................................................................... 9 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 9 
6.1. DEMOGRAPHICS .................................................................................................................. 9 
6.2. BASELINE CHARACTERISTICS ........................................................................................... 10 
6.3. MEDICAL HISTORY ........................................................................................................... 10 
6.3.1. 
General Medical History ........................................................................................... 10 
6.3.2. 
Oncology and Surgical History ................................................................................. 10 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 11 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 11 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 11 
7.2. PRIOR AND CONCOMITANT DRUG THERAPIES AND MEDICATIONS ................................... 11 


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  IV 
7.3. PRIOR AND CONCOMITANT RADIOTHERAPY ..................................................................... 12 
7.4. CONCOMITANT PROCEDURE/SURGERY ............................................................................. 12 
7.5. STUDY TREATMENTS ........................................................................................................ 12 
7.5.1. 
Extent of Exposure .................................................................................................... 12 
8. 
EFFICACY ANALYSIS ................................................................................................. 13 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 13 
8.1.1. 
Objective Response Rate .......................................................................................... 13 
8.2. SECONDARY EFFICACY ENDPOINT .................................................................................... 13 
8.2.1. 
Duration of Response ................................................................................................ 13 
8.2.2. 
Progression Free Survival ......................................................................................... 14 
8.2.3. 
Overall Survival ........................................................................................................ 15 
9. 
SAFETY ANALYSIS ..................................................................................................... 15 
9.1. ADVERSE EVENTS ............................................................................................................. 15 
9.1.1. 
Incidence of Adverse Events .................................................................................... 16 
9.1.2. 
Relationship of Adverse Events to Study Treatment ................................................ 16 
9.1.3. 
Severity of Adverse Event ........................................................................................ 17 
9.1.4. 
Serious Adverse Events ............................................................................................ 17 
9.1.5. 
Adverse Events Leading to Treatment Discontinuation (HER-Vaxx only) ............. 17 
9.1.6. 
Death ......................................................................................................................... 18 
9.1.7. 
DLT ........................................................................................................................... 18 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 18 
9.2.1. 
Hematology ............................................................................................................... 18 
9.2.2. 
Serum Chemistry ...................................................................................................... 18 
9.2.3. 
Thyroid Function Test............................................................................................... 19 
9.2.4. 
Serology .................................................................................................................... 19 
9.2.5. 
Pregnancy .................................................................................................................. 19 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 19 
9.4. PHYSICAL EXAMINATION ................................................................................................. 19 
9.5. ECOG .............................................................................................................................. 19 
9.6. LVEF ............................................................................................................................... 19 
9.7. ELECTROCARDIOGRAM ..................................................................................................... 19 
9.8. IMMUNOGENICITY ............................................................................................................ 20 
10. 
INTERIM ANALYSIS ................................................................................................... 20 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 21 
12. 
REFERENCES ................................................................................................................ 21 
13. 
APPENDICES ................................................................................................................. 22 
13.1. 
ALGORITHM FOR CONFIRMED BEST OVERALL RESPONSE (CBOR) ACCORDING TO 
RECIST V1.1 ............................................................................................................................. 22 
13.2. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 24 
13.2.1. 
Table 1: Schedule of Activities Arm 1 (HER-Vaxx + Chemotherapy) ................. 24 
13.2.2. 
Table 2: Schedule of Activities Arm 2 (HER-Vaxx + Pembrolizumab) ............... 28 
13.3. 
TABLE OF CONTENTS FOR TABLE, LISTING AND FIGURE ............................................... 31 


Imugene Limited 
 
Final Statistical Analysis Plan, Version 1.0 
 
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Date Issued: 08Nov2023 
 
  
 
 
 V
List of Abbreviations 
AE 
Adverse Event 
AECI 
Adverse Event of Clinical Interest 
AESI 
Adverse Events of Special Interest 
AGC 
Advanced Gastric Cancer 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
C1D1 
Cycle 1 Day 1 
CI 
Confidence Interval 
CRF 
Case Report Form 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EAS 
Evaluable Analysis Set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EoT 
End of treatment 
FAS 
Full Analysis Set 
FU 
Follow Up 
GEJ 
Gastroesophageal Junction 
IB 
Investigator’s Brochure 
GC 
Gastric Cancer 
GM 
Geometric Mean 
GMT 
Geometric mean titer 
HER2 
Human Epidermal Growth Factor Receptor 2 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICIs 
Immune Checkpoint Inhibitors 
IM 
Intramuscular(ly) 
IMP 
Investigational Medicinal Product 
IMU 
Imugene Limited, Australia 
IMU-131 
Investigational product consisting of P467-CRM in Montanide 
adjuvant 
irAE 
Immune related AE 
KM 
Kaplan-Meier 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGC 
Metastatic Gastric Cancer 
mL 
Milliliter 
MUGA 
Multiple Gated Acquisition (scan) 


Imugene Limited 
 
Final Statistical Analysis Plan, Version 1.0 
 
IMU.131.203 
 
Date Issued: 08Nov2023 
 
  
 
  VI 
N 
Number 
NGS 
Next Generation Sequencing 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD 
Protocol Deviation 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression Free Survival 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
Quartile 1 
Q3 
Quartile 3 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SD 
Standard Deviation 
SOC 
System Organ Class 
SoC 
Standard of Care 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Events 
TMB 
Tumor mutational burden 
µg 
Microgram 
UK/UNK 
Unknown 
WHO 
World Health Organization 
 
 
 
 


Imugene Limited 
 
Final Statistical Analysis Plan, Version 1.0 
 
IMU.131.203 
 
Date Issued: 08Nov2023 
 
  
 
 
 1
1. Introduction 
This Statistical Analysis Plan (SAP) defines the statistical methods and data presentations to be 
used by PPD Biostatistics department in the analysis and presentation of data for the analysis of 
Imugene Limited study number IMU.131.203, entitled “nextHERIZON: An open-label, signal 
generating, phase 2 study of HER-Vaxx in Combination with chemotherapy or pembrolizumab in 
patients with metastatic HER2/neu over-expressing gastric or gastroesophageal junction (GEJ) 
adenocarcinomas who have previously received trastuzumab and progressed on this treatment”. 
The investigational product, IMU-131, which is composed of 3 individual B-cell epitopes (P467) 
selected from Human epidermal growth factor receptor 2 (HER2/neu) structure and conjugated to 
CRM197, which becomes HER-Vaxx when emulsified with excipient Montanide (ISA 51 VG 
Sterile). IMU- 131 induces the patient’s own B cells to produce endogenous anti-HER2/neu 
antibodies. HER-Vaxx (IMU-131) is being developed for the treatment of patients with HER2/neu 
overexpressing metastatic or advanced adenocarcinoma of the stomach or GEJ (referred to as 
advanced gastric cancer [AGC]).  
Pembrolizumab is a potent humanized Immunoglobulin G4 (IgG4) monoclonal Antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD1) 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 PD1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
In Phase 1, Phase 1b of clinical trial of IMU-131, a marked increase in cellular/clinical response 
was observed. Safety data were also well tolerated with no significant local or systemic reactions. 
The preliminary immunology and clinical response data from Phase 2 reveal that the addition of 
HER-Vaxx to chemotherapy significantly prolonged survival. Safety data of Phase 2 and Phase 2 
also indicate that IMU-131 is well tolerated. 
This SAP covers all specified analysis for the interim analysis based on the following documents: 
• Final Protocol, Amendment 4.0, 4 June 2023 
• Electronic case report form (eCRF), 06 July 2023  
2. Objectives 
2.1. Primary Safety Objective 
• To evaluate the safety and tolerability of HER-Vaxx in combination with chemotherapy 
(ramucirumab plus paclitaxel) or pembrolizumab. 
2.2. Primary Efficacy Objective 
• To evaluate the objective response rate (ORR) of HER-Vaxx in combination with 
chemotherapy or pembrolizumab according to RECIST v1.1. 


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 2
2.3. Secondary Objective 
• To evaluate additional efficacy and survival measures (OS, progression free survival [PFS], 
duration of response [DoR]) of HER-Vaxx in each Arm. 
2.4. Exploratory Objectives 
• To evaluate humoral and cellular immunogenicity data of HER-Vaxx plus chemotherapy 
(ramucirumab plus paclitaxel) or pembrolizumab. 
• To evaluate immunogenicity and serum and biochemical markers of tumor progression to 
clinical outcomes of ORR, PFS and DoR. 
• To evaluate Arm-specific associations between clinical outcome and HER2/neu 
expression, PD-L1 expression, and TMB.  
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This study will evaluate safety and efficacy of HER-Vaxx in combination with chemotherapy 
(ramucirumab plus paclitaxel) or pembrolizumab in patients with metastatic GC (mGC)/GEJ 
cancer who have progressed on or after trastuzumab treatment.  
For Arm 2, all patients must be re-assessed for their HER2/neu status prior to enrollment into the 
study due to potential HER2/neu loss during their previous treatment with trastuzumab (Seo, 
2019). Patients must have confirmed HER2/neu overexpression since last progression by tumor 
biopsy (post-progression fresh or archival tissue, or post-progression pathology report). Sponsor 
may approve inclusion based on liquid (blood-based, ctDNA/NGS) biopsy to assess patients’ 
HER2/neu positivity where tumor biopsy is not clinically indicated.  
The study will include 2 treatment Arms that will be independently assessed for their endpoints. 
• Arm 1: HER-Vaxx + chemotherapy (ramucirumab and paclitaxel)  
• Arm 2: HER-Vaxx + pembrolizumab  
Eligibility for Arm 1 requires patients with mGC/GEJ adenocarcinoma overexpressing HER-2/neu 
who have progressed on or after trastuzumab in combination with chemotherapy as first line 
therapy; patients that subsequently progressed on or after trastuzumab deruxtecan or another anti-
HER2 treatment are eligible for enrolment in Arm 1.  Arm 1 eligibility does not depend on prior 
treatment with immune checkpoint inhibitors (ICIs).  
Eligibility for Arm 2 requires that patients be naïve to immune checkpoint inhibitors and have 
progressed on or after first line treatment with a HER-2 targeted therapy including trastuzumab in 
combination with standard of care chemotherapy.  
In both Arms, HER-Vaxx may continue independently of chemotherapy or pembrolizumab until 
treatment discontinuation criterion is met. In Arm 1, chemotherapy may continue independently 
until treatment discontinuation criterion is met if HER-Vaxx has been discontinued.  In Arm 2, 
pembrolizumab may continue independently of HER-Vaxx until treatment discontinuation 
criterion is met, for a maximum of 35 cycles (approximately 2 years).  


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For each Arm, after 8 evaluable patients are enrolled (Stage 1), if 1 or more patients respond (i.e., 
experience CR or PR), an additional 7 evaluable patients will be enrolled in that Arm (Stage 2). If 
there are no responses in Stage 1, then preliminary anti-tumor activity in the group will not have 
been identified and no further patients will be enrolled in that Arm. If the arm continues to Stage 
2, a total of 15 evaluable patients will be studied for that Arm. The Arm will be considered 
successful if ≥ 4 treated patients respond, and the arm may be expanded to enroll 25 patients. This 
design is applied to each arm separately.  
Arm 1 requires a minimum of 5 of 8 patients in Stage 1 and additional 5 patients (i.e., 10 of the 
total 15 patients enrolled) in Stage 2 must have HER2/neu overexpression as assessed by the 
central lab or post-progression pathology report. 
Arm 2 requires that all patients enrolled must have post-progression HER2/neu overexpression 
confirmed locally for eligibility and subsequently assessed by the central lab or post-progression 
pathology report. 
Stage 1 of each arm will include a safety run-in phase with staggered enrollment, with the first 3 
patients receiving their first treatment dose at least 15 days apart. After 3 patients are treated with 
the combination and are considered evaluable for the safety run-in period as defined below, a SRC 
consisting of study investigators, and Sponsor medical monitor will assess the combination to 
ensure an acceptable safety profile has been established before enrolling the remaining patients.  
The primary objectives are to evaluate safety as well as ORR independently for each treatment 
arm. Additional anti-tumor activity in terms of OS, PFS and DoR serve as secondary objectives. 
Exploratory objectives include biomarker evaluation and arm-specific associations of biomarkers, 
including humoral and cellular responses, with measures of clinical response including ORR, OS, 
PFS and DoR. The nextHERIZON study set up is provided in Figure 1. 
Figure 1. Study Schema 
 
Chemotherapy (ramucirumab 8 mg/kg IV on Days 8 and 22 of a 28-day cycle + paclitaxel 80 mg/m2 IV on Days 8, 
15, and 22 of a 28-day cycle). ORR = objective response rate; OS = overall survival; PFS= progression free survival; 
DoR = duration of response.   
Interim analysis is planned when 8 evaluable patients are enrolled or when stage 1 is completed 
for both arms patients. 


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3.1.1. Safety and HER2 Antibody Consideration  
Both Arms will include a safety run-in phase with staggered enrollment with the first 3 patients 
receiving their first treatment dose at least 15 days apart. After 3 patients are treated with the 
combination and are considered evaluable for the safety run-in period as defined below, a SRC 
consisting of study investigators, and Sponsor medical monitor will assess the combination to 
ensure an acceptable safety profile has been established before enrolling the remaining patients.  
3.1.2. Safety Evaluation for Combination in Arm 1 and Arm 2  
Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab plus paclitaxel)  
This combination safety evaluation will be based on three evaluable patients at a single dose level 
of HER-Vaxx plus chemotherapy (ramucirumab plus paclitaxel). An initial 3 patients will be 
treated and observed for the occurrence of DLTs for a period of 29 days (including 3 doses of 
HER-Vaxx and at least 1 cycle of chemotherapy).  Safety data will be reviewed by the SRC before 
further patients are enrolled.  
Arm 2: HER-Vaxx in combination with pembrolizumab  
This combination safety evaluation will be based on three evaluable patients at a single dose level 
of HER-Vaxx plus pembrolizumab. An initial 3 patients will be treated and observed for the 
occurrence of DLTs for a period of 29 days (including 3 doses of HER-Vaxx and at least 1 dose 
of pembrolizumab). Safety data will be reviewed by the SRC before further patients are enrolled. 
Safety data from both Arms will be reviewed by the SRC on an ongoing basis for the duration of 
the study. 
The decision to continue enrollment or extend the safety run-in will be taken by the SRC after 
reviewing all available safety data (including DLTs) from the first 3 evaluable patients that are 
part of the safety run-in and have completed the DLT observation period. The safety run-in can be 
extended by another 3 patients, or all additional patients can be enrolled for Stage 1 based on the 
occurrence of DLTs. 
On an on-going basis, the SRC will review the safety data and make recommendations on the 
continuation of the study following the procedures outlined in the SRC charter. 
The SRC is comprised of study investigators and Sponsor medical monitor. All decisions will be 
documented in the form of minutes. 
Based on the review of available data on safety, the SRC will make recommendations regarding 
further conduct and the scientific and ethical integrity of the study. The SRC will provide one of 
the following recommendations: 
• Arm 1 / Arm 2 is to be continued  
• Arm 1 / Arm 2 is to be stopped  
• Modification of the study to address safety and dosing issues.  


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3.2. Study Endpoints 
3.2.1. Primary Safety Endpoints 
• Frequency and severity of adverse events (AEs) graded by Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.  
• Frequency and severity of immune-related AEs.  
• Frequency of patients discontinuing study treatment due to AEs.  
• Changes and shifts from baseline in clinical laboratory, vital signs, echocardiogram 
or multiple gated acquisition (MUGA) scan and electrocardiogram (ECG) 
parameters.  
3.2.2. Primary Efficacy Endpoint  
• ORR measured from baseline as the proportion of patients achieving a confirmed 
best overall response of complete response (CR) or partial response (PR) according 
to RECIST v1.1 based on local review.  
3.2.3. Secondary Efficacy Endpoints  
• DoR measured from earliest CR or PR until first documentation of PD based on 
RECIST v1.1 or death due to any cause.  
• PFS defined as the time from first dose of study treatment to first documentation of 
progressive disease (PD) based on RECIST v1.1, or to death from any cause.  
• OS defined as the time from first dose of study treatment to death from any cause.  
3.2.4. Exploratory Endpoints  
• Values and changes from baseline in humoral and cellular immunogenicity 
including P467-specific antibodies, HER2-specific antibodies, vaccine-specific 
cytokine levels and regulatory and effector T and B cells.  
• Evaluation and Arm-specific associations of serum and biochemical markers of 
tumor progression and immunogenicity, including humoral and cellular responses, 
with measures of clinical response including ORR, OS, PFS and DoR.  
• Analysis of HER2/neu expression, PD-L1 expression and TMB in pre- and post-
treatment tumor biopsies / liquid biopsies (circulating tumor DNA [ctDNA]/next 
generation sequencing [NGS]).  
 
 


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3.3. Treatments   
The following treatment supplies will be used in the study: 
Product 
Supplied as: 
HER-Vaxx  
The dose of HER-Vaxx to be used in combination with 
chemotherapy or pembrolizumab will 100 μg. 
A 1.0ml volume of HER-Vaxx will be administered 
Intramuscular(ly) (IM) on Days 1, 15, 29 and 57 and then every 63 
days until treatment discontinuation criterion is met 
Ramucirumab + 
Paclitaxel 
Patients in Arm 1 will receive intravenous (IV) administration of 
chemotherapy (ramucirumab 8 mg/kg IV on Days 8 and 22 + 
paclitaxel 80 mg/m2 IV on Days 8, 15, and 22 of a 28-day cycle). 
Pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg every 
3 weeks (Q3W) starting on Day 8. 
3.4. Dose Adjustment/Modifications 
Dose modification/adjustment are allowed in this study based on Immune related AEs, infusion-
reactions, patient conditions, cumulative toxicities, etc. The details are given in 6.3 of Protocol. 
4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e., n, mean, standard deviation, 
median, minimum, and maximum). Categorical data will be described using the patient count and 
percentage in each category. For the summary statistics of all numerical variables unless otherwise 
specified, minimum and maximum will be displayed to the same level of precision as reported. 
Mean and median will be displayed to one level of precision greater than the data collected. 
Standard deviation / standard error will be displayed to two levels of precision greater than the 
data collected.   
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for missing values. The denominator for all 
percentages will be the number of patients within the analysis set of interest, unless otherwise 
specified. Percentages will be presented to one decimal place except for the display of 100% 
frequency which will be displayed as ‘XX (100)’.  
Data will be displayed in all listings sorted by treatment arm, patient number and visit, if 
applicable. Listings will include all visits including unscheduled visits. 
The arms will be displayed as: 
• Arm 1: HER-Vaxx + chemotherapy (ramucirumab and paclitaxel)  
• Arm 2: HER-Vaxx + pembrolizumab  
Due to a smaller number of patients in any of the arms, it might be possible that table and figure 
will have only one arm displayed, the details of the same are mentioned in respective sections.  


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Along with the treatment arms, “Overall” column will also be displayed for the overall patients in 
both of the arms in all safety tables, unless otherwise stated. 
“No data available for this report” will be presented when there are no data available to report. 
Unless otherwise specified, baseline will be defined as the last non-missing observation prior to 
first dose of study treatment. Study day is defined as:  
• Visit/examination date – date of first study treatment administration when date is prior to 
the date of first study treatment administration (day 1). 
• Visit/examination date – date of first study treatment administration + 1 when date is after 
day 1 
For summaries by visit, if multiple records fall on the same visit, then the record which is closest 
to the target visit will be considered. In case of a tie, the record with the earlier date will be chosen. 
If multiple records on same day, will consider the latest record. Unless otherwise specified, 
unscheduled and early discontinuation results will not be summarized but will be listed. 
The end of treatment visit date is defined as the last dose date + 30 days in case if end of treatment 
visit date is missing. The end of the study is defined as the date mentioned in End of Study eCRF 
page. 
For the purpose of inclusion in tables, incomplete start and stop dates (e.g., AEs and 
prior/concomitant medication) will be imputed as follows: 
Missing start dates (where UK and UNK indicate unknown or missing day and month respectively) 
will be handled as follows: 
• 
UK-MMM-YYYY: If the month and year are different from the month and year of the first 
dose of study treatment, assume 01-MMM-YYYY. If the month and year are the same as 
the first dose of study treatment month and year and the stop date (after any imputation) is 
on or after the first dose of study treatment, then assume the date of the first dose of study 
treatment. If the month and year are the same as the first dose of study treatment month 
and year and the stop date (after any imputation) is prior to the first dose of study treatment, 
then assume the stop date for the start date; 
• 
UK-UNK-YYYY: If the year is different from the year of first dose of study treatment, 
assume 01-JAN-YYYY of the collected year. If the year is the same as the first dose of 
study treatment year and the stop date (after any imputation) is on or after the first dose of 
study treatment, then assume the date of the first dose of study treatment. If the year is the 
same as the first dose of study treatment and the stop date (after any imputation) is prior to 
the first dose of study treatment, then assume the stop date for the start date.  
Missing stop dates (where UK and UNK indicate unknown or missing day and month respectively) 
will be handled as follows:  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
UK-UNK-YYYY: Assume 31-DEC-YYYY. 
If a patient dies during the study and the AE is ongoing at the time of death, then the stop date will 
set to missing.  
In case of missing historical dates which happened before treatment start date, such as initial cancer 
diagnosis date, the missing dates will be handled as follows 


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• 
UK-MMM-YYYY: Assume the 1st day of the month; 
• 
UK-UNK-YYYY: If the year is same as the year of first dose of study treatment, assume 
01-JAN-YYYY of the collected year, else assume 01-JUL-YYYY in case if year is 
different from first dose of study treatment. 
4.1. Sample Size 
The study plans to enroll 15 evaluable patients into each Arm of the study, for a total of 
approximately 30 evaluable patients.  
For each Arm, after 8 evaluable patients are enrolled (Stage 1), an additional 7 evaluable patients 
will be enrolled in that group (Stage 2) if 1 or more patients respond (i.e., experience CR or PR). 
If there are no responses in Stage 1, then preliminary anti-tumor activity in the group will not have 
been identified and no further patients will be enrolled in that Arm. If the Arm continues to Stage 
2, a total of 15 evaluable patients will be studied for that Arm. The Arm will be considered 
successful if ≥ 4 treated patients respond and the Arm may be expanded to enroll 25 patients. This 
design is applied to each Arm separately and is based on a 2-stage Simon Minimax design for a 
total of 15 evaluable patients (null hypothesis that ORR ≤ 11% versus the alternative hypothesis 
that ORR ≥ 40% with alpha=0.07268 and power=90.463%). 
4.2. Randomization and Blinding 
This is an open-label non-randomized study. Randomization and blinding are not applicable. 
4.3. Analysis Set 
The following analysis population sets will be used in this study: 
4.3.1. All Enrolled Set 
The all enrolled set will comprise of all patients who sign an ICF. 
4.3.2. Safety Analysis Set   
The safety analysis set (SAF) consists of all patients who receive at least one dose of study 
treatment (HER-Vaxx). All safety and tolerability evaluations will be based on this analysis set. 
Patients will be analyzed according to the actual treatment arm.  
4.3.3. Full Analysis Set 
The full analysis set (FAS), which includes all enrolled patients who receive at least 1 
administration of study treatment (HER-Vaxx), will be used for analyses of OS and may be used 
for additional analyses of selected efficacy and exploratory endpoints. Patients will be analyzed 
according to the planned treatment arm. 
4.3.4. Evaluable Analysis Set 
The evaluable analysis set (EAS), which includes all patients who receive at least 1 administration 
of study treatment and have an evaluable baseline tumor assessment and who have at least one 
evaluable post-baseline tumor response assessment as per RECIST v1.1 or were discontinued due 


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to toxicity, will be the primary analysis set for analyses of response-based anti-tumor activity 
endpoints. Patients will be analyzed according to the planned treatment arm. 
5. Patient Disposition 
5.1. Disposition 
A summary of the analysis sets based on all enrolled set includes the number and percentage of 
patients for the following categories: all enrolled set, safety analysis set, full analysis set and 
evaluable analysis set. All percentages will be based on the number of patients in safety analysis 
set. A listing will be presented by patients for showing each patient in which analysis population 
set they are included. Screen failure patients will also be presented in this listing.  
Patient disposition will be summarized by treatment arm and overall using all enrolled set. A 
disposition of patients includes the number of screen failure patients, number of patients who 
received at least one dose of study treatments (HER-Vaxx) and the number and percentage of 
patients for following categories: patients who completed study treatment, patients who 
discontinued study treatment, patients who completed the study, patients who discontinued from 
the study and survival status at end of study.  
The primary reasons for study treatment discontinuation and study participation discontinuation 
will also be summarized in this table.   
Patient disposition listing will be presented by treatment arm using all enrolled set. 
5.2. Protocol Deviations 
The number and percentage of patients with significant protocol deviation will be summarized for 
Arm 1. Protocol deviations will be listed with date of occurrence, deviation category, deviation. 
All summaries will be performed by treatment arms using the safety analysis set and listing will 
be based on all enrolled set. 
6. Demographics and Baseline Characteristics 
A summary of demographics and baseline information will be presented by treatment arms using 
safety analysis set. 
6.1. Demographics 
The demographic characteristics consist of age (years), gender, child-bearing potential, height 
(cm), weight (kg), BMI (kg/m2), ethnicity and race. 
Age (years), height (cm), weight (kg) and BMI (kg/m2) will be summarized using descriptive 
statistics. The number and percentage of patients by gender (Male, Female), child-bearing potential 
(Yes, No), ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), race 
(Black or African American, American Indian or Alaska Native, Asian, Native Hawaiian or Other 
Pacific Islander, White, Other and Not reported) will also be summarized. Percentages will be 
based on the total number of patients in the safety analysis set except for fertility status which will 
be based on the number of female patients.  


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6.2. Baseline Characteristics 
Summary for the following disease characteristics will be provided: 
• Baseline Eastern Cooperative Oncology Group (ECOG) performance status  
• Baseline left ventricular ejection function (LVEF) 
• HER2 Status (HER2++ or HER2+++ vs HER2+) 
• Prior Lines of Treatment (≤2 vs ≥3) 
• Prior use of ENHERTU treatment (Yes vs No) 
Demographic and baseline characteristics will be presented in listings using safety analysis set. 
6.3. Medical History 
6.3.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0. The number and percentage of patients with any medical history will be summarized 
by Arm 1, for each system organ class and preferred term. Percentages will be calculated based on 
number of patients in the safety analysis set.  
Patient medical history data including specific details will be presented in a listing using safety 
analysis set. All summaries will be performed by treatment arm using the safety analysis set. 
6.3.2. Oncology and Surgical History 
The number and percentage of patients includes following categories related to oncology history 
will be summarized by Arm 1 using safety analysis set. 
• 
Time from initial gastric cancer diagnosis to start of study treatment (as categories: <1 
month, 1- <6 months, 6- <12 months, ≥12 months): Date of first dose - Date of initial 
gastric cancer diagnosis in months.  
• 
Initial tumor diagnosis type (Gastroesophageal junction (GEJ) adenocarcinoma, Gastric 
adenocarcinoma) 
• 
Overall stage at diagnosis (0, IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV) 
• 
Time from last disease progression prior to screening to start of study treatment (as 
categories: <1 month, 1- <6 months, 6- <12 months, ≥12 months): Date of first dose - Date 
of last disease progression prior to screening. 
• 
Disease extent at initial diagnosis (Resectable, Borderline Resectable, Unresectable locally 
advanced, Unresectable and metastatic) 
• 
Tumor grade at screening (Tumor grade 3, Tumor grade 4) 
• 
Primary tumor (Tx, T0, Tis, T1, T2, T3, T4) 
• 
Regional lymph nodes (Nx, N0, N1, N2, N3) 
• 
Distant metastasis (Mx, M0, M1) 


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The number and percentage of patients includes following categories related to prior surgery will 
be summarized by Arm 1 using safety analysis set. 
• 
Any prior surgery for gastric cancer (yes, no) 
• 
Any surgery for gastric cancer (yes, no) 
• 
Type of Surgical Procedure (Endoscopic resection, Subtotal (partial) gastrectomy, Total 
gastrectomy, Placement of a feeding tube, Lymph node removal, Palliative surgery for 
unresectable cancer, Other) 
• 
Time from surgery to start of study treatment (as categories: <1 month, 1- <6 months, 6- 
<12 months, ≥12 months): Date of first dose - Date of surgery in months. 
All oncology history data will be listed by treatment arms and patient using the safety analysis set.  
To calculate duration in months, days will be converted to months by dividing the number of days 
by 30.4375. 
6.4. Inclusion and Exclusion Criteria 
The details of the inclusion and exclusion criteria can be found in Sections 4 of the protocol. The 
patients who have not met eligibility criteria will be listed using enrolled population along with 
their details of inclusion criteria not met and/or exclusion criteria met. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
All prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHODRUG Version B3-March 2022). The total number of prior and/or concomitant 
medications and the number and percentages of patients with at least one prior and/or concomitant 
medication will be summarized by Arm 1. The number and percentages of patients with all prior 
and/or concomitant medications will be summarized by treatment arm and overall, by Anatomical 
Therapeutic Chemical (ATC) and preferred term. If the ATC level 4 for the drug class is not 
available, level 3 will be used instead. Prior and/or concomitant medications will be presented in 
a listing. All summaries and listing will be performed using the safety population. 
A prior medication is defined as any medication started and ended prior to the first study treatment. 
A concomitant medication is defined as any medication started or continuing or ended after first 
dose of study treatment up to 30 days after the last dose of study treatment.  
In instances where a medication start date is incomplete, it will be conservatively imputed to 
determine whether or not the medication was prior or concomitant. If the start date and end date 
are missing, then it will be assumed to be concomitant. Imputation details for missing concomitant 
medication start and end date are presented in Section 4. 
Prior and concomitant medications will be listed by treatment arms using safety analysis set. 
7.2. Prior and Concomitant Drug Therapies and Medications 
All prior and concomitant systemic therapies and medications will be coded and analyzed similar 
to Section 7.1 .  


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Prior therapies and medications are those with the start and stop dates prior to the first dose of the 
study; while concomitant systemic therapies and medications are those with start or stop dates after 
the first dose of the study. Partial dates will be imputed as per algorithm presented in Section 4. 
Other details include time from last therapy to start of study treatment (as categories: <1 month, 
1- <6 months, 6- <12 months, ≥12 months), regimen number, best overall response and reason 
drug stopped will be summarized with number of patients and percentage by Arm 1. All available 
information related to systemic therapies will be listed separately, by each treatment arms and 
patient using the safety analysis set. 
7.3. Prior and Concomitant Radiotherapy 
The number and percentage of patients having prior radiation therapy or concomitant radiotherapy, 
location, primary reason for radiotherapy will be summarized by Arm 1. The numeric results 
include total dose received will be summarized descriptively by Arm 1, and related details will be 
listed separately by each treatment arms and patient using the safety analysis set. 
7.4. Concomitant Procedure/Surgery 
Concomitant Procedure/Surgery will be coded using Version 25.0 of the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of patients with concomitant 
procedures coded to each MedDRA system organ class (SOC) and preferred term (PT) along with 
reason of procedure will be summarized by Arm 1 and listed by treatment arms using the safety 
analysis set. At each level of summarization, a patient is counted once if the patient reported one 
or more procedure at that level. 
7.5. Study Treatments 
7.5.1. Extent of Exposure 
The following will be summarized using descriptive statistics: 
• Duration of HER-Vaxx (weeks) will be calculated as ((last HER-Vaxx dose date - HER-
Vaxx start date + 1)/7) 
• Duration of exposure (weeks) will be calculated as ((maximum of end date (HER-Vaxx, 
Ramucirumab, Paclitaxel, Pembrolizumab) - HER-Vaxx start date + 1)/7) 
For patients who are still treatment ongoing at the clinical cutoffs, the end date will be earlier date 
of the clinical cutoff date and the maximum date among the exposure data captured on the HER-
Vaxx/ Ramucirumab/ Paclitaxel/ Pembrolizumab Administration eCRF pages depends upon the 
summary. 
• Number of patients started Cycle 1, Cycle 2, Cycle 3 and so on will be presented by count 
and percentage  
• Number of patients completed Cycle 1, Cycle 2, Cycle 3 and so on, will be presented by 
count and percentage 
• Number of HER-Vaxx doses 
• Cumulative actual total volume of HER-Vaxx (mL) administered 


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• Cumulative actual total volume of Ramucirumab (mL) administered 
• Cumulative actual total volume of Paclitaxel (mL) administered 
• Cumulative actual total volume of Pembrolizumab (mL) administered 
All summaries and listings will be performed by treatment arms using the safety analysis set. 
8. Efficacy Analysis 
The objective of efficacy analysis in this study is to assess the objective response rate (ORR) and 
survival measures (Overall Survival [OS], progression free survival [PFS], duration of response 
[DoR]) of HER-Vaxx in combination with chemotherapy or pembrolizumab. Tumor response 
assessment will be based on RECIST v1.1 according to the Schedule of Events given in Appendix 
13.2. 
All the summary of primary and secondary efficacy analysis will be presented for Arm 1 using 
evaluable analysis set, while listing will be for both treatment arms using full analysis set, unless 
otherwise stated. 
8.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is objective response rate (ORR). The confirmed best overall 
response for each patient will be derived using algorithm given in Appendix 13.1.  
8.1.1. Objective Response Rate 
The objective response rate (ORR) is defined as the proportion of patients achieving a confirmed 
best overall response of complete response (CR) or partial response (PR) according to RECIST 
v1.1 based on local review prior to disease progression or initiation of further anti-cancer therapy 
during the study treatment period across all the time points. The non-responders (including missing 
or unknown best objective response (BOR) patients) also be included in denominator.  
The overall response rate will be summarized by using binomial response rates and their 
corresponding two-sided 95% exact confidence intervals using the Clopper-Pearson method by 
Arm 1 using evaluable analysis set. 
8.2. Secondary Efficacy Endpoint 
All radiographic assessment will be done according to Response Evaluation Criteria in Solid 
Tumors version v1.1 (RECIST v1.1). 
8.2.1. Duration of Response 
Duration of response will be calculated in weeks and is defined as the time from the first 
observation of CR or PR to first documented progressive disease (PD), or death due to any cause. 
Duration of response will be censored at the last adequate tumor assessment date if the patient has 
not progressed, or the last assessment showing non-PD or unconfirmed PD. 
Duration of response will each be summarized using the Kaplan-Meier method by Arm 1. The 
median survival times will be estimated by the Kaplan-Meier method and presented along with 
their corresponding 95% CI. The 25th percentile and 75th percentile for the survival times along 
with the corresponding 95% CI for the percentiles will also be displayed, CI will be calculated 
using Brookmeyer and Crowley method. Kaplan-Meier curves will also be produced. 


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The same summary including KM plot for duration of response will be repeated for subgroup 
HER2 status (HER2++ or HER2+++ vs HER2+), prior lines of treatment (≤2 vs ≥3) and prior use 
of ENHERTU treatment (Yes vs No). 
8.2.2. Progression Free Survival 
Progression Free Survival (PFS) will be calculated in weeks and is defined as the time from the 
first dose date of study treatment to first observation of documented progressive disease, or to 
death due to any cause. PFS will be censored at last adequate tumor assessment date showing non-
PD or unconfirmed PD, or death happened from last adequate tumor assessment date showing non-
PD, or if new anti-cancer treatment started. Patients who neither progressed or died, nor initiated 
any alternate anticancer therapy at time of data cutoff for study analysis or who are lost to follow-
up, PFS will be censored at date of last documented response assessment. 
Table 8.1: Censoring Scheme 
Situation 
Date of Progression 
Outcome 
No on study tumor assessments and 
no death/no new anti-cancer 
treatment within 12 weeks after first 
dose 
Date of first dose (C1D1) 
Censored 
New anti-cancer treatment within 12 
weeks after first dose without a prior 
reported progression or tumor 
assessment 
Date of first dose (C1D1) 
Censored 
Death within 12 weeks after first 
dose or previous tumor assessment 
without progression and without 
subsequent anti-cancer therapy 
Date of death 
Death 
PD/death or new anti-cancer 
treatment observed after 12 weeks 
from previous tumor assessment 
Date of last tumor assessment 
performed before the PD/death or 
new anti-cancer treatment 
Censored 
Progression documented between 
scheduled visits within 12 weeks 
from previous tumor assessment.   
Date of the first documented 
tumor progression  
Progressed  
New anticancer treatment started 
without a prior reported progression 
within 12 weeks from previous 
tumor assessment 
Date of last tumor assessment 
performed before new anti-
cancer treatment 
Censored 
On study tumor assessments but No 
progression, No death, No new anti-
cancer treatment 
Date of last adequate tumor 
assessment 
Censored 
PFS will be summarized using the Kaplan-Meier method for Arm 1 in a similar way as DoR 
defined in Section 8.2.1 along with progression free survival rates at different timepoints. 
The same summary including Km plot for progression free survival will be repeated for subgroup 
HER2 status (HER2++ or HER2+++ vs HER2+), prior lines of treatment (≤2 vs ≥3) and prior use 
of enHERTU treatment (Yes vs No). 


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8.2.3. Overall Survival 
Overall Survival (OS) will be calculated from the date of the first dose of study treatment to the 
date of death due to any cause. Patients who alive or lost to follow-up will be censored at the last 
documented date alive.  
Overall survival will be summarized and presented using the Kaplan-Meier method in a similar 
way as DoR defined in Section 8.2.1 along with progression free survival rates at different 
timepoints but based on FAS.  
The same summary including KM plot for progression free survival will be repeated for subgroup 
HER2 status HER2++ or HER2+++ vs HER2+), prior lines of treatment (≤2 vs ≥3) and prior use 
of enHERTU treatment (Yes vs No). 
Responses and survival status will also be presented graphically with a Swimmer plot; each patient 
will be presented with one horizontal line, with the start and end of treatment, start and end of 
response, clinical progression and death marked where applicable. 
9. Safety Analysis 
All analyses of safety will be conducted using the safety analysis set, unless specified otherwise. 
9.1. Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical study patient administered with 
a medicinal product and which does not necessarily have a causal relationship to study treatment.  
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following conditions: 
• begins on or after the first dose of study treatment. 
• begins before the first dose of study treatment and worsens in severity on or after the first 
dose of study treatment. 
• Lasts until 30 days after the last HER-Vaxx dose (for Arm2 also after last pembrolizumab 
dose) 
• is completely missing a start date and stop date. 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as explained in Section 4.0. 
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) according to 
MedDRA (Version 25.0).  
An overview summary of AEs using number and percentage of patients and events for the 
following categories will be provided by treatment arms and overall. Percentages will be calculated 
using number of patients in the safety analysis set.  
• Adverse Events (AEs) 
• Treatment Emergent Adverse Events (TEAEs)  
• Serious TEAEs 
• Dose Limiting Toxicity (DLT) 


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• Grade 3 or higher TEAEs: will be showed by combining CTCAE grading and Intensity 
grading, where Intensity grading is for local injection site adverse events, while CTCAE 
grading is for other remaining adverse events  
• Treatment-related TEAEs: will be showed separately for HER-Vaxx, Ramucirumab, 
Paclitaxel and Pembrolizumab  
• Treatment-related serious TEAEs: will be showed separately for HER-Vaxx, 
Ramucirumab, Paclitaxel and Pembrolizumab  
• TEAE leading to dose reduction or interruption: will be showed separately for HER-Vaxx, 
Ramucirumab, Paclitaxel and Pembrolizumab  
• TEAE leading to treatment discontinuation: will be showed separately for HER-Vaxx, 
Ramucirumab, Paclitaxel and Pembrolizumab 
• AE leading to death. 
• Local Injection Reactions 
• Immune Related Adverse Event (irAE) 
• AE of Clinical Interest (AECI) 
9.1.1. Incidence of Adverse Events 
Summaries of the total number of TEAEs and the number and percentage of patients with at least 
one TEAE will be provided by treatment arms and overall. Treatment-emergent AEs will be 
presented by SOC and PT. Same tables will be repeated by PT (i.e., without SOC) separately. At 
each level of patient summarization, a patient is counted once if the patient reported one or more 
events. Percentages will be calculated using number of patients in the safety analysis set.  
TEAEs will be sorted in descending order of frequency of SOC based on the total of all treatment 
arms.  Within each SOC, PTs will also be sorted in descending order of frequency of preferred 
terms. TEAEs will be sorted in descending order of frequency of PT based on the total of all 
treatment arms in the by PT (i.e., without SOC) table(s). 
All AEs collected in the study will be presented in a listing including, but not limited to, verbatim 
term, preferred term, system organ class, NCI CTCAE/intensity grade and relationship to study 
treatment (HER-Vaxx, Ramucirumab, Paclitaxel and Pembrolizumab) using safety analysis set.   
9.1.2. Relationship of Adverse Events to Study Treatment 
A summary of related TEAEs to study treatment (HER-Vaxx only) will be presented in a table by 
incidence of occurrence. The investigator will provide an assessment of the relationship of the 
event to the study treatment. The possible relationships are ‘Definite’, ‘Probable’, ‘Possible’, 
‘Unlikely’, ‘Not related’ and ‘Not applicable’. The ‘Related’ relation includes ‘Definite’, 
‘Probable’, ‘Possible’. In the TEAE relationship table, if a patient reports multiple occurrences of 
the same TEAE, only the most closely related occurrence will be presented. Treatment emergent 
AEs that are missing a relationship or with a relationship other than listed will be presented in the 
summary table as “Related” but will be presented in the data listing with a missing relationship or 
the actual relationship respectively. Percentages will be calculated using number of patients in the 
safety analysis set. 


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A separate similar table will be created for related TEAEs associated with any treatment (HER-
Vaxx, Ramucirumab, Paclitaxel and Pembrolizumab). 
The related TEAE data will be categorized and presented by SOC, PT in a manner similar to that 
described in Section 9.1.1.  
9.1.3. Severity of Adverse Event 
A summary of TEAEs with Grade 3 or higher will be presented in a table. The severity that will 
be presented represents the most extreme severity captured on the CRF page. The possible 
intensities for local injection site adverse events are “Absent (Grade 0)”, “Mild (Grade 1)”, 
“Moderate (Grade 2)”, “Severe (Grade 3)” while possible gradings for other AEs are “Grade 1 
(Mild)”, “Grade 2 (Moderate)”, “Grade 3 (Severe)”, “Grade 4 (Life-threatening)” and “Grade 5 
(Death)”. 
In the TEAE severity table, if a patient reported multiple occurrences of the same TEAE, only the 
most severe will be presented. Treatment-emergent AEs that are missing severity will be presented 
in tables as missing only.  Percentages will be calculated using number of patients in the safety 
analysis set. 
The TEAE with Grade 3 or higher data will be categorized and presented by SOC, PT in a manner 
similar to that described in Section 9.1.1. The same will be presented in another table for the 
TEAEs related to study treatment.   
9.1.4. Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose results in 
death, is life-threatening, is a congenital anomaly/birth defect, requires in-patient hospitalization 
or prolongation, or results in significant disability/incapacity. 
A serious treatment-emergent AE (Serious TEAE) is defined as an SAE that meets any of the 
following conditions: 
• begins on or after the first dose date of study treatment. 
• begins before the first dose date of study treatment and worsens in severity on or after the 
first dose of study treatment. 
• Lasts until 90 days after the last HER-Vaxx dose (for Arm2 also after last pembrolizumab 
dose) 
Serious treatment-emergent adverse events (Serious TEAEs) will be presented in a table.  
The treatment-emergent SAE data will be categorized and presented by SOC and PT in a manner 
similar to that described in Section 9.1.1. 
A summary of treatment related serious TEAEs to study treatment (HER-Vaxx only) will also be 
presented in a table as mentioned in Section 9.1.2.  
9.1.5. Adverse Events Leading to Treatment Discontinuation (HER-Vaxx only) 
A summary of TEAEs where the answer to “Action Taken with HER-Vaxx” is “Permanently 
discontinued” will be presented in a table by SOC and PT in a manner similar to that described in 
Section 9.1.1. At each level of patient summarization, a patient is counted once if the patient 


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reported one or more events. Percentages will be calculated using number of patients in the safety 
analysis set.   
9.1.6. Death 
A summary of AEs where the answer to “Outcome” is “Death” will be presented in a table by SOC 
and PT in a manner similar to that described in Section 9.1.1. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. Percentages 
will be calculated using number of patients in the safety analysis set.  
9.1.7. DLT 
A listing of DLTs will also be reported for the safety run-in phase of Arm 1 and 2. 
9.2. Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a local laboratory. All summaries and listings will 
be presented in SI units.  
All clinical laboratory test results will be summarized using descriptive statistics or frequency table 
and also presented in listings by treatment arm, patient and visit using safety analysis set. The 
numeric results will be presented for observed and change from baseline values. 
All relevant clinical laboratory tests results will be classified as Low, Normal, and High, or 
Normal/Abnormal according to the normal ranges, and will be presented in listings. 
The numeric parameters will be graded using CTCAE v5.0, for applicable tests. Shift in toxicity 
grades from baseline to worst post-baseline will be presented in a table.  
If any laboratory value falls above or below the upper or lower level of quantification, the value 
of the upper or lower level of quantification will be taken (e.g., <0.2 will become 0.2) for 
summaries but left as recorded in the listing. If multiple results fall on the same visit, these will be 
handled as per the rules mentioned in Section 4.  
9.2.1. Hematology 
Hematology includes complete blood count (CBC), including red blood cell (RBC) count, 
hemoglobin, hematocrit, reticulocyte count, white blood cell (WBC) count with differential 
(neutrophils, bands, eosinophils, basophils, lymphocytes, monocytes, and other cells), platelet 
count, and C-reactive protein (CRP). Descriptive statistics, CTCAE shift tables and listing will be 
presented as described in Section 9.2. 
9.2.2. Serum Chemistry 
Serum chemistry includes Blood urea nitrogen (BUN) or urea, creatinine, sodium, chloride, 
potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, alkaline 
phosphatase, glucose, total bilirubin, direct and indirect bilirubin, lactate dehydrogenase (LDH), 
cholesterol, uric acid, triglyceride levels, gamma glutamyl transpeptidase (GGT), AST, and ALT. 
Descriptive statistics, CTCAE shift tables and listing will be presented as described in Section 9.2. 


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9.2.3. Thyroid Function Test 
Thyroid Function test includes thyroid stimulating hormone (TSH) and free thyroxine (free T4). 
Additional tests may be requested by the investigator in case of abnormal TSH and/or free T4. 
Descriptive statistics, CTCAE shift tables and listing will be presented as described in Section 9.2. 
9.2.4. Serology 
Serology includes HBsAg reactive, Hepatitis C virus antibody and HIV 1/2 antibodies. A summary 
table and listing will be presented as described in Section 9.2. 
9.2.5. Pregnancy 
A listing will be provided for Pregnancy test based on safety analysis set. 
9.3. Vital Sign Measurements 
Summary tables presenting observed values and changes from pre-dose to post-dose will be 
presented for vital sign data, including height (cm), weight (kg), BSA (m2), systolic blood pressure 
(mmHg), diastolic blood pressure (mmHg), heart rate (beats/min), respiratory rate 
(breaths/minute) and temperature (°C) by treatment arms and visit for the patients in the safety 
analysis set. All vital sign result will be presented in a listing by treatment arms, patient and visit 
using safety analysis set.    
9.4. Physical Examination 
The status of a body system and any finding associated with the body system as normal, abnormal 
(clinically significant), abnormal (not clinically significant), not done or not applicable will be 
captured as per schedule of events (Appendix 13.2). Physical examination results will be presented 
in a listing by treatment arms, patient and visit using safety analysis set. 
9.5. ECOG 
Number and percentage of ECOG (Eastern Cooperative Oncology Group) performance status will 
be summarized by treatment arms and visit using safety analysis set. Shifts from baseline to the 
EOT visit in ECOG performance status also will be summarized. A listing of ECOG performance 
grade will be provided by treatment arms, patient and visit using safety analysis set. 
9.6. LVEF 
Actual value and change from baseline in LVEF (%) will be summarized descriptively by 
treatment arms and scheduled visit using safety analysis set. A listing of LVEF data will also be 
provided by treatment arms, patient and visit using safety analysis set.  
9.7. Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at the time points as scheduled 
(Appendix 13.2). 
ECG result values and changes from baseline will be summarized descriptively for all ECG 
parameters including heart rate (beats/minute), PR Interval (msec), QRS Duration (msec), QT 
Interval (msec) by treatment arms for patients in the safety analysis set. Interpretation will be 


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presented with number and percentage of patients by treatment arms and overall and visit using 
safety analysis set.   
All ECG results and interpretation will be presented in a listing by treatment arms, patient and visit 
using safety analysis set. 
9.8. Immunogenicity 
This analysis will be performed using FAS. The level of HER2-specific antibodies and immune 
phenotyping will be assessed in peripheral blood at baseline and at the timepoints as per Appendix 
13.2 while on treatment.  
Values and changes from baseline in immunological data will be summarized by treatment arm 
and visit. Descriptive statistics (minimum, maximum, median, geometric mean, geometric mean 
95% CI, arithmetic mean, standard deviation and Q1, Q3) for actual value and fold rise over 
baseline in HER2-specific antibodies (includes Analysis of HER2/neu expression, PD-L1 
expression and TMB in pre- and post-treatment tumor biopsies / liquid biopsies (circulating tumor 
DNA [ctDNA]/next generation sequencing [NGS])) and immune phenotyping will be tabulated by 
scheduled visit and treatment arms. If results are reported as lower than the minimal limit of assay 
detection, a value equal to half of the minimal limit of assay detection will be imputed in the 
calculation. 
Geometric mean titer (GMT) will be calculated as anti-logarithm of ∑ (log-transformed 
titer/number of patients with titer information). The 95% CI for GMT will be calculated as the 
anti-log transformation of upper and lower limits for a 2-sided CI of the mean of the log-
transformed titers. 
Geometric mean fold rises (GMFR) will be calculated as anti-logarithm of ∑ [log-transformed titer 
ratio of Yi/Bi)/number of patients with titer information], where Yi is the post-dose titer and Bi is 
the baseline titer for patient i. The same data summaries will be provided as GMT. 
Listings of HER2-specific antibodies and immune phenotyping data will be provided using full 
analysis set.  
Associations between immunologic endpoints with clinical outcomes (ORR, OS, PFS and DoR) 
will be assessed by graphical techniques using box plot and scatter plot. 
Analyses of cellular immunogenicity data are conducted by Imugene and is documented 
separately. 
10. Interim Analysis 
This study is designed as a 2- Stage study. Each Arm will be evaluated independently. 
For each Arm, after 8 evaluable patients are enrolled (Stage 1) an additional 7 evaluable patients 
will be enrolled in that Arm (Stage 2) if 1 or more patients respond (i.e., experience CR or PR). If 
there are no responses in Stage 1, then preliminary anti-tumor activity in the group will not have 
been identified and no further patients will be enrolled in that Arm. If the Arm continues to Stage 
2, a total of 15 evaluable patients will be studied for that Arm. The Arm will be considered 
successful if ≥ 4 treated patients respond, and the Arm may be expanded to enroll 25 patients. This 
design is applied to both arms and is based on a 2-Stage Simon Minimax design for a total of 15 


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evaluable patients (null hypothesis that ORR ≤ 11% versus the alternative hypothesis that ORR ≥ 
40% with alpha=0.07268 and power=90.463%). 
The list of Tables, Listings and Figures for Interim analysis are available in Appendix 13.3. 
11. Changes in the Planned Analysis 
The following are the change in the planned analysis.  
• Duration of response is defined as the time from the first observation of CR or PR to first 
documented progressive disease (PD) (confirmed after follow-up scan), or death due to any 
cause in protocol, but SAP consider it as the time from the first observation of CR or PR 
to first documented progressive disease (PD) or death due to any cause. 
• Progression Free Survival (PFS) is defined as the time from the first dose date of study 
treatment to first observation of documented progressive disease (PD; that is confirmed by 
a follow up scan), or to death due to any cause in protocol, but SAP consider it as the time 
from the first dose date of study treatment to first observation of documented progressive 
disease, or to death due to any cause. 
12. References 
• Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median survival 
time. Biometrics, 38, 29-41. doi:10.2307/2530286. 
• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R. et al. New 
response evaluation criteria in solid Tumors: revised RECIST guideline (version1.1). Eur 
J Cancer. 2009; 45:228-47. 
• Shiroiwa T, Fukuda T, Shimozuma K. Cost-effectiveness analysis of trastuzumab to treat 
HER2-positive advanced gastric cancer based on the randomised ToGA trial. Br J 
Cancer, 2011;105(9):1273-8. 
• Wilson, E. B. (1927), “Probable Inference, the Law of Succession, and Statistical 
Inference,” Journal of the American Statistical Association, 22, 209–212. 
 
 


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13. Appendices 
13.1. Algorithm for Confirmed Best Overall Response (CBOR) according to RECIST 
v1.1 
 
1. The best overall response is determined once all the data for the patient is known and is 
defined as the best confirmed response, recorded between the date of first dose and the date 
of the initial objectively documented Tumor progression by the investigator or the date of 
subsequent therapy, whichever occurs first. For patients without documented progression 
or subsequent therapy, all available response will contribute to the CBOR determination. 
The Tumor responses up to progressive disease (PD) will only be considered for CBOR. 
The evaluations after PD will not be considered.   
2. Subsequent assessments for BOR confirmation should be performed no less than 4 weeks 
in between (the sufficient time period is defined on the strength of the schedule of Tumor 
assessments). Patients need to have two consecutive assessments of PR or CR to be a 
responder. As per the study requirement and Schedule of Events defined in Appendix 13.2, 
Tumor imaging assessment is planned at every 8 weeks ± 7 days.  
3. In the case of a stable disease, the follow-up measurements must meet the stable disease 
criteria at least once after the study entry at a minimum interval (usually 6 – 8 weeks) 
similar to the unconfirmed BOR case.  
4. Determine the first time point response as the first assessment of the non-confirmed best 
response (CR > PR > SD > PD) for a patient, then take the first occurrence of the non-
confirmed best response and look at the subsequent assessments within the considered 
period using the following rules given in Table 13-1. 
5. A special case takes place when NE time point assessments occurred. For example, it 
makes sense to consider the following chain of responses PR – NE – PR as a confirmed 
Partial Response.  
6. The following table, based on Appendix from the RECIST v1.1 guidelines, summarizes 
the algorithm describing how Confirmed Response is determined from the overall Tumor 
assessments as assessed by the local Investigator’s review.  
Table 13-1: Confirmed Best Overall Response Algorithm (RECIST v1.1) 
Overall 
Response first 
time point 
Overall 
response at 
subsequent 
time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR  
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 ‘SD’ would depend on whether minimum 
duration for SD was met, otherwise PD.  


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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 
CR 
SD 
SD or PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD or PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD or NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD or PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD or NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
SD 
SD 
SD 
PD 
SD or PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
SD 
NE 
SD or NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
CR, PR, SD 
Missing or 
No further 
assessment 
SD or NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PD 
Missing or 
No further 
assessment 
PD.  
Ignore all assessments after initial overall response of 
PD. 
NE 
NE 
NE 
NE 
Missing or 
No further 
assessment 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
and NE = not evaluable. 
 
  
 
 


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13.2. 
Schedule of Study Procedures 
13.2.1. 
Table 1: Schedule of Activities Arm 1 (HER-Vaxx + Chemotherapy) 
Cycle 
Screening 
(S) 
Cycle 1(T) 
Cycle 2(T) 
Cycle 3 Onwards(T) 
End of 
Treatment(E) 
Survival  
Follow 
Up (U) 
Day 
D-21 to 
D-1 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 
8 
Day 
15 
Day 
22 
  
  
Cumulative Day 
D-21 to 
D-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
 
 
Visit window 
 - 
- 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 7d) 
(+/- 7d) 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
X 
X(A) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy (B) 
X 
  
  
  
  
X 
  
  
  
  
X 
  
Demographics  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical 
Exam (C) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(C) 
X 
X 
X 
X 
  
Weight & Vital 
Signs(D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(D) 
X 
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Radiographic 
Assessment(F)  
  
X 
X(F) 
  
  
Cardiac 
Assessment(G) 
X 
  
  
  
  
  
  
  
  
C4D1(G) 
  
  
  
X 
  
Pregnancy 
Test (H) 
X 
X 
  
  
  
X 
  
  
  
X(H) 
  
  
X 
  
HIV, Hepatitis 
B/C (I) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology, 
Chemistry(J) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(J) 
X 
X 
X 
X 
  
Thyroid 
Function 
Tests(K) 
X 
X 
  
  
  
  
  
  
  
X(K) 
  
  
  
X 
  


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Cycle 
Screening 
(S) 
Cycle 1(T) 
Cycle 2(T) 
Cycle 3 Onwards(T) 
End of 
Treatment(E) 
Survival  
Follow 
Up (U) 
Day 
D-21 to 
D-1 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 
8 
Day 
15 
Day 
22 
  
  
Cumulative Day 
D-21 to 
D-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
 
 
Visit window 
 - 
- 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 
3d) 
(+/- 7d) 
(+/- 7d) 
Exploratory 
Biomarker (L) 
  
X 
X 
  
X 
  
  
X 
  
X(L) 
  
  
  
X 
  
Immunology – 
humoral (M) 
   
X 
X 
  
X 
  
  
X 
  
X 
  
  
  
X 
X  
Immunology –
cellular (N) 
X 
X 
X 
  
X 
  
  
X 
  
X(N) 
  
  
  
X 
  
ctDNA (O) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HER-Vaxx (P) 
  
X 
  
X 
  
X 
  
  
  
X(P) 
  
  
  
  
  
Ramucirumab(Q) 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
Paclitaxel(Q) 
  
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
  
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse 
Events(R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(R) 
Survival/ 
anti-cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Table 1 Footnotes 
A. If screening assessments (Hematology, Blood Chemistry, Thyroid Function Test, Eastern Cooperative Oncology Group [ECOG], Cellular 
Immunology & Pregnancy Test) are performed within 72 hours of the first study treatment administration, the assessments do not have to be 
repeated on Cycle 1, Day 1.   
B. Documentation of HER-2 positivity at diagnosis is required. A screening visit or archival tumor biopsy (either fresh or archival tissue) or post-
progression pathology report should be provided. Cycle 2 and End of Treatment tumor biopsies are optional. The Cycle 2 optional tumor biopsy 
can be taken on any day during Cycle 2. 
C. A limited, symptom-directed physical examination may be performed post Cycle 1, Day 1. Physical exam to be performed at each HER-Vaxx and 
chemotherapy treatment visit. In HER-Vaxx treatment cycles (C3 C5, C7..), physical exam to be performed at each visit in the cycle (while 
chemotherapy continues). In non-HER-Vaxx treatment cycles (C4, C6 C8 ..), physical exam not required at D1, but required at D8, D15, D22 
(while chemotherapy continues). 


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D. Weight and Vital Signs (blood pressure, respiratory rate, heart rate and temperature) to be recorded prior to receiving study treatment. In addition, 
record temperature 30 min (±10 mins) after each HER-Vaxx vaccination. For Arm 1, weight to be used for body surface area (BSA) calculation as 
per institutional practice. Weight & vital signs must be performed at each HER-Vaxx and chemotherapy treatment visit. In HER-Vaxx treatment 
cycles (C3 C5, C7..), weight & vital signs to be performed at each visit in the cycle (while chemotherapy continues). In non-HER-Vaxx treatment 
cycles (C4, C6 C8 ..), weight & vital signs not required at D1, but required at D8, D15, D22 (while chemotherapy continues).  
E. The end of treatment (EoT) visit will be completed at least 30 days after last study treatment.  
F. Radiographic assessments: Cycle 1 assessment can be performed up to 14 days prior to Cycle 1 Day 1 and then every 6 weeks from Cycle 1, Day 
1 within a +/- 3 day window until disease progression, or withdrawal for any other reason. Radiographic assessment is according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 response criteria. Upon PD, a scan will be scheduled 4 to 6 weeks after initial PD scan to 
confirm progression. After discontinuation from the study for any reason other than disease progression, radiographic change will be collected 
every 12 weeks until determination of progressive disease.  
G. Cardiac assessment includes 12-lead ECG and echocardiography or multiple gated acquisition (MUGA) scan. Assessment to be performed at 
Screening, Cycle 4, Day 1 and then Day 1 every 3 cycles and EoT.  Significant abnormal cardiac assessments should be evaluated by a 
cardiologist.   
H. Highly sensitive urine pregnancy test (sensitivity of at least 25 mIU/mL) for all female patients of childbearing potential will be collected once 
each cycle prior to study treatment and/or chemotherapy: 
• on Day 1 of each odd-numbered cycle, starting Cycle 3. 
• on Day 8 of each even-numbered cycle, starting Cycle 4. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Treatment may be delayed until negative 
beta-human chorionic gonadotrophin (BHCG) blood test is received.  
I. 
Testing for human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C is not required unless mandated by a local health authority. 
J. 
Local hematology and chemistry laboratory testing to be collected prior to receiving any study treatment. Local labs can be drawn up to 72 hours 
before any on-study clinic visit. Local labs to be taken at each HER-Vaxx and chemotherapy treatment visit. In HER-Vaxx treatment cycles (C3, 
C5, C7, etc.), safety labs are to be taken at each visit in the cycle (while chemotherapy continues). In non-HER-Vaxx treatment cycles (C4, C6, 
C8, etc.), safety labs are not required at D1, but are required at D8, D15, D22 (while chemotherapy continues). 
K. Thyroid function test to be performed prior to receiving study treatment. Thyroid function test is performed on Day 1 every 2nd cycle from Cycle 3 
onward.  
L. Whole blood for exploratory biomarkers (all exploratory biomarkers except ctDNA which is captured separately per footnote O) to be collected 
prior to administration of study treatment. Exploratory biomarkers to be collected on Day 1 every 2nd cycle from Cycle 3 onward. 
M. Whole blood for humoral immunity samples to be collected prior to administration of study treatment. Blood samples for humoral immunity to be 
collected on Day 1 of every cycle from Cycle 3 onward and every 12 weeks for up to 1 year during Survival Follow Up.  
N. Whole blood for cellular immunity peripheral blood mononuclear cell (PBMC) samples to be collected prior to administration of study treatment. 
Cellular immunity samples to be collected on day 1 of every 2nd cycle from Cycle 3 onward. 
O. Whole blood for ctDNA HER-2 genotyping will be collected prior to administration of study treatment on Day 1 of every cycle. 
P. HER-Vaxx to be administered as indicated for Cycles 1 through 3 and on Day 1 of every 2nd cycle from Cycle 3 (i.e. Cycles 3, 5, 7, …) onward 
until treatment discontinuation criterion is met. Patients to be observed for 30 minutes post HER-Vaxx administration. Note: Please ensure that 
HER-Vaxx is administered at least 48 hours before starting paclitaxel (when scheduled on the same day). 


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Q. Ramucirumab 8 mg/kg IV on Days 8 and 22 of a 28-day cycle + paclitaxel 80 mg/m2 on Days 8, 15, and 22 of a 28-day cycle, for as long as 
clinically indicated. Paclitaxel to be administered at least 48 hours after administration of HER-Vaxx (when scheduled on the same day). 
R. During Survival Follow-Up serious adverse events (SAEs) considered related to study treatment are to be reported 90 days after the final dose of 
study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  
S. Screening can occur across multiple clinic visits within the 21-day screening period.  
T. Each cycle is 28 days. 
U. After study discontinuation and completion of the End of Treatment visit, patients will be followed for survival every 12 weeks (± 7 days) for up 
to 3 years. 
 
 


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13.2.2. 
Table 2: Schedule of Activities Arm 2 (HER-Vaxx + Pembrolizumab) 
Cycle 
Screening 
(T) 
Cycle 1(U) 
Cycle 2(U) 
Cycle 3(U) 
Cycle 4 
Onwards(U) 
End of 
Treatment(F) 
Survival 
Follow Up (V) 
Day 
D -21 to D 
-1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 1 
  
  
Cumulative Day 
D-21 to D-
1 
1 
8 
15 
22 
29 
43 
50 
71 
 
 
Visit window 
 - 
- 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 3d) 
(+/- 7d) 
(+/- 7d) 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
Eligibility 
X 
X(A) 
  
  
  
  
  
  
  
  
  
HER2+ Assessment(B)  
X 
  
  
  
  
  
  
  
  
  
  
Tumor biopsy (C) 
X 
  
  
  
  
X 
  
  
X 
  
Demographics  
X 
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
  
  
  
  
  
  
  
  
  
  
Physical Exam (D) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Weight and vital signs (E) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
ECOG 
X 
X 
  
  
  
  
  
  
  
X 
  
Radiographic 
Assessment(G) 
  
X 
X(G) 
  
  
Cardiac Assessment(H) 
X 
  
  
  
  
  
  
  
X(H) 
X 
  
Pregnancy Test (I) 
X 
X 
  
  
  
X 
  
X 
X 
X 
  
HIV, Hepatitis B/C (J) 
X 
  
  
  
  
  
  
  
  
  
  
Hematology, Chemistry(K) 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
  
Thyroid Function Tests(L) 
X 
X 
  
  
  
  
X 
  
X(L) 
X 
  
Exploratory Biomarker 
(M) 
  
X 
X 
  
X 
  
X 
  
X(M) 
X 
  
Immunology – humoral 
(N) 
  
X 
X 
  
X 
  
X 
  
X 
X 
X  
Immunology – cellular (O) 
X 
X 
X 
  
X 
  
X 
  
X(O) 
X 
  
ctDNA (P) 
 
X 
 
 
 
X 
 
X 
X 
 
 
HER-Vaxx (Q) 
  
X 
  
X 
  
X 
  
 X(Q) 
 
  
  
Pembrolizumab(R) 
  
  
X 
  
  
X 
  
X 
X 
  
  
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Events(S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(S) 
Survival/anti-cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
X 
 


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Table 2 Footnotes 
A. If screening assessments (Hematology, Blood Chemistry, Thyroid Function Test, Eastern Cooperative Oncology Group [ECOG], Cellular 
Immunology, & Pregnancy Test) are performed within 72 hours of the first study treatment administration, the assessments do not have to be 
repeated on Cycle 1, Day 1.  
B. Human epidermal growth factor receptor 2 (HER2/neu+) assessment prior to enrollment. Confirmed HER2/neu overexpression (3+ by 
immunohistochemistry (IHC) or if IHC 2+ confirmed by fluorescent in situ hybridization [FISH], brightfield double in situ hybridization 
[BDISH] or chromogenic in situ hybridization [CISH]) using post-progression fresh or archival tissue, or post-progression pathology report. 
Sponsor may approve inclusion based on liquid (blood based) biopsy to assess patients’ HER2/neu positivity where tumor biopsy is not 
clinically indicated. 
C. A post-progression fresh or archival tumor biopsy sample or post-progression pathology report will be obtained for all patients to confirm 
eligibility. Cycle 2 and End of Treatment tumor biopsies are optional.  The optional tumor biopsy can be taken on any day during Cycle 2. 
D. A limited, symptom-directed physical examination may be performed post Cycle 1, Day 1. The physical exam must be performed prior to 
receiving any study treatment.  
E. Weight and Vital Signs (blood pressure, respiratory rate, heart rate and temperature) to be recorded prior to receiving study treatment. In 
addition, record temperature 30 min (±10 mins) after each HER-Vaxx vaccination.  
F. 
The end of treatment (EoT) visit will be completed at least 30 days after last study treatment. 
G. Radiographic assessments: Cycle 1 assessment can be performed up to 14 days prior to Cycle 1, Day 1 within a +/- 3 day window and then 
every 6 weeks from Cycle 1, Day 1 until disease progression, or withdrawal for any other reason. Radiographic assessment is according to 
response evaluation criteria in solid tumors (RECIST) version 1.1 response criteria. Upon PD, a scan will be scheduled 4 to 6 weeks after 
initial PD scan to confirm progression. After discontinuation from the study for any reason other than disease progression, radiographic 
change will be collected every 12 weeks until determination of progressive disease.  
H. Cardiac assessment includes 12-lead ECG and echocardiography or multiple gated acquisition (MUGA) scan. Assessments to be performed at 
Screening, Cycle 4 Day 1, then every 4 cycles and at EoT.  Significant abnormal cardiac assessments should be evaluated by a cardiologist.           
I. 
Highly sensitive urine pregnancy test (sensitivity of at least 25 mIU/mL) for all female patients of childbearing potential will be collected 
once each cycle prior to study drug treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. Treatment may be delayed until negative beta-human chorionic gonadotrophin (BHCG) blood test is received.  
J. 
Testing for Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C is not required unless mandated by a local health authority. 
K. Local hematology and chemistry laboratory testing to be collected at each study treatment visit prior to receiving any study treatment. Local 
labs can be drawn up to 72 hours before any on-study clinic visit.  
L. Thyroid function test to be performed prior to receiving study treatment. Thyroid function test to be performed on day 1 every 2nd cycle from 
Cycle 4 onward (i.e., cycles 4, 6, 8, 10…).  
M. Whole blood for exploratory biomarkers (all exploratory biomarkers except ctDNA which is captured separately per footnote O) to be 
collected prior to receiving study treatment.  Exploratory biomarker samples to be collected every 3rd cycle from Cycle 4 onward (i.e., cycles 
4, 7, 10…).  
N. Humoral samples to be collected prior to receiving study treatment. Blood samples for humoral immunity to be collected on Day 1 of every 
cycle from Cycle 4 onward and every 12 weeks for up to 1 year during Survival Follow Up. 
O. Cellular immunity peripheral blood mononuclear cell (PBMC) to be collected prior to receiving study treatment. Cellular immunity samples 
to be collected every 3rd cycle from Cycle 4 onwards. 


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P. Whole blood for ctDNA HER-2 genotyping will be collected prior to administration of study treatment on Day 1 of every cycle. 
Q. HER-Vaxx to be administered as indicated for Cycles 1 through 3 and on day 1 of every 3rd cycle from Cycle 3 onward (i.e., cycles 3 6, 9, 
12…)  until treatment discontinuation criterion is met. Patients to be observed for 30 minutes post HER-Vaxx administration. Note: Please 
ensure that HER-Vaxx is administered at least 30-60 minutes before starting pembrolizumab (when scheduled on the same day). 
R. Pembrolizumab 200 mg administered until treatment discontinuation criterion met for a maximum of 35 cycles. Pembrolizumab to be 
administered at least 30-60 minutes following administration of HER-Vaxx (when scheduled on the same day). 
S. During Survival Follow-Up Serious adverse events (SAEs) considered related to study treatment are to be reported 90 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  
T. Screening can occur across multiple clinic visits within the 21-day screening period.  
U. Cycle 1 is 28 days. Cycles from Cycle 2 onwards are 21 days.  
V. After study discontinuation and completion of the End of Treatment visit, patients will be followed every 12 weeks (± 7 days) for up to 3 
years. 
 
 
 


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13.3. Table of Contents for Table, Listing and Figure 
 
S.No. TLF 
Table Title 
Analysis Set 
Required 
 for IA  
1 Table 
Table 14.1.1.1 Analysis Sets 
All Enrolled Set 
Y 
2 Table 
Table 14.1.1.2 Disposition 
All Enrolled Set 
Y 
3 Table 
Table 14.1.1.3 Significant Protocol Deviations 
Safety Analysis Set 
  
4 Table 
Table 14.1.2.1 Demographics and Baseline Characteristics 
Safety Analysis Set 
Y 
5 Table 
Table 14.1.3.1 Medical History 
Safety Analysis Set 
  
6 Table 
Table 14.1.3.2 Oncology and Surgical History 
Safety Analysis Set 
Y 
7 Table 
Table 14.1.4.1 Prior Medication 
Safety Analysis Set 
Y 
8 Table 
Table 14.1.4.2 Concomitant Medications 
Safety Analysis Set 
Y 
9 Table 
Table 14.1.4.3 Prior Drug Therapies and Medications  
Safety Analysis Set 
  
10 Table 
Table 14.1.4.4 Concomitant Drug Therapies and Medications  
Safety Analysis Set 
  
11 Table 
Table 14.1.4.5 Prior and Concomitant Radiotherapies 
Safety Analysis Set 
12 Table 
Table 14.1.4.6 Concomitant Procedures and Surgery 
Safety Analysis Set 
  
13 Table 
Table 14.1.5.1 Drug Exposure  
Safety Analysis Set 
Y 
14 Table 
Table 14.2.1.1 Summary of Confirmed Best Overall Response and 
Objective Response Rate 
Evaluable Analysis 
Set 
Y 
15 Table 
Table 14.2.1.2 Summary of Duration of Confirmed Response using 
KM Method – RECIST v1.1 
Evaluable Analysis 
Set 
Y 
16 Table 
Table 14.2.1.2.1 Summary of Duration of Response using KM 
method RECIST v1.1 by HER2 status 
Evaluable Analysis 
Set 
Y 
17 Table 
Table 14.2.1.2.2 Summary of Duration of Response using KM 
method RECIST v1.1 by prior lines of treatment 
Evaluable Analysis 
Set 
Y 


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18 Table 
Table 14.2.1.2.3 Summary of Duration of Response using KM 
method RECIST v1.1 by prior use of ENHERTU treatment. 
Evaluable Analysis 
Set 
Y 
19 Table 
Table 14.2.1.3 Summary of Progression Free Survival using KM 
method – RECIST v1.1 
Evaluable Analysis 
Set 
Y 
20 Table 
Table 14.2.1.3.1 Summary of Progression Free Survival using KM 
method – RECIST v1.1 by HER2 status 
Evaluable Analysis 
Set 
Y 
21 Table 
Table 14.2.1.3.2 Summary of Progression Free Survival using KM 
method – RECIST v1.1 by prior lines of treatment 
Evaluable Analysis 
Set 
Y 
22 Table 
Table 14.2.1.3.3 Summary of Progression Free Survival using KM 
method – RECIST v1.1 by prior use of ENHERTU treatment 
Evaluable Analysis 
Set 
Y 
23 Table 
Table 14.2.1.4 Summary of Overall Survival using KM Method 
Full Analysis Set 
Y 
24 Table 
Table 14.2.1.4.1 Summary of Overall Survival using KM Method 
by HER2 status 
Full Analysis Set 
Y 
25 Table 
Table 14.2.1.4.2 Summary of Overall Survival using KM Method 
by prior lines of treatment 
Full Analysis Set 
Y 
26 Table 
Table 14.2.1.4.3 Summary of Overall Survival using KM Method 
by prior use of ENHERTU treatment 
Full Analysis Set 
Y 
27 Table 
Table 14.3.1.1 Overall Adverse Events  
Safety Analysis Set 
Y 
28 Table 
Table 14.3.1.2 Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term  
Safety Analysis Set 
Y 
29 Table 
Table 14.3.1.2.1 Treatment-Emergent Adverse Events by Preferred 
Term  
Safety Analysis Set 
  
30 Table 
Table 14.3.1.3 Treatment-Emergent Adverse Events Related to 
Study Drug (HER-Vaxx only) 
Safety Analysis Set 
Y 
31 Table 
Table 14.3.1.4 Treatment-Emergent Adverse Events Related to any 
Study Drug (HER-Vaxx, Ramucirumab, Paclitaxel and 
Pembrolizumab) 
Safety Analysis Set 
32 Table 
Table 14.3.1.5 Treatment-Emergent Adverse Events with Grade 3 
or higher Severity  
Safety Analysis Set 
Y 


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33 Table 
Table 14.3.1.6 Treatment-Emergent Adverse Events with Grade 3 
or higher Severity Related to Study Drug (HER-Vaxx only) 
Safety Analysis Set 
34 Table 
Table 14.3.1.7 Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety Analysis Set 
Y 
35 Table 
Table 14.3.1.8 Treatment Related (HER-Vaxx only) Serious 
TEAEs 
Safety Analysis Set 
Y 
36 Table 
Table 14.3.1.9 Treatment Related (HER-Vaxx, Ramucirumab, 
Paclitaxel and Pembrolizumab) Serious TEAEs Drug  
Safety Analysis Set 
37 Table 
Table 14.3.1.10 Treatment-Emergent Adverse Events Leading to 
Treatment (HER-Vaxx only) Discontinuation  
Safety Analysis Set 
Y 
38 Table 
Table 14.3.1.11 Treatment-Emergent Adverse Events with 
Outcome of Death  
Safety Analysis Set 
Y 
39 Table 
Table 14.3.2.1 Descriptive Statistics of Actual and Change from 
Baseline in Hematology  
Safety Analysis Set 
Y 
40 Table 
Table 14.3.2.2 Shift in Grade from Baseline to worst post-baseline 
in Hematology  
Safety Analysis Set 
Y 
41 Table 
Table 14.3.2.3 Descriptive Statistics of Actual and Change from 
Baseline in Serum Chemistry  
Safety Analysis Set 
Y 
42 Table 
Table 14.3.2.4 Shift in Grade from Baseline to worst post-baseline 
in Serum Chemistry  
Safety Analysis Set 
Y 
43 Table 
Table 14.3.2.5 Descriptive Statistics of Actual and Change from 
Baseline in Thyroid Function Test 
Safety Analysis Set 
Y 
44 Table 
Table 14.3.2.6 Shift in Grade from Baseline to worst post-baseline 
in Thyroid Function Test 
Safety Analysis Set 
45 Table 
Table 14.3.2.7 Summary of Serology 
Safety Analysis Set 
  
46 Table 
Table 14.3.3.1 Descriptive Statistics of Actual and Change from 
Baseline in Vital Signs  
Safety Analysis Set 
Y 
47 Table 
Table 14.3.4.1 Summary of ECOG 
Safety Analysis Set 
Y 


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48 Table 
Table 14.3.4.2 Shift in EOCG Grade from Baseline to EOT 
Safety Analysis Set 
Y 
49 Table 
Table 14.3.5.1 Descriptive Statistics of Actual and Change from 
Baseline in LVEF Results  
Safety Analysis Set 
Y 
50 Table 
Table 14.3.6.1 Descriptive Statistics of Actual and Change from 
Baseline in Electrocardiogram Results  
Safety Analysis Set 
Y 
51 Table 
Table 14.3.6.2 Summary of Interpretation of Electrocardiogram 
Results  
Safety Analysis Set 
Y 
52 Table 
Table 14.3.7.1 Descriptive Statistics of HER2-Specific Antibodies  
Full Analysis Set 
  
53 Table 
Table 14.3.7.2 Descriptive Statistics of Immune Phenotyping 
Full Analysis Set 
  
54 Listing Listing 16.2.1.1 Disposition 
All Enrolled Set 
Y 
55 Listing Listing 16.2.1.2 Inclusion/Exclusion Criteria  
All Enrolled Set 
56 Listing Listing 16.2.2.1 Protocol Deviations  
All Enrolled Set 
57 Listing Listing 16.2.3.1 Analysis Sets 
All Enrolled Set 
Y 
58 Listing Listing 16.2.4.1 Demographics and Baseline Characteristics 
Safety Analysis Set 
Y 
59 Listing Listing 16.2.4.2 Medical History 
Safety Analysis Set 
60 Listing Listing 16.2.4.3 Oncology and Surgical History 
Safety Analysis Set 
Y 
61 Listing Listing 16.2.5.1 Prior and Concomitant Medications 
Safety Analysis Set 
Y 
62 Listing 
Listing 16.2.5.2 Prior and Concomitant Drug Therapies and 
Medications  
Safety Analysis Set 
63 Listing Listing 16.2.5.3 Prior and Concomitant Radiotherapies 
Safety Analysis Set 
  
64 Listing Listing 16.2.5.4 Concomitant Cancer Surgery/Procedures 
Safety Analysis Set 
Y 
65 Listing Listing 16.2.5.6 Study Drug Exposure 
Safety Analysis Set 
Y 
66 Listing Listing 16.2.5.7 HER-Vaxx Administration 
Safety Analysis Set 
Y 
67 Listing Listing 16.2.5.8 Ramucirumab Administration 
Safety Analysis Set 
  
68 Listing Listing 16.2.5.9 Paclitaxel Administration 
Safety Analysis Set 
69 Listing Listing 16.2.5.10 Pembrolizumab Administration 
Safety Analysis Set 
  


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70 Listing Listing 16.2.6.1 Tumor Response Assessment 
Full Analysis Set 
Y 
71 Listing Listing 16.2.6.2 Target, Non-Target and New Lesions 
Full Analysis Set 
  
72 Listing Listing 16.2.6.3 Best Overall Response and Objective Response  
Full Analysis Set 
Y 
73 Listing Listing 16.2.6.4 Duration of Response 
Full Analysis Set 
Y 
74 Listing Listing 16.2.6.5 Progression Free Survival 
Full Analysis Set 
Y 
75 Listing Listing 16.2.6.6 Overall Survival 
Full Analysis Set 
Y 
76 Listing Listing 16.2.7.1 Adverse Events 
Safety Analysis Set 
Y 
77 Listing Listing 16.2.7.2 Serious Adverse Events 
Safety Analysis Set 
  
78 Listing Listing 16.2.7.3 Dose Limiting Toxicity (DLT) 
Safety Analysis Set 
Y 
79 Listing Listing 16.2.8.1 Laboratory Results- Hematology 
Safety Analysis Set 
Y 
80 Listing Listing 16.2.8.2 Laboratory Results- Serum Chemistry 
Safety Analysis Set 
Y 
81 Listing Listing 16.2.8.3 Laboratory Results- Thyroid Function Test 
Safety Analysis Set 
Y 
82 Listing Listing 16.2.8.4 Laboratory Results- Serology 
Safety Analysis Set 
83 Listing Listing 16.2.8.5 Pregnancy Test Results 
Safety Analysis Set 
  
84 Listing Listing 16.2.9.1 Vital Sign Results 
Safety Analysis Set 
Y 
85 Listing Listing 16.2.10.1 Physical Examination Results 
Safety Analysis Set 
  
86 Listing Listing 16.2.11.1 ECOG Results 
Safety Analysis Set 
Y 
87 Listing Listing 16.2.12.1 LVEF Results 
Safety Analysis Set 
Y 
88 Listing Listing 16.2.13.1 Electrocardiogram Results 
Safety Analysis Set 
Y 
89 Listing Listing 16.2.14.1 Immunogenicity Data 
Safety Analysis Set 
Y 
90 Listing Listing 16.2.15.1 Tumor and Liquid Biopsy 
Safety Analysis Set 
91 Listing Listing 16.2.16.1 Biomarker Data 
Safety Analysis Set 
  
92 Figure 
Figure 14.2.1.1 Swimmer Plot for individual patient’s responses 
and survival status 
Evaluable Analysis 
Set 
Y 


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93 Figure 
Figure 14.2.1.2 Best Percent Change in Tumor Size 
Evaluable Analysis 
Set 
94 Figure 
Figure 14.2.1.3 Kaplan-Meier Plot for Duration of Response 
Evaluable Analysis 
Set 
Y 
95 Figure 
Figure 14.2.1.3.1 Kaplan-Meier Plot for Duration of Response by 
HER2 status 
Evaluable Analysis 
Set 
Y 
96 Figure 
Figure 14.2.1.3.2 Kaplan-Meier Plot for Duration of Response by 
prior lines of treatment 
Evaluable Analysis 
Set 
Y 
97 Figure 
Figure 14.2.1.3.3 Kaplan-Meier Plot for Duration of Response by 
prior use of ENHERTU treatment 
Evaluable Analysis 
Set 
Y 
98 Figure 
Figure 14.2.1.4 Kaplan-Meier Plot for Progression-Free Survival  
Evaluable Analysis 
Set 
Y 
99 Figure 
Figure 14.2.1.4.1 Kaplan-Meier Plot for Progression-Free Survival 
by HER2 status 
Evaluable Analysis 
Set 
Y 
100 Figure 
Figure 14.2.1.4.2 Kaplan-Meier Plot for Progression-Free Survival 
by prior lines of treatment 
Evaluable Analysis 
Set 
Y 
101 Figure 
Figure 14.2.1.4.3 Kaplan-Meier Plot for Progression-Free Survival 
by prior use of ENHERTU treatment 
Evaluable Analysis 
Set 
Y 
102 Figure 
Figure 14.2.1.5 Kaplan-Meier Plot for Overall Survival  
Full Analysis Set 
Y 
103 Figure 
Figure 14.2.1.5.1 Kaplan-Meier Plot for Overall Survival by HER2 
status 
Full Analysis Set 
Y 
104 Figure 
Figure 14.2.1.5.2 Kaplan-Meier Plot for Overall Survival by prior 
lines of treatment 
Full Analysis Set 
Y 
105 Figure 
Figure 14.2.1.5.3 Kaplan-Meier Plot for Overall Survival by prior 
use of ENHERTU treatment 
Full Analysis Set 
Y 
106 Figure 
Figure 14.3.1.1 Box Plot for association between Immunology 
(average antibody titer post baseline/patient) and BOR/patient   
Safety Analysis Set 
Y 
107 Figure 
Figure 14.3.1.2 Scatter Plot for association between Immunology 
(average antibody titer post baseline/patient) and DoR/patient 
Safety Analysis Set 


Imugene Limited 
 
 
Final Statistical Analysis Plan, Version 1.0 
IMU.131.203 
 
 
          Date Issued: 08Nov2023 
 
  
 
 
 37 
108 Figure 
Figure 14.3.1.3 Scatter Plot for association between Immunology 
(average antibody titer post baseline/patient) and PFS/patient 
Safety Analysis Set 
Y 
109 Figure 
Figure 14.3.1.4 Scatter Plot for association between Immunology 
(average antibody titer post baseline/patient) and OS/patient 
Safety Analysis Set 
110 Figure 
Figure 14.3.1.4.1 Logarithmic line plot of patient wise antibody 
titer from Baseline to EOT 
Full Analysis Set 
Y