A Phase I/II Trial of TG01 and Gemcitabine as Adjuvant Therapy for Treating Patients With Resected Adenocarcinoma of the Pancreas
Phase: PHASE1
Conditions: Pancreatic Cancer, Resected
Sponsor: Targovax ASA

Document type: 
Study Protocol 
Official Title: 
A Phase I/II Trial of TG01 and Gemcitabine as 
Adjuvant Therapy for Treating Patients with 
Resected Adenocarcinoma of the Pancreas 
NCT Number: 
NCT02261714 
Document date: 
27/06/18 
 

 
 
 
 
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CLINICAL TRIAL PROTOCOL 
 
Trial Protocol No. 
CT TG01-01 
Title 
A Phase I/II Trial of TG01 and Gemcitabine as Adjuvant Therapy 
for Treating Patients with Resected Adenocarcinoma of the 
Pancreas 
EUDRACT/IND # 
2012-002400-40 
Trial Phase 
Phase I/II trial 
Trial Physician 
 
 
Date 
27 June 2018 
Version 
Final version 10.0 
 
 

 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE .................................................................................................. 7 
1. SYNOPSIS ............................................................................................................................... 11 
2. INTRODUCTION ................................................................................................................... 24 
2.1 
Background................................................................................................................ 24 
2.1.1 
Pancreatic cancer ............................................................................................. 24 
2.1.2 
Rationale for the trial ...................................................................................... 24 
2.1.3 
Pre-clinical experience .................................................................................... 25  
2.1.4 
Clinical experience .......................................................................................... 27 
2.2 
Trial objectives .......................................................................................................... 28 
2.2.1 
Primary objective ............................................................................................ 28 
2.2.2 
Secondary objective ........................................................................................ 29 
2.2.3 
Exploratory objectives..................................................................................... 29 
3. INVESTIGATIONAL PLAN .................................................................................................. 29 
3.1 
Overall trial design and plan ...................................................................................... 29 
3.2 
Rationale for trial design, doses and stop decisions .................................................. 44 
3.2.1 
Trial design ...................................................................................................... 44 
3.2.2 
Rationale for dose ........................................................................................... 44 
3.2.3 
Rationale for GM-CSF (Molgramostim) adjuvant .......................................... 45 
3.2.4 
Rationale for dose regimen ............................................................................. 45 
3.2.5 
Use of Gemcitabine as adjuvant chemotherapy .............................................. 47 
3.3 
Selection of trial population ...................................................................................... 48 
3.3.1 
Inclusion criteria .............................................................................................. 48 
3.3.2 
Exclusion criteria ............................................................................................ 48 
3.3.3 
Removal of patients from the trial, therapy or assessment .............................. 49 
3.3.3.1 
Patient withdrawal ........................................................................................... 49 
3.3.3.2 
Trial discontinuation ....................................................................................... 50 
3.3.3.3 
Procedures for discontinuation ........................................................................ 50 
3.4 
Time schedule ............................................................................................................ 51 
4. TRIAL TREATMENT ............................................................................................................. 51 
4.1 
Identity of the investigational product ....................................................................... 51 
4.1.1 
Packaging and labelling of the investigational product ................................... 52 
4.1.1.1 
TG01 ............................................................................................................... 52 
4.1.1.2 
GM-CSF .......................................................................................................... 52 
4.1.1.3 
Chemotherapy ................................................................................................. 52 
4.1.2 
Storage, issue, and return of investigational product ...................................... 52 
4.2 
Assignment of patients to treatment .......................................................................... 53 
4.3 
Preparation of trial treatment ..................................................................................... 53 
4.3.1 
TG01 ............................................................................................................... 53 
4.3.2 
GM-CSF .......................................................................................................... 53 
4.3.3 
Chemotherapy ................................................................................................. 53 
4.3.4 
DTH................................................................................................................. 54 

 
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4.4 
Dosage and administration of trial treatment ............................................................ 54 
4.4.1 
GM-CSF and TG01 dose and administration .................................................. 54 
4.4.2 
Chemotherapy ................................................................................................. 55 
4.4.3 
DTH................................................................................................................. 55 
4.4.4 
Chemotherapy dosing criteria ......................................................................... 56 
4.5 
Management of Toxicity ........................................................................................... 56 
4.5.1 
Anticipated toxicity and management ............................................................. 56 
4.5.2 
Chemotherapy dose interruption/reduction ..................................................... 57 
4.5.3 
GM-CSF and TG01 dose interruption ............................................................. 58 
4.6 
Concomitant medication ............................................................................................ 59 
4.7 
Treatment compliance ............................................................................................... 59 
5. TRIAL MEASUREMENTS AND ENDPOINTS ................................................................... 59 
5.1 
Primary endpoint ....................................................................................................... 59 
5.2 
Secondary endpoints .................................................................................................. 59 
5.3 
Exploratory endpoints ............................................................................................... 59 
5.4 
Screening assessments ............................................................................................... 60 
5.4.1 
Informed consent ............................................................................................. 60 
5.4.2 
Patient eligibility ............................................................................................. 60 
5.4.3 
Demographic data, medical history ................................................................. 60 
5.4.4 
Special examinations ....................................................................................... 60 
5.4.5 
Physical examination ...................................................................................... 61 
5.4.6 
Laboratory safety measurements ..................................................................... 61 
5.5 
Assessments during treatment phase ......................................................................... 61 
5.6 
Immunological effect ................................................................................................. 65 
5.7 
CT-scan ..................................................................................................................... 66 
5.8 
Efficacy measurements and endpoints ...................................................................... 66 
5.8.1 
Immunology response ..................................................................................... 66 
5.8.2 
Disease-free survival ....................................................................................... 66 
5.8.3 
Overall survival ............................................................................................... 66 
5.8.4 
KRAS status expression .................................................................................. 67 
5.8.5 
CA19.9 levels .................................................................................................. 67 
5.8.6 
Other markers levels ....................................................................................... 67 
5.9 
Safety measurements and endpoints .......................................................................... 67 
5.9.1 
Adverse events ................................................................................................ 67 
5.9.1.1 
Definitions ....................................................................................................... 67 
5.9.2 
Laboratory safety measurements and variables ............................................... 67 
5.9.2.1 
Methods of assessment .................................................................................... 67 
5.9.2.2 
Calculation or derivation of endpoint .............................................................. 68 
5.9.3 
ECG ................................................................................................................. 68 
5.9.4 
Performance status .......................................................................................... 68 
6. ANALYSIS OF TRIAL DATA ............................................................................................... 68 
6.1 
Study Endpoints......................................................................................................... 68 
6.1.1 
Primary Endpoint ............................................................................................ 68 
6.1.2 
Secondary Endpoints ....................................................................................... 68 
6.1.3 
Exploratory Endpoints .................................................................................... 69 

 
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6.2 
Definitions of evaluability ......................................................................................... 69 
6.3 
Analytical methods .................................................................................................... 69 
6.3.1 
Primary endpoints ........................................................................................... 69 
6.3.1.1 
Nature, incidence and severity of adverse events ............................................ 69 
6.3.1.2 
Laboratory assessments ................................................................................... 69 
6.3.1.3 
Incidence of and reasons for Study Drug dose interruptions, Study Drug dose 
reductions and withdrawals ......................................................................... 69 
6.3.1.4 
Study Drug exposure ....................................................................................... 69 
6.3.1.5 
Immune response ............................................................................................ 70 
6.3.2 
Secondary endpoints ....................................................................................... 70 
6.3.2.1 
Disease-free survival ....................................................................................... 70 
6.3.2.2 
Overall survival ............................................................................................... 70 
6.3.2.3 
CA19-9 Evaluation .......................................................................................... 70 
6.3.2.4 
Other biomarkers ............................................................................................. 70 
6.4 
Sample size and power .............................................................................................. 70 
7. DRUG SAFETY ...................................................................................................................... 70 
7.1 
Definitions of adverse events and serious adverse events ......................................... 70 
7.1.1 
Adverse events ................................................................................................ 70 
7.1.2 
Serious adverse events .................................................................................... 71 
7.2 
Recording of adverse events ...................................................................................... 72 
7.2.1 
Exposure to GM-CSF and TG01 or chemotherapy during pregnancy/lactation73 
7.3 
Procedure for reporting serious adverse events ......................................................... 73 
7.4 
Death ......................................................................................................................... 74 
7.5 
Procedures to be followed in the event of abnormal laboratory test values .............. 74 
7.6 
Overdosing with the trial medication ........................................................................ 74 
8. RESPONSIBILITIES OF THE INVESTIGATORS ............................................................... 75 
8.1 
Patient information .................................................................................................... 75 
8.2 
Patient consent ........................................................................................................... 77 
8.3 
Ethics review ............................................................................................................. 77 
8.4 
Source data and patient files ...................................................................................... 77 
8.5 
Training of staff ......................................................................................................... 78 
8.6 
Trial agreements ........................................................................................................ 78 
8.7 
Confidentiality ........................................................................................................... 78 
9. TRIAL MANAGEMENT ........................................................................................................ 78 
9.1 
Monitoring ................................................................................................................. 78 
9.2 
Audits and inspections ............................................................................................... 79 
9.3 
Case report form handling ......................................................................................... 79 
9.4 
Amendments to the trial protocol .............................................................................. 79 
9.5 
Deviations from the trial protocol ............................................................................. 80 
9.6 
Trial report and publication policy ............................................................................ 80 
9.7 
Volume of blood sampling and handling of biological samples ............................... 80 

 
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10. REFERENCES ........................................................................................................................ 81 
 
TABLE OF TABLES 
Table 1: 
Schedule of visits ................................................................................................. 38 
Table 2: 
Schedule of visits – Concomitant group ............................................................... 40 
Table 3: 
Schedule of visits – Modified vaccination group ................................................. 42 
Table 4: 
Gemcitabine dose delay/reduction guidelines ...................................................... 57 
Table 5: 
Summary of required laboratory assessments ...................................................... 67 
Table 6: 
Volume of blood to be drawn from each patient in the study .............................. 80 
 
TABLE OF FIGURES 
Figure 1: Study Design – Immune response assessment ................................................................ 33 
Figure 2: Study Design – Dose Limiting Toxicity Assessment ..................................................... 34 
Figure 3: Treatment schedule for patients starting vaccination and receiving chemotherapy later – 
Main group ........................................................................................................... 34 
Figure 4: Treatment schedule for patients starting vaccination and chemotherapy at the same time 
– concomitant group ............................................................................................. 36 
Figure 5: Treatment schedule for patients starting vaccination and receiving chemotherapy later – 
Modified vaccination group ................................................................................. 36 
Figure 6: DTH Skin Reaction Registration (induration and erythaema) ....................................... 66 
 
TABLE OF APPENDICES 
APPENDIX I: FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE 
EVENT (SAE) ...................................................................................................... 85 
APPENDIX II: FURTHER GUIDANCE ON THE ASSESSMENT OF CAUSALITY .............. 86 
APPENDIX III: ........................................................ PATIENT INSURANCE AND INDEMNITY 
87 
 

 
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MEDICAL EMERGENCY CONTACT DETAILS:  
 
Principal Investigator(s): 
[Name(s) and 24 hour contact number(s)] 
 
Trial Physician 
 
Notification of serious adverse events 
SAE Tel/Fax line: 
 
Contact at your study centre: 1. 
 
[Name(s) and 24 hour contact number(s)] 
 
Contact at your study centre: 2 
[Name(s) and 24 hour contact number(s)] 
 
 

 
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Sponsor Signature Page 
Trial number: 
CT TG01-01 
 
Trial Title:   A Phase I/II Trial of TG01 and Gemcitabine as Adjuvant 
Therapy for Treating Patients with Resected 
Adenocarcinoma of the Pancreas 
 
Clinical Trial Sponsor : 
  
Signature: 
 
 
 
 
Date: 
 
 
Responsible Trial Physician: 
 
Signature: 
 
 
 
 
Date: 
 

 
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Investigator Signature Page 
 
 
Trial number: CT TG01-01 
 
Trial Title: 
A Phase I/II Trial of TG01 and Gemcitabine as Adjuvant Therapy for 
Treating Patients with Resected Adenocarcinoma of the Pancreas 
 
 
Trial centre: 
 
 
I agree to conduct this trial in accordance with the protocol including any trial protocol 
amendments and in compliance with Good Clinical Practice and applicable regulatory 
requirements. 
 
 
 
Signature: ..............................………...……...  
Date: ......................……. 
 
 
Printed Name:………………………………... 
 
Address: 
……………………………….…… 
 
 
 
……………………………….…… 
 
 
 
……………………………….…… 
 
Tel:  
……………………….…………… 
 
Fax:  
………………………….………… 
 
Mobile: 
 …………………………….……... 
 

 
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Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCI 
antigen- specific cancer immunotherapy 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CK 
Creatinine kinase 
CRF 
Case report form 
CRA 
Clinical Research Associate 
CR 
Complete response 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common terminology criteria for adverse events 
DC 
Dendritic cell 
DFS 
Disease free survival  
DTH 
Delayed-type hypersensitivity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good clinical practice 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
GMP 
Good manufacturing practice 
hENT1 
Human equilibrative nucleoside transporter 1 
HLA 
Human leucocyte antigene 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
iv 
Intravenous 
kg 
Kilogram(s) 

 
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Abbreviation 
Term 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
L 
Litre 
LDH 
Lactate dehydrogenase 
LPLV 
Last patient Last visit 
mg 
Milligram(s) 
mL 
Millilitre 
mm 
Millimetre(s) 
μM 
Micromolar 
NCI 
National Cancer Institute  
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 
PR 
Partial response 
PS 
Performance status 
PTT 
Prothrombin time 
PV 
Pharmacovigilance 
QoL 
Quality of life 
RAS 
Rat sarcoma 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
Standard of care 
TAA 
Tumour associated antigen 
UNL  
Upper normal limit 
WBC 
White blood cells 
5-FU 
5-Fluorouracil 

 
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1. SYNOPSIS 
 
Title of Trial: 
A Phase I/II Trial of TG01 and Gemcitabine as Adjuvant Therapy for Treating 
Patients with Resected Adenocarcinoma of the Pancreas 
 
Trial Number: 
CT TG01-01 
Sponsor: 
Targovax ASA 
Trial Physician: 
 
Trial Centres: 
4-5 centres located in Norway, UK and Spain 
Estimated 
Trial 
Duration: 
Phase I and  Phase II part (main and concomitant group): 
104 weeks enrolment 
104 weeks treatment 
Duration: 5 years and 4 months 
Survival follow-up until end of life. 
 
Phase II (modified vaccination group): 
48 weeks enrolment 
104 weeks treatment 
Duration: 2 years and 11 months 
Survival follow-up until end of life. 
 
Total study duration:  5 years and 4 months 
Trial Phase: 
Phase I/II Trial 
 
Objectives: 
1. To assess the safety of GM-CSF/TG01 vaccination and adjuvant 
chemotherapy  
2. To assess the  immune response to GM-CSF/TG01 and the effect of 
adjuvant chemotherapy in patients receiving GM-CSF/TG01 after 
primary resection of pancreatic adenocarcinoma 
3. To assess at 2 years the clinical efficacy of GM-CSF/TG01 in patients 
with resected pancreatic cancer  
4. To assess the relationship of KRAS status to recurrence 
5. To monitor CA19-9 levels 
 
Trial Design: 
Phase I Part 
Up to 12 patients will be assessed for safety and the effect of Gemcitabine on 
immune response. 
 
Initially, 6 patients will be treated with GM-CSF/TG01 within 1-8 weeks after 
surgery and when these 6 patients have reached week 11: 
 
• If 0/6 patients have an immune response and/or >3/6 patients have a DLT 
the study will be terminated 
• If 1-3/6 patients have an immune response and/or 3/6 patients have a DLT 
a further 6 patients will be enrolled 

 
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• If ≥ 4/6 patients have an immune response and ≤2/6 patients have a DLT 
then phase II study will be initiated 
 
If the phase I enrolment is expanded to 12 patients then at week 11: 
• If <4/12 patients have an immune response and/or >4/12 patients have a 
DLT the study will be terminated 
• If ≥4/12 patients have an immune response and ≤4/12 patients have a 
DLT, phase II will be initiated 
 
The Phase II part of the study will therefore be initiated if: 
o ≥4/6 patients have an immune response and ≤2/6 patients have a 
DLT or 
o ≥4/12 patients have an immune response and  ≤4/12 patients have a 
DLT 
 
Patients who are withdrawn for reasons other than toxicity may be replaced if 
they received less than 4 weeks of vaccination and have not started Gemcitabine 
 
Phase II Part 
A further 18-25 patients treated with GM-CSF/TG01 + gemcitabine will be 
added in the Phase II part of the study to provide a total of up to 30 patients in 
the study as a whole. 
 
These patients will follow the same schedule of assessment as in the Phase I part 
(Table 1) and will constitute the main group. Vaccination should be initiated as 
soon as possible after surgery. Should for medical or other reasons, a patient be 
unable to start Gemcitabine either within the 12 week window or at all, 
vaccinations will be continued.  In exceptional circumstance, due to medical 
reasons, where vaccination cannot be started soon after surgery, a maximum of 6 
patients can start vaccination at the same time as chemotherapy (Table 2). These 
patients will constitute the concomitant group. 
 
Patients who are withdrawn for reasons other than toxicity may be replaced if 
they received less than 4 weeks of vaccination and have not started gemcitabine. 
 
The above Phase II part has established a vaccination protocol that provides a 
positive immune response. A new cohort with up to 13 patients is to be enrolled 
to test if a modified schedule of administration of GM-CSF/TG01 can induce 
and maintain the same immune response and reduce the severity of or avoid side 
effects related to allergic reactions (Table 3). These patients will constitute the 
modified vaccination group. 
 
Phase I and Phase II Parts  
Patients will receive GM-CSF followed by TG01, 10-15 minutes later.  Between 
3-7 weeks after GM-CSF/TG01 injections have started, patients will also receive 
Gemcitabine on the same day and after TG01 administration.  The patients will 
all be assessed for safety and immune responses by week 11 after receiving at 
least 1 cycle of gemcitabine treatment. In the Phase II part, vaccination will start 

 
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as soon as the vaccination schedule can be adhered to and gemcitabine (or 
5FU/Leucovorin as per protocol in case of impaired liver function) will be 
started at least 3 weeks later and where possible within 12 weeks from surgery 
(main group). Patients for whom chemotherapy timing cannot be assured will 
start vaccination as soon as the vaccination schedule can be adhered to and will 
receive chemotherapy or not according to their needs. Patients, who for medical 
reasons, cannot start vaccination early may start this at the same time as 
chemotherapy to the limit of 6 patients (concomitant group). 
 
Treatment will be interrupted in any individual patient in case of unacceptable 
toxicity.  If the toxicity is considered to be due to gemcitabine alone then 
immunisation with GM-CSF/TG01 will be continued.  With the exception of 
patients who have received less than 4 weeks of immunisation with GM-
CSF/TG01 and no gemcitabine, all patients will complete the study follow up 
(even if withdrawn from therapy) unless they withdraw consent.  
 
After completion of the gemcitabine treatment, patients who are recurrence-free 
(with or without a detected immune response) will continue to receive GM-
CSF/TG01 every 4 weeks until 52 weeks, then every 12 weeks until 2 years or 
until withdrawal of consent or toxicity whichever is the earliest.  Patients who 
recur during the study and had a positive immune response during the study 
treatment period should continue to receive GM-CSF/TG01 every 4 weeks until 
52 weeks, then every 12 weeks until 2 years or until withdrawal of consent or 
toxicity whichever is the earliest. Patients who recur and haven’t had a positive 
immune response during the study treatment period will be withdrawn. The same 
applies to patients who never start chemotherapy. 
 
For all patients, where possible, a survival follow-up will continue to be 
performed every 6 months after the initial 2 years of study period and until the 
last remaining patient in the modified cohort reaches the 2 years study period or 
withdraws consent or experiences toxicity, whichever is the earliest. Thereafter, 
a survival follow-up will continue to be performed approximately every 12 
months until end of life. 
 
Modified vaccination group 
Patients will start vaccination as soon as possible after surgery. Patients will 
receive GM-CSF followed by TG01 15-20 minutes later. Gemcitabine will 
commence preferably at least 3 weeks later and vaccination will be put on hold 
until chemotherapy completion. In the event that chemotherapy cannot be started 
patients should continue to be vaccinated 4-weekly. After completion of the 
gemcitabine treatment, patients who are recurrence-free (with or without a 
detected immune response) will continue to receive 4-weekly GM-CSF/TG01 
(plus one vaccination at week 5 post-chemotherapy) until week 52 then every 12 
weeks until 2 years or until withdrawal of consent or toxicity whichever is the 
earliest.  Patients who recur during the study and had a positive immune 
response during the study treatment period should continue to receive 4-weekly 
GM-CSF/TG01 (plus one vaccination at week 5 post-chemotherapy) until week 
52 then every 12 weeks until 2 years, until withdrawal of consent or toxicity 

 
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whichever is the earliest. Patients who recur and haven’t had a positive immune 
response during the study treatment period will be withdrawn. Where possible, a 
survival follow-up will continue to be performed every 6 months after the initial 
2 years of study period and until the last remaining patient in the modified cohort 
reaches the 2 years study period or withdraws consent or experiences toxicity, 
whichever is the earliest. Thereafter, a survival follow-up will continue to be 
performed approximately every 12 months until end of life. 
The efficiency of this modified vaccination group will be assessed after 6 
patients have data for DTH assessments after 8 weeks. The cohort will continue 
if the tolerability is acceptable and there are at least 4/6 patients with a positive 
immune response by week 8. If <4/6 patients have an acceptable immune 
response, the next patients will revert to the previous induction schedule of 3 
vaccinations in the first week. 
Inclusion Criteria: 
1. Histologically or cytologically confirmed diagnosis of adenocarcinoma 
of the pancreas 
2. Stage I or II disease (clinical stage T1-3, N0-1, M0 by AJCC staging 
criteria). 
3. Successful surgical resection  
• Complete resection (R0) or with microscopic residual disease (R1) 
• Expected to receive gemcitabine monotherapy as adjuvant 
chemotherapy 
4. Laboratory Values: 
• 
Absolute neutrophil count > 1.5 x 109/l 
• 
Platelets > 100 x 109/l 
• 
Haemoglobin > 9 g/dl 
• 
Total bilirubin < 1.5 x UNL 
• 
Serum creatinine < 1.5xUNL 
• 
Albumin > 2.5 g/dl  
• 
AST or ALT < 5 x UNL 
5. 18 years of age or older. 
6. ECOG performance status (PS) of 0-1. 
7. Life expectancy of at least 6 months 
8. Men and women of childbearing potential must be willing to use 
effective methods of contraception to prevent pregnancy 
9. Provide written (signed) informed consent to participate in the trial prior 
to any trial specific screening procedures 
Exclusion Criteria: 
1. Has received an investigational drug within 4 weeks prior to Trial drug 
administration 
2. Has received previous therapy for pancreatic cancer including radiation 
or chemotherapy (except for the primary resection or primary 
neoadjuvant chemotherapy) 
3. 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) 
4. Has any other serious illnesses or medical conditions such as, but not 
limited to: 

 
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• 
Any uncontrolled infection  
• 
Uncontrolled cardiac failure classification III or IV (NY Heart 
Association) 
• 
Uncontrolled systemic and gastro-intestinal inflammatory conditions 
• 
Bone marrow dysplasia 
• 
History of auto-immune disease 
• 
History of adverse reactions to vaccines 
5. Known history of positive tests for HIV/AIDS, hepatitis B or C 
6. Pregnant or lactating females or have no pregnancy test at baseline 
(postmenopausal women must have been amenorrhoeic for at least 
12 months to be considered of non-childbearing potential) 
7. Contraindication to gemcitabine treatment 
8. Have had any other malignancies within last 3 years (except for 
adequately treated carcinoma of the cervix or basal or squamous cell 
skin cancer) 
9. Known  malignant brain lesion(s) 
10. Are unlikely to start chemotherapy within 12 weeks of surgery (e.g. 
delayed wound healing, or infection, etc.) 
11. Are not expected to complete 6 cycles of chemotherapy 
12. Are planned to receive yellow fever or other live (attenuated) vaccines 
during the course of study (see concomitant medication section) 
 
Investigational 
Products and Mode 
of Administration: 
TG01: provided as a lyophilised powder for reconstitution in sterile water for 
injection to be given via intradermal injection.  
GM-CSF: provided as a lyophilised powder for reconstitution in sterile water for 
injection to be given via intradermal injection 
 
GM-CSF to be given 10-15 minutes before TG01 in the main group and 
concomitant group. In the modified vaccination group GM-CSF is to be given 
15-20 minutes before TG01. 
 
Gemcitabine: provided as a lyophilised powder (vials of 200 mg and 1 g) for 
reconstitution in saline to be given via intravenous injection.  To be reconstituted 
according to Prescribing Information for gemcitabine  
Or 
Optional 5-FU and Leucovorin (in patients with ALT/AST >2.5 x ULN at time 
of chemotherapy start):  
5-FU and Leucovorin: To be administered according to the Prescribing 
Information for 5-FU and in accordance with the standard procedure of the 
institution. 
Treatment 
Description: 
GM-CSF/TG01 
Patients will receive the first dose of GM-CSF/TG01 as soon as feasible after 
surgery.  Patients will receive TG01 at a dose of 0.70 mg/injection (individual 
peptides comprising 0.10 mg each) 10-15 minutes (or 15-20 minutes in the 
modified vaccination group) after 30 μg GM-CSF at each time point as an 
intradermal injection into the back of the upper arm.  
Patients will be observed for at least 30 minutes after each injection of TG01.  

 
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Hospitalisation of patients for administrative reasons only will be at the 
investigator’s discretion and would not qualify as a serious adverse event. 
 
TG01 for DTH testing 
As a DTH skin reactivity test control patients will be given TG01 at a dose of 
0.70 mg /injection (individual peptides comprising 0.10 mg each) without 
GM-CSF as an intradermal injection into the lower area of the contralateral arm. 
When a DTH test is being performed the DTH TG01 injection will be given at 
least 30 min before the GM-CSF administration and the TG01 administration 10-
15 minutes after GM-CSF (15-20 minutes in the modified vaccination group). 
 
Chemotherapy 
At start of chemotherapy: 
• Patients who have AST or ALT ≤2. 5 x UNL will receive gemcitabine 
according to protocol 
• Patients who have AST or ALT > 2. 5 x UNL may receive 5-FU and 
continue vaccination with TG01 as per protocol (at the investigator’s 
discretion) 
 
Gemcitabine will be given as 1000 mg/m2 iv over 30 minutes on days 1, 8 and 
15 of a four-week cycle for 6 cycles in total.  
 
Should 5-FU be given instead of gemcitabine, the recommended regimen is 500 
mg/m2,  bolus i.v on day 1 and 2 and leucovorin 60mg/m2 (or 100mg) on day 1 
and 2 every 2 weeks of a four-week cycle for 6 cycles. 
 
When applicable, chemotherapy is to be given on the same day and after TG01 
injection. In this respect, in the main group and concomitant group, patients 
will receive GM-CSF/TG01 in combination with chemotherapy for 6 cycles of 4 
weeks. 
 
Treatment schedule 
The first day of GM-CSF/TG01 treatment will be considered Day 1 for the 
Visits. 
Main group: Chemotherapy should start not less than 3 weeks after the start of 
GM-CSF/TG01 and if possible within 12 weeks from surgery. In the event that 
chemotherapy cannot be started patients should continue to be vaccinated. All 
these patients will follow the schedule of assessments defined in Table 1. GM-
CSF/TG01 will be given on days 1, 3, 5, 8, 15, 22 and then every 2 weeks until 
the end of chemotherapy treatment. 
Concomitant group: Where vaccination cannot be started soon after surgery, it 
is permissible to start GM-CSF/TG01 at the same time as chemotherapy and 
patients will follow Table 2 schedule of assessments. GM-CSF/TG01 will be 
given on days 1, 3, 5, 8, 15, 22 and then every 2 weeks until the end of 
chemotherapy treatment.  
Modified vaccination group: Chemotherapy should start not less than 3 weeks 
after the start of GM-CSF/TG01. Patients will be given GM-CSF/TG01 on days 
1, 8, 15, 22 and 36 then if chemotherapy hasn’t started, 4-weekly until the start 

 
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of chemotherapy at which point vaccination will be put on hold until the end of 
chemotherapy treatment. Vaccination will resume after end of chemotherapy 
treatment (Table 3).  
All groups: In the case of early termination of chemotherapy treatment (prior to 
completion of 6 cycles), GM-CSF/TG01 will be continued as per the treatment 
schedule. 
 
Main group and concomitant group: After the end of chemotherapy treatment 
for all patients who are recurrence-free (with or without a positive immune 
response), further booster injections will be given every 4 weeks until 52 weeks, 
then every 12 weeks until 2 years or until withdrawal of consent or toxicity 
whichever is the earliest.  Patients who recur and have a positive immune 
response during the study treatment period should continue to receive GM-
CSF/TG01 every 4 weeks until 52 weeks, then every 12 weeks until 2 years or 
until withdrawal of consent or toxicity whichever is the earliest. From 26 
January 2015 onward, for all these subsequent GM-CSF/ TG01 administrations 
the patients should be given prophylactic treatment (30 minutes before 
treatment) to prevent possible occurrence of allergic reactions. Patients who 
recur and do not have a positive immune response during the study treatment 
period will be withdrawn from the study. The same applies to patients who 
follow the vaccination schedule but never start chemotherapy. 
Modified vaccination group: Patients will receive under the same rules as 
above, further booster injections 4 and 5 weeks after last chemotherapy injection 
and every 4 weeks from week 8 post-chemotherapy up to week 52, then every 12 
weeks until 2 years or until withdrawal of consent or toxicity whichever is the 
earliest. Prophylactic treatment will not be required. 
 
From 26 January 2015 onward,  
• 
All groups: 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 TG01 
administrations they should be pre-medicated with intravenous antihistamine 
treatment (e.g. chlorpheniramine or dexchlorpheniramine)  30 minutes 
before either the DTH injection (TG01 alone) when done before vaccination 
or  before vaccination  (i.e. before the GM-CSF injection which is followed 
by TG01 10-15 minutes later or 15-20 minutes in the modified vaccination 
group) 
• 
Main group and concomitant group: For patients who have 
completed/finished chemotherapy – All TG01 administrations should be 
preceded by intravenous antihistamine treatment as above 
• 
All groups: 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 
• 
All groups: Where a DTH injection is being performed the TG01 DTH dose 
should 
be 
administered 
30 
minutes 
before 
the 
GM-CSF/TG01 
administration and patients should be observed for at least 30 minutes after 

 
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ALL GM-CSF/TG01 administrations 
Modified vaccination group: Prophylaxis will not be required at any stage of 
the study except if the patient continues vaccination after experiencing an event 
of hypersensitivity reaction. 
Endpoints 
Primary 
• 
Safety 
• Adverse events 
• Laboratory assessments 
• 
Immune response 
• DTH responses 
• Proliferative T-cell responses 
Secondary 
• 
Efficacy at 2 years 
• Disease free survival  
• Overall survival 
Exploratory 
• 
Relationship between KRAS status in resected primary tumour and 
recurrence survival outcomes (including disease recurrence and overall 
survival) 
• 
Monitor CA19-9 levels 
Schedule of Key 
Assessments: 
Screening / Baseline: 
 
The aim of this protocol is to include patients that have undergone pancreatic 
resection with curative intent and to subsequently treat the patients with the 
TG01 vaccine as soon as possible after the surgery.  Patients must have signed 
the informed consent before starting baseline assessments/treatment.  
 
Screening assessments to be done prior to GM-CSF/TG01 treatment 
• 
Surgical Resection (once resection is undertaken, TG01 treatment to 
start as soon as possible)  
• 
Tumour sample from surgery stored for KRAS analysis 
• 
Informed consent 
 
Baseline assessments to be done within 7 days prior to anticipated TG01 
treatment 
• 
Demographic data and medical history  
• 
ECG 
• 
Pregnancy test (if appropriate) 
• 
Physical examination and performance status 
• 
Vital signs  
• 
Haematology / Biochemistry assessment 
• 
Urinalysis 
• 
Assessment of concurrent illness/therapy 
• 
CT-scan  
 
Treatment Period for patients starting TG01 vaccination first – main group 

 
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(timings based on start of GM-CSF/TG01 treatment)- Table 1: GM-
CSF/TG01 +/- chemotherapy  
Initial Treatment Period (possibly up to week 11) +/- chemotherapy cycles 
• 
GM-CSF/TG01 to start as soon as possible after surgical resection.  Day 
1 will be the first day of TG01 treatment.  GM-CSF/TG011 will be 
administered on Days 1, 3, 5, 8, 15 and 22 and then 2-weekly until the 
end of chemotherapy treatment. Patients who do not start chemotherapy 
at all can move to a 4-weekly vaccination from vaccination week 10 to 
week 52 and will follow the “post-chemotherapy-52 weeks” schedule of 
Table 1.  
• 
Chemotherapy will commence at least 3 weeks after start of GM-
CSF/TG01 and preferable within 12 weeks from surgery (e.g. at day 22, 
day 36 or day 50). Patients can, however, start chemotherapy later or not 
start at all if needed. For patients receiving chemotherapy, 6 cycles of 
chemotherapy will be given and GM-CSF/TG01 will be administered on 
Days 1 and 15 of the 4-week cycles. 
• 
DTH skin test injections on days 1, 8, 15, 22 36, 50 and day 64. DTH 
reaction is assessed 48 h ± 4 h after each injection 
• 
Haematology and blood chemistry at days 1,  8, 22, 36, 50, and 64 taken 
prior to injection of GM-CSF/TG01 and Days 1, 8 and 15 of each 
gemcitabine cycle.  Key laboratory values in accordance with the 
Prescribing Information for chemotherapy should be available prior 
to chemotherapy dosing. For patients who do not start chemotherapy at 
all, haematology and blood chemistry should be taken at days 1, 8, 22, 
36, 50 and 64 and then every 12 weeks 
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit. 
• 
Physical examination and Performance Status before the start of each 
gemcitabine cycle. For patients who do not start chemotherapy, these 
assessments should be done every 12 weeks. 
• 
Blood sampling for immunology – samples taken prior to GM-
CSF/TG01 injection on day 1 and day 71 (or 78)  
• 
Blood sampling for CA19.9 on day 1 prior to GM-CSF/TG01, prior 
chemotherapy 1st administration and monthly thereafter until end of 
chemotherapy. For patients who do not start chemotherapy, these 
assessments should be done on Day 1 and prior every 4-weekly 
vaccination cycle 
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and 
stored for potential analysis of additional biomarkers on day 1 prior to 
GM-CSF/TG01, prior chemotherapy 1st administration and monthly 
thereafter until end of chemotherapy. For patients who do not start 
chemotherapy, these assessments should be done on Day 1 and prior 
every 4-weekly vaccination cycle 
• 
CT scan every 6 months from the start of vaccination and at any other 
time point if indicated 
 
Treatment Period for patients starting vaccination and chemotherapy at the 
same time – concomitant group (timings based on start of GM-CSF/TG01 

 
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treatment) – Table 2: GM-CSF/TG01 +/- chemotherapy  
Initial Treatment Period (possibly up to week 13) +/- chemotherapy cycles 
• Day 1 will be the first day of TG01 treatment.  GM-CSF/TG01 will be 
administered on Days 1, 3, 5, 8 and 15 and then 2-weekly until the end 
of chemotherapy treatment.  
• 
Chemotherapy will commence at the same time as GM-CSF/TG01 and 6 
cycles of chemotherapy will be given. 
• 
DTH skin test injections on days 1, 8, 15, 29, 43, 57 and day 71. The 
DTH reaction is assessed 48 h ± 4 h after each injection 
• 
Haematology and blood chemistry at days 1, 8 and 15 of each 
gemcitabine cycle.  Key laboratory values in accordance with the 
Prescribing Information for chemotherapy should be available prior 
to chemotherapy dosing  
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit. 
• 
Physical examination and Performance Status before the start of each 
gemcitabine cycle 
• 
Blood sampling for immunology – samples taken prior to GM-
CSF/TG01 injection on day 1 and week 13  
• 
Blood sampling for CA19.9 on day 1 of each chemotherapy cycle, prior 
to GM-CSF/TG01 administration  
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and 
stored for potential analysis of additional biomarkers on day 1 of each 
chemotherapy cycle, prior to GM-CSF/TG01 administration 
• 
CT scan every 6 months from the start of vaccination and at any other 
time point if indicated 
 
Treatment Period for patients in the modified vaccination group (timings 
based on start of GM-CSF/TG01 treatment)- Table 3: GM-CSF/TG01 +/- 
chemotherapy  
Initial Treatment Period (up to week 8) +/- chemotherapy cycles 
• 
GM-CSF/TG01 to start as soon as possible after surgical resection.  
Day 1 will be the first day of TG01 treatment. All patients will receive at 
least 5 vaccinations independent of the start of chemotherapy (Days 1, 8, 
15, 22 and 36) then if chemotherapy hasn’t started, vaccination will be 
given 4-weekly until the start of chemotherapy at which point 
vaccination will be put on hold until the end of chemotherapy treatment.  
Patients who do not start chemotherapy at all will continue to receive 4-
weekly vaccinations until week 52 (Table 3).  
• 
Chemotherapy will preferably commence at least 3 weeks after start of 
GM-CSF/TG01. Patients can however start chemotherapy later or not 
start at all if more appropriate. For patients receiving chemotherapy, 6 
cycles of chemotherapy will be given. Note that chemotherapy will not 
be delayed if it is considered important to start within 3 weeks of the 
start of vaccinations. 
• 
DTH skin test injections on days 36 and 50. DTH reaction is assessed 
48 h ± 4 h after each injection 

 
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• 
Haematology and blood chemistry at days 1, 8, 22, 36, 50, and 64 taken 
prior to injection of GM-CSF/TG01 and Days 1, 8 and 15 of each 
gemcitabine cycle.  Key laboratory values in accordance with the 
Prescribing Information for chemotherapy should be available prior 
to chemotherapy dosing. For patients who do not start chemotherapy at 
all, haematology and blood chemistry should be taken at days 1, 8, 22, 
36, 50 and 64 and then every 12 weeks 
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit. 
• 
Physical examination and Performance Status before the start of each 
gemcitabine cycle. For patients who do not start chemotherapy, these 
assessments should be done every 12 weeks. 
• 
Blood sampling for immunology – samples taken prior to GM-
CSF/TG01 injection on day 1 and at week 8  
• 
Blood sampling for CA19.9 on day 1 prior to GM-CSF/TG01, prior 
chemotherapy 1st administration and monthly thereafter until end of 
chemotherapy. For patients who do not start chemotherapy, these 
assessments should be done on Day 1 and prior every 4-weekly 
vaccination cycle 
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and 
stored for potential analysis of additional biomarkers on day 1 prior to 
GM-CSF/TG01, prior chemotherapy 1st administration and monthly 
thereafter until end of chemotherapy. For patients who do not start 
chemotherapy, these assessments should be done on Day 1 and prior 
every 4-weekly vaccination cycle 
• 
CT scan every 6 months from the start of vaccination and at any other 
time point if indicated 
 
Post-Chemotherapy period or period from week 10 for patients who do not 
get chemotherapy  
Main group and concomitant group 
• 
GM-CSF/TG01 every 4 weeks until 52 weeks and then every 12 weeks 
for up to 2 years. For all these subsequent GM-CSF/TG01 
administrations the patients should be given prophylactic treatment (30 
minutes before treatment) to prevent possible occurrence of allergic 
reactions.   
• 
DTH skin test injections at the 2nd GM-CSF/TG01 injection after end of 
chemotherapy (8 weeks after last chemotherapy injection) and at week 
52. The DTH reaction is to be assessed 48 h ± 4 h after TG01 injection. 
For patients not starting chemotherapy at all, DTH assessment is to be 
done at week 52 only. 
• 
Blood sampling for immunology– samples taken prior to GM-
CSF/TG01 injection at 52 weeks  
• 
Blood sampling for CA19.9 and additional biomarkers – samples taken 
prior to GM-CSF/TG01 injection at 52 weeks. For patients not starting 
chemotherapy, samples should be taken prior every 4-weekly 
vaccination cycle and at week 52 
• 
Physical examination and performance status at 52 weeks. For patients 

 
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who do not start chemotherapy, these assessments should be done every 
12 weeks and at week 52 
• 
Vital signs, haematology and biochemistry at 12 weekly intervals 
• 
Concomitant medications and adverse events at each visit 
• 
CT scan every 6 months from the start of vaccination and at any other 
time point if indicated 
 
Modified vaccination group: 
• 
GM-CSF/TG01 will be given 4 weeks and 5 weeks after end of 
chemotherapy and then every 4 weeks from week 8 post-chemotherapy 
until week 52.  
• 
DTH skin test at 3rd vaccination post-chemotherapy (8 weeks post-
chemotherapy). The DTH reaction is to be assessed 48 h ± 4 h after 
TG01 injection. For patients not starting chemotherapy at all, the DTH 
test and assessment are to be done at week 52  
• 
Blood sampling for immunology– sample to be collected 4 weeks after 
the last chemotherapy injection (1st vaccination injection) and at week 52  
• 
Blood sampling for CA19.9 and additional biomarkers – samples to be 
taken prior to GM-CSF/TG01 injection at week 52. For patients not 
starting chemotherapy, samples should be taken prior every 4-weekly 
vaccination cycle and at week 52 
• 
Physical examination and performance status to be taken at week 52. For 
patients who do not start chemotherapy, these assessments should be 
done every 12 weeks and at week 52 
• 
Vital signs, haematology and biochemistry at 12 weekly intervals 
• 
Concomitant medications and adverse events at each visit 
• 
CT scan every 6 months from the start of vaccination and at any other 
time point if indicated 
 
End of Study Visit (104 weeks or 4 weeks after last GM-CSF/TG01 injection 
if patients is to be withdrawn)  
• 
Haematology and blood chemistry 
• 
Physical exam and Performance Status 
• 
Vital signs, concomitant medications and adverse events 
• 
CT scan 
• 
Blood sampling for immunology, CA19.9 and additional biomarkers 
 
If patient is recurrence-free with or without an immune response, GM-
CSF/TG01 will be given as per schedule until 52 weeks, then every 12 weeks 
until 2 years or until withdrawal of consent or toxicity whichever is the earliest. 
If patient has a positive immune response and recurs during the study treatment 
period, the patient should continue as per schedule until 52 weeks, then every 12 
weeks until 2 years or until withdrawal of consent or toxicity whichever is the 
earliest. The same applies to patients who do not start chemotherapy. 
 
For all patients where possible, a survival follow-up will continue to be 
performed every 6 months after the initial 2 years of study period and until the 
last remaining patient in the modified cohort reaches the 2 years study period or 

 
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withdraws consent or experiences toxicity, whichever is the earliest. Thereafter, 
a survival follow-up will continue to be performed approximately every 12 
months until end of life.  
 
Sample size 
Up to 32 patients will be enrolled in this study: 
7 patients have been enrolled in the Phase I part  
18-25 will be enrolled in the Phase II part with up to 13 patients enrolled in the 
modified vaccination group 
 
The modified vaccination group will consist of up to 13 patients. A review of 
data of the first 6 patients for DTH assessments after 8 weeks will determine 
whether the cohort should continue. At least 4/6 patients with a positive immune 
response are required to continue 
 
Statistical Methods 
and Planned 
Analyses: 
No formal statistics will be performed. 
 
All patients (treated with chemotherapy or not) will contribute to the 
interpretation of the whole trial. 
 
The proportion of patients with immune responses will be assessed.  
 
The safety and efficacy of the combination of GM-CSF/TG01 and chemotherapy 
will be descriptive.  The incidence of pancreatic cancer recurrence and KRAS 
status during the Trial will be listed. 
 
 

 
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2. INTRODUCTION 
Investigators should be familiar with the Investigator’s Brochure (IB). 
2.1 
Background 
2.1.1 
Pancreatic cancer 
Pancreatic cancer is one of the major causes of cancer death globally, with a 5-year 
survival rate of less than 5%.  The outlook for those patients who can undergo surgical 
resection is better, and in specialised centres, resection rates greater than 15% can be 
achieved.  Although surgery cannot guarantee a cure, the 5-year survival does improve to 
around 10% following resection.  There is a clear need to improve long-term survival in 
these patients.  While the added survival benefit of adjuvant chemoradiotherapy with or 
without maintenance chemotherapy remains unclear, a more certain survival benefit has 
been demonstrated from adjuvant chemotherapy. 
2.1.2 
Rationale for the trial 
TG01 is an antigen-specific cancer immunotherapy (ASCI) containing a mixture of 
7 different synthetic peptides designed to encompass all common RAS mutations at 
positions 12 and 13.  The peptide sequences are identical to the amino acid sequence of 
wild-type RAS, except for one substitution of the amino acid at either position 12 or 13, 
which corresponds to amino acid substitutions found in the mutated p21 RAS protein 
expressed by pancreatic, colon and lung cancer cells.  
 
The occurrence of oncogenic mutations in p21 RAS in pancreatic cancer is very frequent 
(Capella et al., 1991) and may be one of the reasons why every standard chemotherapy 
drug and new “targeted” drug tested in pancreatic adenocarcinomas have uniformly 
failed to significantly increase the survival of patients with pancreatic cancer. 
 
In Europe, chemotherapy alone is now recommended as adjuvant therapy based on the 
results of the ESPAC-1 and CONKO-001 trials (Neoptolemos et al., 2010; Oettle et al., 
2007; Neuhaus et al., 2008).  In particular, the CONKO-001 trial indicates that the use of 
gemcitabine in patients undergoing R0 or R1 resection for pancreatic cancer provides a 
regimen with minimal toxicity and a chance for a prolonged disease-free-survival 
compared to observation alone (13.4 months compared to 6.9 months although there was 
no difference in overall survival).  Gemcitabine is therefore the most frequently used 
adjuvant in this setting. 
 
Combining gemcitabine with an immunotherapy approach would, in theory, offer a 
regimen with minimal toxicity with the aim to improve the recurrence rate and 
potentially offer an improved overall survival. 
 
TG01 is administered to the patients by intradermal injection in combination with an 
adjuvant (GM-CSF/Molgramostim).  After administration, the peptides are taken up by 
antigen presenting cells like dendritic cells (DCs) which thereafter travel to the draining 

 
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lymph nodes and present the vaccine peptides, eventually after being trimmed by 
intracellular enzymatic antigen processing, in HLA molecules.  This will enable the 
induction of T-cells with specificity for the various RAS mutations of TG01.  Finally the 
induced T-cells will enter circulation and get activated upon recognition of cancer cells 
presenting relevant mutated RAS peptide epitopes in their HLA molecules.  In addition 
to efficient killing of cancer cells by T-cells induced by TG01, also a broader immune 
response may be induced locally by enhanced stimulation of cross presentation and 
epitope spreading (local cytokine production by TG01 induced T-helper cells stimulate 
DCs to take up debris from killed cancer cells and present all sorts of tumour associated 
peptide epitopes). 
2.1.3 
Pre-clinical experience 
TG01 is an antigen specific cancer immunotherapy (ASCI) consisting of seven synthetic 
17-mer ras-oncogene peptides aimed to stimulate CD4+ Th-cells against tumour cell 
targets expressing mutated RAS peptides and, intended to be administered at a low dose 
0.7 mg (0.1 mg each peptide) by intradermal injection.  Due to the nature of TG01 a 
number of non-clinical studies that would normally be undertaken as part of a formal 
development programme were not conducted in the case of TG01 and the rationale for 
this is given below. 
 
The seven synthetic, naturally occurring, 17-mer ras-oncogene peptides that comprise 
TG01 have no intrinsic activity per se.  Moreover, the effects of TG01 are not related to 
blood or plasma concentrations but are mediated through local peptide uptake into 
dendritic cells (DC’s) in the skin and immunological processing at the injection site.  
Subsequently DC’s in the skin migrate to the draining lymph node where they activate 
T-cells.  The breakdown of proteins from dead cells takes place locally, in the tissue, 
where peptide fragments are rapidly degraded by tissue proteases/peptidases and do not 
reach the bloodstream.  Indeed, even in an improbable ‘worst case’ scenario, in which the 
peptides where to reach the systemic circulation, evidence indicates that they would be 
rapidly degraded in the blood, being undetectable 1 min after injection (Yamada et al., 
2006). 
 
Thus, taking into account the lack of intrinsic activity of the peptides, the lack of 
systemic exposure following intradermal injection and data from clinical studies, in 
which TG01 has been administered repeatedly to over 80 pancreatic cancer patients with 
only minor, transient adverse effects, a formal development programme, based on 
systemic exposure following administration, was not considered relevant. 
 
The non-clinical pharmacodynamics and rationale for developing TG01 was assessed in 
a number of published in vitro studies using T-cells from patients to demonstrate the 
ability of the peptides to elicit effector T-helper cells and cytotoxic T-lymphocytes (CTL) 
in humans.  Initial studies, investigating whether specific immune responses could be 
generated against RAS, reported that immunization of a number of strains of mice with 
RAS peptides, bearing various point mutations at positions 12 or 61, elicited T-cells that 
specifically proliferated in response to RAS peptide stimulation (Peace et al., 1991).  
Moreover, several studies using synthetic RAS-oncogene peptide-loaded peripheral 

 
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blood mononuclear cells (PBMC’s) from both healthy individuals and cancer patients 
have reported the induction of RAS-specific T-cell responses in vitro.  Furthermore, both 
CD4+ and CD8+ T-cells have been identified and their ability to kill RAS-expressing 
target cells or inhibit the growth of cancer cell lines harbouring the corresponding RAS 
mutations has been demonstrated (Gedde-Dahl et al., 1992 & 1994; Fossum et al., 1993 
& 1994).  Taken together, these reports, in addition to other published observations, 
indicated that targeting RAS by immunotherapy offered a feasible approach to 
potentially controlling pancreatic cancer cell growth in vivo. 
 
Single dose intravenous toxicology studies using either single, two or five KRAS peptide 
mixtures were undertaken in pigs, rabbits, rats and mice.  Collectively, the 2 and 5 KRAS 
peptide single dose toxicity studies used all 7 of the KRAS peptides which comprise 
TG01.  Overall, these studies revealed no significant toxicological findings, presumably 
as a consequence of rapid degradation of the peptides in the blood following intravenous 
bolus injection and subsequent lack of systemic exposure. 
However, an exception to these observations was noted in a single dose, iv study 
following administration of the val 12 peptide in mice (study 927/002).  In this study, 
administration of the highest dose of the val 12 peptide (50 mg/kg) led to subdued 
behaviour or convulsions in all 5 males and 5 females and two males and one female died 
within 2 min of injection.  All surviving animals recovered after 2 h.  In contrast, no 
mortalities or clinical effects were noted following administration of the low (0.5 mg/kg) 
or intermediate (5 mg/kg) dose-levels.  Moreover, no mortalities, clinical signs or 
macroscopic abnormalities were reported when the same doses of the val 12 peptide were 
administered to rats.  Taken together, the most plausible mechanism to account for these 
observations, recorded specifically in the mouse, is related to the exceptionally small 
diameter of blood vessels in the murine brain, which may readily become clogged 
following injection of excessive amounts of peptides or macromolecules resulting in 
rapid death or clinical symptoms such as lethargy, convulsions or subdued behaviour.  
Indeed, the val 12 peptide is considerably less soluble and more hydrophobic than the 
other 6 peptides in TG01, lending support to the idea that blocked microvessels in the 
murine brain resulted in the rapid deaths or clinical symptoms reported.  Moreover, the 
dose of val 12 administered in this study was circa 5000 times the dose (of total peptides 
using the 7-peptide formulation) that has been routinely administered to humans in 
clinical studies.  Hence, it is considered that a sufficient safety margin exists between the 
currently utilised clinical dose and the dose at which toxicity was specifically observed 
following administration of this single peptide in the mouse. 
The complete seven mutated RAS peptide mixture that comprises TG01 has not been 
tested in animal toxicity studies to date.  This was primarily due to the initial 
development plan for TG01 which explored the safety of RAS immunotherapy based on 
the use of single peptides in pancreatic cancer patients.  However, due to the high 
probability of a mismatch between the point mutation in the immunising peptide and the 
mutation expressed by the patients’ tumour, there was a requirement for each patient to 
be genotyped for RAS mutations in order to optimise therapy.  Due to the tedious and 
costly nature of this approach, particularly with respect to the rapid deterioration of 

 
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pancreatic cancer patients and the time required for RAS gene sequencing, it became 
obvious that such a strategy was impractical.  Consequently, it was decided to develop a 
product containing a mixture of seven peptides that encompassed all significant RAS 
mutations, thus negating the requirement for prior tumour typing. 
Although current regulatory guidelines indicate that the range and type of genotoxicity 
studies routinely conducted for pharmaceuticals are not applicable to biotechnology-
derived pharmaceuticals such as synthetic peptides, prior to the issue of these guidelines, 
an Ames test was undertaken using a single KRAS peptide 12-V- p21 RAS(5-21).  
Concentrations of 31.2, 62.5, 125, 250, and 500μg/plate did not result in any mutagenic 
findings either in the presence or absence of liver S-9 mix.  These naturally occurring 
peptides would not be expected to interact directly with DNA or other chromosomal 
material, and in view of the current guideline, no further studies are planned. 
Additionally, these natural peptides have no potential to support or induce proliferation 
of transformed cells or clonal expansion leading to neoplasia and taken together with the 
rapid degradation, consequent lack of systemic exposure and the target patient 
population, no carcinogenicity have been undertaken. 
Moreover, whilst many biotechnology-derived products are immunogenic and have the 
potential to stimulate antibody production, the seven synthetic, 17-mer ras-oncogene 
peptides in TG01 are comprised entirely of naturally occurring amino acids and have no 
capacity to stimulate the formation of antibodies. Indeed, after processing by DC’s, the 
peptides elicit a highly specific immune response, stimulating CD4+ T-cells against 
specific tumour cell targets expressing mutated RAS peptides. This was evidenced in 
clinical data from Phase I/II studies indicating that a specific delayed-type 
hypersensitivity (DTH) reaction could be generated at skin sites in almost 50% of cancer 
patients. 
 
This body of clinical data also provides significant experience concerning local tolerance.  
In the case of TG01, repeated intradermal injections of the seven peptide mixture, 
co-administered with GM-CSF, have been given to more than 80 patients with pancreatic 
cancer using a 1, 2, 3, 4, 6 and 10 week dosing schedule.  These clinical studies reported 
that injections were well tolerated, with only one patient reporting itching and one patient 
showing erythema at injection sites.  Moreover, these injection-related local effects were 
transient and resolved without sequelae.  Consequently, no additional non-clinical studies 
investigating local effects are planned. 
2.1.4 
Clinical experience 
During the earlier phases of development, a significant body of clinical data from over 
230 cancer patients has been established and indicates that the RAS peptides comprising 
TG01 are safe, well tolerated and have the capacity to elicit immune responses in man.  
To date, 120 patients with pancreatic cancer have received treatment with TG01 in 
combination with GM-CSF (studies CTN RAS 98010 and EMR 62200-001) and 
55 patients with pancreatic cancer have received either several injections of RAS 
peptide-pulsed autologous PBMC (7 patients), or active immunization with 1 or 4 
mutated RAS peptides combined with GM-CSF (48 patients; Studies CTN RAS 93001, 

 
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CTN RAS 95002, CTN RAS 97004).  Sixty three patients with colorectal cancer have 
received treatment RAS peptide-pulsed autologous PBMC (8 patients), or active 
immunization with 1 or 5 mutated RAS peptides combined with GM-CSF (55 patients; 
Studies CTN RAS 95003, CTN RAS 97005 and CTN RAS 98008).  
 
Immunization with a single RAS peptide pulsed PBMC in study CTN RAS 93001 
resulted in specific T cell responses in only 2 out of 5 patients which led to the selection 
of active immunization as the optimal approach for induction of measurable immune 
responses.  Using this approach, both DTH and proliferative responses could be 
demonstrated in approximately half of the pancreatic cancer patients who received active 
immunisation with either one or 4 RAS peptide ASCI (Studies CTN RAS 95002 and 
97004).  In the clinical study with the 7 RAS peptide ASCI (CTN RAS 98010), the 
results showed that all (100%) of the evaluable patients in the resected group and 14 
(56%) in the non-resected group reported a DTH immune response. 
 
From all the clinical studies so far in patients with resected and advanced pancreatic 
cancer it seems that the ability to induce an effective immune response may be reduced 
as the disease burden increases.  It is therefore of outmost importance to start to vaccinate 
as soon as possible after diagnosis and to use an aggressive initial immunotherapy 
regimen in order to induce an immune response as quickly as possible.  Long term follow 
up of resected pancreatic cancer patients immunised with a single peptide – specific RAS 
peptide vaccine (Study CTN RAS 95002) and the 7 RAS peptide vaccine 
(Study CTN RAS 98010) suggest that the induction of a RAS-specific cellular response 
may confer a survival advantage since patients who develop a DTH response seem to live 
longer than those who do not.  Five year survival rates were 3 out of 10 patients in 
Study CTN RAS 95002 and 2 out of 11 patients in Study CTN RAS 98010.  Collectively 
these data suggest that vaccination with TG01 could induce potent anti-tumour activities 
capable of improving the patient’s survival and pivotal studies are being planned to test 
this hypothesis. 
Whilst the safety of co-administration of GM-CSF/TG01 with gemcitabine has not been 
established, their mode of action and toxicity profiles should not be additive and it is not 
expected that toxicity will be a factor in progressing to the formal Phase II/III study.  The 
production of immune responses with this combination is also not known and it is 
considered prudent to explore this initially before embarking on the main Phase II/III 
study. 
 
2.2 
Trial objectives 
2.2.1 
Primary objective 
The primary objective of the study is defined as: 
• To assess the safety of GM-CSF/TG01 vaccination and adjuvant chemotherapy  
• To assess the immune response to GM-CSF/TG01 and the effect of adjuvant 
chemotherapy in patients receiving GM-CSF/TG01 after primary resection of 
pancreatic adenocarcinoma. 

 
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2.2.2 
Secondary objective 
The secondary objective of the study is: 
• To assess at 2 years the clinical efficacy of GM-CSF/TG01 in patients with 
resected pancreatic cancer 
2.2.3 
Exploratory objectives 
The exploratory objectives are: 
•    Assess the relationship of KRAS status to recurrence 
• 
Monitor CA19-9 levels 
 
3. INVESTIGATIONAL PLAN 
3.1 
Overall trial design and plan 
This is a Phase I/II trial of TG01 and gemcitabine as adjuvant therapy for treating 
patients with resected adenocarcinoma of the pancreas. 
Patients will be enrolled in 4-5 study centre(s) and the study duration will be 
approximately 5 years. 
 
The phase I part of the study (Figure 1) will be initiated with 6-12 patients enrolled 
within 1-8 weeks after surgery to receive GM-CSF given 10-15 minutes before TG01.  
Gemcitabine will be started at least 3 weeks after the initiation of immunotherapy but not 
later than 12 weeks after surgery. Note that, in some centres where transaminases are > 
2.5 x ULN at the time of chemotherapy, 5-FU/Leucovorin may be substituted. However, 
the number of patients in the study refers to those receiving gemcitabine and therefore, 
for every patient who receives 5-FU rather than gemcitabine, a further patient will be 
added.  The patients’ safety will be reviewed on an on-going basis and the 
immunological response will be monitored (DTH) and assessed by week 11 (DTH and T 
cell proliferation).  
Initially, 6 patients will be treated with GM-CSF/TG01 within 1-8 weeks after surgery 
and when these 6 patients have reached week 11: 
• 
If 0/6 patients have an immune response and/or there are > 3/6 patients with 
GM-CSF/TG01 related dose-limiting toxicities observed, the study will be 
terminated. 
• 
If 1-3/6 patients have an immune response and/or if there are 3/6 patients 
with GM-CSF/TG01 related dose-limiting toxicities observed, 6 new patients 
will be enrolled and will be treated in the same way as the previous patients.  
• 
If ≥ 4/6 patients have an immune response and ≤2/6 patients have a GM-
CSF/TG01 related dose-limiting toxicity, the phase II study will be initiated 
 
If the enrolment of the phase I part is expanded to 12 patients, then at week 11: 

 
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• 
If < 4/12 patients have an immune response and/or there are > 4/12 patients 
with GM-CSF/TG01 related dose-limiting toxicities, the study will be 
terminated 
• 
If ≥ 4/12  patients have an immune response and ≤ 4/12 patients have a GM-
CSF/TG01 related dose-limiting toxicity, the phase II study will be initiated  
 
The Phase II part of the study (an additional 18-24 patients - Figure 2) will be initiated if:  
• 
  ≥ 4/6 patients have an immune response and ≤ 2/6 patients have a GM-
CSF/TG01 related dose-limiting toxicity 
• 
  ≥ 4/12 patients have an immune response and ≤ 4/12 patients have a GM-
CSF/TG01 related dose-limiting toxicity  
 
The above Phase II part has established a vaccination protocol that provides a positive 
immune response. A new cohort with up to 13 patients is to be enrolled to test if a 
modified schedule of administration of GM-CSF/TG01 can induce and maintain the 
same immune response and reduce the severity of or avoid side effects related to allergic 
reactions (Table 3). These patients will constitute the modified vaccination group. 
The efficiency of this modified vaccination group will be assessed after 6 patients have 
data for DTH assessments after 8 weeks. The cohort will continue if the tolerability is 
acceptable and there are at least 4/6 patients with a positive immune response by week 8. 
If <4/6 patients have an acceptable immune response, the next patients will revert to the 
previous induction schedule of 3 vaccinations in the first week. 
 
There will therefore be a total number of up to 32 patients for the whole study. 
 
In both parts of the study, patients who are withdrawing for reasons other than toxicity 
may be replaced if they received less than 4 weeks of vaccination and have not started 
gemcitabine treatment. 
 
Dose Limiting Toxicities will be defined as follows (based on CTCAE V4): 
• 
Injection site reaction of grade 3 
• 
ANC < 0.5 × 109/L associated with fever (temperature > 38.5oC)  
• 
ANC < 0.5 × 109/L lasting ≥ 5 days without fever 
• 
Grade 4 thrombocytopenia for ≥ 5 days 
• 
Grade 3 or 4 renal or hepatic toxicity  
• 
Grade 3 or 4 diarrhoea despite aggressive anti-diarrhoeal therapy 
• 
Other non-haematological toxicity ≥ grade 3 (excluding treatable alopecia or treatable 
nausea and vomiting)  
• 
> Grade 3 'allergic reaction/anaphylactic reaction' in spite of prophylaxis with 
antihistamine and steroids 
• 
Treatment delay > 2 weeks prior to start of next cycle of treatment due to unresolved 
toxicity 

 
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• 
In the case of grade 4 ANC or thrombocytopenia, haematology should be assessed 
daily until recovery to < grade 2 
 
GM-CSF and TG01 
The first day of GM-CSF/TG01 treatment will be considered Day 1 for the Visits.   
Phase I and phase II part - main group: the GM-CSF/TG01 will be given on days 1, 3, 5, 
8, 15 and 22 and then every 2 weeks until the end of chemotherapy treatment. If patients 
do not start chemotherapy at all, they will receive GM-CSF/TG01 on days 1, 3, 5, 8, 15, 
22, 36, 50, 64 and then every 4 weeks until week 52. In the case of early termination of 
chemotherapy treatment (prior to completion of 6 cycles) GM-CSF/TG01 will be 
continued as per the treatment schedule. 
Phase II part - concomitant group: GM-CSF/TG01 will be given on days 1, 3, 5, 8, 15 
and then every 2 weeks until the end of chemotherapy treatment. In the case of early 
termination of chemotherapy treatment (prior to completion of 6 cycles) GM-CSF/TG01 
will be continued as per the treatment schedule. 
Phase II part – modified vaccination group: GM-CSF/TG01 will be given on days 1, 8, 
15, 22 and 36 and then after the end of chemotherapy treatment. If patients start 
chemotherapy after week 10 or do no start chemotherapy at all, they will receive GM-
CSF/TG01 every 4 weeks from week 10 until chemotherapy starts or until week 52. In 
the case of early termination of chemotherapy treatment (prior to completion of 6 cycles) 
GM-CSF and TG01 will be continued as per the treatment schedule. 
 
Main group and concomitant group: Patients who are recurrence-free (with or without 
a detected immune response), will continue to receive GM-CSF/TG01 treatment every 4 
weeks until 52 weeks, then every 12 weeks until 2 years or until withdrawal of consent or 
toxicity whichever is the earliest.  Patients who recur and have an immune response 
during the treatment period should continue every 4 weeks until 52 weeks, then every 12 
weeks until 2 years or until withdrawal of consent or toxicity whichever is the earliest. 
The same applies to patients who do not start chemotherapy. 
Modified vaccination group: patients who are recurrence-free (with or without a 
detected immune response) will continue to receive 4-weekly GM-CSF/TG01 (plus one 
vaccination at week 5 post-chemotherapy) until week 52 then every 12 weeks until 
2 years or until withdrawal of consent or toxicity whichever is the earliest.  Patients who 
recur during the study and had a positive immune response during the study treatment 
period should continue to receive 4-weekly GM-CSF/TG01 (plus one vaccination at 
week 5 post-chemotherapy) until week 52 then every 12 weeks until 2 years or until 
withdrawal of consent or toxicity whichever is the earliest.  
All groups: Patients who recur and do not have an immune response during the treatment 
period will be withdrawn.  
For all patients where possible, a survival follow-up will continue to be performed every 
6 months after the initial 2 years of study period and until the last remaining patient in the 
modified cohort reaches the 2 years study period or withdraws consent or experiences 
toxicity, whichever is the earliest. Thereafter, a survival follow-up will continue to be 
performed approximately every 12 months until end of life. 
 

 
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Chemotherapy 
Phase I and phase II part - main group: Patients will receive chemotherapy starting a 
minimum 3 weeks after the start of GM-CSF/TG01 treatment and not later than 12 weeks 
from surgery.  Chemotherapy will start on a day when TG01 is administered (GM-
CSF/TG01 treatment Day 22, 36 or 50). For patients who do not receive chemotherapy, 
vaccinations will be continued according to the same schedule except that from week 10 
the vaccinations will be 4-weekly until week 52. 
Phase II part - concomitant group: Patients will receive GM-CSF/TG01 and 
chemotherapy starting between 9 and 12 weeks after the surgery and not later than 12 
weeks from surgery.  
Phase II part – modified vaccination group: Chemotherapy will preferably commence at 
least 3 weeks after start of GM-CSF/TG01 on a day when GM-CSF and TG01 is 
administered (TG01 treatment Day 22, 36 or 50). Patients can however start 
chemotherapy later or not start at all if more appropriate. Chemotherapy should however 
not be delayed if it is considered important to start within 3 weeks of the start of 
vaccinations. For patients who do not receive chemotherapy, vaccinations will be 4-
weekly from week 10 until week 52.  
 
Gemcitabine will be given as 1000 mg/m2 iv over 30 minutes on days 1, 8 and 15 of a 
four-week cycle for 6 cycles in total.  
 
However if at start of chemotherapy or prior to next gemcitabine administration, AST 
and ALT are >2.5 x UNL, patients may receive 5-FU/Leucovorin instead of gemcitabine 
and continue vaccination with TG01 as per protocol. The use of 5-FU/leucovorin under 
these circumstances is not mandatory but depending on the usual practice at the study site 
 
When applicable, chemotherapy is to be given on the same day and after TG01 injection.  
In this respect, in the main group and concomitant group, patients will receive GM-
CSF/TG01 in combination with chemotherapy for 6 cycles of 4 weeks. 

 
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Figure 1: Study Design – Immune response assessment 
 
 
 
 
 
 
 
 
 
Phase I Part (if DLT criteria satisfied) 
6 Patients 
GM-CSF+TG01 
DTH and or T cell 
response? 
≥ 4/6 
Proceed to Phase II part 
(if DLT criteria satisfied) 
Terminate Study  
+ 6 Patients 
GM-CSF + TG01 
1-3/6 
DTH and or T cell 
response? 
≥ 4/12 
< 4/12 
0/6 

 
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Figure 2: Study Design – Dose Limiting Toxicity Assessment 
 
 
 
 
6 Patients 
GM-CSF+TG01 
DLT Assessment 
< 2/6 
Proceed to Phase II Part 
(if immune response  criteria satisfied) 
Terminate Study  
+ 6 Patients 
GM-CSF + TG01 
3/6 
DLT Assessment 
≤ 4/12 
> 4/12 
> 3/6 
Phase I Part (if immune response criteria satisfied) 

 
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Figure 3: Treatment schedule for patients starting vaccination and receiving chemotherapy later – Main group 
 
 
 
 
 
 
 
 
TG01 + GM-CSF 
Start as soon as 
possible after 
surgery  
Start of Gemcitabine 
treatment 
or 
or 
Gemcitabine 
Cont. up to 
total 6 cycles 
d8 
w2 
d15 
w3 
 
w11 
d71 
w7 
d43 
w5 
d29 
d22 
w4 
d36 
w6 
w10 
d64 
w8 
d50 
w9 
d57 
Injections  
every 4 
weeks 
w52 
Immune response 
analysis 
w104  
(2 years) or  
4 weeks after 
last treatment 
Survival FU 
Injections  
every 12 
weeks 
Injections  
every 2 weeks 
during 
Gemcitabine 
cycles 
Gemcitabine 
d22  
d36  
d50  
Initial treatment period 
Post-
Gemcitabine 
w1 
d1,3,5 
End of 
study 
visit 

 
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Figure 4: Treatment schedule for patients starting vaccination and chemotherapy at the same time – concomitant group 
 
 
End of 
study 
visit 
TG01 + GM-CSF  
Gemcitabine 
Cont. up to 
total 6 cycles 
d8 
w2 
d15 
w3 
w11 
d71 
w5 
d29 
d22 
w4 
d36 
w6 
w10 
d64 
w8 
d50 
w9 
d57 
Injections  
every 4 
weeks 
w52 
Immune response 
analysis 
w104  
(2 years) or  
4 weeks after 
last treatment 
Injections  
every 12 
weeks 
Injections  
every 2 weeks 
during 
Gemcitabine 
cycles 
Gemcitabine 
Initial treatment period 
Post-
Gemcitabine 
d43 
w7 
w1 
d1,3,5 
Survival FU 

 
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Figure 5: Treatment schedule for patients starting vaccination and receiving chemotherapy later – Modified vaccination group 
 
 
GM-CSF + TG01 
Start as soon as 
possible after 
surgery  
Start of Gemcitabine 
treatment 
or 
or 
Gemcitabine 
Cont. up to 
total 6 cycles 
d8 
w2 
d15 
w3 
 
w11 
d71 
w7 
d43 
w5 
d29 
d22 
w4 
d36 
w6 
w10 
d64 
w8 
d50 
w9 
d57 
At w4 & w5 
post-chemo  
& every 4 
weeks from 
w8 post-
chemo  
w52 
w104  
(2 years) or  
4 weeks after 
last treatment 
End of 
study 
visit 
Injections  
every 12 
weeks 
Gemcitabine 
d22  
d36  
d50  
Initial treatment period 
Post-Gemcitabine 
w1 
d1 
* 
*: vaccination to be continued every 4 weeks until chemotherapy starts or until week 52 (if chemotherapy never starts) 
Immune response 
analysis 
Survival FU 

 
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Table 1: Schedule of visits  
 
Page in 
protocol 
Screening 
Initial Treatment Period* 
Repeat Cycles with 
chemotherapy* 
After 
chemo 
to W52  
*** 
W52-
104 
 
Patient 
end of 
Study 
visit** 
Survival FU 
Study Week (W) 
 
 
 
1 
 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 j 
1 
5 
9 
13 
17 
21 
2 
6 
10 
14 
18 
22 
3 
7 
11 
15 
19 
23 
4 
8 
12 
16 
20 
24 
Every 4 
weeks** 
Every 
12 
weeks 
** 
W104 or  
4 weeks 
after last 
TG01 / 
GM-CSFk 
Every 6 
months and at 
study end** 
Thereafter 
~every 12 
months 
Study Day 
 
 
-56  to -7 
-7 
1 
 
3 
5 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71j 
Cycle 
D1 
Cycle 
D8 
Cycle 
D15 
Cycle 
D22 
 
 
 
 
TG01 /  GM-CSFa 
51 to 59 
 
 
x 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
xn 
xn 
 
 
DTH injectionb 
51 to 59 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
 
 
 
xi 
xe 
 
 
Gemcitabinec 
51 to 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
 
 
5-FU and Leucovoring 
51 to 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
Informed Consent 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eligibility 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical 
history 
60 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resect pancreas 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour sample 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
61, 68 
 
x 
 <----------------------------------------------------------------------------- As clinically indicated ------------------------------------------------------------------------------------- 
 
Physical Exam/ PS 
61, 68 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
xm 
xe 
x 
 
Vital Signs 
61 
 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
xf 
x 
x 
 
Haematology / Chemistryd 
61, 68 
 
x 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
xf 
x 
x 
 
Pregnancy test 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DTH assessmentb 
55, 66 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
 
 
 
xi 
xe 
 
 
Immunology sampled 
65, 66 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
xe 
x 
 
CA19.9 / other biomarkersd 
67 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
xl 
xe 
x 
 
Urinalysis 
61, 68 
 
x 
<------------------------------------------------------------------------------- As clinically indicated ----------------------------------------------------------------- 
 
CT/MRI / assess diseaseh 
61, 66 
 
x 
<------------------------------------------------------------------------------------------------ Every 6 months -------------------------------------------------------- 
x 
 
Adverse events 
67, 71 
 
 
<---------------------------------------------------------------------------------------------- As clinically indicated -------------------------------------------------------------------- 
 
Concomitant medications 
60, 61 
 
x 
<----------------------------------------------------------------------------------------- As clinically indicated -------------------------------------------------------------------------- 
 
Survival follow-up 
 
 
 
 
X 

 
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a:  Start as soon as possible after surgery. GM-CSF given 10-15 min before TG01.  
 
During chemotherapy treatment: every 2 weeks 
 
After end of chemotherapy treatment may be given for up to 2 years or until withdrawal of consent, toxicity or the need for additional treatment for pancreatic cancer whichever 
is the earliest 
 
Patients should be observed for at least 30 minutes after all vaccinations 
b: DTH injection should be performed 30 minutes before  the GM-CSF/TG01 injection. Assessment of DTH injection site to be done 48 hours (+/- 4 hours) after each GM-
CSF/TG01 injections.  
c: Start at Study Day 22, 36 or 50 (once patients are able to receive chemotherapy see repeated cycles)  
d:  Blood samples to be taken prior to all treatments.  
e: At 52 weeks 
f: Every 12 weeks 
g:  Given on Day 1 and 2 every 2 weeks. 5-FU/Leucovorin should be used as an alternative if required due to raised ALT. 
h: CT-scan to be done at baseline (if possible), then every 6 months from the start of vaccination (+/- 4 weeks’ time window) and at end of the study visit. 
i:  Only for patients who received chemotherapy. To be done at 2nd GM-CSF/TG01 injection after end of chemotherapy (8 weeks after last chemotherapy injection).  
j: can be done at day 78 if more appropriate   
k: For patients who discontinue before the 2 years, a survival follow-up will be performed where possible at week 104. 
l: Only for patients not starting chemotherapy at all and to be done prior each vaccination (every 4 weeks) 
m: for patients not starting chemo; to be done every 12 weeks 
n:  For all GM-CSF/TG01 administrations  after chemotherapy the patients should be give prophylactic treatment (30 minutes before treatment)  to prevent possible occurrence of 
allergic reactions.  At visits where the patients will receive a DTH injection(TG01) before the GM-CSF/TG01 administration then the prophylactic treatment should be given 30 
minutes prior the DTH injection. 
 
 
*: +/- 1 day window for visits in the initial treatment period and for other weekly visits (Initial treatment period or chemotherapy treatment period) 
**: window of +/- 1 week for 4 weekly injections and 12 weekly injections 
***: Applies also to patients not starting chemotherapy at all and the period will be from week 10 to week 52 

 
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Table 2: 
Schedule of visits – Concomitant group 
 
Page in 
protocol 
Screening 
Initial Treatment Period (1st 3 Cycles of chemotherapy)* 
Repeat Cycles with 
chemotherapy* 
After 
chemo  
to W52 
W52-104 
 
Patient 
end of 
Study 
visit** 
Survival  FU 
Study Week 
 
 
 
1 
 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
13 
17 
21 
14 
18 
22 
15 
19 
23 
16 
20 
24 
Every 4 
weeks** 
Every 12 
weeks 
** 
W104 or  
4 weeks 
after last 
TG01 / GM-
CSFk 
Every 6 
months and 
at study 
end** 
Thereafter 
~every 12 
months 
Study Day 
 
 
-84  to -7 
-7 
1 
 
3 
5 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
Cycle 
D1 
Cycle 
D8 
Cycle 
D15 
Cycle 
D22 
 
 
 
 
TG01 /  GM-CSFa 
51 to 59 
 
 
x 
 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
xl 
xl 
 
 
DTH injectionb 
51 to 59 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
xi 
xe 
 
 
Gemcitabinec 
51 to 59 
 
 
x 
 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
5-FU and Leucovoring 
51 to 59 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
 
 
 
 
Informed Consent 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eligibility 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography / Medical 
History 
60 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resect pancreas 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour sample 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
61, 68 
 
x 
 <--------------------------------------------------------------------------------- As clinically indicated --------------------------------------------------------------------------------------- 
 
Physical Exam/ PS 
61, 68 
 
x 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
xe 
x 
 
Vital Signs 
61 
 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
xf 
x 
x 
 
Haematology / Chemistryd 
61, 68 
 
x 
x 
 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
xf 
x 
x 
 
Pregnancy test 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DTH assessmentb 
55, 66 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
xi 
xe 
 
 
Immunology sampled 
65, 66 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
xj 
 
 
 
 
xe 
x 
 
CA19.9 / other biomarkersd 
67 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
xe 
x 
 
Urinalysis 
61, 68 
 
x 
<-------------------------------------------------------------------------------------------- As clinically indicated --------------------------------------------------------------------------- 
 
CT/MRI / assess diseaseh 
61, 66 
 
x 
<------------------------------------------------------------------------------------------------- Every 6 months --------------------------------------------------------------- 
x 
 
Adverse events 
67, 71 
 
 
<------------------------------------------------------------------------------------------------- As clinically indicated ----------------------------------------------------------------------- 
 
Concomitant medications 
60, 61 
 
x 
<------------------------------------------------------------------------------------------------- As clinically indicated ------------------------------------------------------------------------ 
 
Survival follow-up 
 
 
 
 
X 

 
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a:  GM-CSF given 10-15 min before TG01 
 
After end of chemotherapy treatment may be given for up to 2 years or until withdrawal of consent, toxicity or the need for additional treatment for pancreatic cancer whichever 
is the earliest 
 
Patients should be observed for at least 30 minutes after all vaccinations.   
b: DTH injection should be performed 30 minutes before  the GM-CSF/TG01 injection Assessment of DTH injection site to be done 48 hours (+/- 4 hours) after each GM-
CSF/TG01 injections.  
c: To start within 12 weeks from surgery  
d:  Blood samples to be taken prior to all treatments.  
e: At 52 weeks 
f: Every 12 weeks 
g:  Given on Day 1 and 2 every 2 weeks. 5-FU/Leucovorin should be used as an alternative if required due to raised ALT. 
h: CT-scan to be done at baseline (if possible), then every 6 months from the start of vaccination (+/- 4 weeks’ time window) and at end of the study visit. 
i: at 2nd GM-CSF/TG01 injection after end of chemotherapy (8 weeks after last chemotherapy injection)  
j: at week 13 only (day 1 of cycle 4) prior study treatment administration 
k: For patients who discontinue before the 2 years, a survival follow-up will be performed where possible at week 104. 
l:  For all GM-CSF/TG01 administrations  after chemotherapy the patients should be give prophylactic treatment (30 minutes before treatment)  to prevent possible occurrence of 
allergic reactions.  At visits where the patients will receive a DTH injections (TG01) before the GM-CSF/TG01 administration then the prophylactic treatment should be given 30 
minutes prior the DTH injection. 
 
 
*: +/- 1 day window for visits in the initial treatment period and for other weekly visits (Initial treatment period or chemotherapy treatment period) 
**: window of +/- 1 week for 4 weekly injections and 12 weekly injections 
 
 
 

 
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Table 3: 
Schedule of visits – Modified vaccination group 
 
Page in 
protocol 
Screening 
Initial Treatment Period* 
Repeat Cycles with 
chemotherapy* 
After 
chemo 
to W52 
*** 
 
W52-
104  
Patient end 
of study 
visit** 
Survival FU 
Study Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1 
5 
9 
13 
17 
21 
2 
6 
10 
14 
18 
22 
3 
7 
11 
15 
19 
23 
4 
8 
12 
16 
20 
24 
Every 4 
weeks 
** 
Every 12 
weeks 
** 
W104 or  
4 weeks after 
last 
GMCSF/TG01 
Every 6 
months and at 
study end** 
Thereafter 
~every 12 
months 
Study Day 
 
 
-56  to -7 
-7 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
Cycle 
D1 
Cycle 
D8 
Cycle 
D15 
Cycle 
D22 
 
 
 
 
GM-CSF /TG01 a 
51 to 59 
 
 
x 
x 
x 
x 
 
x 
 
 
 
xb 
 
 
 
 
xc 
x 
 
 
DTH injectiond 
51 to 59 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
xe 
 
 
 
Gemcitabinef 
51 to 59 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
 
 
5-FU and Leucovoring 
51 to 59 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
Informed Consent 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eligibility 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical 
history 
60 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resect pancreas 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour sample 
60 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
61, 68 
 
x 
 <--------------------------------------------------------------------------- As clinically indicated ----------------------------------------------------------------- 
 
Physical Exam/ PS 
61, 68 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
xh 
Xn 
x 
 
Vital Signs 
61 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
xl 
x 
x 
x 
 
xh 
x 
x 
 
Haematology/Chemistryi 
61, 68 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
xl 
x 
x 
x 
 
xh 
x 
x 
 
Pregnancy test 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent illness 
61 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DTH assessmentd 
55, 66 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
xe 
 
 
 
Immunology samplei 
65, 66 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 xi,j 
Xn 
x 
 
CA19.9 / other biomarkersi 
67 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
xm 
Xn 
x 
 
Urinalysis 
61, 68 
 
x 
<----------------------------------------------------------------------- As clinically indicated ----------------------------------------------------------------- 
 
CT/MRI / assess diseasek 
61, 66 
 
x 
<----------------------------------------------------------------------------- Every 6 months --------------------------------------------------- 
x 
 
Adverse events 
67, 71 
 
 
<----------------------------------------------------------------------------- As clinically indicated ---------------------------------------------------------------- 
 
Concomitant medications 
60, 61 
 
x 
<----------------------------------------------------------------------------- As clinically indicated ---------------------------------------------------------------- 
 
Survival follow-up 
51 to 59 
 
 
 
 
x 
 

 
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a:   Start as soon as possible after surgery. GM-CSF given 15-20 min before TG01. Patients should be observed for at least 30 minutes after each vaccinations 
b:   Patients that have not started chemotherapy by week 10 will receive GM-CSF/TG01 4-weekly, starting at week 10 and until start of chemotherapy or week 52 or withdrawal of 
consent, toxicity or the need for additional treatment for pancreatic cancer whatever comes first. 
c:   After end of chemotherapy, GM-CSF/TG01 treatment will be given 4 and 5 weeks after last chemotherapy injection and thereafter every 4 weeks from 8 weeks post-
chemotherapy up to 1 year (week 52) or until withdrawal of  consent, toxicity or the need for additional treatment for pancreatic cancer whichever is the earliest.  
d:   DTH injection should be performed 30 minutes before the GM-CSF injection. Assessment of DTH injection site to be done 48 hours (+/- 4 hours) after the TG01 and GM-CSF    
injections.  
e:   After end of chemotherapy, a DTH injection and DTH assessment will be done at 3rd vaccination post-chemotherapy (8 weeks post chemotherapy). For patients not starting 
chemotherapy at all, the DTH test and assessment are to be done at week 52  
f:   Start preferably  3 weeks after start of vaccination and preferably at Study Day 22, 36 or 50 (once patients are able to receive chemotherapy see repeated cycles) although can start 
later 
g:  Given on Day 1 and 2 every 2 weeks. 5-FU/Leucovorin should be used as an alternative if required due to raised ALT.  
h: Every 12 weeks 
i:   When blood samples are to be taken these should be done prior to all treatments. 
J:  only 4 weeks after last chemotherapy injection (at 1st post-chemotherapy vaccination) 
k:  CT-scan to be done at baseline, then every 6 months from the start of vaccination (+/- 4 weeks’ time window) and at end of the study visit. CT scans may be done at other times if 
clinically indicated  
l:   If patient hasn’t started chemotherapy 
m: Only for patients not starting chemotherapy at all and to be done prior each vaccination (every 4 weeks)  
n:  at week 52 only 
 
*: +/- 1 day window for visits in the initial treatment period and for other weekly visits (Initial treatment period or chemotherapy treatment period) 
**: window of +/- 1 week for 4 weekly injections and 12 weekly injections 
***: Applies also to patients not starting chemotherapy at all and the period will be from week 10 to week 52 

 
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3.2 
Rationale for trial design, doses and stop decisions 
3.2.1 
Trial design 
Whilst not registered, gemcitabine is the main chemotherapy used as adjuvant treatment 
following resection of pancreatic adenocarcinoma.  It is rational therefore, to see whether 
the use of immunotherapy added to this regimen can improve on the disease-free survival 
and potential overall survival of this condition.  However, before this, it is important to 
assess whether there is any interference with the immune response when TG01 is used 
concomitantly with gemcitabine. 
3.2.2 
Rationale for dose  
The traditional approach to dose selection for cytotoxic anticancer agents is to escalate 
the dose until dose 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.  TG01 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. 
 
In a clinical study (CTN RAS 98010) a total of 38 pancreatic cancer patients, 13 after 
tumour resection and 25 with advanced disease, have been treated with TG01 with 
minimal toxicity and with good immunological outcome.  In the resected group, 11 of 11 
(100%) evaluable patients demonstrated an immune response (DTH response), and in the 
advanced disease group 14 of 25 (56%) patients demonstrated a positive DTH response. 
In this study the immunotherapy dose was 0.7 mg (0.1 mg of each peptide) and 30 µg 
GM-CSF was used an immunomodulator (Weden et al., 2011). 
 
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. 
 
Given the acceptable safety profile and levels of T cell responses observed to date with 
the current dose, the clinical development will continue using a total TG01 dose of 
0.7 mg (0.1mg each peptide) together with GM-CSF as immunomodulator. 

 
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3.2.3 
Rationale for GM-CSF (Molgramostim) adjuvant  
Peptides are poorly immunogenic by themselves.  To induce measurable levels of 
T-helper type 1 (Th1) or type 2 (Th2) immune responses against peptides, adjuvants are 
often required (Gupta et al., 1996).  Several adjuvants have been evaluated in humans for 
adjuvant activity when combined with carbohydrate and protein/peptide-based 
immunotherapy (Gupta et al., 1995; Singh & O'Hagan 1999).  However, the only 
adjuvant licensed for use in human vaccines, aluminium hydroxide (Gupta et al., 1995) is 
a poor enhancer of the type of immune responses (Th1) that may be required for the 
efficacy of peptide-based ASCI, and, therefore, could not be selected for TG01 
development.  Studies in rats show that GM-CSF administered intradermally as a single 
dose with antigens, compared favourably with complete Freund’s adjuvant and 
aluminium hydroxide in eliciting cellular immunity (Disis et al., 1996). 
 
GM-CSF has a number of biological properties making it a strong candidate to function 
as an immunomodulator for ASCI.  It has been shown that GM-CSF can drive both 
humoral and cellular immune responses (Disis et al., 1996).  Moreover, GM-CSF has 
been shown to induce anti-tumour immunity that has been associated with the induction 
of a broader T cell cytokine response (both Th1 and Th2), which has been implicated as 
important in mediating tumour rejection (Hung et al., 1998; Mach et al., 2000; Soiffer et 
al., 1998). 
 
GM-CSF was selected as the immunomodulator for the development of TG01 based on 
its reported potent adjuvant activity when given in combination with protein/peptide 
antigens (Dranoff et al., 1993; Gjertsen et al., 1995; Hunger et al., 2001).  Studies in mice 
(Dranoff et al., 1993) have shown that T-cell responses could be generated in mice 
bearing human pancreatic tumour xenografts.  Potent anti-tumour activity was shown in 
patients with metastatic melanoma following injection of autologous melanoma 
immunotherapy combined with GM-CSF (Leong et al., 1999). 
 
GM-CSF has during recent years been used extensively as an immunomodulator for 
ASCI in clinical trials. GM-CSF has either been used alone (Gjertsen et al., 2001; 
Bernhardt et al., 2006, Dutoit et al., 2002; Lomas et al., 2004; Schaed et al., 2002; Disis 
et al., 1999; Hunger et al., 2001; Brunsvig et al., 2006) or in combination with other 
adjuvants (Chianese-Bullock et al., 2005), normally in the range of 30-250 µg/injection.  
The dose to be used in this study is 30 µg which is consistent with a stimulatory effect of 
low doses of GM-CSF (Parmiani G et al., 2007). 
3.2.4 
Rationale for dose regimen 
ASCI requires a more aggressive and continued treatment than traditional vaccination 
(prophylaxis) against infectious diseases.  In vaccination the antigens used are foreign to 
the human immune system, the vaccinated subjects are healthy with normal immune 
functions and the induced immune response is allowed to down-regulate to a memory 
response ready to be reactivated upon a challenge.  In contrast to this, in ASCI the 
tumour associated antigens (TAA) that are used are “self”, or in the case of RAS 
peptides, slightly altered “self” protein/peptides to the treated subject and consequently 
immunological tolerance is much more difficult to break in this setting.  The treated 
subjects are cancer patients that normally develop immune suppression and often have a 
rapid deteriorating immune system and, finally, a prevailing active anticancer immune 

 
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response is necessary in order to kill the cancer cells which on their side are continuously 
counteracting the anti-cancer immune response by inducing immune suppression. 
 
The scenario described above is highly relevant for patients with pancreatic cancer who 
have a short life expectancy and a rapidly deteriorating immune system.  In order to meet 
the challenges of inducing immune response in a limited time window available, the 
rapid disease progression and deterioration of the immune system, it is important to use 
an aggressive treatment regimen in order to induce efficient immune response as fast as 
possible and to keep the induced anti-cancer immune response in an active state.  Whilst, 
complete resection and cure is the aim of pancreatic surgery, in reality this is rarely the 
case and the need for a rapid immune response to “mop” up any residual cancer cells add 
an urgency even in this setting. 
 
In vaccination either subcutaneous or intramuscular administration are normally used, 
and the vaccine is usually formulated with an adjuvant that provides a depot of antigens 
as well causing irritation and inflammatory reactions at the site of injection.  In order to 
obtain optimal immunisation with TG01 the intradermal administration route is used.  
The resident Langerhans cells in the dermis are highly potent antigen presenting cells 
with strong capacity to endocytose antigens and to elicit subsequent T cell responses. 
 
Intradermal injection is accordingly the preferred route of administration ASCI intended 
to result in protective T-cell immunity.  Due to the architecture (thickness) of the skin 
only small volumes may be injected at a single site and irritants causing ulceration must 
be avoided.  TG01 is reconstituted in water for injection and administered without any 
substances that provide a depot effect.  The only “pharmacologically active” dose of 
peptides to reach the lymph nodes is the amount of peptides taken up by Langerhans cells 
locally before the injected peptides are degraded by tissue proteases.  After migrating to 
the draining lymph nodes the activated Langerhans cells have a very limited life span.  
Thus each administration is followed by only a short period of expansion of specific 
T-cells before the stimulus is lost.  In the absence of a depot effect and thus a continued 
release of antigen and stimulation of T-cells, repeated immunizations over an extended 
time period is required to generate a robust immune response.  This will ensure a 
continued activation and expansion of antigen specific T cells to kill resident tumour 
cells and to replace T-cells that are tolerised/anergised by the tumour. 
 
The dosing regimen was developed using ASCI as standalone treatment but the rationale 
behind also applies when combined with chemotherapy.  However, it is known that many 
anti-cancer chemotherapies also act via immunological pathways and, therefore, there is 
a potential synergy between chemotherapy and active immunotherapy for cancer 
(Lesterhuis et al., 2011).  For adjuvant treatment of pancreatic cancer TG01 will be used 
in combination with gemcitabine.  It has been shown in mice that gemcitabine can 
modulate antigen-specific anti-tumour immune responses by enhancing cross 
presentation of tumour antigens to MHC class I and class II-restricted T-cells (Nowak et 
al., 2002).  In other animal studies gemcitabine could counteract immune suppression by 
depressing myeloid suppressor cells (Suzuki et al., 2005.) and successfully be combined 
with immunotherapy to yield synergistic anti-tumour effects (Nowak et al., 2003; 
Broomfield et al., 2005).  When combined with gemcitabine, the TG01 treatment 
regimen is adapted in order to optimize the potential synergistic effects of the two 
treatments. 

 
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Adjuvant gemcitabine treatment of pancreatic cancer is given in cycles of three weeks 
treatment and one week rest for up to six cycles (ESPAC3), starting within 8 weeks after 
the resection has been done (Van Laethem et al., 2010; Neoptolemos et al., 2010; Oettle 
et al., 2007).  It is considered to be beneficial for the patients to obtain an anti-cancer 
immune response as soon as possible after surgery and TG01 treatment will therefore be 
started as soon as possible but certainly between 1 to 8 weeks after the tumour has been 
removed.  Gemcitabine treatment will be started together with TG01 treatment preferably 
at least 3 weeks after initiation of TG01 immunotherapy.  From when gemcitabine 
treatment is initiated TG01 will either be administered as booster injections every 2 
weeks or will be put on hold until end of chemotherapy.  In patients who have not shown 
recurrence or who had a positive immune response during the study treatment period, 
further booster injections will be given after gemcitabine has been completed. 
 
The current study started 2 years ago and patients in the main group participating for the 
whole length of the study (up to 2 years), could receive 26-28 vaccinations with GM-
CSF/TG01 as a maximum and an additional 9 injections of TG01 (see tables 1 and 2) for 
the purpose of detecting an immune response (which is the goal of the TG01 treatment). 
Vaccination started either before or at the same time as chemotherapy treatment and 
continued during chemotherapy and post-chemotherapy where possible. In total 19 
patients were recruited under this treatment regimen and so far all except one patient 
have shown a positive immune response during the course of the study. It was also 
observed that 4 patients receiving this treatment regimen experienced allergic reactions 
related to TG01 or GM-CSF/TG01 after they received several injections. This type of 
allergic reactions are not uncommon when using these types of medications and, when 
they occur, can be usually prevented by using pre-medication with an antihistamine. It is 
believed that the number of vaccinations could be, in part, responsible for these events 
and as positive immune responses were clearly seen with the previous vaccination 
schedule, Targovax believe that the same immune response can be obtained with a 
reduced number of vaccinations, which will be tested in the proposed modified 
vaccination group. In addition, vaccinations during chemotherapy with gemcitabine will 
be reduced.  Once an immune responses has been obtained by vaccinating up to 6 weeks 
and gemcitabine has been started, vaccination will be put on hold until chemotherapy 
completion. Vaccination will be restarted after chemotherapy has been completed. 
3.2.5 
Use of Gemcitabine as adjuvant chemotherapy 
Gemcitabine has been shown to provide significantly better Disease Free Survival (DFS) 
versus observation alone with a mean DFS of 13.4 months compared with 6.9 months 
although there was no difference for overall survival (median OS 22.1 months (Oettle et 
al., 2007). 
 
The use of 5-FU and folinic acid or gemcitabine–based chemoradiation has also been 
tested as adjuvant therapy but show no advantages over gemcitabine alone for either DFS 
or OS.  The DFS for gemcitabine alone ranged from 10.9 months to 14.3 months and 
median OS from 23 to 24.4 months.  The length of treatment ranged from 4-6 cycles (i.e. 
up to 25 weeks) at a dose of 1000 mg/m2 (Neoptolemos et al., 2010; Van Laethem et al., 
2010).  The start of the gemcitabine adjuvant treatment was up to 8 weeks following 
surgery. 
 

 
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Therefore, it seems appropriate to use gemcitabine as the primary chemotherapy for 
adjuvant treatment and provides a reasonable basis on which to compare disease-free and 
overall survival. However, considering that gemcitabine treatment may result in 
increased ALT/AST, patients may, in these instances, stop gemcitabine and take 5-
FU/Leucovorin and continue GM-CSF/TG01 as planned per protocol or start with 5-
FU/Leucovorin if the enzymes are high at the outset.    
3.3 
Selection of trial population 
6-32 patients with histologically or cytologically confirmed diagnosis of resected 
adenocarcinoma of the pancreas will be enrolled and treated with GM-CSF/TG01 with 
the intention of combining with gemcitabine as adjuvant chemotherapy. 
3.3.1 
Inclusion criteria 
For inclusion in the trial, patients must fulfil the following protocol entry criteria: 
1. Histologically or cytologically confirmed diagnosis of adenocarcinoma of the 
pancreas 
2. Stage I or II disease (clinical stage T1-3, N0-1, M0 by AJCC staging criteria). 
3. Successful surgical resection 
• Complete resection (R0) or with microscopic residual disease (R1) 
• Expected to receive gemcitabine monotherapy as adjuvant chemotherapy 
4. Laboratory Values: 
• Absolute neutrophil count > 1.5 x 109/l 
• Platelets > 100 x 109/l 
• Haemoglobin > 9 g/dl 
• Total bilirubin < 1.5 x UNL 
• Serum creatinine < 1.5 x UNL 
• Albumin > 2.5 g/dl 
• AST or ALT < 5 x UNL 
5. 18 years of age or older. 
6. ECOG performance status (PS) of 0-1. 
7. Life expectancy of at least 6 months 
8. Men and women of childbearing potential must be willing to use effective 
methods of contraception to prevent pregnancy 
9. Provide written (signed) informed consent to participate in the trial prior to any 
trial specific screening procedures 
3.3.2 
Exclusion criteria 
Patients are not eligible for inclusion in this trial if they meet one or more of the 
following criteria: 
1. Has received an investigational drug within 4 weeks prior to Trial drug 
administration 
2. Has received previous therapy for pancreatic cancer including radiation or 
chemotherapy (except for the primary resection or primary neoadjuvant 
chemotherapy). 
3. 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). 
4. Has any other serious illnesses or medical conditions such as, but not limited to: 

 
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• Any uncontrolled infection  
• Uncontrolled cardiac failure classification III or IV (NY Heart Association) 
• Uncontrolled systemic and gastro-intestinal inflammatory conditions 
• Bone marrow dysplasia 
• History of auto-immune disease 
• History of adverse reactions to vaccines 
5. Known history of positive tests for HIV/AIDS, hepatitis B or C 
6. Pregnant or lactating females or have no pregnancy test at baseline 
(postmenopausal women must have been amenorrhoeic for at least 12 months to 
be considered of non-childbearing potential). 
7. Contraindication to gemcitabine treatment 
8. Have had any other malignancies within last 3 years (except for adequately treated 
carcinoma of the cervix or basal or squamous cell skin cancer) 
9. Known malignant brain lesion(s) 
10. Are unlikely to start chemotherapy within 12 weeks of surgery (e.g. delayed wound 
healing, or infection, etc.) 
11. Are not expected to complete 6 cycles of chemotherapy 
12. Are planned to receive yellow fever or other live (attenuated) vaccines during the course 
of study (see concomitant medication section) 
3.3.3 
Removal of patients from the trial, therapy or assessment 
If a patient has to be withdrawn from the trial, the principal investigator (PI) should be 
informed immediately.  If there is a medical reason for the withdrawal, the patient should 
be followed until the condition has either resolved itself or is stable and the individual 
concerned is able to resume care by his/her physician.  Details of the reason for 
withdrawal should be recorded in the patient’s Case Report Form. 
All patients should continue to be included in the assessments of their safety and 
efficacy.  Patients who withdraw should, if possible, have a follow-up examination 
(withdrawal visit), including a physical examination, the appropriate investigations, vital 
signs, and clinical laboratory tests.  All details of this follow-up examination should be 
recorded in the patient’s medical source documents. Then unless patients withdrew their 
consent, a survival follow-up visit should be done every 6 months after the initial 2 years 
of study period and until the last remaining patient in the modified cohort reaches the 2 
years study period or withdraws consent or experiences toxicity, whichever is the 
earliest. Thereafter, a survival follow-up will continue to be performed approximately 
every 12 months until end of life. 
3.3.3.1 
Patient withdrawal 
Participation in the trial is strictly voluntary.  Patients are free to discontinue the trial at 
any time without giving their reason(s).  If a patient withdraws from the trial, the 
Investigators are to be informed immediately. 
A patient must be withdrawn from the trial treatment in the event of any of the following: 
• withdrawal of the patient’s consent 
• 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 
• recurrence of pancreatic cancer with no immune response 

 
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• occurrence of AEs, if discontinuation of trial medication is desired or considered 
necessary by the Investigator and/or patient (if applicable) 
• occurrence of pregnancy 
• intake of non-permitted concomitant medication as defined in Section 4.6 where 
the predefined consequence is withdrawal from the trial 
• lack of patient compliance 
• protocol violation 
If a patient fails to attend scheduled assessments during the course of the trial, the 
Investigators must determine the reasons and the circumstances as completely and 
accurately as possible and document this in the patient’s medical source documents. 
All patients who withdraw from the trial for any reason and at any time should have an 
end of study examination (withdrawal visit).  Patients will be examined for any status 
changes that require further follow-up.  Any new medical condition or event occurring 
during the trial will be followed until the patient is stable and able to resume care by 
his/her physician. 
3.3.3.2 
Trial discontinuation 
The whole trial may be discontinued at the discretion of the PI or the sponsor in the event 
of any of the following: 
• occurrence of AEs unknown to date in respect of their nature, severity and 
duration, or the unexpected incidence of known AEs 
• medical or ethical reasons affecting the continued performance of the trial 
• difficulties in the recruitment of patients 
• cancellation of drug development. 
3.3.3.3 
Procedures for discontinuation 
Subjects who discontinue should always be asked about the reason(s) for their 
discontinuation and the presence of any adverse events.  If possible, they should be seen 
and assessed by an investigator(s).  Adverse events should be followed up. 
 
All patients who have new or worsening Common Toxicity Criteria (CTC version 4) 
grade 3 or 4 laboratory values at the time of discontinuation must have further laboratory 
tests performed and the results recorded on the appropriate CRF until the laboratory 
values have returned to 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 patient’s medical records. 
Laboratory abnormalities should not be reported as adverse events unless any criterion 
for an AE is fulfilled i.e. that it is clinically significant and because it is detrimental to the 
patient, the laboratory abnormality causes study drug dose adjustment, leads to patient’s 
discontinuation from the study, or the investigator insists the abnormality should be 
reported as an AE. Laboratory abnormalities should not be reported as separate adverse 
events if they are part of an overall diagnosis (e.g. fever and leucocytosis for pneumonia). 
 
At discontinuation all on-going study-related toxicities and SAEs must be followed until 
resolution, unless in the investigator’s opinion, the condition is unlikely to resolve due to 
the patient’s underlying disease. 

 
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After discontinuation from treatment, patients must be followed up for all existing and 
new AEs for 28 calendar days after the last dose of study drug.  All new AEs occurring 
during that period must be recorded (if SAEs they must be reported to ICON Safety 
group within 24 hours (Fax Number: +44 870 710 7157) and followed up for resolution 
as above. Life-threatening or fatal events occurring prior to document recurrence should 
be reported to the Medical Monitor by calling +44 203 291 3032 within 2 hours of 
knowledge of the event. 
 
Should protocolled dosing be stopped during the study, the principal investigator/sub-
investigator will perform the best possible observation(s), test(s) and evaluation(s) as 
well as give appropriate medication and all possible measures for the safety of the 
patient.  In addition, they will record on the CRF the date of discontinuation, the reasons, 
manifestation and treatment at the time of discontinuation and also course, treatment and 
outcome after discontinuation.  They will also immediately inform the CRA of the 
discontinuation.  Any SAE should be communicated to ICON Safety group according to 
the procedures defined in Section 7.3. 
3.4 
Time schedule 
Screening must be completed within the 56 days prior to the start of treatment for the 
main group and the modified vaccination group and within 84 days for the concomitant 
group.  Patients will be required to attend the clinic for the administration and evaluation 
of their therapy (See Section 3.1).  For each administration of study drug, patients will be 
observed for at least 30 minutes after each injection of TG01.  Hospitalisation for 
administrative reasons will be at the investigator’s discretion, in accordance with hospital 
standard procedures and will not be considered as a serious adverse event. 
Safety will be monitored for each patient throughout the trial until their end of study visit 
which will be 28 days after their last GM-CSF/TG01 or chemotherapy dose, whichever is 
appropriate.  
For all patients, where possible, a survival follow-up will be performed every 6 months 
after the initial 2 years of study period and until the last remaining patient in the modified 
cohort reaches the 2 years study period or withdraws consent or experiences toxicity, 
whichever is the earliest. Thereafter, a survival follow-up will continue to be performed 
approximately every 12 months until end of life. 
4. TRIAL TREATMENT 
4.1 
Identity of the investigational product 
TG01 is a sterile lyophilisate consisting of a mixture of seven peptides.  The finished 
product is a white powder for injection, consisting only of the active substances 
containing 2.1 mg of peptides (individual peptides comprising 0.3 mg each).  The 
lyophilisate is to be reconstituted with sterile water for injection before use. 
GM-CSF is provided as a lyophilised powder containing 0.1 mg of active substance for 
reconstitution in sterile water for injection to be given via intradermal injection. 
 
Gemcitabine is provided as a lyophilised powder (vials of 200 mg and 1 g) for 
reconstitution in saline to be given via intravenous injection.  To be reconstituted 
according to Prescribing Information for gemcitabine. 

 
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5-FU is provided as a solution for intravenous injection (vials of 500mg in 10 mL). To be 
administered according to the Prescribing Information for 5-FU. 
Leucovorin is provided as a solution for intravenous injection (10mg/ml). To be 
administered according to Prescribing Information for Leucovorin. 
 
All handling of the Investigational Medicinal Product at the supply company and at site 
should be in compliance with normal handling of sterile products for injection and should 
follow the to the current Good Manufacturing Practice (GMP) guidelines. 
 
Further descriptive information on the products can be found in the IB. 
4.1.1 
Packaging and labelling of the investigational product 
From the documentation of the trial medication, it must be possible to retrace the 
handling, composition and pharmaceutical quality of the investigational product 
according to the current Good Manufacturing Practice (GMP) guidelines.  
4.1.1.1 
TG01 
TG01 will be packaged and labelled by ”AndersonBrecon”, a specialised pharmaceutical 
clinical supply company located in Hereford, UK, in accordance with 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 a box containing a 
defined number of vials. 
TG01 will be shipped to the investigational sites under controlled, frozen (-20 oC) 
conditions. 
4.1.1.2 
GM-CSF 
GM-CSF will be package and labelled by “AndersonBrecon”, a specialised 
pharmaceutical clinical supply company located in Hereford, UK, in accordance with 
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 a box containing “a 
defined number of vials”. 
GM-CSF will be shipped to the investigational site(s) under controlled, refrigerated 
conditions (2 -8oC). 
4.1.1.3 
Chemotherapy 
Commercially available chemotherapy (gemcitabine or 5-FU and Leucovorin) will be 
used. 
4.1.2 
Storage, issue, and return of investigational product 
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. A copy of the signed receipt will be 
kept in the trial files. 

 
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TG01 must be kept frozen at -20 oC and GM-CSF must be kept at 2-8 oC during storage 
prior to reconstitution.  After reconstitution the materials can be kept at room temperature 
for 6 hours at all sites with the exception of GM-CSF in the UK where the drug is to be 
kept refrigerated at 2-8°C for 6 hours. All study drugs are to be stored safely and 
separately from other drugs.  The trial medication may not be used for any purpose other 
than the present trial, since the insurance coverage shall otherwise become null and void.  
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.  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. 
4.2 
Assignment of patients to treatment 
Patients are to be registered and assigned to treatment after written informed consent has 
been obtained and all pre-trial evaluations have been completed.  Patient eligibility 
should be documented on the patient eligibility CRF page. 
4.3 
Preparation of trial treatment 
4.3.1 
TG01 
TG01 is provided in 2R glass vials containing 2.1 mg of TG01 and the content of one 
vial of TG01 shall be dissolved in 0.3 mL of sterile water for injection (7 mg/mL).  The 
solution is to be used within 6 hours after reconstitution. 
4.3.2 
GM-CSF 
GM-CSF is provided in vials containing 0.1 mg and the content of one vial shall be 
dissolved in 0.33 mL of sterile water for injection (0.30 mg/mL).  The solution is to be 
used within 6 hours after reconstitution. 
4.3.3 
Chemotherapy 
Gemcitabine will be administered at a dose of 1000 mg/m2.  The drug will be provided in 
vials of 200 mg and 1 g for reconstitution in saline to be given via intravenous injection. 
If gemcitabine is replaced by 5-FU and Leucovorin: 

 
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- 5-FU will be administered at 500mg/m2 
- Leucovorin will be administered at 60mg/m2 or 100mg 
5-FU/Leucovorin will be prepared in accordance with the standard procedure at the 
institution. 
4.3.4 
DTH 
The content of one vial of TG01 shall be dissolved in 0.3 mL sterile water for injection.  
The solution is to be used within 6 hours after reconstitution. 
4.4 
Dosage and administration of trial treatment 
4.4.1 
GM-CSF/TG01 dose and administration 
Phase I and phase II part - main group: GM-CSF/TG01 will be given on days 1, 3, 5, 
8, 15, 22 and every 2 weeks until end of chemotherapy (with day 1 defined as the first 
day of TG01 treatment which should be 1-8 weeks after surgery). For those patients who 
do not receive chemotherapy vaccination will continue as above until week 10 and then 
4-weekly.  
Phase II part – concomitant treatment group: GM-CSF/TG01 will be given on days 1, 
3, 5, 8, 15 and every 2 weeks until end of chemotherapy (with day 1 defined as the first 
day of GM-CSF/TG01 treatment which should be 9-12 weeks after surgery).  
Phase II part – modified vaccination group: GM-CSF/TG01 will be given on days 1, 
8, 15, 22 and 36 then if chemotherapy hasn’t started, 4-weekly until the start of 
chemotherapy at which point vaccination will be put on hold until the end of 
chemotherapy treatment. Patients who do not start chemotherapy at all will continue to 
receive 4-weekly vaccinations from week 10 to week 52. 
 
Main group and concomitant group: After the end of chemotherapy, in patients who 
have not shown recurrence during the study treatment period, further booster injections 
will be given every 4 weeks until week 52 and then every 12 weeks for up to 2 years or 
until withdrawal of consent or toxicity whichever is the earliest. In patients who recur 
and a positive immune response has been seen during the treatment period, further 
booster injections should be given every 4 weeks until week 52 and then every 12 weeks 
for up to 2 years or until withdrawal of consent or toxicity whichever is the earliest. For 
all these GM-CSF/TG01 booster injections the patients should be given prophylactic 
treatment, 30 minutes prior to the GM-CSF injection (see section 4.5.3). 
  
Modified vaccination group: after the end of chemotherapy, GM-CSF/TG01 will be 
given 4 weeks and 5 weeks after end of chemotherapy and then every 4 weeks from week 
8 post-chemotherapy until week 52 and then every 12 weeks for up to 2 years or until 
withdrawal of consent or toxicity whichever is the earliest. In patients who recur and a 
positive immune response has been seen during the treatment period, further booster 
injections should be given as per schedule for up to 2 years or until withdrawal of 
consent or toxicity whichever is the earliest. No prophylactic treatment will be required 
unless an allergic reaction occurs and further vaccinations will be given. 
 
The TG01 dose is 0.70 mg (0.10 mL injection of a TG01 solution at 7 mg/mL) 
reconstituted in water for injection GM-CSF dose is 0.03 mg (- 0.10 mL injection of a 
GM-CSF solution at 0.3 mg/mL) reconstituted in water for injection  
 

 
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Both study drugs will be intradermal injections into the back of the upper arm with 
GM-CSF administered 10-15 min before the injection of TG01. Patients should be 
observed for at least 30 minutes after all vaccinations. 
4.4.2 
Chemotherapy 
Phase I and phase II part - main group and modified vaccination group: Patients 
will receive chemotherapy starting at least 3 weeks after initiation of GM-CSF/TG01 
(Day 22, 36 or 50 of the initial treatment period) and in the main group chemotherapy 
should not start later than 12 weeks from the date of surgery; the day of the first dose will 
be considered Day 1 of the chemotherapy treatment period.   
In part II, patients for whom chemotherapy timing cannot be assured will start 
vaccination as soon as the vaccination schedule can be adhered to and will receive 
chemotherapy or not according to their needs.  
Phase II part – concomitant group: patients who for medical reasons cannot start 
vaccination early will start chemotherapy at the same time as GM-CSF/TG01 and not 
later than 12 weeks from the date of surgery; the day of the first dose will be considered 
Day 1 of the chemotherapy treatment period. 
 
Gemcitabine will be given as 1000 mg/m2 iv over 30 minutes on days 1, 8 and 15 of a 
four week cycle for 6 cycles in total. 
 
If 5-FU/leucovorin needs to be substituted this will be given as 500 mg/m2 iv on days 1 
and 2 every 2 weeks of a four week cycle for 6 cycles in total.  
Leucovorin will be given prior 5-FU as 60 mg/m2 or 100 mg iv on days 1 and 2 every 
2 weeks of a four week cycle for 6 cycles in total. 
4.4.3 
DTH 
Phase I and phase II part - main group: During the initial period, TG01 will be given 
on days 1, 8, 15, 22, 36, 50, and 64 in the lower area of the contralateral arm. TG01 will 
then be administered at the 2nd GM-CSF/TG01 injection after the end of chemotherapy (8 
weeks after the last chemotherapy injection) for patients receiving chemotherapy and at 
week 52 for all patients. At post-chemotherapy visits prophylactic treatment should be 
given 30 minutes prior the DTH injection (see section 4.5.3). 
 
Phase II part – concomitant group: During the initial treatment period, TG01 will be 
given on days 1, 8, 15, 29, 43, 57, and 71 in the lower area of the contralateral arm. TG01 
will then be administered at the 2nd GM-CSF/TG01 injection after the end of 
chemotherapy (8 weeks after the last chemotherapy injection) and at week 52. At post-
chemotherapy visits prophylactic treatment should be given 30 minutes prior the DTH 
injection (see section 4.5.3). 
 
Phase II part – Modified vaccination group: During the initial period, TG01 will be 
given on days 36 and 50 in the lower area of the contralateral arm. TG01 will then be 
administered at the 3rd GM-CSF/TG01 injection after the end of chemotherapy (8 weeks 
after the last chemotherapy injection). For patients not receiving chemotherapy an 
additional TG01 injection will be given at week 52. 
 

 
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The DTH-test dose must be prepared on the day of treatment and is to be given 30 
minutes before GM-CSF/TG01 injection (GM-CSF is to be administered 10-15 min 
before the injection of TG01 in the main group and in the concomitant group and 15-20 
min before the injection of TG01 in the modified vaccination group). 
DTH dose: 0.10 mL of TG01 at 7 mg/mL water for injection solution must be prepared 
for intradermal injection in a sterile syringe. 
4.4.4 
Chemotherapy dosing criteria 
Gemcitabine: 
Before the administration of gemcitabine at the start of each new treatment cycle patients 
must be assessed to ensure that they satisfy the gemcitabine prescribing information of 
the country where the study is conducted or should follow the below criteria if no 
instructions are available. 
• Granulocytes count > 1.5 x 109/L for 1st cycle and > 1 x 109/L for following 
cycles 
• platelets > 100 x 109/L 
• Laboratory evaluation of renal and hepatic function, including serum creatinine 
should be within 1.5 x UNL 
5-FU and Leucovorin: Dosing criteria should follow the standard procedure at the 
institution 
4.5 
Management of Toxicity 
4.5.1 
Anticipated toxicity and management 
TG01 or its individual peptides have been given only to patients with pancreatic or 
colorectal cancer.  Therefore, the majority of adverse events and serious adverse events 
have been related to progression of their disease or concomitant medications.  Several 
cases of local reactions of erythema and induration have been reported and more recently 
four patients experienced allergic reactions related to TG01 or TG01/GMCSF.   Two of 
them experienced a serious adverse event of anaphylaxis soon after TG01 administration 
considered to be related to the GM-CSF/TG01 injections or TG01 alone. The third 
patient experienced on 2 occasions symptoms of an allergic reaction approximately 10 
min after injections (GM-CSF/TG01). The last patient experienced dizziness, 
lightheaded, puffiness of both eyes following GM-CSF/TG01 before starting gemcitabine 
treatment. The mechanism for the anaphylactic reactions occurring so long after the start 
of vaccination, but following the course of gemcitabine, and its similarity to the two 
other cases where gemcitabine has been given for at least 3-4 cycles, might suggest some 
association as yet unexplained. 
In addition flu-like symptoms (including fever), headaches, urticaria and oedema may 
occur.  Back pain, nausea and diarrhoea have also been reported as treatment related and 
there were 2 related serious adverse events of arthritis and hypoglycaemia.  It is difficult 
to dissociate abnormal (Grade 3/4) laboratory toxicities from the patients’ underlying 
disease or medications and in study 98010, which uses all of the peptides of TG01, there 
were 3 events of granulocytopaenia, raised alkaline phosphatase and raised gamma-GT. 
However, there were only 13 patients in this category so carefully monitoring of 
haematology and biochemistry is required. 

 
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GM-CSF is generally well tolerated and, with the low dose anticipated may have few if 
any adverse reactions.  However, in previous studies the most common adverse events 
are: transient myalgia, weakness, mild fatigue, rashes, and mild erythema at the site of 
injection. 
Gemcitabine: Most frequent toxicities reported with gemcitabine given as single agent 
are myelosuppression, nausea and vomiting, transient elevations of one or both serum 
transaminases, proteinuria and haematuria and a few cases of haemolytic uraemic 
syndrome (HUS), fever frequently associated with other flu-like symptoms, rash, 
dyspnoea, oedema, flu-like symptoms with or without fever, infection, alopecia and 
paresthaesias. 
5-FU: most frequent toxicities reported with 5-FU are stomatitis, oesopharyngitis, 
diarrhoea, anorexia, nausea and emesis, alopecia, dermatitis and leucopenia. 
Leucovorin: most frequent toxicities reported with Leucovorin are diarrhoea, stomatitis, 
myelosupression, skin rash, hives, pruritus and wheezing (although rare). 
 
4.5.2 
Chemotherapy dose interruption/reduction 
Gemcitabine 
Institutions should follow the manufacturer’s instructions for dosing modification for the 
country in which the study is being conducted. 
If gemcitabine is delayed, GM-CSF/TG01 should be continued as planned. 
If gemcitabine treatment is stopped, GM-CSF/TG01 may continue as described in section 
3.1. 
 
If no instructions are available, the following guidelines can be followed: 
 
 
Table 4: 
Gemcitabine dose delay/reduction guidelines 
Absolute granulocyte count 
(x 106/L) 
  
Platelet count 
(x 106/L) 
% of full dose 
≥1000 
And ≥100,000 
100 
500-999 
Or 
50,000-99,999 
75 
<500 
Or 
<50,000 
Hold 
 
5-FU and Leucovorin 
Institutions should follow the manufacturer’s instructions for dosing modification for the 
country in which the study is being conducted. 
If 5-FU and Leucovorin are delayed, GM-CSF/TG01 should be continued as planned. 
If 5-FU and Leucovorin treatment is stopped, GM-CSF/TG01 may continue as described 
in section 3.1. 
 

 
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If no instructions are available, the standard procedure at the institution for reduction of 
5-FU/Leucovorin should be followed 
4.5.3 
GM-CSF/TG01 dose interruption  
If a patient experiences GM-CSF or TG01 related toxicity on the days of the scheduled 
GM-CSF/TG01 injections, GM-CSF/TG01 should be delayed until toxicity resolved to 
CTC grade 1.  The patient should then restart at the next planned visit.  Chemotherapy 
should be continued as planned as long as chemotherapy prescribing information 
requirements are fulfilled. 
 
Management of TG01 or GM-CSF related reactions: 
• All groups: 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 TG01 administrations they should be pre-
medicated with intravenous antihistamine treatment (e.g. chlorpheniramine or 
dexchlorpheniramine) 30 minutes before either the DTH injection (TG01 alone) when 
done before vaccination or  before vaccination (i.e. before the GM-CSF injection 
which is followed by the TG01 10-15 minutes later in the main group or concomitant 
group or 15-20 minutes later in the modified vaccination group) 
• Main group and concomitant group ONLY: For patients who have 
completed/finished chemotherapy– All TG01 administrations should be preceded 
by intravenous antihistamine treatment as above 
• All groups: 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 
• All groups: Where a DTH injection is being performed the TG01 DTH dose should 
be administered 30 minutes before the GM-CSF/TG01 administration and patients 
should be observed for at least 30 minutes after ALL GM-CSF/TG01 administration  
• All groups: In patients who have not had prophylaxis  
o If after the TG01 DTH dose the patient exhibits a Grade 1 or 2 allergic reaction 
then the GM-CSF/TG01 administrations should be delayed and the patient given 
intravenous antihistamine treatment as above 
o If a Grade 3 or 4 reaction occurs then no more vaccinations should be given and 
the patient withdrawn from TG01 treatment; if the patient is still receiving 
chemotherapy then this should continue per schedule. 
• All groups: In patients who have had prophylaxis  
o If after the DTH dose the patient exhibits a Grade 1 reaction then the GM-
CSF/TG01 administrations should only be given if the investigator believes it is 
reasonable to do so based on the nature of the reaction  
o If a Grade ≥2 reaction occurs then no more vaccinations should be given and the 
patient withdrawn from TG01 treatment (and continue chemotherapy if this has 
not been completed) 
• All groups: Patients who are to receive no more vaccinations due to an allergic 
reaction but have exhibited a positive immune response may continue in the study 
until completion or earlier if the investigator feels that this is appropriate 
• All groups: Precautions should be in place in case of anaphylaxis 

 
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4.6 
Concomitant medication 
No systemic anti-cancer therapy other than gemcitabine or 5-FU/Leucovorin is to be used 
during the trial before recurrence of the disease.  After recurrence, for patients who have 
an immune response, the standard of care can be used according to the investigational 
site’s usual practise. 
Other vaccination must not be administered during the Initial treatment period (until 
week 11 for the main group, week 13 for the concomitant group and week 8 for the 
modified vaccination group) and should be avoided if possible for the rest of the study 
duration. 
Vaccination with yellow fever or live (attenuated) vaccines is prohibited until at least 3 
months after the last chemotherapy administration.  
Any agent with a known effect on the immune system should be excluded before 
recurrence, unless it is being given 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. 
No specific studies of interactions between TG01 and other agents have been conducted. 
4.7 
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 (Section 4.6). 
5. TRIAL MEASUREMENTS AND ENDPOINTS 
5.1 
Primary endpoint 
Safety  
• Adverse events 
• Laboratory assessments 
 
Immune response by week 11 or 12 (main group) or 13 (concomitant group) or 8 
(modified vaccination group), at end of the treatment period with chemotherapy and at 
end of study assessed by 
• DTH responses  
• Proliferative T-cell responses  
5.2 
Secondary endpoints 
Efficacy at 2 years 
• Disease-free survival 
• Overall survival 
5.3 
Exploratory endpoints 
• Relationship between KRAS status in resected primary tumour and 
recurrence survival outcomes (including disease recurrence and overall survival) 
• CA19-9 levels 

 
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5.4 
Screening assessments 
5.4.1 
Informed consent 
The Investigator must inform the patient verbally about the content of the trial and its 
risks and benefits, as outlined in the information for patients within the informed consent 
document.  The patient should then be given sufficient time to read the information for 
patients and consider participation.  If the patient chooses to participate, the patient and 
Investigator must both sign the Informed Consent Form.  One copy will be given to the 
patient and the original must be documented in the medical source documents.  In this 
study, the informed consent will have to be signed after surgery but before treatment 
start.  
5.4.2 
Patient eligibility 
For trial entry, all patients must fulfil all the inclusion criteria, described under Section 
3.3.1.  No patient with any exclusion criterion from the list described in Section 3.3.2 
may participate.  To assure compliance with the entry criteria, all the assessments 
described in Sections 5.4.3 to 5.4.5 must be completed at screening to determine the 
patients’ eligibility for entry into the trial. 
5.4.3 
Demographic data, medical history 
A medical history (for details see below), including demographics, and physical 
examination of the patient must be completed during the 7 days prior to GM-CSF/TG01 
1st dose. 
Data to be collected at the screening examination are as listed below: 
• Medical History of pancreatic cancer 
o date of initial diagnosis  
o stage of disease at diagnosis 
o Date(s) of surgery and extent of resection (R0 or R1) 
• Concomitant non-malignant diseases and treatments 
• All concomitant medications 
• Medications taken within the 4 weeks prior to enrolment 
• Patients’ procreative potential and contraceptive use must be documented.  For 
childbearing potential/fertile women, a pregnancy test is to be done within 7 days 
prior to the start of treatment and results are to be documented (serum or urine 
testing is acceptable). 
5.4.4 
Special examinations 
• Tumour samples for KRAS status determination will be collected at surgery for 
analysis at the local laboratory 
• ECG within 7 days of start of Study Drugs (as detailed in section 5.9.3) and then 
if clinically indicated 
• CT-scan  after surgery  
A report of the examinations is to be made available in the patient’s source documents 
for the trial. 

 
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5.4.5 
Physical examination  
A full physical examination will be performed and must include a complete, organ-
oriented physical examination of the patient (i.e. head and neck, chest, abdomen, 
superficially the limbs, rudimentary neurological tests such as reflexes and sensation).  
The physical examination findings and relevant parameters are to be documented in the 
medical source documents.  
This examination will also include performance status and vital signs (weight, height, 
heart rate and blood pressure, and body temperature). 
Any new conditions reported during the trial will be recorded on the AE forms.  Only 
those findings that are in addition to the condition being treated will be recorded as AEs.  
Conditions that are considered by the investigator to be unequivocally disease-related 
will not be recorded as AEs. 
5.4.6 
Laboratory safety measurements 
Routine haematology, biochemistry and urine assessments will be performed at the local 
laboratory at the trial centre within 7 days prior to the start of treatment. 
5.5 
Assessments during treatment phase 
Initial Treatment Period with GM-CSF /TG01 +/- chemotherapy 
Main group: Initial Treatment Period (up to week 11) +/- chemotherapy for patients 
starting TG01 vaccination first (timings based on start of GM-CSF/TG01 treatment) – 
Table 1: 
• 
GM-CSF/TG01 to start as soon as possible after the surgical resection.  Day 1 
will be the first day of GM-CSF/TG01 treatment with chemotherapy commencing 
a minimum on day 22 (3 weeks after the first TG01 treatment) but may also be 
started at day 36 or 50 (or later) of GM-CSF/TG01 treatment or may not be 
started at all.  GM-CSF/TG01 treatment will be administered on days 1, 3, 5, 8, 
15, and 22 and then 2-weekly until the end of chemotherapy treatment.  Patients 
who do not start chemotherapy at all can move to a 4-weekly vaccination from 
vaccination week 10 to week 52.  
• 
If given, Gemcitabine will be administered on cycle day 1, 8 and 15 of a four 
week cycle for 6 cycles in total. 5-FU and Leucovorin will be administered on 
cycle day 1, 2, 15 and 16 of a four week cycle for 6 cycles 
• 
DTH application on days 1, 8 15, 22 36, 50 and 64. DTH is assessed 48 h ± 4 h 
after each injection  
• 
Haematology and blood chemistry at days 1, 8, 22, 36, 50 and 64 taken prior to 
injection of GM-CSF/TG01 and at days 1, 8 and 15 of each Gemcitabine cycle 
prior to injection of study treatments.  Key laboratory values in accordance with 
the Prescribing Information for chemotherapy should be available prior to 
chemotherapy dosing. For patients who do not start chemotherapy at all, 
haematology and blood chemistry should be taken at days 1, 8, 22, 36, 50 and 64 
and then every 12 weeks 
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit 

 
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• 
Physical exam and performance status before the start of each chemotherapy 
cycle. For patients who do not start chemotherapy at all, these assessments should 
be done every 12 weeks 
• 
Blood sampling for immunology – samples taken prior to GM-CSF/TG01 
injection on day 1 and day 71 (or 78) 
• 
Blood sampling for CA19.9 will be taken prior GM-CSF/ TG01 injection on day 
1 and prior chemotherapy day 1 of each cycle. For patients who do not start 
chemotherapy at all, these assessments should be done on day 1 and prior every 
4-weekly vaccination cycle 
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and stored for 
potential analysis of additional biomarkers on day 1 prior to GM-CSF/TG01, 
prior chemotherapy 1st administration and monthly thereafter until end of 
chemotherapy. For patients who do not start chemotherapy at all, these 
assessments should be done on day 1 and prior every 4-weekly vaccination cycle 
• 
CT scan every 6 months from start of vaccination and at any time point if 
indicated 
 
Phase II part – concomitant treatment group: Initial Treatment Period (up to week 13) 
+/- chemotherapy for patients starting TG01 vaccination and chemotherapy at the same 
time (Table 2): 
• 
GM-CSF/TG01 will start within 9-12 weeks of the surgical resection.  Day 1 will 
be the first day of GM-CSF/TG01 treatment.  GM-CSF/TG01 treatments will be 
administered on days 1, 3, 5, 8, 15 and then 2-weekly until the end of 
chemotherapy treatment.  
• 
Chemotherapy will start at the same time as GM-CSF/TG01 and no later than 12 
weeks from surgery. Gemcitabine will be administered on cycle day 1, 8 and 15 
of a four week cycle for 6 cycles in total. 5-FU and Leucovorin will be 
administered on cycle day 1, 2, 15 and 16 of a four week cycle for 6 cycles 
• 
DTH application on days 1, 8 15, 29, 43, 57 and 71. DTH is assessed 48 h ± 4 h 
after each injection  
• 
Haematology and blood chemistry at days 1, 8 and 15 of each Gemcitabine cycle 
prior to injection of study treatments.  Key laboratory values in accordance with 
the Prescribing Information for chemotherapy should be available prior to 
chemotherapy dosing 
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit 
• 
Physical exam and performance status before the start of each chemotherapy 
cycle 
• 
Blood sampling for immunology – samples taken prior to GM-CSF/TG01 
injection on day 1 and week 13 
• 
Blood sampling for CA19.9 will be taken on day 1 of each chemotherapy cycle 
prior GM-CSF/TG01 administration  
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and stored for 
potential analysis of additional biomarkers on day 1 of each chemotherapy cycle 
prior GM-CSF/TG01 administration  
• 
CT scan every 6 months from start of vaccination and at any time point if 
indicated 
 

 
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Phase II – modified vaccination group: Initial Treatment Period (up to week 8) +/- 
chemotherapy for patients starting TG01 vaccination first (timings based on start of GM-
CSF/TG01 treatment) - Table 3. 
• 
GM-CSF/TG01 will start as soon as possible after surgical resection.  Day 1 will 
be the first day of TG01 treatment. GM-CSF/TG01 will be administered on Days 
1, 8, 15, 22 and 36 then if chemotherapy hasn’t started vaccination will be given 
4-weekly until the start of chemotherapy at which point vaccination will be put on 
hold until the end of chemotherapy treatment. Patients who do not start 
chemotherapy at all will continue to receive 4-weekly vaccinations from week 10 
to week 52.  
• 
Chemotherapy will commence at least 3 weeks after start of GM-CSF/TG01. 
Patients can however start chemotherapy later or not start at all if more 
appropriate. For patients receiving chemotherapy, 6 cycles of chemotherapy will 
be given. Note that chemotherapy will not be delayed if it is considered important 
to start within 3 weeks of the start of vaccinations. 
• 
DTH skin test injections on days 36 and 50. DTH reaction is assessed 48 h ± 4 h 
after each injection 
• 
Haematology and blood chemistry at days 1, 8, 22, 36, 50, and 64 taken prior to 
injection of GM-CSF/TG01 and Days 1, 8 and 15 of each gemcitabine cycle.  
Key laboratory values in accordance with the Prescribing Information for 
chemotherapy should be available prior to chemotherapy dosing. For patients 
who do not start chemotherapy at all, haematology and blood chemistry should be 
taken at days 1, 8, 22, 36, 50 and 64 and then every 12 weeks 
• 
Urinalysis as clinically indicated 
• 
Vital signs, concomitant medications and adverse events at each visit. 
• 
Physical examination and Performance Status before the start of each gemcitabine 
cycle. For patients who do not start chemotherapy, these assessments should be 
done every 12 weeks. 
• 
Blood sampling for immunology – samples taken prior to GM-CSF/TG01 
injection on day 1 and at week 8  
• 
Blood sampling for CA19.9 on day 1 prior to GM-CSF/TG01, prior 
chemotherapy 1st administration and monthly thereafter until end of 
chemotherapy. For patients who do not start chemotherapy, these assessments 
should be done on Day 1 and prior every 4-weekly vaccination cycle 
• 
A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and stored for 
potential analysis of additional biomarkers on day 1 prior to GM-CSF/TG01, 
prior chemotherapy 1st administration and monthly thereafter until end of 
chemotherapy. For patients who do not start chemotherapy, these assessments 
should be done on Day 1 and prior every 4-weekly vaccination cycle 
• 
CT scan every 6 months from the start of vaccination and at any other time point 
if indicated 
 
After the end of chemotherapy or from week 10 for patients who do not get 
chemotherapy: 
Main group and concomitant group: 
• 
GM-CSF/TG01 every 4 weeks until 52 weeks and then every 12 weeks for up to 
2 years. For all these subsequent GM-CSF /TG01 administrations the patients 
should be given prophylactic treatment (30 minutes before treatment) to prevent 
possible occurrence of allergic reactions. 

 
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• 
DTH skin test injections at the 2nd GM-CSF/TG01 injection after end of 
chemotherapy (8 weeks after last chemotherapy injection) and at week 52. DTH 
reaction is to be assessed 48 h ± 4 h after TG01 injection. For patients who do not 
start chemotherapy at all, these assessments should be done at week 52 only 
• 
Immunology blood samples – samples taken at week 52 prior GM-CSF/TG01 
injection 
• 
CA19.9 and additional biomarkers blood samples – samples taken at week 52 
prior GM-CSF/TG01 injection. For patients not starting chemotherapy, samples 
should be taken prior every 4-weekly cycle and at week 52 
• 
Physical examination and performance status at 52 weeks. For patients who do 
not start chemotherapy, these assessments should be done every 12 weeks and at 
week 52 
• 
Vital signs, haematology and biochemistry at 12 weekly intervals 
• 
Concomitant medications and adverse events at each visit 
• 
CT scan every 6 months from start of vaccination and at any time point if 
indicated 
 
Modified vaccination group: 
• 
GM-CSF/TG01 will be given 4 weeks and 5 weeks after end of chemotherapy 
and then every 4 weeks from week 8 post-chemotherapy until week 52 and then 
every 12 weeks until week 104 (2 years). Patients who do not start chemotherapy 
at all will receive 4-weekly vaccinations from week 10 to week 52 and then every 
12 weeks until week 104 (2 years). 
• 
DTH skin test at 3rd vaccination post-chemotherapy (8 weeks post-
chemotherapy). The DTH reaction is to be assessed 48 h ± 4 h after TG01 
injection. For patients not starting chemotherapy at all, the DTH test and 
assessment are to be done at week 52. 
• 
Blood sampling for immunology – sample to be collected 4 weeks after the last 
chemotherapy injection (1st vaccination injection) and at week 52   
• 
Blood sampling for CA19.9 and additional biomarkers – samples to be taken 
prior to GM-CSF/TG01 injection at week 52. For patients not starting 
chemotherapy, samples should be taken prior every 4-weekly vaccination cycle 
and at week 52 
• 
Physical examination and performance status to be taken at week 52. For patients 
who do not start chemotherapy, these assessments should be done every 12 weeks 
and at week 52 
• 
Vital signs, haematology and biochemistry every 12 weeks 
• 
Concomitant medications and adverse events at each visit 
• 
CT scan every 6 months from the start of vaccination and at any other time point 
if indicated 
 
End of Study Visit (104 weeks or 4 weeks after last GM-CSF /TG01 injection if 
patient is to be discontinued)  
• Haematology and blood chemistry 
• Physical exam and performance status  
• Vital signs, concomitant medications and adverse events 
• Blood sampling for immunology, CA19.9 and additional biomarkers taken prior 
to GM-CSF/TG01 injection 

 
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• 
CT-scan   
 
For all patients where possible, a survival follow-up will continue to be performed every 
6 months after the initial 2 years of study period and until the last remaining patient in the 
modified cohort reaches the 2 years study period or withdraws consent or experiences 
toxicity, whichever is the earliest. Thereafter, a survival follow-up will continue to be 
performed approximately every 12 months until end of life. 
5.6 
Immunological effect 
An immune responder is defined as having a positive DTH and/or a positive T-cell test 
from a blood sample at least once by the end of the initial treatment period (week 11 in 
main group, week 13 in the concomitant group and week 8 in the modified vaccination 
group) (see below): 
 
T-cell Assay 
Patients will have a blood sample taken prior to GM-CSF/TG01 for further testing of 
immune response, at: 
- Day 1  
- Week 11 (main group) or week 13 (concomitant group) or week 8 (modified 
vaccination group)  
- 4 weeks after end of chemotherapy  
- Week 52  
- End of study 
  
All samples will be processed and stored under appropriate conditions until being 
analysed.  Blood samples from each time point will be analysed for TG01 specific T-cell 
responses by proliferation assays.  Specific T-cell responses will be considered positive if 
the stimulation index (SI) is ≥2. 
 
Delayed Type Hypersensitivity (DTH) 
It is performed in order to demonstrate whether an immune response has been elicited. 
Administration of TG01 only (without GM-CSF or proceeded by GM-CSF 
administration) must be injected intradermally in the lower area of the contralateral arm 
acting as a Delayed Type Hypersensitivity (DTH) test. 
Phase I part and phase II part – main group: the DTH test is administered on days 1, 
8, 15, 22, 36, 50, 64, at the 2nd GM-CSF/TG01 injection after the end of the 
chemotherapy (8 weeks after the last chemotherapy injection) and at week 52. For 
patients not receiving chemotherapy at all, the DTH test is administered on days 1, 8, 15, 
22, 36, 50, 64 and at week 52. 
Phase II part – concomitant group: the DTH test is administered on days 1, 8, 15, 29, 
43, 57, 71, at the 2nd GM-CSF/TG01 injection after the end of the chemotherapy (8 
weeks after the last chemotherapy injection) and at week 52. 
Phase II part – modified vaccination group: the DTH test is administered on days 36 
and 50, at the 3rd GM-CSF/TG01 injection after the end of the chemotherapy (8 weeks 
after the last chemotherapy injection) and at week 52. For patients not starting 
chemotherapy at all, the DTH test and assessment are to be done on days 36 and 50 and 
at week 52. 

 
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The DTH skin reaction assessment is to be performed 48 hours (+/- 4 hours) after each 
administration.  The DTH-test will be considered positive if the area of the skin reaction 
has an average diameter* of ≥5mm at the 48 hours (+/- 4 hours) assessment. 
 
Figure 6: DTH Skin Reaction Registration (induration and erythema) 
 
* Average diameter: a mm + b mm 
 
2  
5.7 
CT-scan 
An abdominal CT or MRI scan should be performed for full tumour assessment at 
baseline, every 6 months from the start of vaccination and at the last or end of study visit. 
Additional CT-scans should also be done if indicated during the study period. 
 
5.8 
Efficacy measurements and endpoints 
5.8.1 
Immunology response  
Response by week 11 or 12 (main group) or by week 13 (concomitant group) or by week 
8 (modified vaccination group) assessed by: 
• DTH responses 
• Proliferative T-cell responses   
 
Response at end of chemotherapy treatment assessed by: 
• DTH responses 
• Proliferative T-cell responses   
 
Response at week 52 assessed by: 
• DTH responses  
• Proliferative T-cell responses   
 
Response at end of study assessed by: 
• Proliferative T-cell responses   
5.8.2 
Disease-free survival 
• Time from randomisation to 1st disease progression or death from 
any cause 
Note that although scanning at regular intervals during the study is not 
mandated it is expected that a CT scan will be performed every 6 months 
from the start of vaccination and if there is clinical evidence of disease 
recurrence 
• Number of patients alive and disease free at 1 and 2 years 
5.8.3 
Overall survival 
• Time from randomisation to death due to any cause 
• Number of patients alive at 1 and 2 years 
DTH
a
b
DTH
a
b
 

 
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5.8.4 
KRAS status expression 
Relationship between KRAS status and recurrence 
5.8.5 
CA19.9 levels 
Level of CA19-9 during treatment period, at week 52 and at end of the 
study. 
5.8.6 
Other markers levels 
Level of other biomarkers during treatment period, at week 52 and at end 
of the study. 
 
5.9 
Safety measurements and endpoints 
5.9.1 
Adverse events 
5.9.1.1 
Definitions 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given in 
section 7 of this protocol.  It is extremely important that all staff involved in the trial are 
familiar with the content of this section.  The Principal Investigator is responsible for 
ensuring this. 
5.9.2 
Laboratory safety measurements and variables 
5.9.2.1 
Methods of assessment 
Routine haematology, biochemistry and urinalysis assessments will be performed at the 
laboratory local to the trial centre. 
The following routine laboratory parameters will be investigated (see section 9.7 for the 
total volume of blood samples to be collected):  
 
Table 5: 
Summary of required laboratory assessments 
Chemistry  
Haematology 
Clotting Screen Urinalysis 
Alkaline Phosphate 
Red blood cell 
(RBC) count 
INR 
Blood 
ALT (SGPT)  
Haemoglobin 
 
Proteins 
AST (SGOT) 
Haematocrit 
 
Glucose 
Total Protein 
White blood cell 
(WBC) count 
 
White cells 
Albumin 
Neutrophils 
 
 
Bilirubin 
Lymphocytes 
 
 
Lactate dehydrogenase 
(LDH) 
Monocytes 
 
 
Blood urea nitrogen (BUN) 
or Uric Acid 
Eosinophils 
 
 
Creatinine 
Basophils 
 
 
Sodium 
Platelet count 
 
 
Potassium 
 
 
 
Creatinine kinase (CK) 
 
 
 

 
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5.9.2.2 
Calculation or derivation of endpoint 
Section 7 provides details on how AEs based on laboratory tests will be recorded and 
reported. 
Laboratory test results will be graded according to NCI-CTC version 4.0. 
5.9.3 
ECG 
ECG will be evaluated locally.  Any clinically significant abnormal findings observed 
and recorded during the treatment period will be recorded as AEs.  The same method of 
assessment should be used throughout. 
5.9.4 
Performance status 
Performance status will be evaluated locally using the ECOG scale: 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all 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 
6. ANALYSIS OF TRIAL DATA 
6.1 
Study Endpoints 
6.1.1 
Primary Endpoint 
The primary safety endpoint is the assessment of adverse events and laboratory values 
during the study period. 
The primary efficacy endpoint is immune response by week 11 or 12 (main group) or by 
week 13 (concomitant group) or by week 8 (modified vaccination group), at end of the 
treatment period with chemotherapy and at week 52. 
6.1.2 
Secondary Endpoints 
The secondary target variables for this trial are: 
Efficacy 
• Time from randomisation to first disease progression or death from any cause 
• Time from randomisation to death 

 
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6.1.3 
Exploratory Endpoints 
• Relationship between KRAS status in resected primary tumour and recurrence 
survival outcomes (including disease recurrence and overall survival) 
• CA19-9 levels 
6.2 
Definitions of evaluability 
The definitions of study populations are as follows: 
Population 
Definition 
All treated patients 
(ATT)/safety 
This will comprise all patients who received at 
least one dose of Investigational pharmaceutical 
product (IMP)  
Immune 
This will comprise patients who provided at 
least one set of T cell and/or DTH response 
results  
Modified Immune   
 
This will comprise all patients in the Immune 
population who have received at least one cycle 
of gemcitabine or 5-FU/leucovorin  
 
Patients who withdrew from study before completing 1 cycle of gemcitabine may be 
replaced. 
6.3 
Analytical methods 
Endpoints will be analysed as detailed in the sections below:  
6.3.1 
Primary endpoints  
Summary measures:  
6.3.1.1 
Nature, incidence and severity of adverse events 
Adverse events will be summarised by counts and proportions (percentages) of patients 
reporting an AE expressed as a percentage of all patients.  All premature terminations 
will be summarised by the primary reason for trial withdrawal; ITT population. 
6.3.1.2 
Laboratory assessments 
Summary measures: Standard summary statistics; ITT population. 
Listings will highlight assessments of clinical significance.  
6.3.1.3 
Incidence of and reasons for Study Drug dose interruptions, Study Drug 
dose reductions and withdrawals 
Summary measures: Counts and proportions; ITT population. 
6.3.1.4 
Study Drug exposure  
Summary measures: Standard summary statistics; ITT population. 
Listings will highlight assessments of clinical significance. 

 
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6.3.1.5 
Immune response 
Summary measures: DTH test results, T-cells assay; Per Protocol population and 
Immune population.  The data will be summarised. 
6.3.2 
Secondary endpoints 
6.3.2.1 
Disease-free survival 
Summary measures: Median time to progression or death.  Proportion alive and disease-
free at 1 and 2 years (Median and proportion calculated by Kaplan-Meier, ITT 
population). 
6.3.2.2 
Overall survival  
Summary measures: Median time to death.  Proportion alive at 1 and 2 years.  
(Median and proportion calculated by Kaplan-Meier, ITT population). 
6.3.2.3 
CA19-9 Evaluation 
Summary measures: Changes over time (trend and absolute changes); ITT population. 
6.3.2.4 
Other biomarkers 
Summary measures: Changes over time (trend and absolute changes); ITT population. 
 
6.4 
Sample size and power 
No formal sample size has been calculated. 6-32 patients are deemed sufficient to assess 
the safety and immune response in this pilot study and given an early indication of 
efficacy in terms of DFS and OS based on historical controls. 
7. DRUG SAFETY 
7.1 
Definitions of adverse events and serious adverse events 
It is important that all the staff involved in the trial is familiar with the content of this 
section of the protocol. 
7.1.1 
Adverse events 
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/TG01 or chemotherapy (gemcitabine or 5-FU and Leucovorin)) 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, even if no trial treatment has 
been administered or recently administered.  A grading severity scale is provided for 
each AE term.  The Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 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. 

 
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7.1.2 
Serious adverse events 
A serious AEs (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 hospitalisation 
• 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. 
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 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? (see APPENDIX II for 
guidelines on interpretation of causality). 
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 Pharmacovigilance group is specialised and has the appropriate expertise in 
handling and reporting SAEs. 

 
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7.2 
Recording of adverse events 
For the purpose of this trial, any detrimental change in a patient’s condition, subsequent 
to their entering 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 in 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 anew 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 National Cancer Institute Common 
Toxicity Criteria (NCI-CTC) version 4.0 and recorded on the appropriate CRF page. 
Laboratory/vital signs  abnormalities should not be reported as adverse events unless any 
criterion for an AE is fulfilled i.e. that it is clinically significant and because it is 
detrimental to the patient, the abnormality causes study drug dose adjustment, leads to 
patient’s discontinuation from the study, or the investigator insists the abnormality 
should be reported as an AE. Laboratory/vital signs abnormalities should not be reported 
as separate adverse events if they are part of an overall diagnosis 
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 7.1.2.  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. 

 
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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. 
7.2.1 
Exposure to GM-CSF/TG01 or chemotherapy during 
pregnancy/lactation 
In principle, pregnancy and lactation are exclusion criteria and pregnancy itself is not 
regarded as an AE unless there is a suspicion that the investigational product under trial 
may have interfered with the effectiveness of a contraceptive medication.  In the event of 
a pregnancy occurring during the course of the trial, the patient must be withdrawn from 
trial medication immediately and the pregnancy notified to ICON PV and the sponsor 
without delay.  The patient must be followed-up during the entire course of the 
pregnancy and lactation period.  Perinatal and neonatal outcomes must be recorded even 
if completely normal and without AEs. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs (See Section 8.3 below).  Elective abortions 
without complications should not be handled as AEs.  All outcomes of pregnancy must 
be reported to ICON PV, on the ‘pregnancy outcomes report form’. 
7.3 
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 7.1.2) 
To discuss the medical aspects of the SAE investigators should call: 
 
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: safety@aptivsolutions.com 
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 by day 1 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. 

 
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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. 
7.4 
Death 
All deaths occurring within the trial period or within 28 days of the last dose of Study 
Drug (TG01 and GMCF or chemotherapy (gemcitabine or 5-FU/Leucovorin)) must be 
reported to the safety group, for the purpose of SAE reporting.  However, deaths due 
unequivocally to disease recurrence/progression are not SAEs. Any deaths occurring 
more than 28 days after the last dose of Study Drug (TG01 and GMCF or chemotherapy) 
will not be reported to the regulatory authorities, for the purposes of safety reporting. 
7.5 
Procedures to be followed in the event of abnormal laboratory test values 
The severity grading used for laboratory measurements will be the NCI-CTC, version 4.0 
grading for laboratory parameters.  Laboratory parameters not rated by the NCI-CTC, 
version 4.0, scoring will not be graded.  The AEs based on laboratory tests will be 
recorded and reported as described in Section 7.2. 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until the test values have returned to the normal or baseline 
range, and/or an adequate explanation of the abnormality is found. 
If a clear explanation is established it should be recorded in the patient’s medical source 
documents. 
7.6 
Overdosing with the trial medication 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher 
than specified in the protocol.  For the purposes of this trial, any dose administered to a 
patient that exceeds the planned protocol dose should be reported as an overdose.  It must 
be reported as an SAE irrespective of outcome and even if no toxic effects were 
observed. 
There is no clinically proven antidote available for TG01, GM-CSF or gemcitabine. 

 
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The expected manifestations of overdose are likely to be: 
TG01 
Significant toxicities have not been seen to date and the mode of action of TG01 makes it 
unlikely that an overdose will cause additional toxicity 
GM-CSF 
The dose of GM-CSF used is very low and overdose symptoms are likely to mimic the 
toxicities of doses more commonly used to support neutropenia such as bone and 
musculoskeletal pain 
Gemcitabine: Myelosuppression, paraesthesia, and severe rash were the principal 
toxicities seen when a single dose as high as 5700 mg/m2 was administered by 
intravenous infusion over 30 minutes every 2 weeks to several patients in a Phase 1 
study.  In the event of suspected overdose, the patient should be monitored with 
appropriate blood counts and should receive supportive therapy, as necessary. 
5-FU: most frequent toxicities reported with 5-FU were stomatitis, oesopharyngitis, 
diarrhoea, anorexia, nausea and emesis, alopecia, dermatitis and leucopenia. 
Leucovorin: most frequent toxicities reported with Leucovorin were diarrhoea, 
stomatitis, myelosupression, skin rash, hives, pruritus and wheezing (although rare). 
8. RESPONSIBILITIES OF THE INVESTIGATORS 
The Investigators shall be responsible for ensuring that the trial is performed in 
accordance with the protocol and the Declaration of Helsinki (July 1999), as well as with 
the Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) approved July 
1996 and applicable regulatory requirements.  These documents state that the informed 
consent of the patients is an essential precondition for participation in the clinical trial. 
8.1 
Patient information 
An unconditional prerequisite for participation of a patient in the trial is the patient’s 
written consent after having been informed of the following: 
• that the trial involves research 
• the purpose of the trial 
• the trial treatment(s) 
• the trial procedures to be followed, including all invasive procedures 
• the patient’s responsibilities 
• those aspects of the trial that are experimental (e.g. novel or non-validated 
measurements, which are additional to normal therapeutic assessment.) 
• the reasonably foreseeable risks or inconveniences to the patient and, when 
applicable, to an embryo, foetus, or nursing infant 
• the reasonably expected benefits (when there is no intended clinical benefit to 
the patient, the patient should be made aware of this) 

 
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• the alternative procedure(s) or course(s) of treatment that may be available to 
the patient, and their important potential benefits and risks 
• the compensation and/or treatment available to the patient in the event of 
trial-related injury 
• that the patient's participation in the trial is voluntary and that the patient may 
refuse to participate or withdraw from the trial, at any time, without penalty or 
loss of benefits to which the patient is otherwise entitled 
• that the monitor(s), the auditor(s), the Independent Ethics Committee (IEC), 
and the regulatory authority(ies) will be granted direct access to the patient's 
original medical records for verification of clinical trial procedures and/or 
data, without violating the confidentiality of the patient, to the extent 
permitted by the applicable laws and regulations and that, by signing a written 
informed consent form, the patient or the patient's legally acceptable 
representative is authorizing such access 
• that records identifying the patient will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available even if the results of the trial are published 
• that the patient or the patient's legally acceptable representative will be 
informed in a timely manner if information becomes available that may be 
relevant to the patient's willingness to continue to participate in the trial 
• the person(s) to contact for further information regarding the trial and the 
rights of trial patients, and whom to contact in the event of trial-related injury 
• the foreseeable circumstances and/or reasons under which the patient's 
participation in the trial may be terminated 
• the expected duration of the patient's participation in the trial 
• the approximate number of patients involved in the trial 
• for women, the warning that clinical studies may not be carried out in pregnant 
women and that pregnancy should therefore be avoided.  If pregnancy occurs, 
the investigator must be notified immediately 
• insurance coverage 
• mentioning that the patient may undertake additional medical treatment at any 
time during the clinical trial only with the express permission of the 
Investigators (unless indicated in an emergency) (note condition of insurance 
coverage in APPENDIX III) 
• warning that the patient may not have taken part in any other clinical trial or 
used any other unlicensed medication during the past 28 days 
• mention that any change in any concomitant medication must be reported to 
the Investigator immediately 
• permitted and non-permitted concomitant medication and dietary aspects. 
The information should be given to the patient both verbally and in writing.  The wording 
must be chosen in such a way that the content is fully and readily understandable for 

 
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laypersons.  Patients must be given sufficient time to consider their participation in the 
trial. 
8.2 
Patient consent 
The consent of the patient to participate in the trial has to be given in writing prior to 
participation in the trial.  It must be signed and personally dated by the patient and by the 
Investigator/person designated by the Investigator to conduct the informed consent 
discussion. 
The signed and dated declaration of informed consent will remain at the Investigators’ 
site and must be safely archived by the Investigators so that the forms can be retrieved at 
any time for monitoring, auditing and inspection purposes.  A copy of the signed and 
dated information and consent should be provided to the patient prior to participation and 
a copy maintained in the patient’s source documents if there is a separate archive file for 
the informed consent documents for the trial. 
8.3 
Ethics review 
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. 
8.4 
Source data and patient files 
The Investigators have to keep a written or electronic patient file for every patient 
participating in the trial.  This patient file should contain the available demographic and 
medical information of the patient, in particular the following: name, date of birth, sex, 
height, weight, patient history, concomitant diseases and concomitant medication 
(including changes during the trial), statement of entry into the trial, trial identification, 
the date of informed consent, all trial visit dates, predefined performed examinations and 
clinical findings, observed AEs (if applicable), and reason for withdrawal from the trial if 
applicable.  It should be possible to verify the inclusion and exclusion criteria for the trial 
from the available data in this file. 
It must be possible to identify each patient by using this patient file. 
Additionally, any other documents with source data, especially original print-outs of data 
that were generated by technical equipment, have to be filed.  All these documents have 
to bear at least the patient identification number and the printing date printed by the 
recording device, to indicate to which patient and to which trial procedure the document 
belongs. 
Print-outs of computerised patient files must be signed and dated by the Investigators, 
countersigned by the monitor and kept with the Investigators’ copies of the CRF, as a 

 
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source document.  Data are to be recorded directly onto the CRFs (i.e. there is to be no 
prior written or electronic record of data). 
8.5 
Training of staff 
The principal investigator will maintain a record of all individuals involved in the trial 
(medical, nursing and other staff).  He or she will ensure that appropriate training 
relevant to the trial is given to all these staff, and that they will receive any new 
information of relevance to the performance of this trial. 
8.6 
Trial agreements 
The principal investigator at each centre 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. 
8.7 
Confidentiality 
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. 
9. TRIAL MANAGEMENT 
9.1 
Monitoring 
Before the initiation of the trial, a representative of Targovax will visit the investigational 
site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) (and other personnel involved with the trial) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
Targovax or its representatives 
During the trial, a CRA representing Targovax will have regular contacts with the 
investigational site, including visits to: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are 
being accurately recorded in the CRFs, and that investigational product 
accountability checks are being performed 
• Perform source data verification (a comparison of the data in the CRFs with the 
patients’ records at the hospital or practice, and other records relevant to the trial).  
This will require direct access to all original records for each patient (e.g. clinic 
charts) 
The monitor or another Targovax representative will be available between visits if the 
investigator(s) or other staff at the centre need information and advice. 
The monitoring of the study will be conducted by a Targovax representative who has 
appropriate expertise in monitoring clinical trials such as this to ICH GCP standards. 

 
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9.2 
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. 
9.3 
Case report form handling 
The main objective is to obtain those data required by the trial protocol in a complete, 
accurate, legible and timely fashion.  The data in the CRFs should be consistent with the 
relevant source documents. 
The data recorded during the course of this trial must be documented in the CRFs and 
must be forwarded to the nominated Data Management Group, for processing and 
evaluation on behalf of Targovax.  All data must be stored in an anonymous form in 
accordance with the data-protection regulations. 
The Investigators must ensure that the CRFs forwarded to Data Management and any 
other associated documents, contain no mention of any patient names. 
The CRFs must be filled in completely and legibly (with either black or blue ballpoint 
pen, acceptable for use on official documents).  Any amendments and corrections 
necessary must be undertaken and countersigned by the Investigators, stating the date of 
the amendment/correction.  Errors must remain legible and may not be deleted with 
correction aids (e.g. Tipp-Ex).  The Investigators must state their reasons for the 
correction of important data. 
In the case of missing data/remarks, the entry spaces provided for in the CRF should be 
cancelled out so as to avoid unnecessary follow-up inquiries. 
The CRFs must be suitable for submission to the regulatory authorities. 
The nominated Data Management Group is Syne Qua None Ltd. with headquarters at 
Gostling House, Diss Business Park, Hopper Way, Sandy Lane, Diss, Norfolk, IP22 
4GT, UK and will have the appropriate experience to undertake the data management 
and statistical activities for this study to ICH GCP standards. 
9.4 
Amendments to the trial protocol 
Changes in the trial protocol must take the form of written trial-protocol amendments. 
These will require the approval of all signatories of the final protocol. 
Any amendments to the protocol which affect the patient, e.g. changes in 
procedures/assessments or matters relating to patient safety, require a favourable opinion 
approval from the Ethics Committee for the trial centre(s) concerned, prior to 
implementation.  Changes of a purely administrative nature should be notified to the 
committee(s), but do not require formal approval.  Any amendment affecting the patient 
requires further informed consent from each patient before implementation. 

 
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9.5 
Deviations from the trial protocol 
Deviations from the trial protocol, especially the prescription of doses not scheduled in 
the trial protocol, other modes of administration, other indications, and longer treatment 
periods are not permissible (except in an emergency). 
9.6 
Trial report and publication policy 
After the conclusion of the trial, a report will be written with the co-operation of the 
Investigators and in conjunction with Targovax, which will include a descriptive 
statistical analysis and an appraisal of the results from a medical viewpoint.  This report 
will be based on the items listed in this trial protocol.  Any publication of the results, 
either in part or in total (articles in journals or newspapers, oral presentation, etc.) by the 
Investigators, requires the approval of Targovax. 
9.7 
Volume of blood sampling and handling of biological samples  
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 6: 
Volume of blood to be drawn from each patient in the study 
Assessment 
Sample 
volume (ml) 
No. of 
samples 
Total volume 
(ml) 
Immunology 
 
60 
5 
300 
CA19.9  
 
5 
9 
45 
Other analysis 
 
10 
9 
90 
Safety 
Clinical 
chemistry 
5 
23-31 
115-155 
 
Haematology 
5 
23-31 
115-155 
Total 
 
 
 665-745 ml 

 
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20. Hunger RE, Brand CU, Streit M et al., (2001). Successful induction of immune 
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vaccine mediate tumor regression in patients with metastatic melanoma. J 
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LBA4504 
 
27. Nowak AK, Robinson BW, Lake RA. (2002) Gemcitabine exerts a selective effect 
on the humoral immune response: implications for combination chemo-
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immunotherapy in the treatment of established murine solid tumors. Cancer Res 
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30. Parmiani G et al., (2007) Opposite immune functions of GM-CSF administered as 
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34. Soiffer R, Lynch T, Mihm M et al., (1998) Vaccination with irradiated autologous 
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35. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. (2005) Gemcitabine 
selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-
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36. Van Laethem J-L et al., (2010) Adjuvant Gemcitabine alone versus Gemcitabine-
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randomised EORTC-40013-22012/FFCD-9203/GERCOR Phase II study. J Clin 
Onc. 24 (29): 4450-4456 
 
37. Weden et al., (2011). Long Term Follow-up of Resected Pancreatic Cancer Patients 
Following Vaccination Against Mutant K-RAS. International Journal of Cancer: in 
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38. Yamada A et al., (2006). Nonmutated self-antigen-derived cancer vaccine peptides 
elicit an IgE-independent but mast cell-dependent immediate-type skin reaction 
without systemic anaphylaxis. J Immunol: 176:857-863 
 
 

 
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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: 
PATIENT INSURANCE AND INDEMNITY 
 
 
 
Patients will be covered by an insurance set with Legemiddelansvarsforeningen. A 
certificate of insurance can be provided upon request.