Conditions: Rectal Cancer
Keywords: locally recurrent
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine safety and anti-tumor immune activation generated by TG02 and Granulocyte macrophage colony stimulating factor (GM-CSF), first as monotherapy (Part I), thereafter in combination with the checkpoint inhibitor pembrolizumab (Part II), in patients with locally advanced primary and recurrent colorectal cancer scheduled to have surgery.

Part I will include 4-6 patients and Part II will include up to 10 patients. Part I and Part II are separate and independent sequential components of the study. Patients will only be able to participate in either the Part I cohort or Part II cohort.

Main objective of the study is to investigate safety and immune response after TG02-treatment.

Detailed description:

Arms:
arm 1: Part I: The TG02-treatment consists of an intradermal injection of GM-CSF followed by an injection of TG02. The GM-CSF is to be given 15-30 minutes before TG02. TG02-treatment will be administered on Days 1, 8, 15, 22 and 36. If surgery after week 10, TG02-treatment will also be given at week 10 (Day 64).

Part II: TG02-treatment will be given as described under Part I. In addition pembrolizumab will be administered.

Interventions: intervention 1: TG02-treatment intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
Confidential 
 
Page 1 of 74 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Name:  
CT TG 02-01            
Protocol Title:  
A Non-Randomised Open-Label Phase Ib Exploratory Study of  
 
 
 
 
TG02-treatment as Monotherapy or in Combination with  
 
 
 
 
Pembrolizumab to Assess Safety and Immune Activation in  
 
 
 
 
Patients with Locally Advanced Primary and Recurrent Oncogenic 
RAS Exon 2 Mutant Colorectal Cancer 
                               
Clinical Phase:  
Ib 
 
Version:  
 
Final version 6.0 
 
Date: 
 
 
09 OCT 2018 
 
Sponsor:  
 
Targovax ASA 
 
 
 
 
 
 
 
 
 
 
Statement about proper study conduct 
This study will be conducted in compliance with Good Clinical Practices, according to ICH 
Harmonized Tripartite Guideline. 
 
Confidentiality Statement 
The information in this document is provided to you as an investigator, potential 
investigator, consultant, or contractor, for review by you, your staff, and the appropriate 
Institutional Review Board or Ethics Committee. By accepting this document, you agree that 
the information contained herein will not be disclosed to others without written authorization 
from the lead site/sponsor, except to the extent necessary to initiate the study or conduct 
study-related activities.


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
Confidential 
 
Page 2 of 74 
CLINICAL STUDY PROTOCOL APPROVAL 
 
 
PROTOCOL TITLE: A Non-Randomised Open-Label Phase Ib Exploratory Study of 
TG02-treatment as Monotherapy or in Combination with Pembrolizumab to Assess Safety 
Immune Activation in Patients with Locally Advanced Primary and Recurrent Oncogenic 
RAS Exon 2 Mutant Colorectal Cancer 
 
 
PROTOCOL NAME:  
CT TG02-01                  
 
CLINICAL PHASE: 
 
Ib 
 
VERSION: 
 
 
Final version 6.0 
 
DATE: 
 
 
 
09 OCT 2018 
 
SPONSOR: 
 
 
Targovax ASA 
 
 
This protocol/protocol amendment has been approved by: 
 
 
 
 
 
Magnus Jäderberg                                                           Date 
Chief Medical Officer 
Targovax ASA 
 
 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
Confidential 
 
Page 3 of 74 
CLINICAL STUDY PROTOCOL APPROVAL 
 
 
PROTOCOL TITLE: A Non-Randomised Open-Label Phase Ib Exploratory Study of 
TG02-treatment as Monotherapy or in Combination with Pembrolizumab to Assess Safety 
Immune Activation in Patients with Locally Advanced Primary and Recurrent Oncogenic 
RAS Exon 2 Mutant Colorectal Cancer 
 
 
 
PROTOCOL NAME:  
CT TG02-01                  
 
CLINICAL PHASE: 
 
Ib 
 
VERSION: 
 
 
Final version 6.0 
 
DATE: 
 
 
 
09 OCT 2018 
 
SPONSOR: 
 
 
Targovax ASA 
 
 
This protocol/protocol amendment has been approved by: 
 
 
 
 
 
Dr. Michael Michael                                                       Date       
Medical Oncologist  
Peter MacCallum Cancer Centre 
Melbourne, Australia 
Coordinating Principal Investigator 
 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
Confidential 
 
Page 4 of 74 
CLINICAL STUDY PROTOCOL APPROVAL 
 
 
PROTOCOL TITLE: A Non-Randomised Open-Label Phase Ib Exploratory Study of 
TG02-treatment as Monotherapy or in Combination with Pembrolizumab to Assess Safety 
Immune Activation in Patients with Locally Advancer Primary and Recurrent Oncogenic 
RAS Exon 2 Mutant Colorectal Cancer 
 
 
PROTOCOL NAME:  
CT TG02-01                  
 
CLINICAL PHASE: 
 
Ib 
 
VERSION: 
 
 
Final version  6.0 
 
DATE: 
 
 
 
09 OCT 2018 
 
SPONSOR: 
 
 
Targovax ASA 
 
 
This protocol/protocol amendment has been approved by: 
 
 
 
 
 
 
Oluwaseun Adedeji 
 
 
 
 
Date 
Senior Statistician 
SQN 
 
 
 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
Confidential 
 
Page 5 of 74 
TABLE OF CONTENT 
1. 
ADMINISTRATIVE STRUCTURE AND CONTACT INFORMATION ................. 8 
2. 
ABBREVIATIONS ........................................................................................................ 10 
3. 
PROTOCOL SYNOPSIS .............................................................................................. 12 
4. 
BACKGROUND AND STUDY RATIONALE ......................................................... 20 
4.1. 
Antigen specific anticancer immunotherapy ............................................................... 20 
4.2. 
TG02 ............................................................................................................................ 20 
4.3. 
PD-1 (Programmed Cell Death 1) receptor and its inhibition ..................................... 22 
4.4. 
Pembrolizumab ............................................................................................................ 22 
4.5. 
Locally Advanced Primary Recurrent Colorectal Cancer ........................................... 23 
4.6. 
Rationale for the study ................................................................................................. 24 
4.7. 
Rationale for dose ........................................................................................................ 24 
4.8. 
Rationale for dose regimen .......................................................................................... 25 
5. 
STUDY OBJECTIVES .................................................................................................. 26 
6. 
STUDY DESIGN AND DESCRIPTION OF THE STUDY ....................................... 27 
6.1. 
Endpoints ..................................................................................................................... 27 
6.2. 
Study Design ............................................................................................................... 27 
6.3. 
Study Duration ............................................................................................................. 33 
6.4. 
Study Visit Schedule................................................................................................... 33 
6.4.1. 
Screening Period .................................................................................................. 33 
6.4.2. 
Treatment period (before surgery): ...................................................................... 34 
6.4.3. 
End of Study visit (Up to 6 weeks after surgery) ................................................. 35 
6.4.4. 
Study Flow Chart ................................................................................................. 35 
7. 
SUBJECT SELECTION ............................................................................................... 38 
7.1. 
Description of Study Population ................................................................................ 38 
7.2. 
Number and Source of Subjects ................................................................................. 38 
7.3. 
Inclusion Criteria ........................................................................................................ 38 
7.4. 
Exclusion Criteria ....................................................................................................... 39 
7.5. 
Discontinuation Criteria .............................................................................................. 39 
7.6. 
Replacement Policy .................................................................................................... 40 
8. 
TRIAL TREATMENT(S) AND REGIMEN OF INVESTIGATIONAL 
MEDICINAL PRODUCTS ..................................................................................................... 41 
8.1. 
Identity of Investigational Medicinal Product(s) (IMPs)........................................... 41 
8.2. 
Dosing, Mode of Administration, Duration of Treatment ........................................ 42 


Investigational Product:  
 
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TG02 
 
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8.3. 
Packaging and Labelling ............................................................................................ 43 
8.4. 
Storage, Handling and Dispensing of Investigational Product(s)................................ 44 
8.5. 
Blinding Procedures ................................................................................................... 44 
8.6. 
Randomization and Subject Allocation ..................................................................... 44 
8.7. 
Treatment Compliance ............................................................................................... 45 
8.8. 
Prior and Concomitant Medications .......................................................................... 45 
9. 
STUDY ASSESSMENTS............................................................................................... 47 
9.1. 
Assessment of Efficacy .............................................................................................. 47 
9.1.1. 
Primary Efficacy Variables .................................................................................. 47 
9.1.2. 
Secondary Efficacy Variables .............................................................................. 48 
9.1.3. 
Exploratory Efficacy Variables ............................................................................ 49 
9.2. 
Assessment of Safety .................................................................................................. 49 
9.2.1. 
Adverse Events ..................................................................................................... 49 
9.2.1.1. 
Definitions .................................................................................................... 49 
9.2.1.2. 
Adverse Event Reporting .............................................................................. 50 
9.2.2. 
Safety Laboratory Variables ............................................................................... 52 
9.2.3. 
Other Safety Variables ........................................................................................ 53 
10. 
DATA MANAGEMENT ............................................................................................... 56 
10.1. 
Case Report Forms ................................................................................................... 56 
10.2. 
Data Management Plan and Database Design ......................................................... 56 
10.3. 
Data Entry and Validation ....................................................................................... 56 
10.4. 
Medical Coding ........................................................................................................ 56 
10.5. 
Database Lock .......................................................................................................... 56 
11. 
STATISTICAL ANALYSES......................................................................................... 58 
11.1. 
Power Considerations and Determination of Sample Size ...................................... 58 
11.2. 
Statistical Hypothesis ............................................................................................... 58 
11.3. 
Datasets to be Analysed ........................................................................................... 58 
11.4. 
General Statistical Considerations ........................................................................... 58 
11.5. 
Demographic and Baseline Characteristics ............................................................. 58 
11.6. 
Analysis of Endpoints .............................................................................................. 58 
11.6.1. Primary Endpoints ................................................................................................ 58 
11.6.1.1. 
Safety Endpoints ........................................................................................... 58 
11.6.1.2. 
Immune Endpoints ........................................................................................ 59 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
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11.6.2. Secondary Endpoints ............................................................................................ 60 
11.6.3. Exploratory Endpoints.......................................................................................... 60 
11.7. 
Hardware and Software............................................................................................ 60 
12. 
QUALITY CONTROL AND ASSURANCE ............................................................... 61 
12.1. 
Monitoring ............................................................................................................... 61 
12.2. 
Audits and Inspections ............................................................................................ 61 
12.3. 
Record Keeping and Archiving ............................................................................... 61 
13. 
ETHICS ........................................................................................................................... 62 
13.1. 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ........... 62 
13.2. 
Guidelines and Regulations ..................................................................................... 62 
13.3. 
Subject Information and Consent............................................................................. 62 
13.4. 
Subject Confidentiality ............................................................................................ 62 
13.5. 
Safety Steering Committee (SSC) ........................................................................... 63 
14. 
FINANCING AND INSURANCE ................................................................................ 64 
14.1. 
Financial Issues ........................................................................................................ 64 
14.2. 
Insurance and Indemnity .......................................................................................... 64 
15. 
STUDY REPORT AND PUBLICATIONS ................................................................. 65 
16. 
REFERENCES ............................................................................................................... 66 
 
 
LIST OF TABLES 
Table 6-1: Schedule of visits ................................................................................................................................... 36 
Table 8-1: Treatment schedule ................................................................................................................................. 43 
Table 9-1: Clinical laboratory parameters ................................................................................................................ 52 
Table 9-2: Volume of blood to be drawn from each subject .................................................................................... 53 
Table 9-3: Normal Ranges for Vital Signs for healthy adults .................................................................................. 54 
 
 
LIST OF FIGURES 
Figure 1: Patient flow and timelines ........................................................................................................................ 28 
Figure 2: Study design graphics Part I ..................................................................................................................... 30 
Figure 3: Study design graphics Part II .................................................................................................................... 31 
Figure 4: DTH Skin Reaction Registration (induration and erythema) .................................................................... 47 
 
 
LIST OF APPENDICES 
Appendix I: Further guidance on the definition of a Serious Adverse Event (SAE)................................................ 68 
Appendix II: Further guidance on the assessment of causality ................................................................................ 69 
Appendix III: Declaration of Helsinki ..................................................................................................................... 70 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
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1. ADMINISTRATIVE STRUCTURE AND CONTACT INFORMATION 
 
 
 
 
Sponsor:                  
Targovax ASA 
 
 
 
 
 
Lilleakerveien 2C   
 
 
 
 
 
0283 Oslo  
 
 
 
 
 
Norway 
 
 
 
 
 
Phone: (+47) 21 39 88 10 
  
Principal Coordinating Investigator:  
 
 
 
 
Michael Michael  
 
 
 
 
Peter MacCallum Cancer Centre 
 
 
 
 
St Andrews Place 
 
 
 
 
East Melbourne Victoria 3002 
 
 
 
 
Australia 
 
Medical Officer:  
Magnus Jäderberg  
 
 
 
 
 
Lilleakerveien 2C   
 
 
 
 
 
0283 Oslo  
 
 
 
 
 
Norway 
 
 
 
 
Phone: (+47) 21 39 88 10 
 
Medical Monitor:  
Robert Miller 
 
 
 
 
Targovax AS 
 
 
 
 
Stevenage Bioscience Catalyst,  
 
 
 
 
Gunnels Wood Road, Stevenage,  
 
 
 
 
Hertfordshire, SG1 2FX 
 
 
 
 
UK 
 
 
 
 
Tel: +44 203 291 3032  
 
 
CRO for study management /local sponsor:   
 
 
 
 
 
ICON Clinical Research (Australia and New Zealand) 
 
 
 
 
Australian office: 
 
 
 
 
ICON Clinical Research Pty Ltd 
 
 
 
 
Suite 201, Level 2, 2-4 Lyon Park Road 
 
 
 
 
North Ryde NSW 2113 Australia 
 
CRO for Pharmacovigilance:  
 
 
 
 
ICON Clinical Research UK Ltd 
 
 
 
 
2 Globeside Business Park,  
 
 
 
 
Marlow Buckinghamshire, SL7 1HZ 
 
 
 
 
UK 
 
 
 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
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Statistician 
 
Oluwaseun Adedeji 
Syne Qua Non (SQN) Ltd, UK 
 
 
 
 
Gostling House, Diss Business Park 
 
 
 
 
Hopper Way, Sandy Lane 
 
 
 
 
Diss IP22 4GT 
 
 
 
 
UK 
 
 
CRO for Biometrics and Data Management:  
 
 
 
 
Syne Qua Non (SQN) Ltd, UK 
 
 
 
 
Gostling House, Diss Business Park 
 
 
 
 
Hopper Way, Sandy Lane 
 
 
 
 
Diss IP22 4GT 
 
 
 
 
UK 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
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2. ABBREVIATIONS 
 
List of Abbreviations and definitions of terms: 
 
ADR 
 
Adverse Drug Reaction 
AE 
 
Adverse Event 
CEA 
 
Carcinoembryonic Antigen 
CRC 
 
Colorectal Cancer 
CRT 
 
Conventional chemoradiotherapy 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organisation 
CTC 
 
Circulating Tumour Cells 
DCF 
 
Data Clarification Form 
DE 
 
Data Enterer 
DMP 
 
Data Management Plan 
DTH 
 
Delayed Type Hypersensitivity 
ECG 
 
Electrocardiogram 
ECOG 
 
Eastern Cooperative Oncology Group 
FDG 
 
Fluorodeoxyglucose  
FPFV 
 
First Patient First Visit 
GCP 
 
Good Clinical Practice 
GM-CSF  
Granulocyte Macrophage Colony Stimulating Factor 
ICH 
 
International Conference on Harmonization 
IB  
 
Investigator`s Brochure 
ICH GCP  
International Conference of Harmonization Good Clinical Practice 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
IRB 
 
Institutional Review Board 
KRAS 
 
Kirsten rat sarcoma 
LPLV 
 
Last Patient Last Visit 
MDT 
 
Multi-Disciplinary Team 
MSDC 
 
Myeloid-derived suppressor cells 
MedDRA  
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute, common terminology criteria for  
 
 
 
adverse events 
NSTEMI  
non-ST segment elevation myocardial infarction 
PBMC 
 
Peripheral Blood Mononuclear Cells 
PET-CT  
Positron Emission Tomography - Computed Tomography 
PIS/ICF  
Patient Information Sheet and Informed Consent Form 
RAS 
 
Rat sarcoma 
SCCRT  
Short course chemoradiotherapy 
SAE 
 
Serious Adverse Event 
SDHP 
 
Study Drug Handling Plan 
SmPC 
 
Summary of Product Characteristics 
SSC 
 
Safety Steering Committee 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
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SSCC 
 
Safety Steering Committee Charter 
SUV 
 
Standard Uptake Value 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
WHO DD  
World Health Organization Drug Dictionary 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
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3. PROTOCOL SYNOPSIS  
 
Name of sponsor: Targovax ASA (Oslo, Norway), although ICON Australia will act as 
the local sponsor and legal representative in Australia 
 
Study identification code: CT TG02-01 
 
Title of the study: A Non-Randomised Open-Label Phase Ib Exploratory Study of TG02-
treatment as Monotherapy or in Combination with Pembrolizumab to Assess Safety and 
Immune Activation in Patients with Locally Advanced Primary and Recurrent Oncogenic 
RAS Exon 2 Mutant Colorectal Cancer 
 
Investigational medicinal products (IMP): TG02 administered with granulocyte 
macrophage stimulating factor (GM-CSF) in the form of recombinant human GM-CSF 
expressed in E-coli, the PD-1 inhibitor pembrolizumab (only in Part II)  
 
The TG02-treatment consists of an intradermal injection of GM-CSF followed by an 
injection of TG02. The GM-CSF is to be given 15-30 minutes before TG02. 
 
The doses to be administered are 0.10 mL of reconstituted, lyophilized GM-CSF (0.30 
mg/mL) and 0.1 mL reconstituted, lyophilized TG02 (8.0 mg/mL).  
 
Study period: 
The start date of the study (first patient first visit) is anticipated to be mid-2016.  
The total duration of the study is expected to be 2.5 years, approximately 15 months for 
Part I and 15 months for Part II. The total duration of the study will be dependent on 
whether the study proceeds to Part II or not. Patients will be on study for approximately 
14-20 weeks. 
 
Part I (Monotherapy activation - Only TG02-treatment): 
12 months enrolment (Assumption: 0.3 patients/site/month at 2-5 sites) 
After screening, a minimum of 8 and a maximum of 14 weeks between initiation of TG02 
treatment and surgical resection is anticipated with a follow up period of up to 6 weeks 
after surgery. 
Total study duration for Part I:  approximately 15 months   
First patient first visit (FPFV):  3Q 2016 
Excepted last patient last visit (LPLV):  4Q2018 
 
Part II (Combination activation - TG02-treatment + pembrolizumab): 
12 months enrolment (Assumption: 0.3 patients/site/month at 2-5 sites) 
After screening a minimum of 8 and a maximum of 14 weeks between initiation of TG02-
treatment+pembrolizumab and surgical resection is anticipated with a follow up period of 
up to 6 weeks after surgery. 
Total study duration for Part II: approximately 15 months  
Excepted FPFV:   1Q2019 


Investigational Product:  
 
Protocol Name: CT TG02-01 
TG02 
 
Final Version No. 6.0, 09OCT2018 
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Excepted LPLV:  4Q 2019  
 
Phase of development: Ib 
 
Participating countries and number of sites: 2-5 sites (Australia and New Zealand). 
Other sites may be added as required.  
Number of subjects: In Part I approximately 4-6 patients will be enrolled, in Part II up to 
10 patients will be enrolled. 
 
Study objectives:  
Primary Objectives: 
• To determine the safety of TG02-treatment 
• To evaluate the systemic TG02 specific immune responses and to investigate tumour T 
cell infiltration in tumour specimens 
Secondary Objectives: 
• To investigate changes in immunological and pathological markers in tumour tissue  
• To investigate changes in FDG PET-CT images 
• To investigate changes in CEA  
Exploratory Objectives: 
• 
To investigate changes in circulating tumour cells and/or circulating tumour DNA 
• 
To investigate the functionality of RAS mutation specific T cells in tumour tissue and 
peripheral blood 
 
Study design:  
This is a non-randomised, open label Phase Ib exploratory study to investigate the safety 
of and immune responses to TG02-treatment, first as monotherapy (Part I) and thereafter 
as combination therapy with pembrolizumab (Part II) in patients with locally advanced 
primary and recurrent RAS mutant colorectal cancer eligible for radical pelvic surgery at 
time of enrolment. 
 
Part I 
Approximately 4-6 patients diagnosed with locally advanced and recurrent RAS mutant 
colorectal cancer will be given TG02-treatment for up to 10 weeks (up to six TG02-
treatments; week 1, 2, 3, 4, 6 and 10 if surgery occurs beyond week 10) prior to surgery.  
 
TG02 is an eight peptide vaccine. Significant clinical data exist for its precursor vaccine, 
TG01, which contains 7 of the 8 mutant RAS peptides present in TG02. TG01 in 
combination with GM-CSF has been shown to be immunogenic and well tolerated up to 
11 weeks of treatment.  
 
Since one of the eight peptides in TG02 has not previously been administered to humans, 
the first 3 patients will be enrolled in a sequential manner with a minimum lag time of 4 
weeks between dosing of the first 3 subjects to ensure an acceptable safety profile.  
 


Investigational Product:  
 
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TG02 
 
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The safety data collected during the first 4 weeks for the 3 first patients will be reviewed 
by a Safety Steering Committee (SSC) consisting of Sponsor representatives, the Principal 
Investigator, relevant Sub-Investigators and one Independent Physician.  
As a general rule the following will be reviewed to provide a guide to safety decisions: 
 
Unacceptable toxicities will be defined as follows (based on NCI Criteria for Adverse 
Events (CTCAE) (v4.03: June 14, 2010) for reactions considered related to TG02 and/or 
GM-CSF: 
 • Injection site reaction of  ≥ grade 3 (grade 3: Ulceration or necrosis; severe 
tissue damage; operative intervention indicated, grade 4: Life-threatening consequences; 
urgent intervention indicated, grade 5: death). 
• Other relevant clinically significant toxicity ≥ grade 3 (excluding treatable nausea and 
vomiting). However for certain toxicities such as laboratory assessments without a clear 
clinical correlate, a discussion in the SSC may take place to evaluate if this AE should be 
assessed as DLT. 
• ≥ Grade 3 'allergic reaction/anaphylactic reaction' in spite of prophylaxis with 
antihistamine and steroids. 
 
All AEs and SAEs will be reviewed and will also be compared to those of the precursor 
vaccine TG01 (see Investigator’s Brochure). 
 
If more than 1 out of the 3 patients has DLT the SSC will review the nature of the events 
and make a final decision if the rest of the patients may be enrolled. 
 
When all safety data, systemic immune responses (Delayed-Type Hypersensitivity 
(DTHs)) and tumour material (analysed for intra-tumoural T cells infiltration) are available 
for all patients in Part I of the study, the Safety Steering Committee will evaluate the data 
to assess safety and preliminary immune activity and efficacy to make a recommendation 
whether the study will proceed or not to Part II of this protocol. In Part II 10 new patients, 
not previously treated with TG02, will be recruited. No patients treated in Part I will be 
treated in Part II. The SSC’s recommendation will form the basis for sponsor to make a 
final decision.  
 
Part II 
At the discretion of the sponsor, a decision will be made to initiate Part II of the study 
where up to 10 patients will be treated with TG02-treatment plus pembrolizumab for up to 
10 weeks (up to 6 TG02-treatments) prior to surgery. The first 3 patients will be enrolled 
in a sequential manner with a minimum lag time of 6 weeks between dosing of the first 3 
subjects to ensure an acceptable safety profile.  
The safety data collected during the first 6 weeks for the 3 first patients will be reviewed 
by the SSC in a similar manner as in Part I, as TG02-treatment in combination with 
pembrolizumab is a novel treatment. 
 
Schedule of events: 


Investigational Product:  
 
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TG02 
 
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Patients will be evaluated for safety at scheduled visits until surgery and at the end of study 
visit approximately 4 weeks after surgery. In addition, after any TG02-treatment the 
patients will be monitored for heart rate and blood pressure at 5, 10 and 30 minutes and 
then every 30 minutes thereafter for up to 2 hours post administration. 
A FDG PET-CT will be performed before TG02-treatment is initiated (baseline scan 
should be within the last 4 weeks prior to first TG02-treatment) and a second scan as close 
as possible before surgery.  
Tumour samples for assessment of immune response will be taken pre TG02-treatment in 
the form of a study specific biopsy and at time of surgery by analysis of the resected tumour 
tissue. If a pre TG02-treatment biopsy has been taken for diagnostic workup at the hospital, 
this biopsy, if adequate for the study specific immune analysis and no intervening 
treatment has been given, can be used as the study specific biopsy if taken within the last 
4 week prior to first TG02-treatment. If for any reason the patient does not proceed to 
surgery, a biopsy will be obtained at the time of planned surgery if possible. In addition, 
archival biopsy samples from both initial staging (primary diagnosis) and re staging will 
be utilised, as needed. In the patient information sheet and informed consent form 
(PIS/ICF), patients will be asked to give consent to the use of archived biopsy material. 
These archival samples will be used to assess RAS-mutation status and other baseline 
immune assessments. 
Delayed-Type Hypersensitivity (DTH) tests will be performed at week 1, week 4, week 6 
and week 8 (if surgery is scheduled for week 8, the DTH test should be performed two 
days before surgery). If surgery is scheduled for after week 10, and the patient has had 
only negative DTH tests up to and including week 8, an additional DTH test should be 
performed at week 10. 
Blood samples will be collected for in vitro assessment of TG02-specific immune 
responses (Immunology sample, PBMC) will be collected at baseline (Day 1, Week 1) and 
week 8 (Day 64). If surgery is scheduled to occur after week 10, a third sample will be 
taken as close as possible to the date of surgery. 
 
In total, the study will enrol up to 16 patients for Part I and II. 
 
Subject population: The target population is patients with locally advanced primary and 
recurrent oncogenic KRAS exon 2 mutant colorectal cancer eligible for radical pelvic 
surgery at time of enrolment. 
 
Inclusion Criteria: 
1.  Patients with locally advanced primary and recurrent colorectal cancer (CRC) 
(histologically or cytologically confirmed adenocarcinoma), with a confirmed oncogenic 
KRAS exon 2, codon 12 or 13 mutations, eligible for radical pelvic surgery at time of 
enrolment. 
2. Patient is ≥18 years of age and able to consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
4. Patient has adequate organ and bone marrow function within 28 days of study 
a. Neutrophil count >1.5 x109/L 


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b. Platelets >100 x109/L 
c. Hb >90g/L 
d. Total bilirubin <1.5 upper limit of normal, ULN  
e. ALT and AST <3.0 x ULN 
f. Serum creatinine < 3 x ULN  or Creatinine Clearance ≥  30ml/min (Cockroft-Gault or 
Nuclear GFR method) 
g. PT and APTT <1.3 x ULN 
5. The patient is willing to provide study specific pre TG02-treatment biopsy of tumour mass 
and allow use of archival tumour biopsies. For patients where there are technical reasons 
a baseline biopsy cannot be performed but who fulfil all the other inclusion criteria, the 
investigator shall contact the medical monitor to discuss the possibility of including such 
patient.  
6. The patient is willing and able to comply with the protocol, and agrees to return to the 
hospital for study visits and examinations.  
7. Men and women of childbearing potential must use adequate contraception to prevent 
pregnancy during the study. Adequate contraception is defined in the study as any 
medically recommended method (or combination of methods) as per standard of care. An 
adequate contraception includes hormonal contraception with implants or combined oral, 
transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal 
ligation, hysterectomy, or vasectomy of partner. A combination of male condom with 
either cap, diaphragm or sponge with spermicide are also considered acceptable. For 
women of childbearing potential a negative pregnancy test needs to be confirmed before 
inclusion. 
8. The patient has been fully informed about the study and is willing to participate in the 
study, and has provided written informed consent form prior to any trial specific screening 
procedures. 
Exclusion Criteria: 
1. The patient has previously received an anticancer vaccine or immune checkpoint inhibitor, 
or participated in a trial involving the use of an anticancer vaccine or immune checkpoint 
inhibitor  
2.  Patients where pre-surgery radiotherapy, chemotherapy or other anti-cancer therapy has 
not been completed ≥ 2 weeks prior to TG02-treatment. 
3. The patient is receiving anti-cancer therapy for concurrent illness 
4. The patient has had a prior different malignancy within the last 3 years (excluding 
adequately treated basal cell or squamous cell carcinoma of the skin cancer, or localised 
low grade tumours considered cured and not requiring systemic therapy) 
5. The patient has uncontrolled or significant intercurrent or recent illness including: 
a. auto-immune disorder or history of autoimmune disease requiring immunosuppressive 
treatment. 


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b. cardiac disorder such as uncontrolled cardiac failure, unstable angina or non-ST segment 
elevation myocardial infarction (NSTEMI) or myocardial infarction, uncontrolled 
arrhythmia less than 3 months before screening  
c. stroke or thromboembolic event within 3 months of study commencement 
d. active or uncontrolled severe infection 
e. history of solid organ transplantation or any condition requiring chronic treatment with 
corticosteroids or other immunosuppressive agents 
f. active coagulopathy/bleeding diathesis 
g. cirrhosis, chronic active or untreated persistent hepatitis 
h. history of adverse reactions to peptide vaccines  
6. The patient is pregnant or lactating.  
7. Has received an investigational drug within 4 weeks prior to study drug administration, or 
unless other has been agreed with the medical monitor  
8. Is currently receiving any agent with a known effect on the immune system, unless at dose 
levels that are not immunosuppressive (e.g. prednisone at 10 mg/day or less or as inhaled 
steroid at doses used for the treatment of asthma)  
9. Known history of positive tests for HIV/AIDS  
 
10. Are planned to receive yellow fever or other live (attenuated) vaccines during the course 
of study  
11. For Part II – any contraindication to receiving pembrolizumab: 
If using the 50 mg lyophilized powder; hypersensitivity to the active substance 
(pembrolizumab) or to any of the excipients; L-histidine, L-histidine hydrochloride 
monohydrate, Sucrose, Polysorbate 80. 
If using the 100 mg concentrate; hypersensitivity to the active substance (pembrolizumab) 
or to any of the excipients; L-histidine, Sucrose, Polysorbate 80. 
 
Investigational medicinal product, dose and form of administration: 
The TG02-treatment consists of an intradermal injection of GM-CSF followed by an 
injection of TG02. The GM-CSF is to be given 15-30 minutes before TG02. 
 
TG02: provided as a lyophilised solid powder for reconstitution in sterile water for 
injection to be given via intradermal injection. TG02 is supplied as a single dose in 2 mL 
clear glass vials.  Each vial of TG02 contains 2.4 mg of the drug substance peptides. 
Patients will receive TG02 at a dose of 0.80 mg/injection (individual peptides comprising 
0.10 mg each).  
 
GM-CSF: provided as a lyophilised solid powder for reconstitution in sterile water for 
injection to be given via intradermal injection. Patients will receive GM-CSF at a dose of 
0.03 mg/injection.  
 
 


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GM-CSF and TG02 are administered as 2 separate intradermal injections, 15 to 30 minutes 
apart, at the same site in the upper arm. In addition, TG02 will, at certain time points, be 
administered intradermally (without prior administration of GM-CSF) in the lower area of 
the contralateral arm to test for a DTH response. The administration of GM-CSF (0.10 mL 
reconstituted GM-CSF) and TG02 (0.10 mL reconstituted TG02) has to be strictly 
intradermal. Study staff will be trained appropriately. 
 
Pembrolizumab: a fixed dose of 200 mg pembrolizumab will be administered as an 
intravenous infusion. The product will be provided as a 50 mg lyophilized powder in a 
single-use vial for reconstitution in sterile water for injection, or as a vial of 4 mL of 
concentrate containing 100 mg. When Part II is initiated, pembrolizumab should be 
administered according to the latest version of the Summary of Product Characteristics 
(SmPC). Dependent on time of surgery, a patient will receive pembrolizumab 2 to 4 times 
throughout the treatment period.  
All handling of the Investigation Medicinal Products (IMPs) should be in compliance with 
normal handling of sterile products for injections. 
Reference therapy, dose and mode of administration: 
Not applicable 
 
Duration of treatment:  
Part I:  
TG02-treatment will be given at the same site in the upper arm up to 6 times to the patient 
during the course of the study. In addition to the above mentioned administration of TG02-
treatment, TG02 will be administered intradermally (without prior administration of GM-
CSF)  at given time points (week 1, week 4, week 6, week 8 and possibly week 10), in the 
lower area of the contra lateral arm as a DTH test to evaluate the patient’s immunological 
response to the TG02-treatment. 
Part II: 
TG02-treatment and DTH testing will occur in an identical manner to that described for 
the Part I of the study. Pembrolizumab should be administered as described previously. 
During the course of the study, the patient can expect to receive 2-4 intravenous infusions; 
week 4, week 6, and week 8 if surgery takes place Day51-63/Week8-10, and week 10 if 
surgery is delayed after day 64/Week 10. The dosing regimen should be the same for all 
patients at all sites. 
Baseline and screening assessments:  
Demographic details, medical and medication history, physical examination, vital signs 
(blood pressure, heart rate, tympanic temperature, weight, height), 12-lead ECG, ECOG 
performance status, routine laboratory testing (haematology and clinical chemistry), PET-
CT, tumour biopsy, collection of blood for immune activity (PBMCs, serum and whole 
blood) and CEA.  
 
Efficacy assessments:  
• TG02-specific DTH response 
• Presence of TG02 specific T-cells 
• Change in intra-tumoural lymphocytes 


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• Change in immunological and pathological markers in tumour tissue 
• Changes in FDG PET-CT images e.g. change in standard uptake value (SUV) 
• Changes in CEA from baseline throughout treatment 
• Changes in circulating tumour cells and/or circulating tumour DNA 
• Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
 
Safety assessments: 
Safety will be assessed by incidence and severity of adverse events as per NCI Criteria for 
Adverse Events (CTCAE) (v4.03: June 14, 2010), and by changes from baseline in 
laboratory variables, physical examination, vital signs and ECOG performance status.  
 
Statistics:  
The results from this study will be presented using descriptive statistical methods. 
Data will be presented by time of measurement, e.g. at baseline, week 1, week 4, week 8 
etc.  In general, continuous variables will be described using standard summary statistics 
such as number of observations, mean value, standard deviation, minimum and maximum 
value, median, and first and third quartiles.  Categorical variables will be summarised in 
frequency tables as counts and percentages.  All individual data collected will be presented 
in data listings.  Patients screened but not included in the study will not be presented in 
any tables or listings. 
 
Safety summaries will be provided for treatment exposure, patient disposition, adverse 
events leading to discontinuation, serious adverse events and all events resulting in death 
during the study period. The frequency of adverse events will be tabulated and reviewed 
for potential significance and clinical importance. 
 
 
 


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4. BACKGROUND AND STUDY RATIONALE 
 
4.1. Antigen specific anticancer immunotherapy 
Significant advances in the rapidly evolving area of anticancer immunotherapy over recent 
years have led to the availability of several immunotherapeutic agents for patients with 
various advanced solid tumours. These include checkpoint inhibitors for metastatic 
melanoma and advanced lung cancer, and vaccine therapy for metastatic prostate cancer. 
Sipuleucel T, an autologous cellular vaccine, was shown to increase overall survival in 
patients with metastatic prostate cancer (Kantoff 2010), resulting in FDA approval of the 
vaccine. Previously, clinical trials evaluating various antigen specific immunotherapeutic 
agents in patients with colorectal cancer have shown promising results, however, none of 
these agents have since translated to clinical use and the effect of generating RAS-specific 
immunity is not known. 
 
 
KRAS mutations occur in about 50% of colorectal cancers, and mostly (40%) within exon 
2 codons 12 and 13 of the RAS oncogene (Markman 2014). In patients with KRAS mutant 
colorectal tumours, mutant RAS peptides are considered to be attractive targets for vaccine 
therapy with the aim of improving overall survival and/or reducing recurrence rate. 
Previous immunotherapeutic strategies using KRAS mutant peptides as vaccines have been 
shown to be feasible for colorectal cancer, lung cancer, and pancreatic cancer, with 
evidence for their induction of specific immune responses and early phase studies 
supporting their safety and tolerability. In a Phase I/II study by Gjertsen et al., a KRAS 
mutant peptide vaccine in combination with GM-CSF administered to patients with 
advanced pancreatic cancer resulted in RAS mutation specific T cell immune responses 
(DTH and/or T cell proliferation) in 58% of the evaluable patients, with increased overall 
survival in this patient subgroup (Gjertsen 2001). 
 
The presence of RAS mutations has also been shown to be a negative factor for the 
additional treatment of patients with EGFR inhibitors and data generated has demonstrated 
that patients receiving cetuximab in combination with chemotherapy do not derive any 
benefit versus chemotherapy alone (Sorich 2014; Van Cutsem 2015). Even in patients 
eligible for cetuximab therapy, resistance may occur due to RAS mutation (Misale 2012). 
This demonstrates a need for therapy targeted at RAS mutated colorectal cancer. 
 
To further enhance patient immune response to a mutant RAS peptide vaccine, the addition 
of a checkpoint inhibitor, e.g. pembrolizumab, may be of benefit.  Preclinical data suggests 
that colorectal cancer, considered in general poorly immunogenic even in the presence of 
RAS mutations, may potentially become more responsive to checkpoint inhibition through 
priming of the immune system e.g. following radiation, cytotoxics, vaccination, or a 
combination of such therapies (Dovedi 2014; Cross 2015). Very recently FDA has granted 
breakthrough therapy designation to pembrolizumab, an anti-PD-1 therapy for treating 
patients with microsatellite instability high (MSIhigh) metastatic colorectal cancer (FDA 
News Nov. 9, 2015) (Le 2015). Since patients with both RAS mutation and MSIhigh 
colorectal cancer are very uncommon (Breivik 1997) this represent a further step forward 
for check point inhibitors for the treatment of colorectal cancer. 
 
4.2. TG02 
RAS exon 2 mutations are only found in cancer cells and mutant RAS peptide vaccines 
can, if given in combination with GM-CSF, induce specific anti-cancer immune response 


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and underlie the rationale for RAS peptide vaccination in colorectal cancer patients. The 
presence of peptides reflecting the common single amino acid substitutions found in RAS 
exon 2 mutations leads to host T cell recognition of the specific tumoural targets containing 
these single amino acid substitutions in mutant RAS proteins. A number of clinical studies 
have been performed confirming the feasibility of vaccination of patients with colorectal 
cancer using vaccines containing mutated RAS peptides (of codons 12 and 13) in colorectal 
and pancreatic cancer patients. Pilot studies have been performed demonstrating safety with 
17-mer mutant RAS peptide vaccination in pancreatic and colorectal cancer patients, with 
no systemic side effects or delayed toxicities. The addition of immune adjuvants e.g. IL-2, 
GM-CSF or both, to mutant RAS peptide vaccines has also been evaluated (Rahma 2013).  
 
TG02 is a peptide vaccine that contains a mixture of 8 synthetic peptides (all 17-mer) 
representing fragments of the 8 most common RAS exon 2 oncogenic mutant p21RAS 
proteins. The induction of host immune response against these RAS mutant epitopes would 
potentially result in tumour cell killing. Subsequent in-situ exposure of the RAS mutant 
antigens to specific T cells previously induced and activated by TG02 may lead to further 
epitope spreading i.e. cross presentation and T cell recognition of a range of tumour 
associated antigens.   
 
The pre-clinical development of TG02 to date has comprised of a series of in-vitro studies 
using human lymphocytes and murine splenocytes as well as repeated dosing in the mouse 
using the intended clinical route.  As expected, the resultant toxicology study findings were 
unremarkable. In a local tolerance study in mice, TG02 was shown to induce slight 
erythema and to bear minimal inflammatory potential (GM-CSF was considered the major 
trigger of inflammation, which supports the use as adjuvant). In-vitro studies confirmed the 
generation of immune responses with increased cellular proliferation and cytokine release 
following repeated administration of TG02. As the effects of TG02 are thought to be 
mediated via local immunological processing at the intradermal administration site, its 
effects are not considered to be directly associated with serum concentrations of drug and 
thus would be immeasurable; consequently, formal pharmacodynamics studies have not 
been conducted  (TG02 Investigator Brochure). 
 
TG02 has been administered to 4 humans. The RAS oncogene peptides have no intrinsic 
activity per se, but in combination with GM-CFS immune activity can be elicited. The 
Safety Steering Committee evaluated the safety data after 3 patients had each completed 4 
weeks of treatment. There were no safety issues in these patients. Furthermore, no SAE 
related to trial medication has been reported for any patients including the 4th patient who 
has completed the trial. In addition, significant clinical data exists for its precursor vaccine, 
TG01, which contains 7 of the 8 mutant RAS peptides present in TG02. TG01 in 
combination with GM-CSF has been shown to be immunogenic, with acceptable 
tolerability. TG01 has been investigated in an early Phase II clinical trial, with evaluation 
of its efficacy in the adjuvant setting for pancreatic cancer patients in combination with 
gemcitabine. In the modified cohort of this trial, where the induction course of TG01 is 
similar to that used in the TG02 study, only expected adverse events have been related to 
the treatment and all of these have been mild in severity (see Investigators Brochure) with 
the exception of one Grade 3 event of fatigue. No SAEs related to TG01 or GM-CSF were 
reported. The trial has completed recruitment. Final report is expected Q4 2018. 
 
As TG01 has been shown to be immunogenic with acceptable tolerability with the 
exception of hypersensitivity reactions which appear to be associated with the use of 


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gemcitabine as events occurred only after several cycles of chemotherapy or in the period 
immediately after the end of gemcitabine treatment (Palmer 2015). It is anticipated that 
TG02 will have a similar good safety profile in the absence of chemotherapy. 
 
TG02 has no intrinsic activity per se and is administered in combination with the 
immunomodulator GM-CSF. This GM-CSF/TG02 combination is referred to as TG02-
treatment in this study protocol. 
 
4.3. PD-1 (Programmed Cell Death 1) receptor and its inhibition 
PD-1 is a key immune inhibitory receptor present on the surface of T lymphocytes that on 
binding to programmed cell death ligands (PD-L1 or PD-L2) on tumour cells or antigen 
presenting cells, results in a negative T cell effector immune response. Phase I studies 
assessing efficacy of anti-PD-1 antibodies, including nivolumab, have shown anti-tumour 
efficacy in melanoma, renal cell carcinoma, and lung carcinoma; these tumours were found 
to have upregulation of PD-L1 on cell surfaces. This suggested that disruption of the PD-
1/PD-L1 signalling pathway mediated the objective response of the anti-PD-1 antibody. 
Several recent clinical studies of nivolumab and pembrolizumab showed impressive 
response rates and significantly increased overall survival in melanoma and non-small cell 
lung cancer patients, leading to FDA and TGA approval for these agents.   
 
4.4. Pembrolizumab  
Pembrolizumab (MK3475, formerly known as lambrolizumab), is a fully humanized 
humanised monoclonal IgG4-kappa isotype antibody against PD-1.  A Phase I study of 
pembrolizumab confirmed safety and tolerability at doses of 1 mg/kg, 3 mg/kg and 10 
mg/kg administered intravenously every two weeks, with maximal tolerated dosing not 
reached, and efficacy demonstrated in all dose levels.  Subsequently, data from a Phase I 
study expansion cohort of melanoma patients receiving 10 mg/kg every 2 weeks, 10 mg/kg 
every 3 weeks or 2 mg/kg every 3 weeks showed equivalent response rates across all three 
cohorts, with significantly reduced toxicities in the latter two groups of 4% and 9% 
respectively. More recently, a Phase I study of pembrolizumab in non-small cell lung 
cancer patients, previously treated or untreated, revealed objective response rates of 19.4% 
in unselected patients, versus 45% in those with greater than 50% of PD-L1 expression; in 
this enriched population, the median progression free survival was 6.3 months, with overall 
survival not reached (Garon 2015).  
 
In a long term follow up study of patients who had received the anti-PD1 antibody BMS-
936558, one patient with metastatic colorectal cancer patient, of MSI high subtype, 
undergoing intermittent dosing of BMS-936558 achieved a complete and prolonged 
response, remaining disease free at 3 years (Lipson 2013).  Subsequently, a Phase II study 
showed that pembrolizumab (at 10 mg/kg administered intravenously 2 weekly) increased 
progression free survival in microsatellite unstable metastatic colorectal cancer patients 
with a disease control rate of 90% and overall response rate of 40%. Unfortunately, results 
from this study, in addition to previous first in human Phase I anti-PD-1 antibody trials 
revealed minimal response rates in patients with microsatellite stable disease, which 
comprises the majority of colorectal cancers (Le 2015).  
Data from preclinical models suggest that colorectal cancers could potentially be converted 
to a more “immunogenic” cancer type through priming of the immune system e.g. 
following radiation or vaccine therapy, leading to increased responses to check point 
inhibitors and immunomodulation (Dovedi 2014; Cross 2015; Gerber 2014). Thus, the 


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combination of anti-PD1 therapy and mutant RAS peptide vaccine therapy may be a 
promising strategy. 
 
4.5. Locally Advanced Primary and Recurrent Colorectal Cancer 
Neo-adjuvant chemoradiation prior to total mesorectal excision is considered the standard 
of care in patients with locally advanced rectal cancer where R0 resection can be expected, 
with significant improvements in long term overall survival rates over the past two decades. 
Chemoradiotherapy, either conventional or short course (CRT or SCCRT)), is usually given 
as neoadjuvant treatment. Standard total mesorectal excision should achieve a curative 
resection. The use of CRT or SCCRT aims to reduce local recurrence (Glynne-Jones 2017). 
Despite this, 5-20% of these patients will experience local recurrence, at which time, their 
disease is more often than not incurable, with five year survival rates reported between 13% 
and 47% (Rahbari 2011). 
Patients presenting with pelvic disease recurrence are often considered for resection, 
including aggressive radical debulking surgery or pelvic exenteration, which is associated 
with significant operative risks. Pre-operative re-irradiation may be offered prior to 
resection in selected patients, however, late toxicities are of concern with some patients not 
being suitable candidates. A recent publication evaluating five year survival rates of 
patients who achieved an R0 resection was 39% compared to only 22% in patients who 
were treated without surgery or underwent subtotal tumour removal. 
 
Routinely there is a period of more than 8 to 12 weeks between diagnosis and resection and 
treatment of locally advanced disease or recurrence to resection according to the usual 
practise of the hospital, which allows a window of opportunity for patients to undergo 
systemic therapy (e.g. with vaccination and/or check point inhibition) whilst awaiting 
surgery. As per Figure 1, patients will be consented for the trial at the time of the diagnosis 
of the disease recurrence, once they have completed other anti-cancer therapy as applicable 
(such as radiotherapy/chemoradiotherapy). 
 
The presence of locally advanced disease or recurrence will be confirmed by appropriate 
diagnostic imaging (the actual types of scans and other tests can vary in different 
institutions and this protocol does not define the nature of these tests) as per standard 
clinical practice at each hospital.   
 
This provides justification for evaluation of TG02, with or without PD-1 inhibition, in 
patients with newly diagnosed locally advanced primary and recurrent colorectal cancer 
prior to radical surgery.  
 
This is a window of opportunity study and, because surgery will not be delayed as a result 
of the TG02-treatment, it is not expected that the immunotherapy will have any direct 
benefits on the outcomes of surgery or the rate of cure. In the time that the patient is 
normally expected to wait from the time of the diagnosis and treatment of their disease  and 
the time of surgery there is an opportunity to see what effect immunotherapy with this 
specific RAS vaccine has in eliciting a specific intra-tumoural T cell response. 
 
While it would not be anticipated that any clinically relevant changes to tumour size would 
occur as a result of vaccination alone the ability to generate RAS specific T cells is 
important for two principal reasons: 1. The finding of cytotoxic T cells in the tumour will 
provide a rationale for vaccination overall and 2. It would add weight to the argument that 


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even if R0 resection is possible, adjuvant immunotherapy might be an important addition 
to other therapy post-surgery, which may enhance disease-free and overall survival. 
 
4.6. Rationale for the study 
Patients with locally advanced primary and recurrent colorectal cancer are often 
considered for radical pelvic surgery. This “window” allows an opportunity to use RAS 
peptides to induce an immune response and study whether this promotes a cytotoxic T-
cell infiltration into the tumour and induce histologically at least tumour cell death.  
TG02-treatment alone or in combination with a PD-1 inhibitor, given prior to resection in 
patients with locally advanced primary and recurrent colorectal cancer may stimulate this 
immune response and provide evidence that vaccination with TG02 peptides induces 
enhanced specific T-cell tumour killing and this provides an important therapeutic 
intervention in the treatment of colorectal cancer. The hypothesis that there may be a 
requirement for a PD-1 inhibitor to facilitate the immune response induced by the TG02 
vaccination is supported by the preliminary data from Part 1 of the study. The data 
suggest that PD-1 expression is seen on the cytotoxic T-cells as well as the T-helper cells 
in the peripheral blood as well as PDL-1 and PD-1 expression is seen on T cells in the 
surgical specimens. These results may indicate that the tumours would possibly respond 
to the addition of a PD-1 inhibitor. 
 
4.7. Rationale for dose 
The traditional approach to dose selection for cytotoxic anticancer agents is to escalate the 
dose until dse limiting toxicity.  This concept of maximum tolerated dose is not applicable 
for peptides that generally lack any inherent toxicity and that are for local administration 
in the skin.  TG02 is for induction of cellular immune responses, and consequently the 
immune response rate is the most important parameter to consider for determining an 
appropriate dose. 
 
The rationale for the dose is based on studies performed with its precursor vaccine, TG01, 
which contains 7 of the 8 mutant RAS peptides present in TG02. The rationale for 
selecting the dose of 0.1 mg of each peptide per administration stems from the 
observations from a dose exploring study in colorectal cancer patients (CTN RAS 97005).  
In this trial the patients were first given four weekly administrations of a single RAS 
peptide at the dose of 0.1 mg per administration and subsequently, after three weeks rest, 
four weekly administrations of 0.3 mg peptide.  An additional dose of 0.1 mg peptide was 
administered without GM-CSF at a separate site to elicit DTH.  Indeed, more immune 
responders were seen after the second cycle, 13 versus 7 after the first cycle.  Other 
studies with constant dose (0.1 mg per peptide) have demonstrated a similar increase in 
number of recorded immune responders after administration of boosters after the initial 4 
week cycle.  In a study with a cocktail containing four RAS peptides (dose 0.10 mg per 
peptide) in patients with advanced pancreatic cancer (CTN RAS 97004) the number of 
DTH responders was increased from 11 after the initial 4 week cycle, to 16 responders 
after only two additional administrations (week 6 and 10).  This suggested that the 0.10 
mg and 0.30 mg per peptide were immunologically equivalent in the CTN RAS 98005 
study and that increasing the TG01 dose beyond the current 0.7 mg dose (0.1 mg per 
peptide) is unlikely to heighten further the levels of specific immune responses.  
Alternatively, reducing the TG01 dose to levels lower than 0.1 mg per peptide may result 
in sub-optimal T cell responses. 
 


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Given the acceptable safety profile and levels of T cell responses observed to date with 
the current dose of  0.7 mg (0.1mg each peptide) of TG01 , the clinical development of 
TG02 will commence using the same dose for each peptides (0.1 mg) with a total TG02 
dose of 0.8 mg. TG02 will be given together  with GM-CSF as immunomodulator. Please 
see the TG02 Investigators Brochure (IB) for more information. 
 
4.8. Rationale for dose regimen 
 
TG02 
 
TG02 given in the TG02-treatment will be administered to the patient at week 1, 2, 3, 4, 
and 6. If surgery is scheduled after week 10 one more TG02-treatment will be given in 
week 10. In addition to this TG02 will at certain time points (week 1, week 4, week 6, 
week 8 and possible week 10), be administered intradermally (without prior 
administration of GM-CSF) as a DTH test to evaluate the immunological response. The 
rationale for this regimen is based on the results from the previous and ongoing studies 
with TG01/GM-CSF that demonstrate that prevailing RAS mutation specific T cells 
responses are induced in cancer patients after 4-6 weeks of vaccination. 
 
Pembrolizumab 
 
Although the licensed dosing regimen for pembrolizumab is 3-weekly, in this window 
of opportunity study there is limited time between the start of TG02 vaccinations and 
surgery. Also, in order that the scheduling of study visits can be minimised to avoid 
extra patient visits, it is proposed to administer the pembrolizumab 2-weekly. Based on 
the data reported from the KEYNOTE 006 study for melanoma (Schachter 2017), the 
efficacy was similar between the 2-weekly and 3-weekly schedule with very similar 
safety profiles. Additionally, time needs to be allowed for a TG02 specific immune 
response to be induced; therefore, pembrolizumab will be started at week 4 and 
continued two-weekly until surgery 
 
 


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5. STUDY OBJECTIVES 
 
Primary Objectives: 
• To determine the safety of TG02-treatment 
• To evaluate the systemic TG02 specific immune responses and to investigate tumour 
T cell infiltration in tumour specimens 
 
Secondary Objectives: 
• To investigate changes in immunological and pathological markers in tumour tissue  
• To investigate changes in FDG PET-CT images 
• To investigate changes in CEA  
 
Exploratory Objectives: 
• To investigate changes in circulating tumour cells and/or circulating tumour DNA 
• To investigate the functionality of RAS mutation specific T cells in tumour tissue and 
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6. STUDY DESIGN AND DESCRIPTION OF THE STUDY 
 
This is a non-randomised open labelled Phase Ib exploratory study to investigate the 
safety and immune responses of TG02-treatment.  
 
The study is divided into two parts, where after Part I the sponsor will make a decision 
as to the initiation of Part II. Part II will start after Part I has been completed. Patients 
will only be allowed to participate in either Part I or Part II of the study. 
 
Part I is designed to investigate the objectives of the study with TG02-treatment as 
monotherapy, and the Part II is to investigate TG02-treatment in combination with 
pembrolizumab. Part I and Part II will enrol approximately 4-6 and up to 10 patients 
respectively.  
 
6.1. Endpoints 
Primary endpoints: 
• Safety: 
– Adverse events  
– Laboratory assessments 
– Vital signs 
• Systemic immune responses assessed by: 
– TG02-specific DTH response 
– Presence of TG02 specific T-cells in peripheral blood 
– Change in intra-tumoural lymphocytes   
 
Secondary endpoints: 
• Immune suppression factors in tumour specimens 
• Pathological responses and markers of apoptosis in tumour specimens  
• Change in standard uptake values (SUV) assessed by FDG PET-CT 
• Change in CEA 
 
Exploratory Endpoints:  
• Change in circulating tumour cells and/or circulating tumour DNA 
• Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
 
6.2. Study Design 
The patients with locally advanced primary and recurrent colorectal cancer will be 
considered for the study. A multi-disciplinary team (MDT) at the sites will coordinate the 
staging and work up of the patients and select appropriate patients for curative surgery.  
Selected patients for surgery will either receive chemo-radiation treatment (3-5 weeks) or 
have no further treatment before they are being consented for the study, see patient flow 
and timelines in Figure 1.


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Figure 1: Patient flow and timelines
 
 
Diagnosis CRC and 
diagnostic work up 
Restage 
MRI 
Plan surgery 
Surgery 
(minimum of 8 weeks and 
maximum 14 weeks after 
initiation of TG02-treatment) 
Diagnosis CRC and 
diagnostic work up 
Restage 
MRI 
Plan surgery 
Surgery 
(minimum of 8 weeks and 
maximum 14 weeks after 
initiation of TG02-treatment) 
       
 
              
 
 
0-2 weeks 
 
Set up radiation 
 
Radiation+5FU 
PET/CT 
Patients will then be 
selected for the study and 
offered the biopsy (min. 2 
weeks) 
3-5 weeks 
2-4 weeks 
 
 
TG02-treatment with or 
without pembrolizumab 
8-10 weeks 
End of study visit 
PET/CT 
Patients will then be 
selected for the study and 
offered the biopsy (min. 2 
weeks) 
 
 
TG02-treatment with or 
without pembrolizumab 
End of study visit 
2-4 weeks 
8-10 weeks 
Patient flowchart with pre-surgery chemo/radiation 
Patient flowchart without pre-surgery chemo/radiation 


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The patient will be defined as on study from the date of signed informed consent until 
the end of study (EOS) visit which should be scheduled after surgery.  
  
The study is divided into two parts, Part I followed by Part II if decision of such will be 
made by the sponsor. Part II may start when all safety data, systemic immune responses 
(Delayed-Type Hypersensitivity (DTHs)) and tumour material (analysed for intra-
tumoural T cell infiltration) are available for 4-6 patients in Part I of the study.  The 
sponsor, after input from the Steering Committee, will evaluate the data to assess safety 
and preliminary immune activity and efficacy of TG02-treatment, and make a 
recommendation to proceed or not to Part II of this protocol.  
 
Patients from Part I will not participate in Part II. 
 
The study design for Part I is shown in Figure 2 and the study design for Part II in 
Figure 3.


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Page 30 of 74 
 
Figure 2: Study design graphics Part I 
 
 
 
 
 
1: Core needle biopsy pre TG02-treatment. 
2: Tumour tissue at resection, at time of surgery. 
3: If no surgery before week 10, a TG02-treatment will be given. 
4: Only to be taken for patients who have surgery at week 10 or later and had a negative DTH outcome at week 8. 
5: If surgery is after week 10, a sample will be taken as close as possible to surgery. 
 


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                   Final Version No. 6.0, 09OCT2018 
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Figure 3: Study design graphics Part II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1: Core needle biopsy pre TG02-treatment. 
2: Tumour tissue at resection, at time of surgery. 
3: If no surgery before week 10, a TG02-treatment will be given. 
4: Only to be taken for patients who have surgery at week 10 or later and had a negative DTH outcome at week 8. 
5: If surgery is after week 10, a sample will be taken as close as possible to surgery. 
6: If surgery is scheduled after Day50/Week 8, pembrolizumab will be given at Day 50/Week 8. If surgery scheduled after Day 64/Week 10, a further   
pembrolizumab infusion will be given at Day 64/Week 10. 
TG02-treatment 
W1 
W2 
W3 
W4 
W6 
W8 
Surgery 
Treatment period 
Time window for surgery if 
delayed 
4±2 weeks 
after surgery 
End of study 
Tumour specimen 
Screening 
DTH 
DTH 
DTH 
DTH 
PBMC 
d1 
d8 
d15 
d22 
d36 
d50 
Pembrolizumab 
Safety assessment 
d64 
W10 
(DTH) 
3 
1 
2 
2 
Safety 
follow up 
W14 
d92 
DTH-test 
4 
2 
2 
5 
5 
6 
6 


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Part I 
Approximately 4-6 patients diagnosed with locally advanced primary and recurrent 
colorectal cancer will be given TG02-treatment for up to 10 weeks (up to 6 TG02-
treatments) prior to surgery.  
 
TG02 is an eight peptide vaccine. Significant clinical data exists for its precursor vaccine, 
TG01, which contains 7 of the 8 mutant RAS peptides present in TG02. TG01 in 
combination with GM-CSF has been shown to be immunogenic and well tolerated up to 11 
weeks of treatment.  
 
Since one of the eight peptides in TG02 has not previously been administered to 
humans, the first 3 patients will be enrolled in a sequential manner with a minimum lag 
time of 4 weeks between dosing of the first 3 subjects to ensure an acceptable safety 
profile.   
 
The safety data collected during the first 4 weeks for the three first patients will be 
reviewed by a SSC consisting of Sponsor representatives, the Principal Investigator, 
relevant Sub-Investigators and one Independent Physician.  
 
As a general rule the following will be reviewed to provide a guide to safety decisions: 
 
Unacceptable toxicities will be defined as follows (based on NCI Criteria for Adverse 
Events (CTCAE) (v4.03: June 14, 2010) for reactions considered related to TG02 and/or 
GM-CSF: 
 • Injection site reaction of  ≥ grade 3 (grade 3: Ulceration or necrosis; severe 
tissue damage; operative intervention indicated, grade 4: Life-threatening consequences; 
urgent intervention indicated, grade 5: death). 
• Other relevant clinically significant toxicity ≥ grade 3 (excluding treatable nausea and 
vomiting). However, for certain toxicities such as laboratory assessments without a clear 
clinical correlate, a discussion in the SSC may take place to evaluate if this AE should be 
assessed as DLT. 
• ≥Grade 3 'allergic reaction/anaphylactic reaction' in spite of prophylaxis with 
antihistamine and steroids. 
 
All AEs and SAEs will be reviewed and will also be compared to those of the precursor 
vaccine TG01 (see Investigator’s Brochure). 
 
If more than 1 out of the 3 patients has DLT the SSC will review the nature of the events 
and make a final decision if the rest of the patients may be enrolled. 
 
When all safety data, systemic immune responses (DTHs) and tumour material 
(analysed for intra-tumoural T cells infiltration) are available for all patients in Part I of 
the study, the sponsor, with input from the Steering Committee, will evaluate the data 
to assess safety and preliminary immune activity and  efficacy to make the decision to 
proceed or not to Part II of this protocol. In Part II up to10 new patients, not previously 
treated with TG02, will be recruited. No patients treated in Part I will be treated in Part 
II. 
 
The SSC will review the tolerability of TG02-treatment in accordance with the SSC 
charter and this review will be based on an assessment of adverse events, laboratory 


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findings and, in particular the occurrence of hypersensitivity reactions. Toxicity grading 
will use NCI CTCAE version 4.03. 
 
Part II 
Up to 10 patients will be treated with TG02-treatment plus pembrolizumab for up to 10 
weeks (up to six TG02-treatments and up to 4 pembrolizumab infusions) prior to 
surgery.  
Again, since one of the eight peptides in TG02 is first in human, and that the use of 
pembrolizumab will be in a novel setting, as a precaution, the combination of TG02-
treatment and pembrolizumab will be initiated first in 3 patients and evaluated for safety 
prior to subsequent recruitment of patients according to the same procedure as described 
above for Part I. The first 3 patients will be enrolled in a sequential manner with a minimum 
lag time of 6 weeks between dosing of the first 3 subjects to ensure an acceptable safety 
profile. The safety data collected during the first 6 weeks for the 3 first patients will be 
reviewed by the SSC. 
  
6.3. Study Duration 
The total duration of the study is expected to be 2.5 years, approximately 15 months for 
Part I and 15 months for Part II. The total duration of the study will be dependent on 
whether the study proceeds to Part II or not.  
The patient will be in the study for a maximum of 20 weeks. The treatment period will be 
up to 10 weeks, dependent on the timing of scheduled surgery. The patient will be 
followed up to 6 weeks after surgery.   
 
6.4. Study Visit Schedule 
The schedule of visits (Table 6-1, Schedule of visits) reflects the assessments that will occur 
during the study, i.e. screening period, treatment period, and end of study. Patients will be 
screened for the study over a period of 14 days. The TG02-treatment period will be up to 
maximum 10 weeks and the end of study visit will be approximately 6 weeks after surgery. 
• Weekly visits should occur within a window of ± 2 days.  
• Two weekly visits should occur within a window of ± 4 days.  
• End of study visit (EOS) should occur within 6 weeks after surgery. 
Surgery should occur between week 8 and 14, if not postponed due to some unforeseen 
reasons, which will be documented. If for any reason, the patient will not have surgery, a 
biopsy will be obtained at the time of planned surgery if possible. 
All trial treatment-related toxicities and SAEs must be followed until resolution 
unless, in the investigator’s opinion, the condition is unlikely to resolve because of the 
patient’s underlying disease. 
 
6.4.1. Screening Period 
Before initiating any screening activities, the scope of the study should be explained to 
each patient. Patients should be advised of any known risks inherent in the planned 
procedures, of any alternative treatment options, of their right to withdraw from the 
study at any time for any reason, and of their right to privacy. After this explanation, 
patients should be asked to sign an EC approved statement of informed consent. 
The screening visit will determine patient eligibility according to the inclusion/ 
exclusion criteria (section 7.3 and 7.4). The following assessments will be performed 
during this period: 
 


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• Demographics and medical history (including detailed information about medical 
history of colorectal cancer and previous treatments) 
• Medication and treatment history and concomitant medication (including 
medication taken in the 4 weeks before screening period, relevant information 
should be captured in the CRF) 
• Urine or serum pregnancy test (for women of childbearing potential) 
• Physical exam (review of the major body systems, vital signs (height, weight, heart 
rate, blood pressure, tympanic body temperature) 
• 12-lead ECG evaluation 
• ECOG Performance status  
• Blood samples for routine haematology, serum biochemistry and CEA biomarker 
(Table 6-1) 
• FDG PET-CT scan for tumour assessment of standard uptake value (SUV-max) as 
close as possible to first visit (should be within the last 4 weeks prior to first TG02-
treatment) 
• For patients receiving chemo-radiation before enrolment into study, core biopsy of 
target colorectal tumour should be taken after chemo-radiation and during the 
screening window (2 week) and as close as possible to the first TG02-treatment (day 
1, week 1). For patients not having chemo-radiation before enrolment into the study, 
a core biopsy of target colorectal tumour can be taken within the last 4 weeks but as 
close as possible to the first TG02-treatment (day 1, week 1). If a pre TG02-treatment 
biopsy has been taken for diagnostic workup as hospital procedure, this biopsy, if 
adequate for the study specific immune analysis and no intervening treatment has 
been given, can also be used. 
• Diagnostic CT/MRI scan according to hospital practice 
6.4.2. Treatment period (before surgery): 
The treatment period will be from Day 1 (Week 1) and up to surgery, which is planned for 
week 8 but can occur in a window up to week 14. The following assessments will be 
performed on Day 1, Day 8, Day 15, Day 22, Day 36, Day 50 and if surgery is after week 
10 (Day 64):  
• 
Vital signs (heart rate, blood pressure and tympanic body temperature) and ECOG 
performance status  
• 
Concomitant medications and adverse events will be monitored continuously  
• 
Physical examination, haematology and serum biochemistry (Table 9-1) before 
treatment (Day 1) and during treatment on Day 15, Day 36, Day 50 and if surgery after 
week 10 (Day 64).  
• 
TG02 treatment will be administered on Days 1, 8, 15, 22 and 36. If surgery after week 
10 TG02 treatment will also be given at week 10 (Day 64).  
• 
Pembrolizumab will be given on Days 22 and 36. If surgery is scheduled after 
Day50/Week 8, pembrolizumab will be given at Day 50/Week 8. If surgery scheduled 
after Day 64/Week 10, a further pembrolizumab infusion will be given at Day 64/Week 
10. 
• 
DTH tests will be performed at baseline (Day 1), week 4 (Day 22), week 6 (Day 36) 
and week 8 (Day 50) (if surgery is scheduled for week 8 the DTH test should be 
performed two days before surgery). If surgery is after week 10, and the patient has had 
negative DTH tests up to and including week 8, an additional DTH test should be 
performed at week 10 (Day 64). 


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• 
Blood samples for in vitro assessment of TG02-specific immune responses 
(Immunology sample, PBMC) will be taken at baseline (Day 1) and Day 50. If surgery 
is after week 10, an additional sample should be taken as close as possible up to the date 
of surgery (see separate Immune monitoring plan). 
• 
The CEA biomarker will be evaluated at Day 50. If surgery is after week 10 a third 
sample will be taken at Day 64 or just prior to surgery, whichever is the more 
appropriate.  
• 
Tumour samples for assessment of immune response will be taken at time of surgery. If 
for any reason the patient will not have surgery a biopsy will be obtained if possible at 
the latest by week 14 (see separate Immune monitoring plan). 
• FDG PET-CT scan for tumour assessment of standard uptake value (SUV-max) as 
close as possible up to date of surgery. 
• Circulating Tumour Cells (CTC) will be evaluated at Day 1 and Day 50. If surgery 
is after week 10, an additional sample can be taken as close as possible up to the 
date of surgery. 
 
Additional monitoring during the first 2 hours after any TG02-treatment: 
Following any TG02-treatment patients will be monitored for signs and symptoms of 
hypersensitivity as well as heart rate and blood pressure. A finger pulsometer or 
similar should be used to monitor heart rate for the first 30 minutes and blood pressure 
should be measured at 5 and 10 and 30 minutes and then every 30 minutes for up to 2 
hours post administration. Additional blood pressure measures should be taken if the 
patient experiences any of the following: dizziness, feeling cold or clammy, sweating, 
tingling in the mouth/tongue, itchy palms, feeling lightheaded, abdominal pain or 
breathlessness. 
Measures in case of anaphylaxis should follow the hospital policy and include the 
availability of intravenous access, oxygen, adrenaline and hydrocortisone. 
The administration of TG02 and post-treatment monitoring will occur in the 
Chemotherapy Treatment Unit or equivalent unit for each the institution with the patient 
sitting in an appropriate treatment chair or similar. 
 
 
6.4.3. End of Study visit (Up to 6 weeks after surgery) 
End of study visits to be scheduled during the hospitalized post-operative recovering 
period, up to 6 weeks after surgery. 
 
• Physical exam (review of the major body systems, vital signs (weight, heart rate, 
blood pressure and tympanic body temperature) 
• ECOG Performance status  
• Blood samples for routine haematology and serum biochemistry (Table 9-1) or will 
be recorded if already available in the patient medical record.   
• Adverse events and concomitant medications deemed to be related to TG02-
treatment 
 
6.4.4. Study Flow Chart 
The schedule of visits is presented in Table 6-1. After screening a minimum of eight and 
maximum 14 weeks between initiation of TG02-treatment and resection surgery is 
anticipated with a follow up period of 4 weeks after surgery.


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Table 6-1: Schedule of visits 
 
Screening 
within 2 
weeks  
Treatment period 
(Pre-surgery)  
(weeks 1-6) 
Wk 8±4 days 
Surgery 
If Surgery 
Wk 8-10 
 
If surgery is  
Wk 10 
If Surgery 
Wk 10-14 
 
End of study visito  
Up to 6 wk after 
surgery    
Week 
 
1 
2 
3 
4 
6 
8 
8-10 
10 
10-14 
See footnoteo 
Day 
 
1 
8 
15 
22 
36 
50 
51-63 
64 
65-92 
See footnoteo 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Patient eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationh 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
Vital Signsh 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
ECOGh 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
DTH (TG02) testjq 
 
X 
 
 
X 
X 
Xb 
 
(Xi) 
 
 
Immunology Sampleh (PBMC) 
 
X 
 
 
 
 
Xe 
 
 
Xg 
 
TG02-treatment p 
(TG02/GM-CSF) 
 
X 
X 
X 
X 
X 
 
 
(Xf) 
 
 
Pembrolizumabk  
 
 
 
 
X 
X 
Xs 
 
Xt 
 
 
Haematologyh 
X 
X 
 
X 
 
X 
X 
 
X 
 
Xn 
Biochemistryh 
X 
X 
 
X 
 
X 
X 
 
X 
 
Xn 
CEA (biomarker) 
X 
 
 
 
 
 
Xl 
 
Xg 
Xg 
 
CTC (Circulating Tumour Cells) 
 
 
X 
 
 
 
 
 
Xl 
 
 
 
 
Xg 
 
CT chest/abdomen/ 
Pelvic  
X 
 
 
 
 
 
 
 
 
 
 
MRI (if standard Hospital procedure (re-
staging) 
X 
As indicated 
 
 
 
 
 
FDG PET/CT 
Xr 
 
 
 
 
 
Xg 
Xg 
Xg 
Xg 
 
Tumour Biopsy 
Xc 
 
 
 
 
 
 
 
 
 
 
Surgery and resection  of  tumour tissuem 
 
 
 
 
 
 
Xd 
Xd 
Xd 
Xd 
 
Adverse Events 
 
Continuously  
Xa 
Concomitant medications 
X 
Continuously 
Xa 
 


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a:  Deemed to be related to TG02-treatment 
 
b:  If surgery is scheduled to be done in week 8, DTH (TG02) injection to be done approximately 48 hours 
prior to surgery. 
 
c:  For patients receiving chemo-radiation before enrolment into study, core biopsy of target colorectal 
tumour should be taken after chemo-radiation and during the screening window (2 week) and as close as 
possible to the first TG02-treatment (day 1, week 1). For patients not having chemo-radiation before 
enrolment into the study, a core biopsy of target colorectal tumour can be taken within the last 4 weeks 
but as close as possible to the first TG02-treatment (day 1, week 1). If a pre TG02-treatment biopsy has 
been taken for diagnostic workup as hospital procedure, this biopsy, if adequate for the study specific 
immune analysis and no intervening treatment has been given, can also be used. 
d:  Tumour tissue taken during resection. If for any reason, the patient will not have surgery a biopsy will be 
obtained if possible. 
e:  To be done 2-0 days before surgery 
f:  If surgery is scheduled for week 10, there will be no TG02-treatment given at week 10. If no surgery at 
week 10, the last TG02-treatment to be given at week 10. 
g:  As close as possible up to the date of surgery. 
h:  At the visits when TG02 and/or TG02-treatment (and pembrolizumab in Part II) is scheduled, the 
assessments should be performed prior to the treatments. 
i:  Only to be taken for patients who have surgery after week 10 and had a negative DTH outcome at week 8. 
DTH (TG02) injection to be done 48 hours prior to surgery. 
j:  Assessment of DTH (TG02) injection site to be done 48 hours (+/- 4 hours) after each DTH (TG02) 
injections by the patient in a study specific diary. 
k:  Only applicable in Part II of the protocol 
l:  To be done prior to surgery 
m:  Allowed time for surgery (resection specimen) scheduled for week 8 is + 2 week and allowed time 
for surgery (resection specimen) scheduled for week 10 is + 4 week  
n:  Blood samples for routine haematology and serum biochemistry to be recorded if already available 
in the patient medical record (standard of care) 
o:  End of study visits to be scheduled during the hospitalized post-operative recovering period, up to 6 
weeks after surgery. 
p:  TG02-treatment is a combination of the two IMPs: GM-CSF and TG02. When TG02-treatment is 
administered, GM-CSF is to be given as an intradermal injection 15-30 minutes before the TG02 
intradermal injection. GM-CSF and TG02 are administered as 2 separate intradermal injections, 15 
to 30 minutes apart, at the same site in the upper arm. After any TG02-treatment the patients will be 
monitored for heart rate and blood pressure at 5, 10 and 30 minutes and then every 30 minutes 
thereafter for up to 2 hours post administration 
q:  In addition, TG02 will, at certain time points, be administered intradermally (without prior 
administration of GM-CSF) in the lower area of the contra lateral arm as DTH test. The administration 
of GM-CSF (0.10 mL reconstituted GM-CSF) and TG02 (0.10 mL reconstituted TG02) has to be 
strictly intradermal.  
r:  Should be within the last 4 weeks prior to first TG02-treatment. 
s:  If surgery is scheduled after Day 50/Week 8, pembrolizumab will be given at Day 50/Week 8. 
t:  If surgery is scheduled after Day 64/Week 10, a further pembrolizumab infusion will be given at Day 
64/Week 10.  
 


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7. SUBJECT SELECTION 
 
7.1. Description of Study Population 
The target population is patients with locally advanced primary and recurrent colorectal 
cancer, with confirmed positive RAS mutation eligible for radical pelvic surgery at time 
of enrolment. 
 
7.2. Number and Source of Subjects 
In this study approximately 4-6 (Part I) and up to 10 patients (Part II) will be enrolled, 
divided into the two sequential parts of the study. Patients will only be allowed to 
participate in either Part I or Part II of the study. Part II will only start after Part I has been 
completed. As stated above the start of Part II of the study will depend upon the level of 
immune activation and the safety profile in Part I. Patients will be recruited at 3-5 sites. 
Potential patients will be identified when patients are diagnosed with locally advanced 
primary and recurrent colorectal cancer by referrals. 
 
7.3. Inclusion Criteria 
1.  Patients with locally advanced primary and recurrent colorectal cancer (CRC) 
(histologically or cytologically confirmed adenocarcinoma), with a confirmed oncogenic 
KRAS exon 2, codon 12 or 13 mutations, eligible for radical pelvic surgery at time of 
enrolment. 
2. Patient is ≥18 years of age and able to consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
4. Patient has adequate organ and bone marrow function within 28 days of study 
a. Neutrophil count >1.5 x109/L 
b. Platelets >100 x109/L 
c. Hb >90g/L 
d. Total bilirubin <1.5 upper limit of normal, ULN  
e. ALT and AST <3.0 x ULN 
f. Serum creatinine < 3 x ULN or Creatinine Clearance ≥  30ml/min (Cockroft-Gault or 
Nuclear GFR method) 
g. PT and APTT <1.3 x ULN 
5. The patient is willing to provide study specific pre TG02-treatment biopsy of tumour 
mass and allow use of archival tumour biopsies. For patients where there are technical 
reasons a baseline biopsy cannot be performed but who fulfil all the other inclusion 
criteria, the investigator shall contact the medical monitor to discuss the possibility of 
including such patient. 
6. The patient is willing and able to comply with the protocol, and agrees to return to the 
hospital for study visits and examinations  
7. Men and women of childbearing potential must use adequate contraception to prevent 
pregnancy during the study. Adequate contraception is defined in the study as any 
medically recommended method (or combination of methods) as per standard of care. 
An adequate contraception includes hormonal contraception with implants or combined 
oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral 
tubal ligation, hysterectomy, or vasectomy of partner. A combination of male condom 
with either cap, diaphragm or sponge with spermicide are also considered acceptable. 


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For women of childbearing potential, a negative pregnancy test needs to be confirmed 
before inclusion. 
8. The patient has been fully informed about the study and is willing to participate in the 
study, and has provided written informed consent form prior to any trial specific 
screening procedures. 
 
7.4. Exclusion Criteria 
1. The patient has previously received an anticancer vaccine or immune checkpoint 
inhibitor, or participated in a trial involving the use of an anticancer vaccine or immune 
checkpoint inhibitor  
2.  Patients where pre-surgery radiotherapy, chemotherapy or other anti-cancer therapy 
has not been completed ≥ 2 weeks prior to TG02-treatment. 
3. The patient is receiving anti-cancer therapy for concurrent illness 
4. The patient has had a prior different malignancy within the last 3 years (excluding 
adequately treated basal cell or squamous cell carcinoma of the skin cancer, or 
localised low grade tumours considered cured and not requiring systemic therapy) 
5. The patient has uncontrolled or significant intercurrent or recent illness including: 
a. auto-immune disorder or history of autoimmune disease requiring 
immunosuppressive treatment 
b. cardiac disorder such as uncontrolled cardiac failure, unstable angina or non-ST 
segment elevation myocardial infarction (NSTEMI) or myocardial infarction, 
uncontrolled arrhythmia less than 3 months before screening  
c. stroke or thromboembolic event within 3 months of study commencement 
d. active or uncontrolled severe infection 
e. history of solid organ transplantation or any condition requiring chronic 
treatment with corticosteroids or other immunosuppressive agents 
f. active coagulopathy/bleeding diathesis 
g. cirrhosis, chronic active or untreated persistent hepatitis 
h. history of adverse reactions to peptide vaccines  
6. The patient is pregnant or lactating.  
7. Has received an investigational drug within 4 weeks prior to study drug administration, 
or unless other has been agreed with the medical monitor  
8. Is currently receiving any agent with a known effect on the immune system, unless at 
dose levels that are not immunosuppressive (e.g. prednisone at 10 mg/day or less or as 
inhaled steroid at doses used for the treatment of asthma)  
9. Known history of positive tests for HIV/AID.S 
11. Are planned to receive yellow fever or other live (attenuated) vaccines during the 
course of study 
12. For Part II – any contraindication to receiving pembrolizumab: 
For the 50 mg lyophilized powder: Hypersensitivity to the active substance 
(pembrolizumab) or to any of the excipients; L-histidine, L-histidine hydrochloride 
monohydrate, Sucrose, Polysorbate 80 
For the 100 mg concentrate: Hypersensitivity to the active substance 
(pembrolizumab) or to any of the excipients; L-histidine, Sucrose, Polysorbate 80. 
7.5. Discontinuation Criteria 
Patient Withdrawal 


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Single patient termination is by definition when the patient is withdrawn or when the 
patient has died or completed the study. The study termination page in the eCRF must 
be completed. 
 
In accordance with the Declaration of Helsinki, each patient is free to withdraw from the 
study at any time without giving their reason(s). 
The investigator also has the right to withdraw patients from the study in the event of: 
• withdrawal of the patient’s consent 
• surgery does not proceed and the patient is unable or unwilling to provide a biopsy at 
the time of cancelled surgery 
• occurrence of an exclusion criterion which is clinically relevant and affects the patient’s 
safety, and discontinuation is considered necessary by the Investigators and/or 
Targovax. 
• therapeutic failure requiring urgent additional medication (if applicable) 
• occurrence of AEs, if discontinuation of trial medication is desired or considered 
necessary by the Investigator and/or patient (if applicable) 
• intake of non-permitted concomitant medication where the predefined consequence is 
withdrawal from the trial 
• patient non-compliance with study procedures/requirements 
• major protocol violation which potentially impacts the study endpoints 
 
Study Termination 
The whole study may be discontinued at the discretion of the Investigator or Sponsor in 
the event of any of the following: 
• 
Occurrence of AEs not seen previously which by virtue of their nature, severity and 
duration are considered to necessitate study termination; OR the unexpected 
incidence of known AEs 
• 
Medical or ethical reasons affecting the continued performance of the study 
• 
Difficulties in the recruitment of patients 
• 
Cancellation of the drug development as such or for the given indication 
 
7.6. Replacement Policy 
If a patient during the treatment period before surgery is withdrawn, the patient will be 
considered to be replaced. All safety data collected will remain part of the safety analysis. 
 


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8. TRIAL TREATMENT(S) AND REGIMEN OF INVESTIGATIONAL 
MEDICINAL PRODUCTS 
 
8.1. Identity of Investigational Medicinal Product(s) (IMPs) 
The TG02-treatment (GM-CSF/TG02) is manufactured according to Good Manufacturing 
Practice (GMP) standard. 
 
In Part I the IMPs consists of two different products in two separate vials, 1 vial 
containing TG02 and 1 vial containing GM-CSF. In Part II, in addition to TG02 and GM-
CSF, a third IMP, pembrolizumab will be used.  
 
TG02 
TG02 is a sterile dry white solid powder consisting of the eight drug substance peptides in 
equal amounts (weight net peptide) (Baccinex SA, Courroux, Switzerland/Bachem 
Distribution Services, GmbH). 
 
 
TG02 is produced by lyophilisation of a sterile aqueous solution of the drug substance 
peptides. No additional ingredients are present in the TG02 drug product. Each vial of 
TG02 contains 2.4 mg of the drug substance peptides. 
 
TG02 is supplied as a single dose in 2 mL clear glass vials. All the primary packaging 
materials used are in conformance with the European Pharmacopoeia (EP) and US 
Pharmacopoeia (USP). 
 
TG02 drug product is to be reconstituted in water for injection (WFI) before 
administration to the patient. Patient will receive TG02 at a dose of 0.80 mg/injection. 
 
An accountability log will be kept to track the use of TG02. 
 
GM-CSF (Immunomodulator)  
GM-CSF in the form of lyophilised recombinant human GM-CSF expressed in E-coli 
(Amoytop Biotech Co, Ltd, Xiamen, China) is used as immunomodulatory.  
 
GM-CSF is a sterile dry white solid powder consisting of human recombinant GM-CSF 
and the excipients mannitol, macrogol 4000, human albumin, dibasic sodium phosphate 
and monobasic potassium phosphate. Each vial of GM-CSF contains 100 µg (1.0x106 IU) 
Molgramostim. GM-CSF is supplied in a 2 mL clear glass vial.  
 
GM-CSF is to be reconstituted in water for injection (WFI) before administration to the 
patient. 
 
An accountability log will be kept to track the use of GM-CSF. 
 
Pembrolizumab (Only Part II):  
A fixed dose of 200 mg pembrolizumab will be administered as an intravenous infusion. 
The product will be provided as a 50 mg lyophilized powder in a single-use vial for 
reconstitution in sterile water for injection, or as a vial of 4 mL of concentrate containing 
100 mg. Pembrolizumab should be administered according to the latest version of the 


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Summary of Product Characteristics (SmPC), and dosed according to available guidelines 
for the use of this drug.  
 
An accountability log will be kept to track the use of Pembrolizumab. 
 
8.2.  Dosing, Mode of Administration, Duration of Treatment 
TG02 and GM-CSF will be given as intradermal injections by trained study staff 
authorized to do such procedures. Training of study staff will be performed by Sponsor 
before any patients are treated. In addition, the administration of TG02 and GM-CSF is 
described in the Study Drug Handling Plan (SDHP). 
 
GM-CSF and TG02 are administered as 2 separate intradermal injections, 15 to 30 
minutes apart, at the same site in the upper arm. In addition, TG02 will at certain time 
points be administered intradermally (without prior administration of GM-CSF) in the 
lower area of the contra lateral arm as DTH test. 
 
The administration of GM-CSF (0.10 mL reconstituted GM-CSF) and TG02 (0.10 mL 
reconstituted TG02) has to be strictly intradermal. Utmost care has to be taken that no 
material is administered subcutaneously. When done correctly, a small bleb should appear 
following the injection. An injection that is too superficial will result in loss of volume 
from the injection site during injection or after withdrawal of the needle. The 
administration should be performed at the same site every time, if possible. 
 
TG02: provided as a lyophilised solid powder for reconstitution in sterile water for 
injection to be given via intradermal injection.  
 
TG02 given in the TG02-treatment will be administered in the upper arm at weeks 1, 2, 3, 
4, and 6. If surgery is scheduled after week 10 one more TG02-treatment will be given in 
week 10. TG02 is to be given 15-30 minutes after GM-CSF.  
 
TG02 will at certain time points (week 1, week 4, week 6, week 8 and possible week 10), 
be administered intradermally (without prior administration of GM-CSF) in the lower 
area of the contra lateral arm as a DTH test to evaluate the immunological response (see 
Table 6-1). 
 
Where a  DTH (TG02) injection is being performed the TG02 DTH dose should be 
administered 30 minutes before the TG02-treatment and patients should be observed for 
at least 30 minutes after ALL TG02 treatments. 
 
GM-CSF: provided as a lyophilised solid powder for reconstitution in sterile water for 
injection to be given via intradermal injection.  
 
GM-CSF given in the TG02-treatment will be administered in the upper arm at weeks 1, 
2, 3, 4, and 6. If surgery is scheduled after week 10 one more TG02-treatment will be 
given in week 10 (see Table 6-1). 
 
In the TG02-treatment GM-CSF is to be given 15-30 minutes before TG02.  
 
The drug handling of TG02-treatment will be described in a separate Study Drug 
Handling Plan. 


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Table 8-1: Treatment schedule 
Time point 
DTH test 
(TG02) 
TG02-treatment 
(GM-CSF followed by TG02) 
Pembrolizumab 
(Part II of the study) 
Week 1 
X 
X 
 
Week 2 
 
X 
 
Week 3 
 
X 
 
Week 4 
X 
X 
X 
Week 6 
X 
X 
X 
Week 8 
X* 
 
X*** 
Week 10 (only if 
surgery is after 
week 10) 
X** 
X 
X 
*If surgery is scheduled to be done in week 8, DTH (TG02) injection to be done approximately 48 hours 
prior to surgery. 
** Only to be taken for patients who have surgery at week 10 or later and had a negative outcome at week 
8. 
*** If surgery is taking place Day 51-63, pembrolizumab will be given at Day 50/Week 8. 
 
Pembrolizumab: A fixed dose of 200 mg pembrolizumab will be administered as an 
intravenous infusion. Pembrolizumab should be administered according to the latest 
version of the Summary of Product Characteristics (SmPC), and dosed according to 
available guidelines for the use of this drug. Dependent on time of surgery, a patient will 
receive pembrolizumab 2 to 4 times throughout the treatment period.  
 
All handling of the IMPs/drug products should be in compliance with normal handling of 
sterile products for injections. 
 
8.3. Packaging and Labelling 
From the documentation of the trial medication, it must be possible to retrace the 
handling, composition and pharmaceutical quality of the investigational products 
according to the current Good Manufacturing Practice (GMP) guidelines. 
 
TG02 will be packed and labelled by ”AndersonBrecon UK” (PCI Pharma Services, UK), 
a specialised pharmaceutical clinical supply company located in Hereford, UK, in 
accordance with GMP and International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) requirements.  The vials and boxes will be labelled according to 
local regulatory requirements. 
The trial medication will be supplied to the investigational site(s) in boxes containing a 
defined number of vials. TG02 will be shipped to the investigational sites under 
controlled, frozen (-20±5 oC) conditions. 
 
GM-CSF will be packed and labelled by “AndersonBrecon UK” (PCI Pharma Services 
UK), a specialised pharmaceutical clinical supply company located in Hereford, UK, in 
accordance with GMP and International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) requirements.  The vials and boxes will be labelled according to 
local regulatory requirements. 
The trial medication will be supplied to the investigational sites in boxes containing “a 
defined number of vials”. GM-CSF will be shipped to the investigational site(s) under 
controlled, refrigerated conditions (2 -8 oC). 
 


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Pembrolizumab, in the Part II of the study, will be supplied from commercial stock at the 
clinical site(s) or sourced, packed and labelled and supplied by “AndersonBrecon UK” 
(PCI Pharma Services, UK), a specialised pharmaceutical clinical supply company 
located in Hereford, UK, in accordance with GMP and International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) requirements.  The vials and boxes 
will be labelled according to local regulatory requirements. 
 
The trial medication will be supplied to the investigational sites in boxes containing “a 
defined number of vials”. Pembrolizumab will be shipped to the investigational site(s) 
under controlled, refrigerated conditions (2 -8 oC). 
 
8.4. Storage, Handling and Dispensing of Investigational Product(s) 
Upon receipt of the medication, the Investigators, or the responsible pharmacist, will 
inspect the medication and send back the acknowledgment of receipt form that is enclosed 
with the parcel, duly completed and signed and further follow up on the instructions given 
in the shipment documents. A copy of the signed receipt will be kept in the trial files. 
TG02 must be kept frozen at -20±5 °C and GM-CSF must be kept at 2-8 °C during 
storage prior to reconstitution.  Pembrolizumab must be stored at 2-8 °C in original carton 
to protect from light. Do not freeze. Do not shake. 
All study drugs are to be stored safely and separately from other drugs. The trial 
medication cannot be used for any purpose other than the present study. After the trial is 
completed, all unused trial medication must be destroyed by the pharmacy after sponsor’s 
approval. 
The Investigators will be responsible for the storage, dispensing, inventory, and 
accountability of all clinical supplies at the clinical sites.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory 
must be available for inspection by the designated representatives of the Sponsor 
(Targovax) on request, and must include the information below: 
• the identification of the patient to whom the drug was dispensed 
• the date(s) and quantity of the drug dispensed to the patient 
• the product lot number 
The preparation of the Study Drugs must be documented on a ‘Drug Preparation and 
Dispensing Log Form’. 
 
A copy of the inventory record and a record of any clinical supplies that have been 
destroyed must be submitted by the Investigators to the Sponsor (Targovax).  This form 
must include the information below: 
• the number of administered units 
• the number of unused units 
• the number of units destroyed at the end of the trial  
• the date and method of destruction and the location 
 
8.5. Blinding Procedures 
The study will be an open labelled study. 
 
8.6. Randomization and Subject Allocation 
This is a non-randomized study. 
 


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8.7. Treatment Compliance 
The Investigator(s) will record the time and dose of all administrations in the medical 
source documents. Any reasons for non-compliance will also be documented, including: 
• missed visits  
• interruptions in the schedule of administration  
• non-permitted medications  
 
Management of Toxicity 
If a patient experiences GM-CSF or TG02 related toxicity on the days of the scheduled 
TG02 treatment, TG02 treatment should be delayed until toxicity resolved to CTC grade 1.  
The patient should then restart at the next planned visit.   
 
Management of TG02 or GM-CSF related reactions: 
• At any time during the vaccination schedule – if a patient exhibits signs of an allergic 
reaction (not just a local reaction) then they should be treated symptomatically and for 
all subsequent TG02-treatment administrations they should be pre-medicated with 
intravenous antihistamine treatment (e.g. chlorpheniramine or dexchlorpheniramine) 
30 minutes before any TG02-treatment administration.  
• Patients who have local reactions only – It is permissible to use topical therapies such 
as anti-histamine or steroid creams or EMLA cream for pain 
• Where a DTH injection is being performed the TG02 DTH dose should be 
administered 30 minutes before the TG02-treatment and patients should be observed 
for at least 30 minutes after ALL TG02-treatments. 
• In patients who have not had prophylaxis  
– If after the TG02 DTH dose the patient exhibits a Grade 1 or 2 allergic reaction 
then the TG02-treatment should be delayed and the patient is to be given 
intravenous antihistamine treatment as above 
– If a Grade 3 or 4 reaction occurs then no more vaccinations should be given. 
• In patients who have had prophylaxis  
– 
If after the DTH dose the patient exhibits a Grade 1 reaction then the TG02-
treatment should only be given if the investigator believes it is reasonable to do 
so based on the nature of the reaction 
– 
if a Grade ≥2 reaction occurs then no more vaccinations should be given. 
• Precautions should be in place in case of anaphylaxis 
 
Management of pembrolizumab related reactions: 
• Toxicities should be managed according to SmPC for pembrolizumab. The patient 
should be discontinued if immunosuppressive agents are used at immunosuppressive 
doses. Please see Section 8.8 Prior and Concomitant Medication for further details. 
8.8. Prior and Concomitant Medications 
No systemic anti-cancer therapy is to be used during the study treatment period before 
surgery.   
 
Other vaccinations must not be administered during the treatment period.  
Vaccination with yellow fever or live (attenuated) vaccines is prohibited until after 
surgery. 
 
Any agent with a known effect on the immune system should be excluded during the 
treatment period before surgery, unless it is being given at dose levels that are not 


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immunosuppressive, e.g. prednisone at 10 mg/day or less or as inhaled steroid at doses 
used for the treatment of asthma. 
 
No specific studies of interactions between TG02 and other agents have been conducted. 


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9. STUDY ASSESSMENTS 
 
9.1. Assessment of Efficacy 
9.1.1. Primary Efficacy Variables 
A systemic immune response is defined as having a positive in vivo DTH and/or a 
positive in vitro T-cell response at least once during the treatment period. Change intra-
tumoural T-cells in resected tumour tissue at surgery compared to pre TG02-treatment 
core biopsy will be investigated.  
 
Delayed Type Hypersensitivity (DTH) 
DTH tests are performed in order to demonstrate whether a TG02 RAS mutation specific 
immune response has been elicited. 
Administration of TG02 only (without GM-CSF or proceeded by TG02-treatment) must 
be injected intradermally in the lower area of the contralateral arm to TG02-treatment as a 
Delayed Type Hypersensitivity (DTH) test. 
The DTH test is administered at baseline (Day 1 before treatment) week 4, week 6 and 
week 10 if surgery is scheduled after week 10 and the patient has not shown positive 
DTH reaction. 
 
The DTH skin reaction assessment is to be performed 48 hours (+/- 4 hours) after each 
administration by the patient in a study specific diary. The patient will be instructed by 
the study nurse how to record the DTH response and how to enter the results into the 
diary. The DTH-test will be considered positive if the area of the skin reaction has an 
average diameter* of  ≥ 5 mm at the 48 hours (+/- 4 hours) assessment (Figure 4). 
 
 
Figure 4: DTH Skin Reaction Registration (induration and erythema) 
 
 
* Average diameter: a mm + b mm                
 
  2  
 
 
                        
T-cell Analyses  
Immunology-processed blood samples (PBMC) will be taken at baseline (Day 1, Week 1) 
and week 8 (Day 50). If surgery is after week 10, a third sample will be taken as close as 
possible up to the date of surgery. All samples will be processed and stored under 
appropriate conditions until being analysed in batches to minimize day to day assay 
variability.  PBMCs will be analysed for the presence of TG02 specific T-cells which will 
be described in a study specific Immune Monitoring Plan. 
 
Tumour biopsy assessment  
Tumour samples for assessment of immune response will be taken pre TG02-treatment 
(baseline) in the form of a study specific biopsy as per site specific standard protocol 
(optimally 2 cores will be needed) and at time of surgery in the form of resected tumour 
tissue (post treatment sample). If for any reason the patient does not proceed to surgery, a 
biopsy will be obtained at the time of planned surgery if possible. In addition, archival 
biopsy samples from both initial staging (primary diagnosis) and re staging will be 
utilised, as needed. 
DTH
a
b
DTH
a
b


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The tissue samples should be fixed in 10% neutral buffered formalin as soon as practical 
after collection of the specimen. Processing of tumour tissue into blocks will occur 
according to the respective sites standard histology sampling procedure. These tumour 
tissue samples will be used for pathological review and subsequent 
immunohistochemically evaluation of potential biomarkers. 
 
In addition, from some patients, fresh tumour tissue will be sent directly to the laboratory 
at Peter MacCallum Cancer Centre following the respective sites standard procedures.  
These fresh tissue samples will be processed to isolate tumour infiltrating cells (TILs) and 
to generate tumour-derived organoid/spheroid cultures as part of other outcome measures.  
 
As for the primary efficacy variables, tumour infiltrating lymphocytes in resected tumour 
tissue at surgery and baseline biopsies will be analysed by immunohistochemistry. 
 
The collection, storage, shipment, parameters and analyses to be used will be described in 
the study specific Immune Monitoring Plan. 
 
9.1.2. Secondary Efficacy Variables 
Tumour biopsy assessment  
The same processing procedure as described for primary efficacy variables will be 
followed.  
 
Immunohistochemical staining will be performed to investigate; pathological responses 
and markers of apoptosis (such as activated Caspase 3, granzyme B), immune cell subsets 
(such as T effector cells, B cells, NK cells, T-regs, MDSC), and PD-L1 expression on 
epithelial cells in baseline biopsies and resected tumour tissue at surgery.  
 
The collection, storage, parameters and analyses to be used will be described in a study 
specific Immune Monitoring Plan. 
 
FDG PET/CT assessment  
FDG uptake reflects the tumour activity independent of the morphologic characteristics.  
Sequential FDG-PET/CT can provide vital information in monitoring treatment response 
in tumour.  
 
FDG PET/CT images will be performed at screening (should be within the last 4 weeks 
prior to first TG02-treatment), and as close as possible up to the date of surgery. The 
scans will be captured according to the site’s standard imaging procedure. 
Standard uptake value (SUV) will be measured at baseline and post treatment will be 
assessed. 
 
The images will be anonymized and provided with a unique study identification number, 
one for the Investigators file and one for the Sponsor file  
 
Changes in Tumour Marker CEA 
Tumour marker assessment will be done to follow the evolution of the disease under 
treatment.  The marker of choice will be CEA. This marker will be evaluated at screening, 
week 8 and if surgery is after week 10, a sample will be taken as close as possible to 
surgery. 


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The analysis of this marker will be performed locally at each site according to local 
procedures. 
 
9.1.3. Exploratory Efficacy Variables 
Changes in circulating tumour cells and/or circulating tumour DNA 
Change in circulating tumour cells (CTC) will be measured to follow the evolution of 
levels of CTC during the treatment period. The Investigators will arrange to have the 
plasma sample transported directly to the central laboratory for analyses according to the 
procedures detailed in a laboratory manual.  
 
Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
Cytotoxic functionality of RAS mutation specific T cells grown from fresh tumour tissue 
or PBMC will be studied as described in the study specific Immune Monitoring Plan. 
 
9.2. Assessment of Safety 
 
9.2.1. Adverse Events 
It is important that all the staff involved in the trial is familiar with the content of this   
section of the protocol. 
 
9.2.1.1. 
Definitions 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition in a patient under clinical investigation 
who has been administered an investigational pharmaceutical product (in this case GM-
CSF/TG02 but which does not necessarily have a causal relationship with this treatment.  
An undesirable medical condition can be symptoms (e.g., nausea, chest pain) signs (e.g., 
tachycardia, enlarged liver) or abnormal results of an investigation (e.g., laboratory 
findings, ECG).  An AE can include any undesirable condition occurring at any time after 
inclusion in the study, even if no trial treatment has been administered or recently 
administered.  A grading severity scale is provided for each AE term.  NCI Criteria for 
Adverse Events (CTCAE) (v4.03: June 14, 2010) includes five grades (1-5), with grade 5 
being death.  
 
Any events that are unequivocally due to disease recurrence must not be reported as 
AEs. 
 
A serious AE (SAE) is an event that is known with certainty, or suspected with good reason, 
to constitute a threat to life or to cause severe or permanent damage.  A SAE can occur 
during any phase of the trial and at any dose of the investigational product.  This is 
particularly true for an AE that: 
• results in death 
• is immediately life-threatening 
• requires patient hospitalisation or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity or 
• is a congenital anomaly/birth defect 
• is an important medical event that may have jeopardised the patient or may have 
required medical intervention to prevent one of the outcomes listed above. 


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Medical and scientific judgment is to be exercised in deciding on the seriousness of a case.  
Important medical events may not be immediately life-threatening or result in death or 
hospitalisation, but may jeopardise the patient or may require intervention to prevent one 
of the listed outcomes in the definitions above.  In such situations, or in doubtful cases, the 
case should be considered as serious.  Drug misuse and drug overdose and should be 
regarded as serious, even if they may not result in the above mentioned outcomes. 
Hospitalisation for administrative reason (for observation or social reasons) is allowed at 
the investigator’s discretion and will not qualify as serious unless there is an associated 
adverse event warranting hospitalisation (see Appendix I and Appendix II for additional 
safety information). 
 
The causality of AE/SAEs (i.e., their relationship to trial treatment) will be assessed by the 
individual investigators at each trial centre who must while completing the CRF answer 
yes/ no to the question ‘do you consider that there is a reasonable possibility that the 
AE/SAE may have been caused by the investigational drug? 
 
Any events that are unequivocally due to disease recurrence must not be reported as 
AEs. 
 
The specialist group handling the pharmacovigilance for the study is:  
 
ICON Clinical Research UK Ltd 
2 Globeside Business Park, Marlow Buckinghamshire United Kingdom, SL7 1HZ  
 
The ICON’s Pharmacovigilance & Safety Services department is specialised and has the 
appropriate expertise in handling and reporting SAEs. 
 
9.2.1.2. 
Adverse Event Reporting 
For the purpose of this trial, any detrimental change in a patient’s condition, subsequent to 
their entry into the trial and during the 28-day follow-up period after the final treatment, 
should be considered an AE. 
The development of a new cancer should be regarded as an AE.  New cancers are those that 
are not the primary reason for the administration of the trial treatment and have been 
identified after the patient’s inclusion into this clinical trial. 
 
Any events that are unequivocally due to disease recurrence must not be reported as 
AEs. 
 
If the same AE occurs at several investigation times in one patient, then the AE in question 
must be documented and assessed as new each time. 
All AEs are to be recorded on the CRFs provided and Serious Adverse Events also on the 
Serious Adverse Event Form.  A description of the event, including its severity, duration, 
any action taken (e.g. treatment and follow-up tests) and the outcome is to be provided, 
along with the investigator’s assessment of the relationship to the trial treatment. AEs and 
laboratory values will be graded according to the NCI Criteria for Adverse Events 
(CTCAE) (v4.03: June 14, 2010) and recorded on the appropriate CRF page. 
The reporting of laboratory/vital signs abnormalities as both laboratory findings and 
adverse events should be avoided. They should not be reported as AEs unless any criterion 
of clinical significance and/or a SAE is fulfilled, the laboratory/vital signs abnormalities 
cause study drug dose adjustment, lead to patient discontinuation of their trial treatment, or 
the investigator insists that the abnormality is reported as an AE.  If an abnormal laboratory 


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value/vital sign is associated with clinical signs and symptoms, the sign/symptom should 
be reported as an AE and the associated laboratory result/vital sign should be considered 
additional information that must be collected on the relevant CRF. 
All patients who have new or worsening NCI-CTC grade 3 or 4 laboratory values at the 
time of withdrawal must have further tests performed and the results recorded on the 
appropriate CRF, until the laboratory values have returned to NCI-CTC grade 1 or 2, unless 
these values are not likely to improve because of the underlying disease.  In these cases, the 
investigators must record their opinions on the CRFs and in the patients’ medical records. 
For an AE to be a suspected drug-related event there should be at least a reasonable 
possibility of a causal relationship between the trial medicinal product and the AE (see 
Appendix II for guidelines on interpretation of causality). 
 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in section 9.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but is not an SAE.  On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke, 
but would be an SAE. 
 
Lack of efficacy 
When there is deterioration in the condition for which the medicine is being used there may 
be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless 
Targovax or the reporting physician considers that the medicine contributed to the 
deterioration or local regulations state to the contrary, the deterioration should be 
considered to be a lack of efficacy and not an AE. 
 
Handling unresolved SAEs/AEs at completion/withdrawal 
All trial treatment-related toxicities and SAEs must be followed until resolution unless, in 
the investigator’s opinion, the condition is unlikely to resolve because of the patient’s 
underlying disease. 
 
Procedure for reporting serious adverse events 
Investigators and other site personnel must inform the study monitor of any SAE that occurs 
in the course of the study as soon as possible but definitely within 24 hours of when he or 
she becomes aware of it. 
 
The following minimal information must be faxed immediately to +44 870 710 7157 
• Patient identifier – patient number, investigator 
• Details of the event or outcome (see section 9.2) 
 
To discuss the medical aspects of the SAE investigators should call: 
 
Medical Monitor: Dr Robert Miller, or deputy, on +44 203 291 3032 
 
This number should also be called to report a life-threatening or fatal adverse event within 
2 hours of knowledge of the event if this occurs before recognised recurrence of disease. 
 
The dedicated email address for SAE information is:  
ICON-Safety-CentralReceipt@iconplc.com 


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The SAE must be documented in the patient’s medical source documents and the outcome 
described. 
 
The monitor will work with the investigator to compile all the necessary information and 
ensure that the appropriate Drug Safety Department receives a report within 24 hours for 
all fatal and life-threatening cases and by day 5 for all other SAEs. 
Follow-up information on SAEs must also be reported by the investigator within the same 
time frames. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided to safety group within 24 hours as described above. 
All SAEs have to be reported, whether or not considered causally related to the 
investigational product.  All SAEs will be recorded in the CRF.  The investigator is 
responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE 
as per local requirements. 
 
Additional information will be requested, if necessary, by the Trial Physician within 5 days 
of the receipt of the SAE report.  This is to ensure that the initial reporting of SAEs is made 
to the regulatory authorities within the required time-frame.  All withdrawals from trial 
treatment must be notified to the trial physician.  Withdrawals from treatment due to a new, 
previously unreported SAE must be notified to the Trial Physician, along with the SAE.  
Withdrawal from trial treatment for a previously reported SAE can be made within the 7 
days after the decision has been made to withdraw the patient and for a non-serious AE 
within 21 days of the decision to withdraw.  After withdrawal from treatment patients must 
be followed up for AEs for 28 days after the last dose of trial medication.  All SAEs recorded 
during that period must be reported to the safety group, and followed up until resolved 
unless in the Investigator’s opinion the condition is unlikely to resolve due to the patient’s 
underlying progressive disease. 
 
9.2.2. Safety Laboratory Variables 
Safety serum chemistry and haematology parameters will be analysed at hospitals local 
laboratory. 
 
Blood samples for the determination of serum chemistry and haematology will be drawn 
at pre-specified time-points, see Schedule of visits (Table 6-1) Additional haematology 
and chemistry are under the investigator’s judgement. 
The following laboratory tests will be performed: 
 
Table 9-1: Clinical laboratory parameters 
Chemistry 
Haematology 
Total Alkaline Phosphatase (total ALP) 
RBC count 
ALT (SGPT) 
Hb 
AST (SGOT) 
Haematocrit 
Lactate Dehydrogenase (LDH) 
PLT count 
Gamma-GT 
WBC count 
Total Protein 
WBC diff. 
Albumin 
 
Neutrophils 
Bilirubin 
 
Lymphocytes 
Creatinine 
 
Monocytes 
Sodium 
 
Eosinophils 


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Chemistry 
Haematology 
Potassium 
 
Basophils 
Magnesium 
 
Calcium 
 
Phosphate 
 
Chloride 
 
Urea 
 
Oestradiol (females at screening only) 
 
 
Reference ranges from each laboratory will be provided to the Sponsor.  If during the study, 
ranges should be changed, investigators are requested to provide updated laboratory normal 
values. 
 
Laboratory values with CTCAE grade 3 or higher and/or considered clinically significant 
by the treating physician have to be reported as an AE during the treatment period. At the 
follow-up visit only changes in laboratory values judged to be related to the study drug will 
be reported. 
 
Volume to be drawn from each patient 
The total volume of blood that will be drawn from each patient in this trial will vary 
depending on how long the patient stays on study.  Table 9-2 indicates the range for patients 
completing the whole study period. 
 
Table 9-2: Volume of blood to be drawn from each subject  
Assessment 
Sample 
volume (ml) 
No. of 
samples 
Total volume 
(ml) 
PBMC 
50 ml 
2-3 
100-150 ml 
Biomarkers (CEA)/ 
other immune subsets 
7 ml 
2-3 
14-21 ml 
Safety 
Clinical chemistry 
7 ml 
5-6 
35-42 ml 
Haematology 
7 ml 
5-6 
35-42 ml 
CTCs 
6 ml 
2-3 
12-18 ml 
Total 
67 ml 
 
196-273 ml 
 
9.2.3. Other Safety Variables 
Medical and surgical history of colorectal cancer 
A summary of the patient’s relevant medical and surgical history of colorectal cancer (i.e. 
time period from diagnosis of underlying malignancy to enrolment in the study) should be 
recorded on the appropriate CRF page. 
 
Vital Signs 
Vital signs variables include measurements of body temperature, heart rate, systolic and 
diastolic blood pressures.  Vital signs will be assessed pre- and post-treatment as detailed 
in Schedule of visits (see Table 6-1).  Additional vital signs assessments will be done 
under investigator’s judgment.  Normal ranges for vital signs are provided below (Table 
9-3). 
 
 
 
 


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Table 9-3: Normal Ranges for Vital Signs for healthy adults 
Vital signs parameter 
Normal range 
Low 
High 
Systolic BP (mm Hg) 
85 
139 
Diastolic BP (mm Hg) 
60 
89 
Heart rate (bpm) 
60 
100 
Body temperature 
36.4 °C 
97.5 °F 
37.7 °C 
99.5 °F 
 
In addition, after any TG02-treatment the patients will be monitored for heart rate and blood 
pressure at 5, 10 and 30 minutes and then every 30 minutes thereafter for up to 2 hours post 
administration. 
 
Notable vital signs results should be interpreted in conjunction with the clinical situation of 
the patient.  Once AE notification is decided upon, investigators are required to follow the 
procedure described for AE notification and document the clinically notable abnormality 
on the AE eCRF page.  Any notable abnormal vital signs finding or related AE must be 
followed until the outcome is known. 
 
Before vital signs are recorded, the patient should be resting for at least 5 minutes.  The 
same position will be used each time vital signs are recorded for a given patient and blood 
pressure will be measured preferably from the same arm. 
 
Physical examination 
An abbreviated physical examination consisting of general appearance, lungs, 
cardiovascular system and abdomen and other physical findings will be done at each 
hospital visit where the patient meets with the treating physician. 
 
Any physical examination finding that is classified by the Investigator as a clinically 
significant change (worsening compared to previous examination) will be considered as an 
AE, documented on the patient’s eCRF, and followed until the outcome is known. 
ECOG performance status 
 
Performance status will be evaluated using the ECOG scale: 
Grade ECOG Performance Status 
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 selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
12-lead ECG  
A standard 12–lead ECG will be performed at screening.  Results will be recorded as 
normal or abnormal; abnormal findings will be described in the CRF and when clinically 


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relevant, findings should be recorded as an AE and should be followed up during study as 
needed per investigator’s judgement. The 12-lead ECG will be evaluated by the local 
Investigator.  A copy of the 12-lead ECG page, signed, dated and diagnosed should be 
stored in the patient’s medical record.  
 
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10. DATA MANAGEMENT 
 
10.1. Case Report Forms 
Electronic CRFs (eCRF) will be used to capture study results and data. The study 
coordinator or other authorised study personnel will transcribe data from source 
documents to the eCRFs. All eCRFs will be reviewed and source-verified by the study 
monitor during periodic site visits, and the study monitor will ensure that all data in the 
eCRF are correct and completed. Once the eCRF are completed and source-verified, the 
investigator must electronically sign and date all required pages, verifying the accuracy of 
all data in the eCRF. Specific instructions for completing and submitting eCRFs will be 
provided. 
All data recorded directly in the eCRF, for which no other written or electronic record 
will be maintained in the patient’s medical record, will be considered source data such as 
the patient DTH diary. 
 
10.2. Data Management Plan and Database Design 
The data management plan will be a live documents detailing the processes used by the 
Sponsor’s representatives handling the data management. Any updates to the processes 
employed during the course of the study will be reflected in the data management plan. 
The system is completed within a fully validated clinical database data management 
system. The system is built in a development environment before being moved to the 
testing environment. All testing must be completed prior to the release of the live system. 
 
10.3. Data Entry and Validation 
All computerized data processing will be performed by Sponsor’s representative. All 
eCRFs will be entered electronically by staff into a validated database. Data entry will be 
source data verified by a sponsor representative. Comprehensive edit checks will be used 
to clean data. Patient data will be entered continuously. All changes to the data and the 
database structure will be recorded in an automatic audit trail. 
Data queries will be generated at data entry or if questions arise during the data validation 
or detected during a manual review (safety data). The queries are entered into the eCRF 
and resolved according to the electronic data capture user manual. 
AEs and SAEs will be handled in the same way as the other data reported in the eCRF. 
However, in addition the initial notification of SAEs will be entered into the safety 
database for coding, medical assessment and for reporting to authorities according to 
national regulatory requirements. Before the study database is locked, reconciliation of 
the data will be performed between the two databases. 
 
10.4. Medical Coding 
Medical coding of AEs and medical history will be performed according to the latest 
version of MedDRA and coding of concomitant medication, prior anti-cancer therapy and 
further therapy will be performed according to World Health Organization (WHO) drug 
dictionary.  
 
10.5. Database Lock 
A final database will be declared when all data has been entered, the data verified, the 
data validated and the database defined clean by the Responsible Data Manager. After 
declaration of a final database the data will be exported from the database to SAS datasets 
and both the database and the SAS datasets will locked and protected from changes. All 


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statistical analyses for the final analysis will be performed on the locked datasets. Data 
management will be carried out as described in the sponsor’s representative’s SOPs for 
clinical studies. 


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11. STATISTICAL ANALYSES   
 
11.1. Power Considerations and Determination of Sample Size 
The study will include up to 16 patients; approximately 4-6 patients in Part I and up to 10 
patients in Part II if sponsor decision to initiate such. As this is an exploratory study, no 
formal sample size calculation has been performed. However, it is estimated that a sample 
size of approximately 6 subjects in each group (monotherapy and combined treatment) is 
sufficient to explore the potential effect of TG02 to induce immune responses and to 
assess safety in the induction phase.  
 
11.2. Statistical Hypothesis 
 No statistical hypothesis is defined, only descriptive statistics will be produced. 
 
11.3. Datasets to be Analysed 
 
Efficacy analysis set 
The efficacy analysis set comprises all patients who go to the surgery after treatment 
period. This analysis set will be applied for demography, baseline and efficacy data. 
 
Per protocol analysis set  
The per protocol analysis set is a subset of efficacy, but patients with major protocol 
deviations are excluded. This analysis set will be applied for efficacy data. 
 
Safety analysis set 
The safety analysis set comprises all patients who receives any amount of TG02/GM-
CSF and/or pembrolizumab. This analysis set will be applied for demography and 
baseline and safety data. 
 
11.4. General Statistical Considerations 
Data will be presented by time of measurement.  In general, continuous variables will be 
described using standard summary statistics such as number of observations, mean value, 
standard deviation, minimum and maximum value, median, and first and third quartiles.  
Categorical variables will be summarised in frequency tables as counts and percentages.  
All individual data collected will be presented in data listings.  Patients screened but not 
included in the study will not be presented in any tables or listings. 
 
A detailed plan for data presentation will be prepared for the Statistical Analysis Plan, 
which will be finalized before completion of Part I of the study. 
 
11.5. Demographic and Baseline Characteristics 
Demographic data, medical and cancer history, all other relevant background data will be 
summarised in terms of descriptive statistics as described in section 11.4. 
 
 
 
11.6. Analysis of Endpoints 
11.6.1. Primary Endpoints 
11.6.1.1. Safety Endpoints 
 


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Adverse events 
All adverse events will be classified by MedDRA, version 19 or higher.  
 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date/time on 
or after the first administration of investigational medicinal product (IMP). A pre-
treatment AE is defined as an AE with start date/time prior to the first administration of 
IMP. 
 
The following summary tables will be created, reporting number of events and number of 
patients with events by MedDRA System Organ Class and Preferred Term for the 
TEAEs: 
• total TEAEs 
• total serious TEAEs 
• total IMP related serious TEAEs  
• TEAEs leading to GM-CSF/TG02 withdrawal 
• TEAEs leading to study withdrawal 
• TEAEs leading to death 
• TEAEs by severity  
• Related TEAEs by severity 
• TEAEs by relationship to each IMP (related, not related) separately 
 
Safety laboratory data 
Numerical laboratory data, separately for each parameter, will be summarized in terms of 
descriptive statistics, as described in section 11.4, by time point of measurement, for 
absolute value, absolute and relative change from baseline. Further, number of patients 
with abnormal and/or clinical significant values will be presented by time point. 
 
Vital signs 
Blood pressure, heart rate and body temperature will be summarized in terms of 
descriptive statistics, as described in section 11.4, by time point of measurement, for 
absolute value, absolute and relative change from baseline.  
 
ECG 
Number of patients with abnormal findings in ECG evaluation will be reported by time 
point of measurement. 
 
11.6.1.2. Immune Endpoints 
 
Immune response 
TG02-specific DTH immune response is defined as any positive DTH test during the 
course of the study. Number of patients with TG02-specific DTH response will be 
reported. Furthermore, the number of patients with TG02-specific DTH response by time 
point measurement will be reported. 
 
Presence of TG02 specific T-cells: 
Number of patients with TG02 specific T-cells at Day 1, Day 50 and, if applicable, at Day 
64 (pre-surgery) will be reported. 
 
Change in intra-tumoural lymphocytes (TILs): 


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The absolute count and relative change in TILs measured from tumour tissue collected 
prior TG02 treatment and from resected tumour will be presented in terms of descriptive 
statistics, as described in section 11.4. 
 
11.6.2. Secondary Endpoints 
 
Immune suppression factors in tumour specimens 
Immune suppression factors (PD-L1, Treg, MSDC) and pathological responses (cleaved-
casp3) are measured with IHC from tumour tissue, similarly to TILs. The data 
presentation will follow the same principles. 
  
Details of any further analysis from tissue or blood will be described in the Statistical 
Analysis Plan, which will be finalized before end of Part 1 of the trial. 
 
PET Imaging and biomarkers 
Change in SUV by FDG PET-CT 
The change in SUV from pre TG02 treatment to pre surgery in primary tumour, measured 
by PET-CT will be summarized in terms of descriptive statistics, as described in section 
11.4.  
 
Change in CEA 
The absolute value, absolute and relative change as compared to pre-treatment value of 
CEA will be summarized by time point of measurement in terms of descriptive statistics, 
as described in section 11.4. 
 
11.6.3. Exploratory Endpoints 
• Change in circulating tumour cells and/or circulating tumour DNA: including the 
absolute value, absolute and relative change as compared to pre-treatment value. These 
will be summarized by time point of measurement in terms of descriptive statistics, as 
described in section 11.4 
• Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
 
11.7. Hardware and Software 
All statistical analyses will be produced using SAS software. 
 


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12. QUALITY CONTROL AND ASSURANCE 
 
12.1. Monitoring 
The study will be monitored regularly, according to a monitoring plan that will be written 
specifically for this study. The monitoring plan will define the monitoring frequency and 
detailed procedures. In general, during monitoring visits the monitor will ensure that the 
study is being conducted according to the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP) guidelines and other applicable 
regulations, and will compare the eCRF entries to original source data. He or she will 
make sure the informed consent procedure has been appropriately carried out and will 
ensure that all SAEs have been reported within applicable timeframes. He or she will also 
ensure that IMP accountability has been maintained and will, after completion of the 
study, perform final accountability and arrange for the return or destruction of IMP. 
 
12.2. Audits and Inspections 
Authorised representatives of Targovax, a regulatory authority, an IEC or an IRB may visit 
the centre to perform audits or inspections, including source data verification.  The purpose 
of an audit or inspection is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted, and whether 
data were recorded, analysed and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonisation 
(ICH), and any applicable regulatory requirements. The investigator should contact 
Targovax immediately if they are contacted by a regulatory agency about an inspection at 
their centre. 
 
12.3. Record Keeping and Archiving 
The study specific essential documents must be retained until at least 15 years after the 
completion of the study. The Investigator must not destroy any study specific 
documentation before receiving written permission for this from the Sponsor. Hospital 
records will be archived according to local regulations.  


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13. ETHICS  
 
13.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
The final trial protocol, including the final version of the Written Informed Consent Form, 
must be approved or given a favourable opinion in writing by an IEC or IRB as appropriate.  
The investigator must submit written approval to the sponsor before he or she can enrol any 
patient into the trial. 
The principal investigator(s) is responsible for informing the IEC or IRB of any amendment 
to the protocol in accordance with local requirements.  In addition, the IEC or IRB must 
approve all advertising used to recruit patients for the trial.  The protocol must be 
reapproved by the IEC or IRB annually, as local regulations require. 
Either the investigator(s) or Targovax must submit progress reports to the IEC or IRB 
according to local regulations and guidelines.  The principal investigator(s) must also 
provide the IEC or IRB with any reports of SAEs from the trial site. 
 
13.2. Guidelines and Regulations 
The   trial   will   be   conducted   in   compliance   with   the   protocol,  International   
Conference   of Harmonization Good Clinical Practice (ICH GCP), the applicable 
regulatory requirement(s) and the Declaration of Helsinki. 
 
13.3. Subject Information and Consent 
Written (which has been approved by the IRB/IEC) and oral information about the study in 
a language understandable by the patient will be given to all patients. The Investigator will 
explain the nature of the study, its purpose and associated procedures, the expected 
duration, and potential benefits, constraints and risks associated with the study. Written 
informed consent will be obtained from each patient before any procedures or assessments 
are done and after the aims, methods, anticipated benefits, potential hazards, and insurance 
arrangements in force are explained.  It will also be explained to the patients that they are 
free to refuse entry into the study and free to withdraw from the study at any time without 
prejudice to future treatment. 
The patient’s willingness to participate in the study will be documented in writing in a 
consent form, which will be signed and personally dated by the patient. The same form will 
be signed and dated by the Investigator.  The Investigator will keep the original consent 
forms and copies will be given to the patients. 
If new information becomes available that potentially affects the patient’s safety or 
willingness to continue in the study, or if a protocol amendment is issued that affects 
patient’s safety, study procedures or any aspects of the study that may influence the 
patient’s willingness to continue in the study, the patient information leaflet and informed 
consent form will be revised. After the new documents have received approval from the 
IRB/IEC and regulatory authorities, the patient will be asked to sign a new consent form to 
confirm his or her willingness to continue in the study. 
 
13.4. Subject Confidentiality 
The Investigator(s) must assure that the privacy of the patients, including their personal 
identity and all other personal medical information, will be maintained at all times.  In the 
eCRFs and other documents or image material (including materials from all bone scans, 
CT, MRI examinations) submitted to the Sponsor, patients will not be identified by their 
names, but by an identification code (e.g., allocation number).  Personal medical 
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This may be done by the monitor(s), properly authorised persons on behalf of the 
Sponsor, the quality assurance unit, or regulatory authorities.  Personal medical 
information will always be treated as confidential.  
The Investigators must agree to maintain the confidentiality of the trial at all times and 
must not reveal information relating to the Investigator's Brochure, protocol, CRFs or 
associated documents to unauthorised third parties. 
 
13.5. Safety Steering Committee (SSC) 
A SSC will be appointed to oversee the safety findings as the study progresses. The SSC 
will consist of the sponsor, the principal investigator, relevant sub-investigators and one 
independent physician. The work of the SSC will be described in a Safety Steering 
Committee Charter (SSCC). In particular, the safety of TG02-treatment will be evaluated 
by the SSC. All available data will be taken into account in the evaluation.  
 
The SSC will review every patient until three patients have been recruited into the study. 
The first three patients will be enrolled in a sequential manner with a minimum lag time of 
4 weeks between dosing of the first 3 subjects to ensure an acceptable safety profile.  The 
safety data collected during the first 4 weeks for the 3 first patients will be reviewed by a 
SSC consisting of Sponsor representatives, the Principal Investigator, relevant Sub-
Investigators and one Independent Physician. If no safety concerns arise, then subsequent 
patients will be recruited when they are ready to enrol. In addition, when all safety data, 
systemic immune responses (Delayed-Type Hypersensitivity (DTHs)) and tumour material 
(analysed for intra-tumoural T cells infiltration) are available for all patients in Part I of the 
study, the SSC will evaluate the data to assess safety and preliminary immune activity and 
efficacy to make a recommendation to proceed or not to Part II of this protocol. The SSC 
recommendation will form the basis for sponsor’s final decision.  
  
The same staggered recruitment approach as for Part I will be performed in Part II as TG02-
treatment and pembrolizumab in combination is a novel treatment. 
 
The SSC will meet by teleconference on a regular basis and email correspondence as 
required in between.  


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14. FINANCING AND INSURANCE 
 
14.1. Financial Issues 
According to the Food and Drug Administration (FDA) 21 CFR, part 54, the Sponsor is 
required to completely and accurately disclose or certify information to the FDA 
concerning the financial interests of a clinical Investigator(s) who is not a full-time or part-
time employee.  Therefore, the Investigator must provide the Sponsor with sufficient, 
accurate financial certification that no financial arrangements (further defined in 21CFR 
54.2) exist with the Sponsor, or fully disclose the nature of the arrangement. 
A separate financial agreement (Clinical Trial Agreement) will be signed between the 
Sponsor and the Investigators and/or the institution involved.  Before the study begins, the 
Investigator will provide the Sponsor with a proposed budget, itemised on a per patient 
basis and the payee name(s) and tax identification number(s).  Additionally, the Investigator 
should not begin the study until the Sponsor has confirmed the agreed final budget in 
writing.  The investigator must comply with all the terms, conditions and obligations of the 
trial agreement for this trial.  In the event of any inconsistency between this protocol and 
the trial agreement, the trial agreement shall prevail 
 
14.2. Insurance and Indemnity 
This study is covered under the sponsor’s liability insurance policy. A certificate of 
insurance can be provided upon request.  


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15. STUDY REPORT AND PUBLICATIONS 
 
All information concerning TG02 and Targovax research and product development 
including patent applications and manufacturing processes not previously published 
are considered confidential and shall remain the sole property of Targovax. 
 
Targovax is responsible for preparing a Clinical Study Report, in cooperation with the 
co-ordinating Investigator.  The report will be added to the Targovax data file and may be 
used for regulatory purposes and/or in company publications.  The Clinical Study Report 
will be made after sufficient events have been observed according to the statistical 
hypothesis. 
 
If the trial is terminated prematurely for any reason an abbreviated report will be prepared. 
By signing the protocol, the Investigators agree that the results of this study may be used 
for submission to national and/or international registration and supervising authorities.  The 
authorities will be notified of the Investigators name, address, qualifications and extent of 
involvement. 
 
The publication of study results will be agreed between the sponsor and the 
investigator(s).  The sponsor is interested in publishing the results of  the  study  but  
to  prevent  publication  of  any confidential information, the sponsor retains right to 
review all publications and presentations before they are made public. 
 


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16. REFERENCES  
 
Breivik J , Lothe R. A., Meling G. I., Rognum T. O., Børresen-Dale A-L. and Gaudernack 
G. (1997) Different genetic pathways to proximal and distal colorectal cancer influenced 
by sex-related factors. Int. J. Cancer (Pred. Oncol.) 74, 664-669 (1997). 
 
Cross, R.S., et al., Therapeutic DNA vaccination against colorectal cancer by targeting 
the MYB oncoprotein. Clin Transl Immunology, 2015. 4(1): p. e30. 
 
Dovedi, S.J., et al., Acquired resistance to fractionated radiotherapy can be overcome by 
concurrent PD-L1 blockade. Cancer Res, 2014. 74(19): p. 5458-68. 
 
Garon, E.B., et al., Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N 
Engl J Med, 2015 
 
Gerber, S.A., et al., Radio-responsive tumors exhibit greater intratumoral immune activity 
than nonresponsive tumors. Int J Cancer, 2014. 134(10): p. 2383-92 
 
Gjertsen, M.K., et al., Intradermal ras peptide vaccination with granulocyte-
macrophage colony-stimulating factor as adjuvant: Clinical and immunological 
responses in patients with pancreatic adenocarcinoma. Int J Cancer, 2001. 92(3): p. 
441-50. 
 
Glynne-Jones R, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol 2017; 28 (Supplement 4): iv22–iv40. 
 
Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate 
cancer. N Engl J Med, 2010. 363(5): p. 411-22. 
 
Le DT, Uram JN,Wang H et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Engl J Med 2015;372:2509–2520 
 
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J 
Med, 2015. 372(26): p. 2509-20. 
 
Lipson, E.J., Durable cancer regression off-treatment and effective reinduction therapy 
with an anti-PD-1 antibody. Clin Cancer Res, 2013. 
 
Lipson, E.J., Re-orienting the immune system: Durable tumor regression and successful 
re-induction therapy using anti-PD1 antibodies. Oncoimmunology, 2013. 2(4): p. e23661. 
 
Markman M. Colorectal Cancer and KRAS/BRAF. Mescale 2014 
(http://emedicine.medscape.com/article/1690010-overview#showall) 
 
Misale S, Yaeger R, Hobor S, Scala E, et al. Emergence of KRAS mutations and 
acquired resistance to anti EGFR therapy in colorectal cancer. Nature 2012; 486: 532–
536. 
 
Palmer, D. H., Dueland, S., Valle, J. W., Otterhaug, T., Eriksen, J. A., Muller, H., Iversen, 
B., Miller, R. M.. A prospective, single-arm, phase I/II trial of RAS peptide vaccine 


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TG01/GM-CSF and gemcitabine as adjuvant therapy for patients with resected pancreatic 
adenocarcinoma. ASCO 2015 
 
Rahbari, N.N., et al., Surgery for locally recurrent rectal cancer in the era of total 
mesorectal excision: is there still a chance for cure? Ann Surg, 2011. 253(3): p. 522-33. 
 
Rahma, O.E., et al., The immunological and clinical effects of mutated ras peptide 
vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J 
Transl Med, 2014. 12: p. 55 
 
TG02 An Antigen-Specific Cancer Immunotherapy (ASCI) Targeting RAS Mutations, 
INVESTIGATOR’S BROCHURE, Edition Number: 1.0, Date: 4 Dec 2015 
 
Schachter J, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final 
overall survival results of a multicentre, randomised, open-label phase 3 study 
(KEYNOTE-006). Lancet 2017; 390: 1853–1862. 
 
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, et al. Extended RAS mutations 
and anti-EGFR monoclonal 
antibody survival benefit in metastatic colorectal 
cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 2015; 26: 13-21. 
 
Van Cutsem E, Lenz H-J, Köhne C-H, Heinemann V, et al, Fluorouracil, Leucovorin, 
and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer. J 
Clin Oncol 2015; 33: 692-700. 


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Appendix I: Further guidance on the definition of a Serious Adverse Event (SAE) 
 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the adverse 
event as it occurred or it is suspected that use or continued use of the product would result 
in the patient’s death.  ‘Life-threatening’ does not mean that had an adverse event occurred 
in a more severe form it might have caused death (i.e. hepatitis that resolved without hepatic 
failure). 
 
Hospitalisation 
Out-patient treatment in an emergency room is not in itself a serious adverse event, although 
the reasons for it may be (e.g. bronchospasm, laryngeal oedema).  Hospital admissions 
and/or surgical operations planned before or during a study are not considered adverse 
events if the illness or disease existed before the patient was enrolled in the study, provided 
that it did not deteriorate in an unexpected way during the study. 
 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious 
in a situation where important medical events may not be immediately life-threatening or 
result in death, hospitalisation, disability or incapacity, but may jeopardise the patient or 
may require medical intervention to prevent one or more outcomes listed in the definition 
of serious.  These should usually be considered as serious.  Examples of such events are: 
 
• 
Angio-oedema not severe enough to require intubation but requiring iv. 
hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (e.g. neutropenia or anaemia requiring blood transfusion, etc) 
or convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 


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Appendix II: Further guidance on the assessment of causality 
 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an adverse event (AE) may have been caused by the investigational 
product. 
 
• 
Time course of events and exposure to suspect drug. Has the patient actually 
received the suspect drug? Did the AE occur in a reasonable temporal relationship 
to the administration of suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the 
same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 
• 
Dechallenge experience. Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another 
aetiology such as the underlying disease, other drugs, other host or environmental 
factors. 
• 
Rechallenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? Targovax would not normally 
recommend or support a rechallenge. 
• 
Laboratory tests. Has a specific laboratory investigation confirmed the 
relationship? 
 
A “reasonable possibility” could be considered to exist for an AE where one or 
more of these factors exist. 
 
In contrast, there would not be a “reasonable possibility” of causality if none of 
the above criteria apply or where there is evidence of exposure and a reasonable 
time course but any dechallenge (if performed) is negative or ambiguous or there 
is another more likely cause of the AE. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. 
 
Any events that are unequivocally because of progression of disease must not be reported 
as an adverse event. 


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Appendix III: Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including 
research 
on 
identifiable 
human 
material 
and 
data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these 
principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The 
health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act in the patient's best interest when 
providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual 
research subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 
current interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 


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consent for themselves and those who may be vulnerable to coercion or undue 
influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
1. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. 
2. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be respected.  
3. Appropriate caution must be exercised in the conduct of medical research that may 
harm the environment. 
4. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this 
Declaration have been addressed. The protocol should include information regarding 
funding, sponsors, institutional affiliations, other potential conflicts of interest, 
incentives for subjects and provisions for treating and/or compensating subjects who 
are harmed as a consequence of participation in the research study. The protocol should 
describe arrangements for post-study access by study subjects to interventions 
identified as beneficial in the study or access to other appropriate care or benefits. 
5. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must 
be independent of the researcher, the sponsor and any other undue influence. It must 
take into consideration the laws and regulations of the country or countries in which 
the research is to be performed as well as applicable international norms and standards 
but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the 
committee, especially information about any serious adverse events. No change to the 
protocol may be made without consideration and approval by the committee. 
6. Medical research involving human subjects must be conducted only by individuals 
with the appropriate scientific training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professional 
and never the research subjects, even though they have given consent. 


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7. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
8. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities 
involved in the research in comparison with foreseeable benefits to them and to other 
individuals or communities affected by the condition under investigation. 
9. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
10. Physicians may not participate in a research study involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive 
and beneficial results. 
11. Medical research involving human subjects may only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the research subjects. 
12. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community 
leaders, no competent individual may be enrolled in a research study unless he or she 
freely agrees. 
13. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study 
on their physical, mental and social integrity. 
14. In medical research involving competent human subjects, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of 
individual potential subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject's 
freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed. 
15. For medical research using identifiable human material or data, physicians must 
normally seek consent for the collection, analysis, storage and/or reuse. There may be 
situations where consent would be impossible or impractical to obtain for such 
research or would pose a threat to the validity of the research. In such situations the 
research may be done only after consideration and approval of a research ethics 
committee. 


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16. When seeking informed consent for participation in a research study the physician 
should be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed 
consent should be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
17. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is 
intended to promote the health of the population represented by the potential subject, 
the research cannot instead be performed with competent persons, and the research 
entails only minimal risk and minimal burden. 
18. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject's 
dissent should be respected. 
19. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research population. In such circumstances the physician should seek informed 
consent from the legally authorized representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research should be obtained as soon as possible from the 
subject or a legally authorized representative. 
20. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly available 
the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. They should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results should be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest should be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be 
accepted for publication.  
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
1. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the patients who serve as research subjects. 
2. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances:  


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 
The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists; or 
 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of 
serious or irreversible harm. Extreme care must be taken to avoid abuse of this 
option. 
3. At the conclusion of the study, patients entered into the study are entitled to be 
informed about the outcome of the study and to share any benefits that result from it, 
for example, access to interventions identified as beneficial in the study or to other 
appropriate care or benefits. 
4. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
5. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in 
the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, this intervention should be made the object of 
research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available. 
22.10.2008 
 

SAP_001.pdf: 
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Page 1 of 16 
Date: 16APR2018 
Version: Final 
ST/form/010/6 
 
 
 
 
 
 
 
 
 
 
A Non-Randomised Open-Label Phase Ib Exploratory 
Study of TG02-treatment as Monotherapy or in 
Combination with Pembrolizumab to Assess Safety 
Immune Activation in Patients with Locally Advanced 
Primary and Recurrent Oncogenic RAS Exon 2 Mutant 
Colorectal Cancer 
 
Targovax ASA Study No: CT TG02-01 
Syne qua non Ltd Study No: TAX15001 
 
Statistical Analysis Plan 
 
Version: Final 
Date: 16th April 2019 
 
For Syne qua non Ltd – Lead Statistician 
 
 
 
 
For Targovax ASA 
If signing manually, please include:  Signature + Date + Full Name + Position 


DocuSign Envelope ID: CA1A865C-14C6-4C47-8C9E-93457B520EC9 
Syne qua non study no: TAX15001 
Targovax ASA study no: CT-TG02-01 
Page 2 of 16 
Date: 16APR2018 
Version: Final 
ST/form/010/6 
 
 
 
 
Contents 
ABBREVIATIONS ................................................................................................................................... 3 
1 
INTRODUCTION ............................................................................................................................. 4 
2 
GENERAL PRINCIPLES ................................................................................................................. 4 
3 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 4 
3.1 
Study Objectives ......................................................................................................................... 4 
3.2 
Study Design ............................................................................................................................... 5 
3.3 
Visit Structure .............................................................................................................................. 6 
3.4 
Sample Size ................................................................................................................................ 6 
3.5 
Changes from the Protocol Planned Analysis ............................................................................ 6 
4 
STUDY PATIENTS.......................................................................................................................... 7 
4.1 
Disposition of Patients ................................................................................................................ 7 
4.2 
Analysis Sets .............................................................................................................................. 7 
4.3 
Eligibility ...................................................................................................................................... 8 
4.4 
Protocol Deviations ..................................................................................................................... 8 
4.5 
Background and Demographic Characteristics .......................................................................... 8 
4.5.1 
Demography ............................................................................................................................ 8 
4.5.2 
Medical History of Colorectal Cancer ...................................................................................... 8 
4.5.3 
Medical History (Excluding Colorectal Cancer) ....................................................................... 9 
4.5.4 
Previous Cancer Treatment ..................................................................................................... 9 
4.5.5 
Prior and Concomitant Medications ......................................................................................... 9 
4.5.6 
Diagnostic Imaging ................................................................................................................ 10 
4.6 
Administration of Investigational Product.................................................................................. 10 
4.7 
Surgery ..................................................................................................................................... 10 
5 
SAFETY EVALUATION ................................................................................................................ 10 
5.1 
Study Drug Exposure ................................................................................................................ 10 
5.2 
Adverse Events ......................................................................................................................... 11 
5.3 
Clinical Laboratory Evaluation .................................................................................................. 12 
5.3.1 
Haematology .......................................................................................................................... 12 
5.3.2 
Clinical Chemistry .................................................................................................................. 13 
5.4 
Vital Signs ................................................................................................................................. 13 
5.5 
Electrocardiogram (ECG) ......................................................................................................... 13 
5.6 
Physical Examination and ECOG Performance Status ............................................................ 13 
6 
EFFICACY EVALUATION ............................................................................................................. 14 
6.1 
Primary Immune Endpoints ....................................................................................................... 14 
6.1.1 
TG02-specific DTH response ................................................................................................ 14 
6.1.2 
Presence of TG02-specific T-cells ......................................................................................... 14 
6.1.3 
Change in intra-tumoural lymphocytes .................................................................................. 15 
6.2 
Secondary Efficacy Variables ................................................................................................... 15 
6.2.1 
Immune suppression factors in tumour specimens ............................................................... 15 
6.2.2 
Pathological responses and markers of apoptosis in tumour specimens.............................. 15 
6.2.3 
Change in standard uptake values assessed by FDG PET-CT ............................................ 15 
6.2.4 
Non-Target Lesions ............................................................................................................... 15 
6.2.5 
Change in CEA ...................................................................................................................... 15 
6.3 
Exploratory Efficacy Variables .................................................................................................. 16 
6.3.1 
Change in ctDNA ................................................................................................................... 16 
6.3.2 
Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood .......... 16 
6.4 
Statistical Analysis .................................................................................................................... 16 
6.4.1 
Hypotheses to be Tested ....................................................................................................... 16 
6.4.2 
Handling of Dropouts or Missing Data ................................................................................... 16 
6.4.3 
Interim Analyses and Data Monitoring .................................................................................. 16 
 


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Date: 16APR2018 
Version: Final 
ST/form/010/6 
 
 
ABBREVIATIONS 
 
Abbreviation Term 
 
AE 
Adverse Event 
CEA 
Carcinoembryonic Antigen 
CPI 
Checkpoint Inhibitor 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumour DNA 
DLT 
Dose Limiting Toxicity 
DTH 
Delayed Type Hypersensitivity 
DNA 
Deoxyribonucleic acid 
EAS 
Efficacy Analysis Set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FDG 
Fluorodeoxyglucose 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
IMP 
Investigational Medicinal Product 
KRAS 
Kirsten Rat Sarcoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
PBMC 
Peripheral Blood Mononuclear Cells 
PET-CT 
Positron Emission Tomography – Computed Tomography 
PPAS 
Per Protocol Analysis Set 
PT 
Preferred Term 
RAS 
Rat Sarcoma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set 
SD 
Standard Deviation 
SI 
Stimulation Index 
SOC 
System Organ Class 
SSC 
Safety Steering Committee 
SUV 
Standard Uptake Value 
TEAE 
Treatment-emergent Adverse Event 
TNM 
Tumour, Nodes, Metastasis 
WHO Drug 
World Health Organization Drug dictionary 


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Date: 16APR2018 
Version: Final 
ST/form/010/6 
 
 
 
1 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on protocol version 6.0 dated 9 October 
2018. 
The SAP will be reviewed prior to database lock to ensure that any relevant changes 
in study conduct, data issues etc. are captured. Any additional details or 
amendments required as a result of this review will be discussed with the sponsor 
and included in a revised version of the SAP if applicable. The SAP will be finalised 
prior to any analysis of data and prior to database lock. 
The table, listing and figure shells will be supplied in a separate document. 
 
2 GENERAL PRINCIPLES 
The analysis and statistical reporting will be conducted at Syne qua non using SAS® 
version 9.4 or higher. 
Data will be presented separately for patients in Part I and Part II. The same set of 
tables, listings and figures will be used for the two parts. 
Summary statistics for continuous variables will consist of number of non-missing 
observations (n), mean, standard deviation (SD), minimum, median and maximum, 
unless specified otherwise. The precision of these variables is defined in the table, 
figure and listing shells document. 
Categorical variables will be summarised in frequency tables as counts and 
percentages. 
All individual data collected will be presented in data listings. Patients screened but 
not included in the study will not be presented in any tables. Screen failures will not 
be entered into the database. 
 
3 STUDY OBJECTIVES AND DESIGN 
 
3.1 Study Objectives 
The primary objectives of the study are: 
• To determine the safety of TG02-treatment (Part I) in combination with 
pembrolizumab (Part II) 
• To evaluate the systemic TG02-specific immune responses and to investigate 
tumour T cell infiltration in tumour specimens 
The secondary objectives of the study are: 
• To investigate changes in immunological and pathological markers in tumour 
tissue 
• To investigate changes in fluorodeoxyglucose (FDG) positron emission 
tomography – computed tomography (PET-CT) images 
• To investigate changes in carcinoembryonic antigen (CEA) 


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Date: 16APR2018 
Version: Final 
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The exploratory objectives of the study are: 
• To investigate changes in circulating tumour cells and/or circulating tumour DNA 
(ctDNA) 
• To investigate the functionality of rat sarcoma (RAS) mutation specific T cells in 
tumour tissue and peripheral blood 
 
3.2 Study Design 
This is a non-randomised, open label Phase Ib exploratory study to investigate the 
safety of and immune responses to TG02-treatment, first as monotherapy (Part I) 
and thereafter as combination therapy with pembrolizumab (Part II) in patients with 
locally advanced primary and recurrent RAS mutant colorectal cancer eligible for 
radical pelvic surgery at time of enrolment. 
Part I 
Approximately 4-6 patients diagnosed with locally advanced and recurrent RAS 
mutant colorectal cancer will be given TG02-treatment for up to 10 weeks (up to six 
TG02 treatments; week 1, 2, 3, 4, 6 and 10 if surgery occurs beyond week 10) prior 
to surgery. 
TG02 is an eight-peptide vaccine. Significant clinical data exist for its precursor 
vaccine, TG01, which contains 7 of the 8 mutant RAS peptides present in TG02. 
TG01 in combination with granulocyte macrophage colony stimulating factor (GM- 
CSF) has been shown to be immunogenic and well tolerated up to 11 weeks of 
treatment. 
Since one of the eight peptides in TG02 has not previously been administered to 
humans, the first 3 patients will be enrolled in a sequential manner with a minimum 
lag time of 4 weeks between dosing of the first 3 patients to ensure an acceptable 
safety profile. 
The safety data collected during the first 4 weeks for the first 3 patients will be 
reviewed by a safety steering committee (SSC) consisting of Sponsor 
representatives, the Principal Investigator, relevant Sub-Investigators and one 
Independent Physician. 
As a general rule the following will be reviewed to provide a guide to safety 
decisions: 
Unacceptable toxicities will be defined as follows (based on National Cancer Institute 
Criteria for Adverse Events (NCI CTCAE) v4.03: June 14, 2010) for reactions 
considered to be related to TG02 and/or GM-CSF: 
• Injection site reaction of > grade 3 (grade 3: ulceration or necrosis, severe tissue 
damage, operative intervention indicated, grade 4: life-threatening 
consequences, urgent intervention indicated, grade 5: death) 
• Other relevant clinically significant toxicity > grade 3 (excluding treatable nausea 
and vomiting). However, for certain toxicities such as laboratory assessments 
without a clear clinical correlate, a discussion in the SSC may take place to 
evaluate if this adverse event (AE) should be assessed as a dose limiting toxicity 
(DLT). 


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Date: 16APR2018 
Version: Final 
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• > Grade 3 'allergic reaction/anaphylactic reaction' in spite of prophylaxis with 
antihistamine and steroids 
All AEs and serious adverse events (SAEs) will also be compared to those of the 
precursor vaccine TG01. 
If more than 1 out of the 3 patients has DLT the SSC will review the nature of the 
events and make a final decision if the rest of the patients may be enrolled. 
When all safety data, systemic immune responses (Delayed-Type Hypersensitivity 
tests (DTHs)) and tumour material (analysed for intra-tumoural T cells infiltration) are 
available for all patients in Part I of the study, SSC will evaluate the data to assess 
safety, preliminary immune activity and efficacy to make a recommendation whether 
the study will proceed or not to Part II of this protocol. In Part II 10 new patients, not 
previously treated with TG02, will be recruited. No patients treated in Part I will be 
treated in Part II. The SSC’s recommendation will form the basis for sponsor to make 
a final decision. 
Part II 
At the discretion of the sponsor, a decision will be made to initiate Part II of the study 
where up to 10 patients will be treated with TG02-treatment plus pembrolizumab for 
up to 10 weeks (up to six TG02-treatments) prior to surgery. The first 3 patients will 
be enrolled in a sequential manner with a minimum lag time of 6 weeks between 
dosing of the first 3 patients to ensure an acceptable safety profile. 
The safety data collected during the first 6 weeks for the first 3 patients will be 
reviewed by the SSC in a similar manner as in Part I, as TG02-treatment in 
combination with pembrolizumab is a novel treatment. 
 
3.3 Visit Structure 
The visit structure and scheduled assessments are detailed in Table 6-1: Schedule 
of visits, of the protocol. 
 
3.4 Sample Size 
The study will include up to 16 patients; approximately 4-6 patients in Part I and up 
to 10 patients in Part II if sponsor decision to initiate such. As this is an exploratory 
study, no formal samples size calculation has been performed. However, it is 
estimated that a sample size of 6 patients in each group (monotherapy and 
combined treatment) is sufficient to explore the potential effect of TG02 to induce 
immune responses and to assess safety in the induction phase. 
 
3.5 Changes from the Protocol Planned Analysis 
The efficacy analysis set is defined in Section 11.3 of the protocol and includes all 
patients who undergo surgery after the treatment period. This analysis set has been 
modified to include patients from whom a biopsy is obtained at the time of surgery, for 
patients who do not proceed to surgery. 


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Date: 16APR2018 
Version: Final 
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4 STUDY PATIENTS 
The tables will present the two treatment groups for both parts of the study side-by- 
side as ‘Part I (TG02)’ and ‘Part II (TG02 + Checkpoint Inhibitor (CPI))’. 
 
4.1 Disposition of Patients 
The number and percentage of all patients enrolled and included in the efficacy 
analysis set, per protocol analysis set and safety analysis set, who completed the 
study and prematurely withdrew (including a breakdown of the primary reason for 
withdrawal) will be presented. 
 
4.2 Analysis Sets 
The Safety Analysis Set (SAF) comprises all patients who receive any amount of 
TG02/GM-CSF and/or pembrolizumab. This analysis set will be applied for 
demographic, baseline and safety data. 
The Efficacy Analysis Set (EAS) comprises all patients who undergo surgery after 
the treatment period or patients from whom a biopsy was obtained at the time of 
planned surgery (for patients who do not proceed to surgery). This analysis set will 
be applied for demography, baseline and efficacy data. 
The Per Protocol Analysis Set (PPAS) is a subset of the EAS but patients with 
major protocol deviations are excluded. The analysis set will be applied for efficacy 
data. 
The list of patients to be included in each of the analysis sets is to be agreed 
between the study statistician and the sponsor prior to database lock, once all study 
data are available. 
All enrolled patients will be listed indicating their membership to each analysis set 
together with the reason for exclusion. 
All listings will be based on all enrolled patients separately for Part I and Part II 
unless specified otherwise. 
The outputs will be reported using the following analysis sets: 
Output 
SAF 
EAS 
PPAS 
Demography 
× 
× 
Medical History 
× 
× 
Details of Previous Cancer Treatment (Before/After 
+ up to First IMP) 
× 
× 
Concomitant Medications 
× 
× 
Administrations (Patient + Visit Level) 
× 
× 
Standard Uptake Value (kBq/mL) Values and 
Change from Baseline over Time 
× 
× 
Carcinoembryonic Antigen (ug/L) Values and 
Change from Baseline over Time 
× 
× 


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Immune Response 
× 
× 
DTH Skin Test Reactions 
× 
× 
T-cell Responders / Biopsy / Cytokines / ctDNA 
× 
× 
AE / Labs / Vitals / ECOG 
× 
Listings + Figures 
× 
If any of the analysis sets overlap (e.g. SAF = EAS) the outputs will not be repeated. 
 
4.3 Eligibility 
All eligibility data will be listed in full. 
 
4.4 Protocol Deviations 
Prior to database lock, Targovax ASA will review the individual deviations and 
classify them as major or minor during a data review meeting. Details of all protocol 
deviations including start and end dates, deviation category (treatment deviation, 
subject not withdrawn as per protocol requirements, eligibility criteria not met, 
assessment outside time window), classification as major/minor and deviation details 
will be listed separately for patients in Part I and Part II. 
 
4.5 Background and Demographic Characteristics 
For sections 4.5.1 to 4.5.5, including disposition, the data will be summarized for 
each treatment group (Part I and Part II) and Overall. 
4.5.1 
Demography 
Demographic characteristics (age, sex and race) and body measurements (height 
and weight) will be summarised. 
Age will be calculated in years from date of birth to the date of informed consent. 
Individual patient demographic and baseline data, including pregnancy test results 
and details, will be listed. 
4.5.2 
Medical History of Colorectal Cancer 
Details of colorectal cancer history will include: 
• Diagnosis at time of screening 
• Time from diagnosis primary advanced disease or recurrent disease, 
whichever is latest, to first investigational medicinal product (IMP) 
administration (weeks), calculated as (date of first IMP administration – date 
of diagnosis primary advanced disease or recurrent disease, whichever is 
latest + 1)/7 
• Time from diagnosis primary advanced disease or recurrent disease, 
whichever is latest, to surgery (weeks), calculated as (date of surgery – date 
of diagnosis primary advanced disease or recurrent disease, whichever is 
latest,+ 1)/7 


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• Tumour, nodes, metastasis (TNM) stage at diagnosis primary advanced 
disease and at diagnosis of recurrent disease 
• Number and percentage of patients with Kirsten rat sarcoma (KRAS) mutation 
detected (yes/no) 
• Mutation type (12/13) and specific KRAS mutation, where percentages are 
based on the number of patients with oncogenic KRAS confirmation 
• Extent of disease 
All colorectal cancer medical history details will be listed. 
4.5.3 
Medical History (Excluding Colorectal Cancer) 
Medical history events will be coded using the latest Medical Dictionary for 
Regulatory Activities (MedDRA) version. 
Previous medical history is defined as anything that started and ended prior to the 
first IMP administration. Medical history that is ongoing at the first IMP administration 
or started after first IMP administration will be deemed to be current. If medical 
history dates are incomplete and it is not clear whether the medical history was 
ongoing, it will be assumed to be current. 
The number and percentage of patients who had any previous or current medical 
history will be presented by system organ class (SOC) and preferred term (PT) 
SOCs will be ordered in decreasing frequency of the total number of patients with the 
medical histories reported in each SOC and PTs will be ordered within a SOC in 
decreasing frequency of the total number of patients with each medical history. 
All medical history events (excluding colorectal cancer) will be listed by SOC and PT. 
4.5.4 
Previous Cancer Treatment 
Previous cancer treatment will be divided into treatment before and after recurrence 
of the disease. 
The number and percentage of patients with any previous cancer treatment and with 
each type of cancer therapy will be presented separately for previous cancer 
treatment administered before and after recurrence of disease but before entering 
the study. 
All previous cancer treatment data will be listed in full and previous cancer treatment 
after recurrence of disease will be flagged. 
4.5.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to the latest World Health 
Organization Drug dictionary (WHO Drug) version. 
Prior medications are defined as those that started and ended prior to the first IMP 
administration. Medications that are ongoing at the first IMP administration or started 
after first IMP administration will be deemed to be concomitant medications. If 
medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant. 


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The number and percentage of patients who had any concomitant medications will 
be presented separately by medication class and standardised medication name 
sorted alphabetically. 
All prior and concomitant medication data will be listed. All medications which start 
up to four weeks prior to the first dose of IMP will also be flagged in the listings. 
4.5.6 
Diagnostic Imaging 
Details of diagnostic imaging collected at screening will be listed. 
 
4.6 Administration of Investigational Product 
All details of GM-CSF, TG02 and pembrolizumab administration are described in 
Section 5.1 
 
4.7 Surgery 
All surgery data will be listed in full. 
 
5 SAFETY EVALUATION 
All safety evaluations will be performed on the safety analysis set unless specified 
otherwise. 
The safety endpoints of interest are the incidence and severity of AEs by NCI Criteria 
for Adverse Events (CTCAE v4.03) and changes from baseline in laboratory 
variables, physical examination, vital signs and European Cooperative Oncology 
Group (ECOG) performance status. 
 
5.1 Study Drug Exposure 
The duration of exposure to TG02-treatment in days, as well as the total dose of GM- 
CSF and the total dose of TG02 separately for vaccination, DTH testing and 
vaccination and DTH testing combined will be summarised. 
Duration of exposure to study drug will be calculated as: date of administration of the 
last dose – date of administration of the first dose of study drug + 1. 
The dose of study drug administered for DTH testing, vaccination and DTH testing 
and vaccination combined will be calculated in the following way: 
• the total dose of GM-CSF will be calculated as the sum of the dose administered 
at each visit 
• the total dose of TG02 for DTH testing will be calculated as the sum of the dose 
administered for DTH testing at each visit 
• the total dose of TG02 for vaccination will be calculated as the sum of the dose 
administered for vaccination at each visit 
• the total dose of TG02 for vaccination and DTH testing combined will be 
calculated as the sum of the dose administered for vaccination at each visit + 
sum of dose administered for DTH testing at each visit, 


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where the dose administered is calculated as dose strength*volume. 
The number of injections of GM-CSF and TG02, the number of injections of TG02 for 
DTH testing and the total number of injections (GM-CSF and TG02, including DTH 
testing) will be summarised. The number and percentage of patients with dose 
delays and discontinuation with GM-CSF/TG02, together with the frequency and 
reasons for such dose modifications will be summarised by visit and overall. A 
summary of whether TG02-treatment was received (yes/no) will also be presented 
by visit. 
For all patients in Part II of the study, the duration of exposure to pembrolizumab, the 
number of injections of pembrolizumab, as well as the total dose and reason for 
reduction, delay or discontinuation with pembrolizumab will be summarised. The total 
dose of pembrolizumab administered is the sum of the doses administered at each 
injection. 
All IMP administration data will be listed. 
 
5.2 Adverse Events 
Any events that are unequivocally due to progression of disease will not be reported 
as AEs or SAEs. 
Adverse events will be coded according to the latest MedDRA dictionary version. 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date/time 
on or after the first administration of IMP. A pre-treatment AE is defined as an AE 
with start date/time prior to the first administration of IMP. 
There will be no imputation of unknown dates for the calculation of duration or study 
day. However, for sorting and assignation, if the start date is unknown then it will be 
assumed to be treatment emergent unless the partial start date or other data (i.e. 
stop date) indicates differently. 
Assessment of AE severity will be based on the NCI CTCAE which includes five 
grades, with grade 5 being death. If the severity of an event changes during the 
course of that event, only the maximum severity/grade will be summarised in the 
tables. 
The relationship to each IMP (TG02, GM-CSF, pembrolizumab) is assessed as not 
related or related. 
An overview summary table will summarise the number of events and the number 
and percentage of patients with at least one of the following TEAEs: 
• total TEAEs 
• total serious TEAEs 
• total IMP related serious TEAEs 
• TEAEs leading to TG02 and GM-CSF withdrawal 
• TEAEs leading to pembrolizumab withdrawal 
• TEAEs leading to study withdrawal 
• TEAEs leading to death 
• TEAEs by severity 


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• TEAEs by relationship to each IMP (related, not related) separately 
• SAEs by relationship to each IMP separately 
The number of events and the number and percentage of patients experiencing 
TEAEs will be presented by SOC and PT for the following TEAEs: 
• Total TEAEs: If a patient experienced more than one TEAE, the patient will be 
counted once for each SOC and once for each PT. This summary will be 
repeated for serious TEAEs only. 
• Total TEAEs by severity: If a patient experienced more than one TEAE, the 
patient will be counted once for each severity experienced during the study. 
• TEAEs by relationship to each IMP: If a patient experienced more than one 
TEAE, the patient will be counted once for each SOC and once for each PT at 
the closest relationship to study drug. This summary will be repeated for serious 
TEAEs only. 
• TEAEs related to TG02 by severity. For this table, grade 1 and 2 events will be 
pooled. If a patient experienced more than one TEAE, the patient will be counted 
once for each severity experienced during the study. TEAEs related to GM-CSF, 
TEAEs related to TG02 and/or GM-CSF, TEAEs related to TG02 and/or GM-CSF 
only (i.e. events not related to pembrolizumab) and TEAEs related to 
pembrolizumab only will be summarised in an identical fashion. 
• TEAEs leading to death. 
In all of the tables described above, SOC and PT will be presented in decreasing 
frequency of the total number of patients with TEAEs. 
All TEAEs will be listed with a separate listing for pre-treatment AEs. Separate 
listings of serious TEAEs and pre-treatment SAEs will also be presented. 
 
5.3 Clinical Laboratory Evaluation 
The clinical laboratory tests to be performed are presented in Table 9-1: Clinical 
laboratory parameters of the protocol. For each laboratory parameter, the baseline 
value will be defined as the last scheduled or unscheduled value collected prior to 
the first dose of IMP. If the times of assessments have not been recorded, 
assessments carried out on the day of first IMP administration are considered to 
have taken place before IMP administration. For post baseline, only data from 
scheduled visits will be included in the summary tables. Percent change from 
baseline will be calculated as 100 * (observed value – baseline value)/baseline 
value. 
5.3.1 
Haematology 
Summary statistics of haematology observed values, change from baseline and 
percent change from baseline will be presented for all patients by parameter and 
visit. 
In addition, a shift table showing the movement of patients with respect to CTC 
grade (according to NCI CTCAE v4.03) from baseline to each study visit will be 
presented by parameter. Patients will only be included in the missing category if they 
attended the respective post baseline visit but have no data available for that 


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parameter. Patients withdrawing prior to baseline will not be included in the missing 
category. 
Individual patient haematology values will be plotted, with separate pages for each 
treatment group and parameter. Additionally, box plots will be produced to 
summarize values over time, with separate pages for each treatment group and 
parameter. 
All haematology values will be listed showing reference ranges and flagging all 
abnormal findings and their clinical significance. Out of reference ranges will be 
flagged as high (H) or low (L). 
5.3.2 
Clinical Chemistry 
Clinical chemistry data will be summarised and plotted in the same way as the 
haematology data. 
All clinical chemistry values will be listed showing reference ranges and flagging all 
abnormal findings and their clinical significance. Out of reference ranges will be 
flagged as high (H) or low (L). 
 
5.4 Vital Signs 
Summary statistics of vital sign observed values and change from baseline from 
baseline will be presented by parameter and visit for all patients. For each 
parameter, the baseline value will be defined as the last scheduled or unscheduled 
value collected prior to the first dose of IMP. If the times of assessments have not 
been recorded, assessments carried out on the day of first IMP administration are 
considered to have taken place before IMP administration. 
All vital sign data will be listed in full, flagging any unscheduled assessments. 
 
5.5 Electrocardiogram (ECG) 
All ECG data will be listed. 
 
5.6 Physical Examination and ECOG Performance Status 
The number and percentage of patients will be presented by ECOG performance 
status and study visit. In addition, a shift table presenting the shift from baseline in 
ECOG performance status by visit will be produced. The baseline value will be 
defined as the last scheduled or unscheduled value collected prior to first dose of 
IMP. Assessments carried out on the day of first IMP administration are considered 
to have taken place before the IMP administration, if the corresponding times have 
not been recorded. For post baseline, only data from scheduled visits will be 
included in the tables. Patients who attended a visit but have no ECOG data 
available will be included in the missing and total categories. Patients who withdrew 
prior to the visit will not be included in the summary for that visit and will be excluded 
from the denominator for calculation of percentages at that visit. 
A listing will present ECOG assessment date and ECOG performance status 
together with whether a physical examination was performed and the date and time 
of examination. 


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6 EFFICACY EVALUATION 
All efficacy evaluations will be performed on the efficacy and per protocol analysis 
sets unless specified otherwise. 
 
6.1 Primary Immune Endpoints 
A systemic immune response is defined as having a positive in vivo DTH and/or a 
positive in vitro T-cell response at least once during the study. Change in intra- 
tumoural T-cells in resected tumour tissue at surgery compared to pre-TG02- 
treatment core biopsy will be investigated. 
The systemic immune responses are assessed by: 
• TG02-specific DTH response. The DTH test is considered positive if erythema 
and/or induration are recorded as positive on the DTH response electronic case 
report form (eCRF) page. 
• Presence of TG02 specific T-cells in peripheral blood. A patient is considered to 
have a positive T-cell response if the stimulation index (SI) is ≥ 2. 
The SI will be derived as follows: 
Mean (T cells + PBMC + TG02) 
Mean (T cells + PBMC (negative control)) 
For SI, mean is derived as the sum of the non-missing measurements divided by the 
number of non-missing measurements, rounded to the nearest whole number. 
• Change in intra-tumoural lymphocytes in resected tumour tissue at surgery 
compared to pre-TG02-treatment core biopsy will be investigated. 
6.1.1 
TG02-specific DTH response 
A TG02-specific DTH immune response is defined as any positive DTH test during 
the course of the study. A DTH-test will be considered positive if erythema and/or 
induration are recorded as positive on the DTH response assessment eCRF. 
The number of positive DTH skin reactions (categorical variable) as well as the 
number and percentage of patients who have at least one positive DTH skin 
reactions will be presented by time point and overall. 
All DTH assessment data will be listed in full. 
6.1.2 
Presence of TG02-specific T-cells 
Immunology-processed blood samples for peripheral blood mononuclear cells 
(PBMC) will be drawn at baseline and week 8 (Day 50). If surgery is after week 10, a 
third sample will be drawn as close as possible to the date of surgery. PBMCs will be 
analysed for the presence of TG02-specific T-cells. Summary statistics of patients 
with TG02-specific T-cells will be presented by time point and overall. 
All PBMC and TG02-specific T-cell data will be listed. 


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6.1.3 
Change in intra-tumoural lymphocytes 
Tumour samples will be taken pre TG02-treatment in the form of a study specific 
biopsy and at the time of surgery in the form of resected tumour tissue (the post 
treatment sample). If for any reason a patient does not proceed to surgery, a biopsy 
will be obtained at the time of planned surgery if possible. Summary statistics of 
intra-tumoural lymphocytes observed values and change from baseline will be 
presented. 
All intra-tumoural lymphocyte data will be listed. 
 
6.2 Secondary Efficacy Variables 
 
6.2.1 
Immune suppression factors in tumour specimens 
Immune suppression factors (such as PD-L1, Treg and MDSC) will be summarised 
in the same way as the intra-tumoural lymphocyte data. 
All PD-L1, Treg and MDSC data will be listed. 
6.2.2 
Pathological responses and markers of apoptosis in tumour specimens 
Pathological response and markers for apoptosis (such as Granzyme B, Cleaved 
caspase-3) data will be summarised in the same way as the intra-tumoural 
lymphocyte data. 
All pathological response data will be listed. 
6.2.3 
Change in standard uptake values assessed by FDG PET-CT 
FDG uptake reflects the tumour activity independent of the morphologic 
characteristics. FDG PET-CT images will be obtained at screening and as close as 
possible up to the date of surgery. Standard uptake value (SUV) at baseline and post 
treatment will be assessed. 
Summary statistics of SUV observed values and change from baseline will be 
presented by time point and overall for all patients. 
All FDG PET-CT examination and assessment data will be listed. 
6.2.4 
Non-Target Lesions 
Non-target lesion data will be listed in full. 
6.2.5 
Change in CEA 
Tumour marker assessment will take place at screening and week 8 and if surgery is 
after week 10, a sample will be taken as close to possible to surgery. Summary 
statistics of observed values of CEA, change from baseline and percent change from 
baseline will be presented by time point for all patients. 
All CEA data will be presented in the listings. 


 
 
6.3 Exploratory Efficacy Variables 
 
6.3.1 
Change in ctDNA 
Change in ctDNA will be measured to follow the levels of ctDNA during the treatment period. Summary 
statistics of observed individual values of ctDNA, mean of the observed results together with fold change 
from baseline will be reported by time point for all patients. 
If only one result is available, no mean will be calculated, and this value will be used to produce the fold 
change from baseline. 
All ctDNA data will be listed. 
The above will be repeated for cytokines. 
6.3.2 
Functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
The reporting of the functionality of RAS mutation specific T cells in tumour tissue and peripheral blood 
will be reported separately per patient and included as an appendix to the study report. 
 
6.4 Statistical Analysis 
 
6.4.1 
Hypotheses to be Tested 
No statistical hypothesis is defined, only descriptive statistics will be produced. 
6.4.2 
Handling of Dropouts or Missing Data 
In general, the denominator for percentage calculations will be the number of patients in the analysis set. 
However, unless specified otherwise, for tables by time points the percentages and summary statistics 
will be calculated using the number of patients with available data at that time point. 
6.4.3 
Interim Analyses and Data Monitoring 
No interim analysis is planned for this study.