Safety, Tolerability, Immunogenicity and Efficacy of Multiple PolyPEPI1018 Vaccinations as an Add-on Immunotherapy to the Standard-of-Care Maintenance Therapy in Subjects With Metastatic Colorectal Cancer
Phase: PHASE1
Conditions: Colorectal Cancer
Sponsor: Treos Bio Zrt

Treos Bio ZRT 
OBERTO-101 Amendment 3 
Product: PolyPEPI1018 Colorectal Cancer Vaccine 
Page 1 of 81 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1, Multiple doses, Multicenter, Open-label Study to 
Evaluate Safety, Tolerability, Immunogenicity and Efficacy of 
Subcutaneous Injections of PolyPEPI1018 Vaccine as an Add-on 
Immunotherapy to the Standard-of-Care Maintenance Therapy in 
Subjects with Metastatic Colorectal Cancer (OBERTO) 
Short Protocol Title: 
Safety and Immunogenicity of PolyPEPI1018 Vaccine in the 
Treatment of Metastatic Colorectal Cancer (OBERTO) 
Protocol Number: 
OBERTO-101 Amendment 3 
Name of Investigational 
Product: 
PolyPEPI1018 CRC Vaccine (PolyPEPI1018) 
IND Number: 
17887 #0001 
EudraCT Number: 
2017-003850-18 
Sponsor: 
Treos Bio ZRT 
Viola utca, 2 
8200 Veszprém 
Hungary 
Study Medical Monitor: Franco Lori, M.D., Ph.D. 
Chief Medical Officer at Treos Bio ZRT 
Phone: +39 347 0723942 
FAX: +36-1-332-3636 
E-mail: franco.lori@treosbio.com 
Original Protocol Date: 
15 November 2017 
Amendment 1 Date 
15 January 2018 
Amendment 2 Date 
August 21 2018 
Amendment 3 Date 
April 10 2019 
Confidentiality 
Statement: 
This document contains information that is the confidential and proprietary 
property of Treos Bio ZRT. Any use, distribution, or disclosure without the 
prior written consent of Treos Bio ZRT is strictly prohibited except to the 
extent required under applicable laws or regulations. 
Compliance Statement: 
This study will be conducted in accordance with Good Clinical Practice (GCP) 
as defined in International Conference on Harmonisation (ICH) guidelines and 
United States (US) Code of Federal Regulations Title 21, Parts 11, 50, 54, 56, 
and 312, and Title 45 Parts 46, 160, and 164; the International Council for 
Harmonisation (ICH) document ICH Harmonised Guideline, E6(R2) Integrated 
Addendum to ICH E6(R1):Guideline for Good Clinical Practice; the European 
Union (EU) Directives 2001/20/EC and 2005/28/EC; the Declaration of 
Helsinki (version as currently endorsed by the European Medicines Agency 
[EMA] and the US Food and Drug Administration [FDA], 1989); Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) Guidelines; and 
applicable local legal and regulatory requirements. 

Treos Bio ZRT 
OBERTO-101 Amendment 3 
Product: PolyPEPI1018 Colorectal Cancer Vaccine 
Page 2 of 81 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 1, Multiple doses, Multicenter, Open-label Study to 
Evaluate Safety, Tolerability, Immunogenicity and Efficacy of 
Subcutaneous Injections of PolyPEPI1018 Vaccine as an Add-
on Immunotherapy to the Standard-of-Care Maintenance 
Therapy in Subjects with Metastatic Colorectal Cancer 
(OBERTO) 
Protocol Number: 
OBERTO-101 
Date of Original 
Protocol: 
15 November 2017 
Date of Amendment 1 
15 January 2018 
Date of Amendment 2 
August 21 2018 
Date of Amendment 3 
April 10 2018 
 
APPROVAL STATEMENT 
 
The undersigned has reviewed the format and content of the above protocol and approved for 
issuance. 
Approved by: 
 
 
 
Franco Lori, M.D., Ph.D. 
Chief Medical Officer 
 
10th April  2019 
 
 
 
 
 

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OBERTO-101 Amendment 3 
Product: PolyPEPI1018 Colorectal Cancer Vaccine 
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CONFIDENTIAL 
INVESTIGATOR ACCEPTANCE PAGE 
Issue/Date:                             15 November 2017 
Date of Amendment 1: 
15 January 2018 
Date of Amendment 2: 
21 August 2018 
Date of Amendment 3: 
10 April 2019 
 
 
I have read this protocol for Study OBERTO-101 entitled: 
A Phase 1, Multiple doses, Multicenter, Open-label Study to Evaluate Safety, 
Tolerability, Immunogenicity and Efficacy of Subcutaneous Injections of 
PolyPEPI1018 Vaccine as an Add-on Immunotherapy to the Standard-of-Care 
Maintenance Therapy in Subjects with Metastatic Colorectal Cancer (OBERTO) 
 
 
By signing below, the investigator acknowledges that he/she has read and understands this 
protocol, and will comply with the requirements for obtaining informed consent from all 
study subjects prior to initiating any protocol-specific procedures, obtaining written initial 
and ongoing Ethics Committees protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements. 
 
 
 
 
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
 
 

Treos Bio ZRT 
OBERTO-101 Amendment 3 
Product: PolyPEPI1018 Colorectal Cancer Vaccine 
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CONFIDENTIAL 
SYNOPSIS 
Name of 
Sponsor/Company: 
Treos Bio ZRT 
Name of Product: 
PolyPEPI1018 CRC Vaccine (PolyPEPI1018) 
Title of Study: 
A Phase 1, Multiple doses, Multicenter, Open-label Study to Evaluate Safety, 
Tolerability, Immunogenicity and Efficacy of Subcutaneous Injections of 
PolyPEPI1018 Vaccine as an Add-on Immunotherapy to the Standard-of-
Care Maintenance Therapy in Subjects with Metastatic Colorectal Cancer 
(OBERTO) 
Phase of Development: 
Phase 1; First-in-Human 
Planned Study Period: 
Initiation: Second quarter of 2018 (first subject first visit) 
Primary Completion: Third quarter of 2019 (last subject Week 12 
assessment) 
Study Objective(s): 
Primary Objective: 
• 
To evaluate the safety and tolerability of multiple doses of 
PolyPEPI1018 as an add-on to maintenance therapy in subjects with 
metastatic colorectal cancer (mCRC) 
Secondary Objective(s):  
• 
To identify PEPIs (Personal EPItopes capable of inducing T cell 
responses in an individual) from PolyPEPI1018 in each study subject 
• 
To evaluate the immunogenicity of PolyPEPI1018 by measuring both 
effector and memory T cell responses  
• 
To evaluate initial efficacy of PolyPEPI1018 by evaluating Objective 
Response Rate (ORR)  
Exploratory Objective(s):  
• 
To explore the correlation between PEPIs and T cell responses  
• 
To explore the correlation between PEPIs and tumor infiltrating 
lymphocytes  
• 
To explore the correlation between T cell responses and tumor 
infiltrating lymphocytes  
• 
To explore the correlation between PEPIs  and ORR  
• 
To explore the correlation between T cell responses and ORR 
Study Design: 
This is a Phase 1, open-label, non-randomized, multicenter study to evaluate 
the safety, tolerability, immunogenicity and efficacy of multiple 
subcutaneous (SC) injections of PolyPEPI1018 as an add-on immunotherapy 
to the standard-of-care maintenance therapy in approximately 10 subjects 
with mCRC. This is an amended Study Design only in the USA: 5 subjects in 
Italy are under evaluation after a single SC injection of the same vaccine, as 
originally planned (no amendment contemplated in Italy). 
The study is composed of a 3-week Screening Period, the administration of 
multiple doses vaccine (Day 1, Week 0; Day 92, Week 13; Day 183, week 
26), a 13-week Follow-up Period between the first and second vaccination 
and a 12-week Follow-up Period after the last vaccination. The study will be 
conducted on an outpatient basis. 
Screening should be performed in parallel with the subject’s completion of 
the standard-of-care first-line treatment and initiation of the standard-of-care 
maintenance treatment.  

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CONFIDENTIAL 
The first dose of PolyPEPI1018 will be administered after the subject 
initiates the maintenance regimen, and within 3 weeks after the eligibility CT 
scan was performed (should be performed at the completion of the first-line 
treatment). 
Subjects will be monitored every 3 weeks for 12 weeks after first 
administration of PolyPEPI1018 (i.e. Weeks 3, 6, 9 and 12), then vaccinated 
again at week 13 and  monitored every 3 weeks for 12 weeks after second 
administration of PolyPEPI1018 (i.e. Weeks 16, 19, 22 and 25), then 
vaccinated again at week 26 and  monitored every 3 weeks for 12 weeks after 
third administration of PolyPEPI1018 (i.e. Weeks 29, 32, 35 and 38) 
Number of Investigational 
Sites: 
Two sites, 1 in the United States (US) and 1 in Europe (Italy) 
Planned Number of 
Subjects: 
Approximately 10 subjects in the USA, to be vaccinated 3 times (USA), in 
addition to 5 subjects to be vaccinate only 1 time (Italy) 
Planned Duration of 
Subject Participation: 
Approximately 41 weeks, including a 3-week Screening Period and 12-week 
Follow-up Period after third and last PolyPEPI1018 dose is administered 
Study Population: 
Patients with mCRC who have achieved partial response (PR) or stable 
disease during first-line treatment with chemotherapy plus a biologic drug 
will be enrolled 
Test Product, Dose, and 
Mode of Administration: 
The final dosage form of PolyPEPI1018 is an emulsified solution prepared 
onsite, by mixing 2 separate solutions of multiple peptides 
(PolyPEPI1018-Mix1 and PolyPEPI1018-Mix2) and Montanide™ as an 
adjuvant. 
The sponsor will provide the following:  
• 
PolyPEPI1018-Mix1 - a solution of 2 × 30-mer peptides at 
0.2 mg/peptide/mL in 1.5 mL solution (20% DMSO, 80% water) and 
stored at -20ºC 
• 
PolyPEPI1018-Mix2 - a solution of 4 × 30-mer peptides at 
0.2 mg/peptide/mL in 1.5 mL solution (20% DMSO, 80% water) and 
stored at -20ºC 
The site staff will follow the written vaccine preparation procedure and mix 
1.2 mL of PolyPEPI1018-Mix1, 1.2 mL of PolyPEPI1018-Mix2, and 2.4 mL 
of Montanide™ to produce the emulsified vaccine solution. After preparing 
the mixture, 1 mL of the mixture must be injected SC into each of 4 selected 
injection sites (1 mL SC injection per site). After the injections are 
administered, the subject should be observed for at least 1 hour for any local 
and/or systemic allergic reactions.  
Dosage Form: Emulsified solution consisting of PolyPEPI1018-Mix1, 
PolyPEPI1018-Mix2, and Montanide™ (adjuvant), prepared onsite and used 
immediately post preparation. 
Dose Level: 0.2 mg/ peptide, 6 peptides total 
Mode of Administration: SC injection 
Reference Therapy, Dose, 
and Mode of 
Administration: 
No reference therapy is used in this study 
Inclusion Criteria: 
1. Male or female subjects, 18-75 years of age at time of Screening who 
provide written informed consent prior to initiation of any study 
procedure  
2. Histologically confirmed metastatic adenocarcinoma originating from 
the colon or the rectum 

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Product: PolyPEPI1018 Colorectal Cancer Vaccine 
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CONFIDENTIAL 
3. Presence of at least 1 measurable reference lesion according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
criteria  
4. Experienced PR or stable disease during first-line treatment with a 
systemic chemotherapy regimen and 1 biological therapy regimen  
5. Maintenance therapy with a fluoropyrimidine (5-fluorouracil or 
capecitabine) plus the same biologic agent (bevacizumab, cetuximab or 
panitumumab) used during induction, scheduled to initiate prior to the 
first day of treatment with the study drug 
6. No more than 1 line of chemotherapy regimen for mCRC (adjuvant 
therapy for non-metastasized disease is allowed if terminated more than 
6 months before Screening and without recurrence within 6 months after 
the end of adjuvant treatment) 
7. Last CT scan at 3 weeks or less before the first day of treatment 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 
9. Women of childbearing potential must agree to appropriately use an 
effective form of contraception (failure rate of <1% per year) for 
3 months from the day of the treatment. An effective form of 
contraception is defined as using hormonal contraceptives or an 
intrauterine device combined with at least 1 of the following forms of 
contraception: a diaphragm, cervical cap or condom 
10. Men must agree to use an effective form of contraception (as defined 
above), and not donate sperm for 3 months from the day of the treatment 
11. White blood cell count ≥3.0 × 109/L with neutrophils ≥1.5 × 109/L  
12. Platelets ≥100 × 109/L, hemoglobin ≥5.6 mmol/L (corresponding to 
9 g/dL) 
13. Serum bilirubin ≤1.5 × upper limit of normal (ULN) set by the site 
14. Alanine amino transferase (ALAT) and aspartate amino transferase 
(ASAT) ≤2.5 × ULN in the absence of liver metastases. ALAT and 
ASAT ≤5 × ULN set by the site in the presence of liver metastases 
15. Serum creatinine ≤1.5 × ULN set by the site and creatinine clearance 
>30 mL/min using Cockroft formula 
16. Relevant toxicities of prior therapies must have resolved to ≤Grade 1, 
except for oxaliplatin-related neuropathy or alopecia 
17. Anticipated life expectancy ≥6 months 
18. Subject is willing and able to comply with the requirements of the 
protocol 
Exclusion Criteria: 
1. Received chronic systemic immune therapy or immunosuppressant 
medication other than steroids within the last 6 weeks prior to start of 
study treatment 
2. Received continuous systemic steroid treatment within the last 2 weeks 
prior to start of study treatment 
3. Colorectal cancer with documented high microsatellite instability 
(MSI-H)  
4. Colorectal cancer with documented BRAF mutations 
5. Pre-existing systemic autoimmune or antibody-mediated diseases or 
immune deficiency diseases 
6. Central nervous system (CNS) metastases 
7. Active or uncontrolled severe infections or undiagnosed febrile 
condition >38ºC 

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CONFIDENTIAL 
8. Acute or subacute intestinal obstruction or history of chronic intestinal 
inflammatory diseases 
9. Symptomatic peritoneal carcinomatosis  
10. Peritonitis  
11. Serious, non-healing wounds, ulcers or bone fractures 
12. Nephrotic syndrome  
13. Arterial thromboembolisms or severe hemorrhages within 6 months 
before study enrolment (except bleeding tumor before tumor resection 
surgery)  
14. Hemorrhagic diathesis or thrombotic tendency  
15. Major surgery or radiotherapy within 12 weeks prior to the study 
treatment or anticipation of needing such procedure during the study 
period 
16. Uncontrolled pleural effusion, pericardial effusion or ascites requiring 
repeated drainage more than once every 28 days 
17. Participants with active malignancy (other than colorectal cancer [CRC]) 
or a prior malignancy within the past 12 months 
18. Participant with myocardial infarction within 6 months prior to 
enrollment or New York Heart Association Class III or IV heart failure, 
uncontrolled angina, severe uncontrolled ventricular arrhythmias or 
electrocardiographic evidence of acute ischemia or active conduction 
system abnormalities. Prior to the first dose of study treatment, any 
electrocardiogram (ECG) abnormality at Screening must be documented 
by the investigator as not medically relevant 
19. Administration of a live, attenuated vaccine within 4 weeks before 
randomization or anticipation of a live attenuated vaccine will be 
required during the study 
20. Participant has participated in another clinical study involving an 
investigational product (IP) or investigational device within 30 days 
prior to enrollment or is scheduled to participate in another clinical study 
involving an IP or investigational device during the course of this study 
21. Known hypersensitivity to any component of the investigational drug  
22. If female, participant is pregnant (exclusion confirmed with beta-human 
chorionic gonadotropin [hCG] test) or lactating at the time of enrollment, 
or has plans to become pregnant or start breastfeeding during the study 
23. Pre-existing alcohol or drug abuse  
24. Medical or mental impairments which make it impossible to obtain the 
patient’s consent or to conduct the study 
25. A significant concomitant medical condition which the clinical 
investigator believes precludes the patient from enrolling in the study  
26. Absent or limited legal competence 
Primary Endpoint: 
Occurrence of at least 1 ≥Grade 4 local adverse event (AE) or 1 ≥Grade 3 
systemic AE and/or signs/symptoms, lab toxicities, and/or clinical events that 
is probably or definitely related to study treatment, any time from Day 1 until 
21 days after administration of each dose of the vaccine.  
Criteria for 
Evaluation/Outcome 
Measures: 
Primary Outcome Measures: 
• 
The incidence and severity of all adverse events (AEs), related AEs, all 
serious adverse events (SAEs), related SAEs, and temporally-associated 
AEs according to the National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.0 (v4.0) 

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CONFIDENTIAL 
• 
Change from baseline in clinical laboratory safety parameters and vital 
signs 
• 
Number and proportion of subjects with any clinically significant 
change in vital signs (i.e., blood pressure, pulse rate, respiratory rate, 
body temperature) during the vaccine administration or within 
60 minutes following administration 
Secondary Outcome Measure(s): 
• 
PEPIs as identified by the PEPI Test 
• 
Effector T cell response against 12 selected epitopes of PolyPEPI1018 
as measured by interferon (IFN)-gamma Enzyme-Linked ImmunoSpot 
(ELISPOT) assay for the following: 
o 
Number and proportion of subjects with 0, ≥1, ≥2, ≥3, ≥4, ≥5 
effector T cell responses, respectively, detected at the Baseline 
Visits (Week -3 to -1 and Week 0) and at 3, 6-, 9-, and 12-weeks 
after administration of the vaccine  
o 
For each subject, the number of effector T cell responses  
o 
For each subject, the time course of effector T cell response at 
Baseline Visits (Week -3 to -1 and Week 0) and at 3-, 6-, 9-, and 
12-weeks after administration of the vaccine  
• 
Memory T cell response against 12 selected epitopes of PolyPEPI1018 
as measured by the Precursors with High Proliferation Capacity (PHPC) 
assay for the following: 
o 
Number and proportion of subjects with 0, ≥1, ≥2, ≥3, ≥4, ≥5 
memory T cell response, respectively, detected at the Baseline 
Visits (Week -3 to -1 and Week 0) and at 3-, 6-, 9-, and 12-weeks 
after administration of the vaccine 
o 
For each subject, the number of positive memory T cell responses 
o 
For each subject, the time course of memory T cell response at 
Baseline Visits (Week -3 to -1 and Week 0) and at 3-, 6-, 9-, and 
12-weeks after administration of the vaccine  
• 
Objective Response Rate (ORR) measured by CT scan at Screening 
Visit (Week -3 to -1), and at 6-, and 12-weeks after administration of 
each dose of the vaccine  
Exploratory Outcome Measures: 
• 
Correlations between PEPIs identified by the PEPI Test and effector and 
memory T cell responses measured by ELISPOT and PHPC 
immunogenicity assays 
• 
Change in relative counts of tumor infiltrating lymphocytes (TILs) in 
accessible tumor biopsies at Baseline (Week -3 to -1) and at Week 12 as 
measured by immunohistochemistry 
• 
Correlation between PEPIs identified by the PEPI Test and infiltrating 
lymphocyte in tumor biopsies measured by immunohistochemistry 
• 
Correlations between T cell responses measured by ELISPOT and 
PHPC and infiltrating lymphocyte in tumor biopsies measured by 
immunohistochemistry 
• 
Correlations between PEPIs identified by the PEPI Test and effector and 
ORR 
• 
Correlations between T cell responses measured by ELISPOT and 
PHPC and ORR 
 

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Product: PolyPEPI1018 Colorectal Cancer Vaccine 
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CONFIDENTIAL 
Sample Size Justification: 
Approximately 10 subjects will be enrolled in the study to receive three 
vaccinations. The study is not statistically powered to assess the primary or 
secondary outcomes measures. 
Assuming that the human leukocyte antigen (HLA) sets from the subjects 
follow the distribution observed in the HLA sets from the in-house database, 
at least 39 positive immune responses are expected from 10 subjects. The 
distribution of the expected number of positive tests is displayed in 
Figure S1, which is generated from 10,000 simulations. The x-axis shows the 
number of positive tests, and the y-axis shows the probabilities. 
Figure S1. 
Distribution of the Expected Number of Positive Tests 
 
Based on the simulation, at least 7 subjects are expected to have an immune 
response against 2 or more cancer antigens with at least 97.5% probability. 
The expected distribution of probabilities having a given number of subjects 
with positive immune response for 2 or more antigens is displayed in 
Figure S2, the x-axis shows the number of subjects with a given probability 
and the y-axis shows the probability. 
Figures S2. 
Expected Distribution of Probabilities Having a Given 
Number of Subjects with Positive Immune Response for Two or More 
Antigens 
 
Statistical Methods and 
Analyses: 
Demographic and baseline characteristics will be summarized using 
descriptive statistics. 
Safety/tolerability will be assessed by tabulating the number and percentage 
of subjects who develop 1 or more related Grade 3 or higher systemic SAEs 
and/or Grade 4 or higher local SAEs.  
The incidence of AEs, the incidence of treatment-related AEs, and the 
severity of AEs will be summarized using descriptive statistics. Other safety 
parameters (injection site reactions, clinical laboratory parameters, vital 
signs, ECG measures) and the change from Baseline in these parameters will 
be summarized using descriptive statistics.  
0
0.02
0.04
0.06
0.08
0
20
40
60
80
0
0.1
0.2
0.3
0.4
0.5
0
5
10

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CONFIDENTIAL 
Immunogenicity parameters versus time will be plotted for each subject; 
similar summary plots will be constructed for the 10 subjects.  
Efficacy parameters versus time will be plotted for each subject; similar 
summary plots will be constructed for the 10 subjects.  
Correlation and significance tests will be performed on the results of 
exploratory measures. 
 

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CONFIDENTIAL 
TABLE OF CONTENTS 
Page 
 
CLINICAL STUDY PROTOCOL .........................................................................................1 
CLINICAL STUDY PROTOCOL APPROVAL SIGNATURE PAGE .............................2 
INVESTIGATOR ACCEPTANCE PAGE ...........................................................................3 
SYNOPSIS ................................................................................................................................4 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF TABLES .................................................................................................................15 
LIST OF FIGURES ...............................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................16 
1 
BACKGROUND INFORMATION .........................................................................18 
1.1 
Colorectal Cancer Background ........................................................................18 
1.2 
PolyPEPI1018 and Companion Diagnostic Vaccine Overview ......................19 
1.2.2 
Preclinical and Clinical Background for PolyPEPI1018 ..................22 
1.3 
Rationale for Study Design and Dose Regimen ..............................................24 
1.4 
Benefits and Risks............................................................................................26 
2 
STUDY OBJECTIVES ..............................................................................................28 
2.1 
Primary Objectives...........................................................................................28 
2.2 
Secondary Objectives.......................................................................................28 
2.3 
Exploratory Objectives ....................................................................................28 
3 
STUDY DESIGN ........................................................................................................29 
3.1 
Overall Study Design .......................................................................................29 
3.2 
Outcome Measures...........................................................................................31 
3.2.1 
Primary Outcome Measures ..............................................................31 
3.2.2 
Secondary Outcome Measures ..........................................................31 
3.2.3 
Exploratory Outcome Measures .......................................................32 
3.3 
Estimated Study Duration ................................................................................32 
3.4 
Randomization and Blinding ...........................................................................33 
3.5 
Study Stopping Rules .......................................................................................33 
4 
SUBJECT SELECTION ...........................................................................................34 
4.1 
Inclusion Criteria .............................................................................................34 

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4.2 
Exclusion Criteria ............................................................................................35 
4.3 
Subject Withdrawal and Discontinuation ........................................................36 
4.3.1 
Permanent Treatment Discontinuation .............................................38 
4.3.2 
Premature Treatment Discontinuation ..............................................38 
5 
STUDY TREATMENTS ...........................................................................................39 
5.1 
PolyPEPI1018 CRC Vaccine ...........................................................................39 
5.1.1 
Description ........................................................................................39 
5.1.2 
PolyPEPI1018 Product Preparation and Administration ..................39 
5.1.3 
Packaging and Labeling ....................................................................40 
5.1.4 
Supply, Distribution, and Pharmacy .................................................40 
5.1.5 
Storage ..............................................................................................41 
5.2 
Reference Therapy ...........................................................................................41 
5.3 
Investigational Product Accountability ............................................................41 
5.4 
Concomitant Medications ................................................................................42 
5.4.1 
Required Medications .......................................................................42 
5.4.2 
Prohibited Medications .....................................................................42 
5.4.3 
Precautionary Medications................................................................43 
5.5 
Dose Modification Guidelines and Toxicity Management ..............................43 
5.5.1 
Local Reactions .................................................................................43 
5.5.2 
Systemic Reactions ...........................................................................44 
5.5.3 
Anticancer Drugs ..............................................................................44 
5.5.4 
Dose Limiting Toxicity (DLT) .........................................................45 
6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES .................46 
6.1 
Informed Consent Form ...................................................................................46 
6.2 
Subject Identification Code ..............................................................................46 
6.3 
Screening Log ..................................................................................................46 
6.4 
Vaccine Site Evaluation ...................................................................................47 
6.5 
Evaluation of Response to First-line Therapy .................................................47 
6.6 
Immunogenicity and Efficacy Assessments ....................................................47 
6.6.1 
PEPI Test ..........................................................................................48 
6.6.2 
Effector T Cell Response ..................................................................48 
6.6.3 
Memory T Cell Response .................................................................48 
6.6.4 
Tumor Infiltrating Lymphocyte (TILs) .............................................49 

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6.6.5 
CT scan and RECIST/ irRECIST evaluation ....................................49 
6.7 
Safety Assessments ..........................................................................................50 
6.7.1 
Adverse Events .................................................................................50 
6.7.2 
Urgent Safety Measures ....................................................................50 
6.7.3 
Untoward Medical Occurrences .......................................................50 
6.7.4 
Non-Medical Complaints ..................................................................51 
6.7.5 
Medical, Medication, and Non-Drug Therapy History .....................51 
6.7.6 
Physical Examinations ......................................................................52 
6.7.7 
Vital Signs .........................................................................................52 
6.7.8 
Clinical Laboratory Parameters ........................................................53 
6.7.9 
Patient Diary .....................................................................................54 
6.8 
Procedures for Monitoring Subject Compliance..............................................54 
7 
ASSESSMENTS AND PROCEDURES BY STUDY VISIT ..................................55 
7.1 
Screening Period (Visit 1 - Days -21 to Day -1 – Weeks -3 to -1) ..................55 
7.2 
PolyPEPI1018 Administration (Visit 2 – Day 1 - Week 0), (Visit 7 – 
Day 92 ±2 - Week 13) and (Visit 12 – Day 183 ±2 - Week 26), .....................55 
7.3 
Follow-Up Period.............................................................................................56 
7.3.1 
Visit 3 (Day 22 - Week 3), Visit 5 (Day 64 - Week 9), Visit 8 
(Day 113 ±2 - Week 16), Visit 10 (Day 155 ±2 - Week 22), 
Visit 13 (Day 204 ±2 - Week 29) and Visit 15 (Day 246 ±2 - 
Week 35) ...........................................................................................56 
7.3.2 
Visit 4 (Day 43 - Week 6), Visit 6 (Day 85 - Week 12), Visit 9 
(Day 134 ±2 - Week 19), Visit 11 (Day 176 ±2 - Week 25), 
Visit 14 (Day 225 ±2 - Week 32) and Visit 16 (Day 267 ±2 - 
Week 38) ...........................................................................................56 
7.4 
Last Visit ..........................................................................................................57 
8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................58 
8.1 
Definitions........................................................................................................58 
8.1.1 
Adverse Event ...................................................................................58 
8.1.2 
Serious Adverse Event ......................................................................58 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...........59 
8.1.4 
Non-Serious Adverse Event ..............................................................59 
8.1.5 
Unexpected Adverse Events .............................................................59 
8.1.6 
Preexisting Diseases..........................................................................59 
8.2 
Assessment of Adverse Events ........................................................................60 

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8.2.1 
Severity .............................................................................................61 
8.2.2 
Causality ...........................................................................................61 
9 
STATISTICS ..............................................................................................................63 
9.1 
Analysis Populations ........................................................................................63 
9.2 
Replacement of Subjects ..................................................................................63 
9.3 
Handling of Missing, Unused, and Spurious Data ...........................................63 
9.3.1 
Missing Data Resulting from Study Withdrawal ..............................63 
9.3.2 
Intermediate Missing Data ................................................................63 
9.4 
Primary Endpoint .............................................................................................63 
9.5 
Statistical Analyses ..........................................................................................64 
9.5.1 
Safety Analysis .................................................................................64 
9.5.2 
PEPI and Immunogenicity Analyses ................................................65 
9.5.3 
Efficacy Analyses .............................................................................65 
9.5.4 
Exploratory Analyses ........................................................................66 
9.6 
Determination of Sample Size .........................................................................66 
10 
ETHICAL AND LEGAL CONSIDERATIONS .....................................................69 
10.1 
Compliance Statement .....................................................................................69 
10.2 
Ethics Committee and Regulatory Authorities ................................................69 
10.3 
Informed Consent and Human Subject Protection...........................................69 
10.4 
Confidentiality .................................................................................................70 
11 
ADMINISTRATIVE CONSIDERATION ..............................................................71 
11.1 
Investigator’s Responsibilities .........................................................................71 
11.2 
Study Training .................................................................................................71 
11.3 
Study Monitoring .............................................................................................71 
11.4 
Safety Monitoring ............................................................................................72 
11.5 
Audits ...............................................................................................................72 
11.6 
Documentation .................................................................................................72 
11.6.1 
Case Report Forms and Study Records ............................................72 
11.6.2 
Direct Access to Source Data, Source Documents, and Study 
Records .............................................................................................73 
11.6.3 
Source Data .......................................................................................73 
11.6.4 
Document and Data Retention ..........................................................74 
11.7 
Non-Compliance with the Protocol .................................................................74 

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11.8 
Financing and Insurance ..................................................................................75 
11.9 
Publication Policy ............................................................................................75 
12 
REFERENCES ...........................................................................................................76 
APPENDIX A. 
SCHEDULE OF STUDY ASSESSMENTS ..................................78 
APPENDIX B. 
THE WORLD ALLERGY ORGANIZATION 
SUBCUTANEOUS IMMUNOTHERAPY SYSTEMIC REACTION 
GRADING SYSTEM .................................................................................................81 
 
 
 
LIST OF TABLES 
Table 1. 
Synthetic Peptide Sequences..................................................................................20 
Table 2. 
Local Reaction Assessment Scale ..........................................................................44 
 
 
LIST OF FIGURES 
Figure 1. Cancer Testis Antigens Targeted by PolyPEPI1018 .............................................21 
Figure 2. Mechanism of Action of Precision PolyPEPI1018 CRC Vaccine .........................22 
Figure 3. Study Design Schema ............................................................................................30 
Figure 4. Distribution of the Expected Number of Positive Tests ........................................67 
Figure 5. Expected Distribution of Probabilities Having a Given Number of Subjects 
with Positive Immune Response for Two or More Antigens ................................68 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALAT 
alanine amino transferase 
ASAT 
aspartate amino transferase 
CA 19-9 
cancer antigen 
CDx 
companion diagnostic 
CEA 
carcinoembryonic antigen 
CNS 
central nervous system 
CPI 
checkpoint inhibitors 
CRC 
colorectal cancer 
CRF 
case report form 
CTA 
cancer testis antigen 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T lymphocyte 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EU 
European Union 
5FU 
5-fluorouracil 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
HLA 
human leukocyte antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IFN 
interferon 
IHC 
immunohistochemistry 
IP 
investigational product 
IRB 
Institutional Review Boards 
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MEK 
MAPK/ERK kinase 
MSI-H 
high microsatellite instability 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NMC 
non-medical complaint 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PEPI 
personal epitope 
PHPC 
Precursors with High Proliferation Capacity 
PR 
partial response 
RAS 
Rat Sarcoma Viral Oncogene Homolog 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAER 
SAE report 
SAS 
Safety Analysis Set 
SC 
subcutaneous(ly) 
SIC 
subject identification code 
SoA 
Schedule of Study Assessments 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TIL 
tumor‐infiltrating lymphocyte 
ULN 
upper limit of normal 
US 
United States 
WT 
wildtype 
 

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1 
BACKGROUND INFORMATION 
1.1 
Colorectal Cancer Background 
Colorectal cancer is a leading cause of cancer-related mortality worldwide. In the European 
Union (EU-28) and the World Health Organization Europe Region, the mean mortality rates 
per 100,000 population are respectively 15.2 and 15.7 for men and 9.0 and 9.7 for women 
(Ferlay 2015). The mean incidence rate of colorectal cancer in the EU-28 is 31.3 per 
100,000 population (39.5 per 100,000 population for men and 24.4 per 100,000 population 
for women), with 345,000 new cases per year. 
Colorectal cancer is the third most common cancer and the third leading cause of cancer 
death in men and women in the United States (US). In 2010, the US spent $14 billion for the 
management of colorectal cancer (Mariotto 2011).  
While multidisciplinary care is employed in the treatment of localized colon cancer, systemic 
chemotherapy is the mainstay of treatment in metastatic colorectal cancer (mCRC). There are 
currently 10 Food and Drug Administration (FDA) approved drugs for the management of 
mCRC, including 5-fluorouracil (5FU), oxaliplatin, irinotecan, capecitabine, bevacizumab, 
cetuximab, panitumumab, ziv- aflibercept, regorafenib and ramucirumab. There are a variety 
of regimens with different combinations of these drugs, for use in first-, second-, and 
third-line settings of treatment. For example, 5FU, oxaliplatin (FOLFOX) and bevacizumab 
are commonly used as a first-line therapy (Saltz 2008). The Rat Sarcoma Viral Oncogene 
Homolog (RAS) is a family of genes including KRAS and NRAS that are often found to be 
mutated in colorectal cancer. When a tumor is RAS wildtype (WT), patients derive benefit 
from monoclonal antibodies, such as cetuximab or panitumumab, which target the epidermal 
growth factor receptor (EGFR). Thus, EGFR targeted therapy, in addition to chemotherapy, 
is a common second-line strategy for patients with RAS WT disease (Seymour 2013). The 
chemotherapy backbone used in second-line treatment is often 5FU and irinotecan 
(FOLFIRI), with regorafenib monotherapy commonly used as a third-line option (Grothey 
2013). More recently it has been shown that FOLFOXIRI plus bevacizumab compared with 
FOLFIRI plus bevacizumab, improve the outcome in patients with mCRC (Loupakis 2014). 

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Despite the available treatment options, response rates to mCRC remain low. Multiple 
therapies with novel mechanisms of actions are being developed to treat mCRC, including 
small molecule tyrosine kinase inhibitors, and MAPK/ERK kinase (MEK; also known as 
MAP2K) inhibitors. BRAF mutations, usually associated with poor prognosis, are found in 
~10% of patients with colorectal cancer (CRC), and small molecule inhibitors of BRAF are 
being developed as combination treatments with other available therapies (Cassidy 2017).  
Immunotherapy is an attractive treatment option since it is more tolerable than conventional 
chemotherapy with potential long-lasting durable responses. Novel checkpoint inhibitors 
(CPIs) have demonstrated unprecedented clinical activity in a wide range of cancers. The 
observation of clinical activity in microsatellite instability-high (MSI-H) mCRC was the first 
indication of a potential for mCRC to respond to these agents, and has led to a breakthrough 
designation by the FDA for CPI use in this subset of patients (estimated as 5% to 10% of the 
patient population with mCRC). However, a proportion of MSI-H, and nearly all 
microsatellite stable disease, does not respond to single-agent checkpoint inhibition, and 
clinical trials are ongoing to increase responses to immunotherapy in mCRC through both 
better patient selection and novel combinations of immunotherapeutic agents (Bever 2017).  
1.2 
PolyPEPI1018 and Companion Diagnostic Vaccine Overview 
PolyPEPI1018 CRC Vaccine (PolyPEPI1018) and companion diagnostic (CDx) product is a 
precision CRC vaccine that takes into account an individual patient’s genetics and tumor 
heterogeneities using information technology during product design and responder selection 
processes. The subcutaneously (SC) injected vaccine product is a mixture of 6 synthetic 
peptides (Table 1) and the adjuvant Montanide™.  
The CDx is a pharmacogenetic test to be co-developed with PolyPEPI1018, which will select 
patients who most likely respond to vaccine treatment. The CDx uses the complete human 
leukocyte antigen (HLA) genotype of the patient for the identification of personal epitopes 
(PEPIs) that induce T Cell responses. To identify PEPIs the sponsor developed the novel 
PEPI Test. As described in Section 6.6.1, the PEPI Test selects, from HLA restricted 
epitopes, certain PEPIs that are capable of activating T cells in an individual. PEPIs are 
genetic biomarkers specific to the HLA genotype of an individual patient. The 

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PolyPEPI10108 CDx will use the PEPI Test to identify the patient’s PEPIs from 
PolyPEPI1018. Data from a retrospective correlation study performed by the sponsor suggest 
that patients with PEPIs derived from multiple CRC antigens are likely to benefit from 
PolyPEPI1018 vaccination. 
Table 1. 
Synthetic Peptide Sequences 
ID 
Sequence 
CRC_P1 
PSTTMETQFPVSEGKSRYRAQRFWSWVGQA 
CRC_P2 
VRTYWIIIELKHKARTAKKVRRAIEQLAAM 
CRC_P3 
YVDEKAPEFSMQGLKDEKVAELVRFLLRKY 
CRC_P6 
PKSMTMMPALFKENRSGAVMSERVSGLAGS 
CRC_P7 
KFMNPYNAVLTKKFQKVNFFFERIMKYERL 
CRC_P8 
AQKMSSLLPTMWLGAFKKTMSTFHNLVSLN 
The 6 peptides in PolyPEPI1018 contain 12 novel and distinct selected epitopes which are 
derived from 7 conserved cancer testis antigens (CTAs) that act in combination to activate 
T cells against CRC antigens in a high proportion of patients.   
The 7 most frequently expressed CTAs in CRC were selected as targets of PolyPEPI1018, 
and statistical analysis demonstrates a 95% probability that 3 of these 7 CTAs are expressed 
in any CRC cell (Figure 1). Given the high probability of targeting CRC expressed CTAs by 
PolyPEPI1018, tumor biopsy and CTA expression analysis, a risky, inaccurate and costly 
procedure1, is not required prior to vaccination with PolyPEPI1018. 
                                                 
1 There is no validated diagnostic device available to perform tumor antigen expression profiling from tumor 
biopsies. In addition, a biopsy does not comprehensively characterize a heterogeneous tumor, especially in the 
metastatic stage. 

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Figure 1. Cancer Testis Antigens Targeted by PolyPEPI1018 
 
Abbreviations: CRC = colorectal cancer; CTA = cancer testis antigen 
Left: Expression rate in CRC obtained from 2,391 CTA expression analyses in tumor specimens. 
Right: Probability of expression in CRC tumor shows that 3 out of 7 CTAs are expressed in each tumor with 
>95% probability. 
1.2.1 
Mechanism of Action 
Cancer vaccines represent the next generation immunotherapies (Chen 2013). They induce 
specific immune responses against tumor antigens, thereby boosting the immune system to 
attack cells expressing the targeted antigens. Tumor antigens that are currently being targeted 
by available immunotherapies include MUC1 and NY-ESO-1. Though current cancer 
vaccines have an excellent safety profile, the response rate is low due to poor antigen 
selection and the absence of a biomarker for identification of likely responders. 
PolyPEPI1018 induces PEPI-specific immune responses against multiple CTAs that are 
expressed in CRC and are not typically expressed beyond embryonic development in healthy 
cells. One PEPI derived from one tumor antigen can activate one cytotoxic T lymphocyte 
(CTL) to proliferate (clonal expansion) and kill tumor cells that present the same PEPI. If the 
patient has a homogenous tumor that consists of a single type of cell which presents the same 
PEPI, treatment with a single peptide vaccine could be successful. However, most tumors, 
especially at the metastatic stage, represent a fast-evolving group of heterogeneous tumor 
cells which differ in antigen expression and PEPI presentation. Therefore, boosting several 
CTL clones (i.e., polyvalent immune responses) using a combination of vaccines increases 
the probability of tumor cell recognition and tumor killing (Figure 2). 

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Figure 2. Mechanism of Action of Precision PolyPEPI1018 CRC Vaccine 
 
Abbreviations: CTL = cytotoxic T lymphocyte; HLA = human leukocyte antigen; PEPI = personal epitope 
A: One peptide in the vaccine is processed to PEPI in the body of the patient by antigen presenting cells (APC). 
The patient’s HLA molecules on the APC bind and present the PEPI to activate a CTL. This CTL proliferates 
and differentiates to a PEPI-specific CTL.  
B: A PEPI-specific CTL is able to recognize and destroy the tumor cells presenting the same PEPI.  
C: PolyPEPI1018 is based on the combination of several vaccines capable to induce multiple different 
PEPI-specific CTLs.  
D: These CTLs may recognize and destroy heterologous tumor cells in the patient presenting the same PEPIs. 
1.2.2 
Preclinical and Clinical Background for PolyPEPI1018 
PolyPEPI1018 will be evaluated in patients with mCRC. Since this is a first-in-human study, 
clinical safety and efficacy data from other peptide vaccines are summarized in the sections 
below.  
1.2.2.1 
Safety of Peptide Vaccines and MontanideTM 
Overall there is a well-established safety profile for peptide vaccines and the adjuvant 
Montanide™. To date, there are 22 published clinical trials, in 813 patients, on peptide 

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vaccines formulated with the adjuvant Montanide™ (details are provided in the Investigator 
Brochure). 
The most common side effect of peptide vaccines is inflammation at the injection site, 
including redness, pain, swelling, warming of the skin, itchiness, and rash. Occasionally, but 
rarely, unacceptable local skin reactions developed after 10 or more vaccinations, causing 
treatment to be terminated. After receiving a peptide vaccine, patients occasionally 
experienced flu-like symptoms, including fever, chills, weakness, dizziness, nausea or 
vomiting, muscle ache, fatigue, headache, and occasional breathing difficulties. Blood 
pressure was also affected in some subjects who received a peptide vaccine. Many of these 
side effects, which last for a short time, are signs/symptoms of inflammation (similar to those 
occurring after an acute viral infection), likely indicating that the patient was mounting an 
immune response. 
Peptide vaccines, like any other medication affecting the immune system, can cause adverse 
effects that may prove life threatening. For example, severe hypersensitivity (allergic) 
reactions to specific vaccine ingredients have occurred following vaccination; however, such 
severe reactions are very rare (Yoshida 2011). Furthermore, the design of PolyPEPI1018 
excludes peptides containing self-epitopes, thus reducing to a minimum the risk of 
autoimmune and/or hypersensitivity reactions. 
In the 813 subjects from the 22 published clinical trials on peptide vaccines formulated with 
Montanide™ the most serious adverse events (SAEs) were caused by cancer progression. 
Vaccine-related Grade 3 events were very rare (6 events, 0.7%), and consisted of skin 
reactions or cellulitis at the injection site, edemas of the head and neck regions, colitis, rectal 
bleeding and bladder-vaginal fistulae.  
1.2.2.2 
Efficacy of Peptide Vaccines 
PolyPEPI1018 belongs to the class of peptide vaccines. Previous clinical studies have 
demonstrated that peptide vaccines induce CTL responses. However, the main limitation of 
these peptide vaccines is the absence of the induction of CTL responses against multiple 
antigens expressed in tumor cells.  

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The sponsor hypothesized that induction of antigen specific immune response against 
multiple antigens that are expressed by the tumor cells will substantially improve the immune 
response rate and efficacy of the cancer vaccine. Consistent with this expectation, 
preliminary clinical results with IMA901 peptide vaccines demonstrated that polyvalent 
tumor specific CTL responses led to clinical benefit in renal cancer patients (Walter 2012); 
two independent studies with personalized cancer vaccines confirmed these findings in 
melanoma patients (Ott 2017; Sahin 2017). 
A retrospective clinical study conducted by the sponsor demonstrated significant correlation 
between objective response rate (ORR) of cancer vaccines containing multiple antigens and 
PEPIs on at least 2 vaccine antigens (see the Investigator Brochure). These data suggest that 
that patients with PEPIs derived from multiple CRC antigens are likely to benefit from 
PolyPEPI1018 vaccinations.  
1.3 
Rationale for Study Design and Dose Regimen 
Treos Bio ZRT (sponsor) has developed a vaccine, PolyPEPI1018, which has the potential to 
elicit an immune response in most individuals with mCRC. Such an immune response is 
expected to control, reduce, or eliminate cancer in those patients.  
The sponsor elected to move from a single vaccination (as originally planned) to multiple 
(N=3) vaccinations during this first-in-human study to establish the rate, intensity, and 
evolution of immune responses to PolyPEPI1018 as well as initial efficacy. Since a sufficient 
time (typically 3 months/12 weeks) is required after vaccination to observe the time course of 
both effector and memory T cell responses, the maintenance phase following first-line 
therapy of mCRC (a 4 to 6 month period when the tumor, therapy, and patient’s condition are 
expected to remain stable [Heinemann 2014; Cremolini 2015; Venook 2017]) is the preferred 
period for treatment with PolyPEPI1018 since it offers optimal conditions for monitoring the 
time course of immune response after at least the initial vaccination. If a progression occurs 
during the course of the trial the subject will still be immunized at the expected times (Weeks 
13 and 26), even when a second line therapy is needed and administered. 
Understanding the evolution of T cell response after vaccination will provide valuable 
information to design the vaccine administration schedule in future clinical studies. 

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Moreover, a clean readout of immune responses after single vaccination with adequate 
follow-up will allow a better assessment of whether the PEPI Test can accurately predict 
immune responses. Clarifying such correlation will provide a predictive tool that can be used 
as a CDx in future trials. Therefore, multiple vaccinations 13 week apart  with a 12-week 
follow-up period after third and final vaccination will provide information to design 
subsequent Phase 2/3 trials.  
Only 1 line of prior mCRC chemotherapy treatment is allowed for subjects in this study since 
response to second- and third-line therapy is often associated with worse and shorter 
response compared with first-line therapy. Therefore, allowing more than 1 line of prior 
chemotherapy would not fulfil the expectation of stable conditions during the 12-week 
follow-up period after first vaccination. 
Male or female subjects must be between 18 years and 75 years of age at time of Screening 
since a robust immune system is needed to elicit an appropriate immune response to 
vaccination with PolyPEPI1018. Also for this reason, subjects must have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
The sponsor intends to explore whether multiple vaccinations are able to elicit an immune 
response that is sufficiently robust to generate tumor infiltrating lymphocytes (Klintrup 
2005), and whether this correlates with PEPIs. The sponsor also intends to explore the initial 
efficacy of PolyPEPI1018 multiple vaccinations. Consequently, subjects must have 
histologically confirmed metastatic adenocarcinoma originating from the colon or the 
rectum, with the presence of at least 1 measurable reference lesion according to the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.  
The progression of CRC during the 12 weeks following each vaccination will be monitored 
by CT scan every 6 weeks not only to measure efficacy but also to establish whether subject 
need to start a second line induction therapy.  
Subjects in the study will receive maintenance therapy with a fluoropyrimidine (5-
fluorouracil or capecitabine) plus the same biologic agent (bevacizumab, cetuximab or 
panitumumab) used during induction. It is typically assumed that chemotherapy is immune 

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suppressive; however, recent advances have shown that in several instances chemotherapy 
might exert positive effects on immune responses by inducing mechanisms that potentiate 
immunity (Emens 2015). It is also anticipated that treatment with a biologic drug during 
maintenance therapy will not interfere with vaccination. Studies have shown that EGFR 
inhibitors do not interfere with immunotherapies and bevacizumab potentiates immune 
responses (Terme 2013; Mansfield 2013). Therefore, subjects will be immunized even when 
a second line therapy is administered. 
Finally, maintenance therapy is allowed with 1 biological therapy regimen with or without a 
systemic chemotherapy regimen scheduled to initiate prior to vaccination and to continue 
throughout the 12-week follow-up period. Thus, patients may receive standard-of-care 
treatment while participating in this study, including introducing a second line therapy, if 
needed. 
1.4 
Benefits and Risks 
It is expected that PolyPEPI1018 will induce PEPI-specific immune responses against 
multiple CTAs expressed in CRC cells. Previous clinical studies have demonstrated that 
peptide vaccines similar to PolyPEPI1018 induce CTL responses. Recently, 2 independent 
studies have shown that personalized vaccination of melanoma patients, with selected mutant 
proteins identified as being the most likely to generate an immune response, resulted in 
atypically long relapse-free durations after vaccination (Ott 2017; Sahin 2017).  
Limitations of most vaccines include a lengthy period needed to identify the targets, 
formulate and manufacture vaccines. The present study would provide information for 
vaccine improvement. As described in Section 1.2, PolyPEPI1018 consists of the 7 most 
frequently expressed CTAs in CRC, and there is a 95% probability the 3 of these 7 CTAs are 
expressed in any CRC cell. It is expected that PolyPEPI1018 will induce cytotoxic T cell 
responses against CTAs expressed in CRC cells, thereby matching the vaccines to patient’s 
tumor antigens and whole HLA genotype. Only a saliva sample, not the traditionally required 
tumor biopsy, will be required for performing the PEPI Test for the identification of likely 
responders, thus simplifying and accelerating the selection procedure.  

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In order to examine whether the PEPI Test can predict immune responses and identify 
potential responders (thus providing the basis and the rationale for its use as CDx in future 
studies) it is essential that the present study allows 12 weeks of follow-up after each 
vaccination. This will also provide useful information to inform us on scheduling (how often 
vaccination should be repeated) during future multiple-vaccination studies. 
As described in Section 1.2.2.1, based on the safety profile of similar vaccines, 
PolyPEPI1018 is expected to be safe and well-tolerated. Side effects are typically mild 
(Section 1.2.2.1.). Local erythema and edema in the site of vaccination are expected, as well 
as a flu-like syndrome with minor fever and fatigue. Vaccines, like any other medication that 
affects the immune system, can cause adverse effects that may prove life threatening. For 
example, severe hypersensitivity (allergic) reactions to specific vaccine ingredients have 
occurred following vaccination; however, such severe reactions are very rare (Yoshida 
2011). Furthermore, the design of PolyPEPI1018 excludes peptides containing self-epitopes, 
thus reducing the risk of autoimmune and/or hypersensitivity reactions to a minimum. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of this study is: 
• To evaluate the safety and tolerability of a multiple doses of PolyPEPI1018 as an add-
on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC) 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To identify PEPIs (Personal EPItopes capable of inducing T cell responses in an 
individual) from PolyPEPI1018 in each study subject 
• To evaluate the immunogenicity of PolyPEPI1018 by measuring both effector and 
memory T cell responses 
• To evaluate initial efficacy of PolyPEPI1018 by evaluating Objective Response Rate 
(ORR)  
2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To explore the correlation between PEPIs and T cell responses  
• To explore the correlation between PEPIs and tumor infiltrating lymphocytes  
• To explore the correlation between T cell responses and tumor infiltrating 
lymphocytes 
• To explore the correlation between PEPIs  and ORR  
• To explore the correlation between T cell responses and ORR  

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3 
STUDY DESIGN 
3.1 
Overall Study Design  
This is a Phase 1, open-label, non-randomized, multicenter study to evaluate the safety, 
tolerability, immunogenicity and efficacy of multiple subcutaneous (SC) injections of 
PolyPEPI1018 as an add-on immunotherapy to the standard-of-care maintenance therapy in 
approximately 10 subjects with mCRC. This is an amended Study Design only in the USA: 5 
subjects in Italy are under evaluation after only a single SC injection of the same vaccine, as 
originally planned.  
The study is composed of a 3-week Screening Period, the administration of multiple doses 
vaccine (Day 1, Week 0; Day 92, Week 13; Day 183, week 26), a 13-week Follow-up Period 
between the first and second vaccination and a 12-week Follow-up Period after the last 
vaccination. The study will be conducted on an outpatient basis. 
The Screening Period will occur between 21 days and 1 day prior to administration of 
PolyPEPI1018 administration. Screening should be performed in parallel with the subject’s 
completion of the standard-of-care first-line treatment and initiation of the standard-of-care 
maintenance treatment. During this study period, results from a CT scan, which should be 
performed at the completion of the first-line treatment regimen, must be obtained. The results 
from the CT scan must confirm that the subject has responded to first-line chemotherapy with 
documentation of cancer regression or lack of progression, according to the RECIST version 
1.1 criteria. Once informed consent has been obtained, the subject will undergo a biopsy 
procedure in one of the accessible tumors (primary or metastasis) to check for tumor 
infiltrating lymphocytes (TILs). 
The first dose of PolyPEPI1018 will be administered on Day 1 of Week 0 and must be 
(1) after the subject initiates the maintenance regimen, and (2) within 3 weeks after the 
eligibility CT scan was performed. Vaccination will be performed at 4 anatomic sites 
(preferably draining to axillary or inguinal lymph nodes) and administered by SC injection. 
After the last injection, the subject must remain at the site for at least 1 hour to be monitored 
for any local and/or systemic allergic reactions. A buccal swab will be collected to determine 

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HLA types. A subject diary will be distributed to subjects to collect local signs related to the 
injection sites, physical fatigue, and body temperature. 
Subjects will be monitored every 3 weeks for 12 weeks after first administration of 
PolyPEPI1018 (i.e. Weeks 3, 6, 9 and 12), then vaccinated again at week 13 and monitored 
every 3 weeks for 12 weeks after second administration of PolyPEPI1018 (i.e. Weeks 16, 19, 
22 and 25), then vaccinated again at week 26 and  monitored every 3 weeks for 12 weeks 
after third administration of PolyPEPI1018 (i.e. Weeks 29, 32, 35 and 38).  
The timing of the study assessments and procedures are summarized in the Schedule of Study 
Assessments (SoA) in Appendix A. 
Figure 3. Study Design Schema 
Five subjects in Italy will follow the original Study Design 
 
Ten Subjects in the USA will follow the amended Study Design; those who have already 
signed an Informed Consent Form for the original Study Design will be asked to sign a new 
Informed Consent Form at the end of the first 12-week follow-up period. 

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3.2 
Outcome Measures 
3.2.1 
Primary Outcome Measures 
• The incidence and severity of all adverse events (AEs), related AEs, all SAEs, related 
SAEs, and temporally-associated AEs according to the National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (v4.0) 
• Change from baseline in clinical laboratory safety parameters and vital signs 
• Number and proportion of subjects with any clinically significant change in vital 
signs (i.e., blood pressure, pulse rate, respiratory rate, body temperature) during the 
vaccine administration or within 60 minutes following administration 
3.2.2 
Secondary Outcome Measures 
• PEPIs as identified by the PEPI Test 
• Effector T cell response against 12 selected epitopes of PolyPEPI1018 as measured 
by interferon (IFN)-gamma Enzyme-Linked ImmunoSpot (ELISPOT) assay for the 
following: 
o Number and proportion of subjects with 0, ≥1, ≥2, ≥3, ≥4, ≥5 effector T cell 
responses, respectively, detected at the Baseline Visits (Week -3 to -1 and 
Week 0) and at 3, 6-, 9-, and 12-weeks after administration of the vaccine  
o For each subject, the number of effector T cell responses  
o For each subject, the time course of effector T cell response at Baseline Visits 
(Week -3 to -1 and Week 0) and at 3-, 6-, 9-, and 12-weeks after administration of 
the vaccine  

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• Memory T cell response against 12 selected epitopes of PolyPEPI1018 as measured 
by the Precursors with High Proliferation Capacity (PHPC) assay for the following: 
o Number and proportion of subjects with 0, ≥1, ≥2, ≥3, ≥4, ≥5 memory T cell 
response, respectively, detected at the Baseline Visits (Week -3 to -1 and Week 0) 
and at 3-, 6-, 9-, and 12-weeks after administration of the vaccine 
o For each subject, the number of positive memory T cell responses 
o For each subject, the time course of memory T cell response at Baseline Visits 
(Week -3 to -1 and Week 0) and at 3-, 6-, 9-, and 12-weeks after administration of 
the vaccine 
• Objective Response Rate (ORR) measured by CT scan at Screening Visit (Week -3 to 
-1), and at 6-, and 12-weeks after administration of each dose of the vaccine  
 
 
3.2.3 
Exploratory Outcome Measures 
• Correlations between PEPIs identified by the PEPI Test and effector and memory 
T cell responses measured by ELISPOT and PHPC immunogenicity assays 
• Change in relative counts of TILs in accessible tumor biopsies at Baseline (Week -3 
to -1) and at Week 12 as measured by immunohistochemistry 
• Correlation between PEPIs identified by the PEPI Test and infiltrating lymphocyte in 
tumor biopsies measured by immunohistochemistry 
• Correlations between T cell responses measured by ELISPOT and PHPC and 
infiltrating lymphocyte in tumor biopsies measured by immunohistochemistry 
• Correlations between PEPIs identified by the PEPI Test and effector and ORR 
• Correlations between T cell responses measured by ELISPOT and PHPC and ORR 
3.3 
Estimated Study Duration  
Four out of ten subjects have already been accrued under the original single-dose Study 
Design, the first one being accrued in May 2017. These subjects will be asked to sign a new 
informed consent for multiple dosing and it is anticipated that they will be willing to agree. It 
is also anticipated that subject accrual rate for the remaining six subjects will be one subject 
every 20 days. Based on this rate it will take approximately 4 months to accrue a total of 10 
subjects. Since subjects are followed for 38 weeks after the PolyPEPI1018 initial vaccination, 
the total duration of the study is approximately 14 months from the date of amendment, that 
is approximately 17 months from the initiation of the OBERTO study.  

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3.4 
Randomization and Blinding 
This is a non-randomized, open-label study. 
3.5 
Study Stopping Rules 
The sponsor has the right to terminate the study at any time. The study will be stopped if any 
of the following occur: 
• New information leading to an unfavorable risk-benefit judgement of PolyPEPI1018, 
including the following (applicable after every vaccination and every five patients): 
o 3 or more DLTs within 21 days of peptide vaccine administration 
o 1 or more deaths (other than death related to progressive disease) that occurs 
within 30 days of peptide vaccine administration  
o Other unfavorable safety findings 
• Sponsor’s decision that continuation of the study is unjustifiable for medical or 
ethical reasons 
• Poor enrollment of subjects making completion of the study within an acceptable time 
frame unlikely 
• Discontinuation of the development of PolyPEPI1018 
• Specific request of a health authority 
In accordance with applicable regulations, health authorities and Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) will be informed by the sponsor if 
the study is discontinued. 
If a study is discontinued, the investigator will inform the subject’s primary health care 
provider, as applicable, to ensure the subject receives the appropriate follow-up and care. 

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4 
SUBJECT SELECTION 
A total of 10 subjects with mCRC who have achieved partial response (PR) or stable disease 
during first-line treatment with chemotherapy plus a biologic drug will be enrolled.   
4.1 
Inclusion Criteria 
Subjects who meet ALL of the following criteria are eligible for this study: 
1. Male or female subjects, 18-75 years of age at time of Screening who provide written 
informed consent prior to initiation of any study procedure  
2. Histologically confirmed metastatic adenocarcinoma originating from the colon or the 
rectum 
3. Presence of at least 1 measurable reference lesion according to the RECIST 
version 1.1 criteria  
4. Experienced PR or stable disease during first-line treatment with a systemic 
chemotherapy regimen and 1 biological therapy regimen  
5. Maintenance therapy with a fluoropyrimidine (5-fluorouracil or capecitabine) plus the 
same biologic agent (bevacizumab, cetuximab or panitumumab) used during 
induction, scheduled to initiate prior to the first day of treatment with the study drug 
6. No more than 1 line of chemotherapy regimen for mCRC (adjuvant therapy for 
non-metastasized disease is allowed if terminated more than 6 months before 
Screening and without recurrence within 6 months after the end of adjuvant 
treatment) 
7. Last CT scan at 3 weeks or less before the first day of treatment 
8. ECOG performance status of 0 or 1 
9. Women of childbearing potential must agree to appropriately use an effective form of 
contraception (failure rate of <1% per year) for 3 months from the day of the 
treatment. An effective form of contraception is defined as using hormonal 
contraceptives or an intrauterine device combined with at least 1 of the following 
forms of contraception: a diaphragm, cervical cap or condom 
10. Men must agree to use an effective form of contraception (as defined above), and not 
donate sperm for 3 months from the day of the treatment 
11. White blood cell count ≥3.0 × 109/L with neutrophils ≥1.5 × 109/L  
12. Platelets ≥100 × 109/L, hemoglobin ≥5.6 mmol/L (corresponding to 9 g/dL) 
13. Serum bilirubin ≤1.5 × upper limit of normal (ULN) set by the site 

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14. Alanine amino transferase (ALAT) and aspartate amino transferase (ASAT) 
≤2.5 × ULN in the absence of liver metastases. ALAT and ASAT ≤5 × ULN set by 
the site in the presence of liver metastases 
15. Serum creatinine ≤1.5 × ULN set by the site and creatinine clearance >30 mL/min 
using Cockroft formula 
16. Relevant toxicities of prior therapies must have resolved, except for 
oxaliplatin-related neuropathy or alopecia 
17. Anticipated life expectancy ≥6 months 
18. Subject is willing and able to comply with the requirements of the protocol 
4.2 
Exclusion Criteria 
Subjects who meet ANY of the following criteria are not eligible for this study: 
1. Received chronic systemic immune therapy or immunosuppressant medication other 
than steroids within the last 6 weeks prior to start of study treatment 
2. Received continuous systemic steroid treatment within the last 2 weeks prior to start 
of study treatment 
3. Colorectal cancer with documented MSI-H  
4. Colorectal cancer with documented BRAF mutations 
5. Pre-existing systemic autoimmune or antibody-mediated diseases or immune 
deficiency diseases 
6. Central nervous system (CNS) metastases 
7. Active or uncontrolled severe infections or undiagnosed febrile condition >38ºC 
8. Acute or subacute intestinal obstruction or history of chronic intestinal inflammatory 
diseases 
9. Symptomatic peritoneal carcinomatosis  
10. Peritonitis  
11. Serious, non-healing wounds, ulcers or bone fractures 
12. Nephrotic syndrome  
13. Arterial thromboembolisms or severe hemorrhages within 6 months before study 
enrolment (except bleeding tumor before tumor resection surgery)  
14. Hemorrhagic diathesis or thrombotic tendency  
15. Major surgery or radiotherapy within 12 weeks prior to the study treatment or 
anticipation of needing such procedure during the study period 

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16. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated 
drainage more than once every 28 days 
17. Participants with active malignancy (other than CRC) or a prior malignancy within 
the past 12 months 
18. Participant with myocardial infarction within 6 months prior to enrollment or New 
York Heart Association Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to the first dose of study 
treatment, any electrocardiogram (ECG) abnormality at screening must be 
documented by the investigator as not medically relevant 
19. Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation of a live attenuated vaccine will be required during the study 
20. Participant has participated in another clinical study involving an investigational 
product (IP) or investigational device within 30 days prior to enrollment or is 
scheduled to participate in another clinical study involving an IP or investigational 
device during the course of this study 
21. Known hypersensitivity to any component of the investigational drug  
22. If female, participant is pregnant (exclusion confirmed with beta-human chorionic 
gonadotropin [hCG] test) or lactating at the time of enrollment, or has plans to 
become pregnant or start breastfeeding during the study 
23. Pre-existing alcohol or drug abuse  
24. Medical or mental impairments which make it impossible to obtain the patient’s 
consent or to conduct the study 
25. A significant concomitant medical condition which the clinical investigator believes 
precludes the patient from enrolling in the study  
26. Absent or limited legal competence 
4.3 
Subject Withdrawal and Discontinuation 
Any subject may voluntarily withdraw consent (i.e., reduce the degree of participation in the 
study) for aspects of continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study Case Report Form (CRF). Assessments to be performed 
at the Last Visit are described in Section 7.4.  
Discontinuation (i.e., complete withdrawal from study participation) may be due to dropout 
(i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation by subject 
without notice or action). Additionally, the investigator and sponsor have the discretion to 

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discontinue any subject from the study if, in their judgment, continued participation would 
pose an unacceptable risk for the subject.  
During the initial study period, that is during the 12 weeks following the first vaccination, if a 
patient experiences disease progression and needs to start a second-line therapy, the patient 
will be withdrawn from the study. This is required to obtain a complete (12 weeks) 
measurement of the immunological response curve after the initial vaccination, that is one of 
the original study objectives. In contrast, if a patient experiences disease progression and 
needs to start a second-line therapy after the second vaccination, the patient will remain in 
the study, receive the third vaccination as scheduled and complete follow-up. This will allow 
to gain a better sense of initial efficacy of the PolyPEPI1018 vaccine, that is another study 
objective. 
If a subject must be withdrawn from the study, the responsible designee medical monitor will 
be informed immediately, and this person will then notify the sponsor’s medically 
responsible party. All subjects who prematurely discontinue from the study, regardless of 
cause, should be seen as soon as possible and undergo the assessments specified for the Last 
Visit (see Section 7.4). 
If there is a medical reason for withdrawal, the subject will remain under the supervision of 
the investigator until satisfactory health has returned or health has stabilized. The investigator 
will inform the subject’s primary health care provider (as applicable) as agreed by the 
subject, to ensure the subject receives the appropriate follow-up and care. 
If the subject is prematurely discontinuing due to withdrawal of consent, the investigator 
should clarify the level of consent withdrawal with the subject (i.e., consent withdrawal with 
regard to permission to utilize samples already collected but not analyzed and willingness to 
return for safety follow-up assessments). The level of consent withdrawal should be 
documented this in the electronic case report form (eCRF)  
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 

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should show “due diligence” by documenting in the source documents all steps taken to 
contact the subject (e.g., dates of telephone calls and registered letters). 
Subjects who discontinue or are withdrawn from the study, including withdrawal after receipt 
of the study’s IP on or after Day 1 of Week 0, will be replaced, except for subjects who 
experience a DLT: a subject who experiences a DLT will be withdrawn from the study and 
will not be replaced. 
 
4.3.1 
Permanent Treatment Discontinuation 
Subjects will be permanently withdrawn from treatment for the following reasons: 
• Vaccine-related toxicity (Section 5.5) 
• Requirement of prohibited concomitant medications (Section 5.4.2) 
• Request by subject to terminate study 
• Completion of the study treatment as defined by the protocol 
• Clinical reasons believed life threatening by the physician, even if not addressed in 
Section 5.5 
4.3.2 
Premature Treatment Discontinuation 
Subjects will be prematurely discontinued from treatment for the following reasons: 
• Failure by the subject to attend two consecutive clinic visits 
• Request by the subject to withdraw 
• Pregnancy 
• Development of an exclusionary condition as outlined in Section 4.2 
• Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the subject 
• Subject judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results 
• Subject reaches a defined study endpoint, as outlined in Section 3.2, if applicable 
• At the discretion of the health authority, IRB/IEC, investigator, or pharmaceutical 
supporter 

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5 
STUDY TREATMENTS 
5.1 
PolyPEPI1018 CRC Vaccine 
5.1.1 
Description 
5.1.1.1 
Vaccine Substance 
The vaccine is composed of 6 synthetic peptides and is manufactured according to Good 
Manufacturing Practices (GMP) using solid phase peptide synthesis. The vaccine substance 
should be stored in vials as a peptide solution (0.2 mg/mL in DMSO/water) at -20ºC. 
5.1.1.2 
Adjuvant 
The adjuvant Montanide™ (ISA 51 VG) is a mixture of highly purified mineral oil and 
mannide monooleate (derived from vegetable grade olive oil). It is manufactured according 
to GMP and should be stored in vials as an emulsion at room temperature. 
5.1.2 
PolyPEPI1018 Product Preparation and Administration 
PolyPEPI1018 final vaccine product will be prepared at the clinical site prior to injection by 
the physician or the nurse according to standard operating procedure and should be 
administered as soon as possible following preparation. 
The peptide solutions (see Section 5.1.1.1) should be thawed and incubated at room 
temperature with the adjuvant Montanide™. A 4-mL volume of the final PolyPEPI1018 
product will be prepared by mixing (emulsifying) each of the peptide solutions with an equal 
volume of the adjuvant Montanide™. Each dose of the final PolyPEPI1018 product will 
contain 0.8 mg peptides per 1 mL (4 peptides) solution + 0.4 mg peptides per 1 mL 
(2 peptides) solution plus 2 mL adjuvant. 
Prior to the PolyPEPI1018 administration, the subject’s body temperature should be checked 
and the vaccine should only be administered if the subject’s body temperature is <38ºC. 
Each subject will receive a total of four 1 mL SC injections of the final PolyPEPI1018 
product (i.e., one 1 mL SC injection per predetermined anatomic site, (preferably draining to 
axillary or inguinal lymph nodes). A pause of a few minutes should be observed after the first 

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injection to check for side effects. The remaining injections can be subsequently 
administered without pause. 
Additional details are provided in the Study Procedures Manual. 
5.1.3 
Packaging and Labeling 
PolyPEPI1018 peptide solutions will be supplied in pre-labeled boxes by the sponsor and the 
labels will be compliant with country specific regulatory requirements. Each box will contain 
vials of PolyPEPI1018-Mix1 and vials of PolyPEPI1018-Mix2 that needs to be stored in the 
freezer (-20oC). Each box will contain a label firmly attached to the box, with the company 
name, lot number, storage temperature, expiry date and a statement that the box contains 
vials of PolyPEPI1018-Mix1 and PolyPEPI1018-Mix2, respectively. Vials themselves will 
have label containing the vaccine name and lot number, content of the vial, strength of the 
solution, route of administration and storage temperature. One vial of each box will be used 
per subject for the preparation of the vaccine product at the clinical site. 
Adjuvant Montanide™ will be shipped by Seppic in pre-labeled boxes that need to be stored  
at room temperature (15ºC to 30ºC). Each box will contain 3 mL vials labeled as 
Montanide™ ISA 51 VG sterile, lot number, composition, manufacturer and expiration date. 
One vial will be used per peptide mixture, 2 vials per subject. 
5.1.4 
Supply, Distribution, and Pharmacy 
The following study supplies are needed and will be provided as described below: 
• PolyPEPI1018 vials will be distributed by the sponsor as described in Section 5.1.3. 
• Montanide™ adjuvant will be distributed by the supplier, Seppic SA, as described in 
Section 5.1.3. 
• Single use plastic equipment for PolyPEPI1018 vaccine emulsification procedure will 
be supplied by the Sponsor. Syringes, I-connector and vial adapters will be packaged 
together without harming the individual sterile packing of the devices. Each set will 
contain enough supplies for one emulsification procedure. 
Each package contains: 
o 2 pieces of Disposable latex, silicone and rubber free syringe (3 ml B.Braun, 
Injekt® Solo, VWR cat nr.: 720-2522). 

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o 1 piece of I-connector (Double Female Luer Lock Adapter, Promepla, Ref: 
ODG0015ST). 
o 2 pieces of Vial adaptors (West Pharma, 13 mm, Luer Lock, sterile). 
5.1.5 
Storage 
5.1.5.1 
PolyPEPI1018 
Intact vials containing PolyPEPI1018 should be stored between -25ºC and -15ºC. Thawed 
vials may be stored for up to 3 hours at room temperature. Re-freezing is not allowed. 
Records must be available showing periodic temperature checks of storage freezer material. 
Vaccine emulsions consisting of peptide admixed with Montanide™ are stable for 4 hours at 
4ºC, but should be administered as soon as possible following preparation. 
5.1.5.2 
Adjuvant 
Montanide™ should be stored between 15ºC and 30ºC. 
5.2 
Reference Therapy 
Not applicable 
5.3 
Investigational Product Accountability 
The investigator will ensure that the IP (i.e., PolyPEPI1018 and Montanide™) is stored as 
specified in Section 5.1.5 and that the storage area is secured, with access limited to 
authorized study personnel. The investigator will maintain records that the IP was received, 
including the date received, drug identity code, date of manufacture or expiration date, 
amount received and disposition. The IP must be dispensed only at the study site or other 
suitable location. Records will be maintained that includes the subject identification code 
(SIC), dispensation date, and amount dispensed. All remaining partially used and/or unused 
IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance with 
applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator will 
provide documentation in accordance with sponsor’s specifications. 

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5.4 
Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. All concomitant medications from the initiation of the 
first-line CRC therapy until 85 days after the subject’s vaccination must be recorded on the 
eCRF.   
5.4.1 
Required Medications 
Subjects must be on maintenance therapy with a fluoropyrimidine (5-fluorouracil or 
capecitabine) plus the same biologic agent (bevacizumab, cetuximab or panitumumab) used 
during induction,  prior to Day 1 (Week 0, Visit 2). Modifications may be allowed for 
toxicity/tolerability reasons, but must be approved by the medical monitor to determine 
whether the subject can remain on study treatment/on study. 
5.4.2 
Prohibited Medications 
The concomitant use of the following immunomodulator therapies, which have potential 
putative effects on immunologic and/or virologic indices, are prohibited while on study: 
• Systemic (intravenous and oral) corticosteroids 
• Thalidomide 
• Cyclosporine 
• Interferons 
• Interleukins 
• IgG-containing products 
• Cimetidine (Tagamet) 
• Acetylcysteine (NAC) 
• Sargramostim (GM-CSF) 
• Dinitrochlorobenzene (DNCB) 
• Thymosin alpha 1 (thymosin alpha) 
• Thymopentin 
• Inosiplex (Isoprinosine) 
• Polyribonucleoside (Ampligen) 

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• Ditiocarb sodium (Imuthiol) 
• Hydroxyurea 
• Checkpoint Inhibitors 
• Experimental vaccines 
• Investigational agents 
5.4.3 
Precautionary Medications 
The following medications may be used during the study with caution: 
• Treatment with topical corticosteroids is allowed except at the proposed vaccination 
sites within 2 weeks prior to vaccination 
• Use of local skin treatments is allowed, except in the targeted vaccination sites, 
within 2 weeks prior to vaccination. During the vaccination period, subjects should 
avoid manipulation of vaccinated areas to enable monitoring of possible 
vaccine-related toxicity. Sites may be rinsed with water, but soap and other possible 
irritants should be avoided. In the case of discomfort at the vaccination site, cold 
packs may be administered as needed. All other local treatments should only be 
administered after consultation with the investigator. 
5.5 
Dose Modification Guidelines and Toxicity Management 
A safety review team, internal to the sponsor, will regularly monitor all aspects of patient 
safety throughout this study. This team will be comprised of the medical monitor, a 
statistician, and ad hoc authorized representatives as appropriate. The safety review team will 
meet regularly to review all SAEs and will examine non-serious AEs, clinical laboratory data 
and other relevant safety data. 
5.5.1 
Local Reactions 
Local reactions, resulting from the vaccine will be graded using the local reaction assessment 
scale (Table 2). 

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Table 2. 
Local Reaction Assessment Scale 
Grade 
Description 
0 = None 
Not Applicable. 
1 = Mild 
Macular or papular eruption, erythema, or induration that is 
asymptomatic or mildly symptomatic. 
2 = Moderate 
Macular or papular eruption, erythema or induration with pruritus, or 
other associated moderate symptoms. 
3 = Severe 
Ulceration, superinfection, blistering, or phlebitis. 
4 = Potentially Life-Threatening 
Necrosis of the skin. 
If the subject develops a potentially life-threatening (Grade 4) local reaction thought to be 
probably or definitely related to vaccination, the safety review team must be notified within 
24 hours. 
The safety review team will determine whether local reactions are due to the vaccine. 
5.5.2 
Systemic Reactions 
Systemic reactions will be graded according to the World Allergy Organization 
Subcutaneous Immunotherapy Systemic Reaction Grading System (Cox 2010) (Appendix B). 
The safety review team should be contacted within 48 hours for any non-local Grade 3 or 4 
reactions (i.e., elevated temperature following vaccinations) thought probably or definitely 
related to vaccination.  
The safety review team will determine whether systemic reactions are due to the vaccine. 
5.5.3 
Anticancer Drugs 
Unanticipated and anticipated toxicities from the anticancer maintenance therapy regimen 
will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm).  
Any Grade 3 or 4 toxicities that result in a temporary or permanent change in an anticancer 
therapy must be reported to the safety review team within 4 days of knowledge of the 
change. 

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Anticipated toxicities resulting from components of the anticancer maintenance therapy 
regimen will be managed by the subject's clinician according to best clinical practice 
including dose reductions when indicated. 
Subjects who change and/or permanently discontinue their anticancer maintenance therapy 
will be handled on a case-by-case basis through discussions with the safety review team to 
decide whether they can remain on study treatment/on study. 
5.5.4 
Dose Limiting Toxicity (DLT) 
DLT is defined as any of the following occurring any time from Day 1 (Visit 2) until 21 days 
after administration of the vaccine (according to NCI CTCAE version 4.0, 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm):  
Hematologic 
• Grade 4 hematologic toxicity which lasts at least 5 days  
• Grade 3 or higher thrombocytopenia which lasts at least 5 days   
 
Non-hematologic:  
• Grade 4 or greater non-hematological local (at the site of vaccine injection) adverse 
events  
• Grade 3 or greater non-hematological systemic adverse events with the exception of 
alopecia, anorexia, nausea, vomiting and fatigue, constipation and dehydration 

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6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES 
The timing of the study assessments and procedures are summarized in the SoA in 
Appendix A.  
The investigator and sponsor will conduct the study in accordance with International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) and local regulations. Adherence to 
the study design requirements, including those specified in the SoA, is essential and required 
for study conduct, and the investigator must ensure that study procedures are performed as 
described in the protocol. During the study, procedures and observations will be monitored to 
confirm that study requirements are being followed as outlined in the SoA. 
6.1 
Informed Consent Form 
Any patient who provides informed consent (i.e., signs and dates the informed consent form 
and assent form, if applicable) is considered a subject in the study. Subjects presently on 
study who have signed an informed consent form for a single vaccination will be asked to 
sign a new informed consent form for multiple (N=3) vaccinations. 
6.2 
Subject Identification Code 
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) to 
be provided by the sponsor, 2- or 3-digit study site number (e.g., 02) to be provided by the 
sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order of providing 
informed consent. For example, the third subject who signed an informed consent form at the 
site 02 will be identified as Subject 090701-020003. All study documents (e.g., CRFs, 
clinical documentation, sample containers, drug accountability logs, etc.) will be identified 
with the SIC. Additionally, a uniquely coded SIC(s) is permitted if it does not contain a 
combination of information that allows identification of a subject (e.g., collection of a 
subject’s initials and birth date would not be permitted), in compliance with laws governing 
data privacy. 
6.3 
Screening Log 
The study site is responsible for maintaining a Screening log that includes all subjects who 
provided informed consent. The log also will serve to document the reason for screening 

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failure. All screening data will be collected and reported in CRFs, regardless of screening 
outcome. If a subject is re-screened, the End of Study CRF should be completed, and a new 
informed consent form (ICF), new SIC and new CRF are required for that subject.  
6.4 
Vaccine Site Evaluation 
A vaccine site evaluation for local and/or systemic adverse reactions will be performed in the 
clinic 1 hour after vaccination. If there are no adverse reactions noted within 1 hour after 
vaccination, subjects may be released from the clinic.  
Results of the site evaluation and toxicity grade, if appropriate, must be recorded in the 
source documents and documented on the CRF. 
For subsequent visits, vaccine site evaluation must be repeated.  
The following vaccination steps must be recorded in the source documents and documented 
on the CRF: 
• Vaccination sites 
• Disinfection of vaccination sites 
• Time of application 
6.5 
Evaluation of Response to First-line Therapy 
During the Screening Period, results from a CT scan which was performed at the completion 
of the first-line treatment regimen must be obtained (i.e., eligibility CT scan). The results will 
be evaluated by the investigator and must confirm that the subject has responded to first-line 
chemotherapy with documentation of cancer regression or lack of progression, according to 
RECIST version 1.1 criteria 
(https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf) 
6.6 
Immunogenicity and Efficacy Assessments 
The following immunogenicity and efficacy parameters will be assessed: 
• PEPI Test 
• Effector T cell response 
• Memory T cell response 

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• TILs assessment 
• CT assessment  
6.6.1 
PEPI Test 
To identify PEPIs the sponsor developed a novel PEPI Test. The PEPI Test selects from 
HLA restricted epitopes certain PEPIs that are capable of activating T cells in an individual. 
PEPIs are genetic biomarkers specific to the HLA genotype of an individual patient. The 
PEPI Test will be used to identify PEPIs among the 12 selected epitopes of PolyPEPI1018 in 
each study subject.  
To perform the PEPI Test a buccal swab sample will be collected on Day 1 (Visit 2) and sent 
to LabCorp for HLA genotyping. LabCorp will send the HLA genotype data to Treos Bio 
ZRT (sponsor) to perform the PEPI Test. The sponsor will perform the PEPI Test before any 
immunology or efficacy assessment becomes available, essentially in a blinded fashion. The 
PEPI Test results will be unblinded and the data compared with immunology and efficacy 
results as described in Section 9.5.2. 
6.6.2 
Effector T Cell Response 
Effector T cells are generated through activation of naïve or memory T cells following 
recognition of epitopes presented by the HLA molecules. ELISPOT assay is a routine test to 
be utilized for the detection of effector T cells that respond to PolyPEPI1018 treatment from 
a population of peripheral blood mononuclear cells (PBMCs). 
6.6.3 
Memory T Cell Response 
Memory T cells are a subset of antigen specific T cells that previously encountered and 
responded to their cognate epitope. Such T cells are primed by HLA-restricted peptides and 
originate either from cancer cells or from the vaccine. During a second activation, memory 
T cells can proliferate faster than during priming. This behavior is captured by the PHPC 
assay, abbreviated from “T cell precursors with high proliferation capacity” that allows the 
expansion of memory cells during prolonged culture and then detects the progeny of the 
antigen-specific memory T cell clone by IFN-γ ELISPOT. It has been previously 

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demonstrated that the PHPC assay identifies expandable memory T cells that can reveal 
previous exposure to specific peptide antigens (Calarota 2008). 
6.6.4 
Tumor Infiltrating Lymphocyte (TILs)  
The presence of TILs is associated with favorable long‐term outcome in several cancers, 
including breast cancer and CRC (DeNardo 2007; Schmidt 2008; Klintrup 2005). 
During the procedure tumor specimens are fixed in 10% formalin, embedded in paraffin, and 
4‐μm‐thick sections are prepared for hematoxylin and eosin staining or other appropriate 
staining and immunohistochemistry (IHC). All stainings and data reading are performed and 
reviewed by the same pathologist. The unused tumor sections will be retained according to 
the site procedure. 
TILs are assessed according to published criteria (Klintrup 2005) using a 4-degree scale at 
the deepest area of the invasive margin. A score of 0 is given when there is no increase in 
inflammatory cells, 1 denotes a mild and patchy increase in inflammatory cells, 2 denotes a 
moderate and band like inflammatory infiltrate with some destruction of cancer cell islands, 
and 3 denotes a marked and florid cuplike inflammatory infiltrate with frequent destruction 
of cancer cell islands. These scores can be subsequently classified as low grade (scores 0 and 
1) and high grade (scores 2 and 3).  
6.6.5 
CT scan and RECIST/ irRECIST evaluation  
CT scan will be performed at the site and original data will be retained either in a CD-ROM 
format or in a data room.  
RECIST criteria will be evaluated at baseline, week 6 (Visit 4), week 12 (Visit 6), week 25 
(Visit 11), week 38 (Visit 16) based on the CT scan results. If progressive disease (PD) is 
suspected at week 6, irRECIST evaluation 
(https://www.parexel.com/files/7914/2186/7838/irrecist-path-PDF.pdf) will be implemented; 
if the subject remains in the study, the CT scan on Wk 12 will be evaluated according to 
irRECIST criteria.  

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6.7 
Safety Assessments 
6.7.1 
Adverse Events 
Details on definitions and reporting of AEs are provided in Section 8. 
All AEs will be recorded from the time of signing of the ICF until completion of the Last 
Visit. Patients should be monitored for AEs consistent with the current Investigator’s 
Brochure for PolyPEPI1018. 
6.7.2 
Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the protocol, 
to protect subjects participating in a clinical trial from immediate harm. Urgent safety 
measures may be taken by the by the investigator or the safety review team, and may include 
any of the following:  
1. Immediate change in study design or study procedures 
2. Temporary or permanent halt of a given clinical trial or trials 
3. Any other immediate action taken to protect clinical trial participants from immediate 
hazard to their health and safety 
The investigator or the safety review team may take appropriate urgent safety measures to 
protect subjects against any immediate hazard to their health or safety. The measures should 
be taken immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
medical monitor immediately by phone and confirm notification to the safety review team in 
writing as soon as possible, but within 1 calendar day after the change is implemented. The 
sponsor will also ensure the responsible ethics committee(s) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to local 
regulations. 
6.7.3 
Untoward Medical Occurrences 
Untoward medical occurrences occurring before the first exposure to IP are not considered 
AEs (according to the definition of AE, see Section 8). However, each serious untoward 
medical occurrence experienced before the IP exposure (i.e., from the time of signed 

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informed consent up to but not including the IP exposure) will be described on the AE CRF 
and on the SAE Report Form. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs.  
For the purposes of this study, each non-serious untoward medical occurrence experienced 
by a subject undergoing study-related procedure(s) before the IP exposure will be recorded 
on the AE CRF; these events will not be considered as AEs and will not be included in the 
analysis of AEs.  
6.7.4 
Non-Medical Complaints 
A non-medical complaint (NMC) is any alleged product deficiency that relates to identity, 
quality, durability, reliability, safety, and performance of the product but did not result in an 
AE. NMCs include but are not limited to the following: 
1. A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g. reconstitution difficulty 
2. Missing components 
3. Damage to the product or unit carton 
4. A mislabeled product (e.g., potential counterfeiting/tampering) 
5. A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims 
Any NMCs of the product will be documented on an NMC form and reported to the sponsor 
within 1 business day. If requested, defective product(s) will be returned to the sponsor for 
inspection and analysis according to procedures. 
6.7.5 
Medical, Medication, and Non-Drug Therapy History 
At Screening, the subject’s medical history will be described for the following body systems 
including severity (defined in Section 8.2.1) or surgery and start and end dates, if known: 
eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; musculoskeletal; 
neurological; endocrine; hematopoietic/lymphatic; dermatological; and genitourinary. 

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All medications taken and non-drug therapies received from 3 months prior to enrollment 
until completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs. 
6.7.6 
Physical Examinations 
Complete and targeted physical examinations will be performed as summarized in 
Appendix A.  
Complete physical examinations will be performed on the following body systems: general 
appearance, signs and symptoms (including, but not limited to the head and neck, eyes and 
ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, skin, 
and neurological). Moreover, diagnoses, Karnofsky score, height, weight and vital signs will 
be registered. Finally, skin observation will be performed. 
At Screening, if an abnormal condition is detected, the condition will be described on the 
medical history CRF. At study visits, if a new abnormal or worsened abnormal pre-existing 
condition is detected, the condition will be described on the AE CRF. If the abnormal value 
was not deemed an AE because it was due to an error, due to a preexisting disease (described 
in Section 8.1.6), not clinically significant, a symptom of a new/worsened condition already 
recorded as an AE, or due to another issue that will be specified, the investigator will record 
the justification on the source record. 
At Visits 3 and 5, a targeted physical examination including vital signs should be driven by 
any new or previously identified signs and symptoms that the subject has experienced since 
the last visit. 
6.7.7 
Vital Signs 
Vital sign values (including seated blood pressure, pulse, respirations, and oral temperature) 
are to be measured at every visit as part of the complete and targeted physical examinations, 
and recorded on the CRF. At Day 1, measurement of vital signs must be performed in two 
occasions: before vaccination and 1 hour after last vaccination. For each abnormal vital sign 
value, the investigator will determine whether to report an AE (see definition in Section 8.1.1 
and record the medical diagnosis [preferably], symptom, or sign on the AE CRF) to the 

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safety review team. Additional tests and other evaluations required to establish the 
significance or etiology of an abnormal value, or to monitor the course of an AE should be 
obtained when clinically indicated. Any abnormal value that persists should be followed at 
the discretion of the investigator. 
6.7.8 
Clinical Laboratory Parameters 
6.7.8.1 
Hematology and Clinical Chemistry 
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [i.e., red blood cell count], and leukocytes [i.e., white blood cell count]) with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts.  
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
protein, albumin, ALAT, ASAT, gamma-glutamyl transpeptidase, total bilirubin, uric acid, 
blood urea nitrogen, creatinine, lactate dehydrogenase, creatine phosphokinase, alkaline 
phosphatase and glucose.  
Urinalysis will include description of color and clarity, specific gravity, pH, content of 
protein, glucose, nitrites and ketones. A microscopic analysis will be performed to check for 
red or white blood cells, casts, crystals, bacteria, yeast cells, parasites, and squamous cells. 
Urine and blood samples will be obtained for assessment of hematology and clinical 
chemistry at Screening, at Visit 2 (Day 1, Week 0), Visit 4 (Week 6), Visit 6 (Week 12), 
Visit 9 (Week 19), Visit 11 (Week 25), Visit 14 (Week 32) and Visit 16 (Week 38). 
Hematology and clinical chemistry assessments will be performed at the local laboratory at 
the investigator site.  
6.7.8.2 
Tumor Biomarkers 
Blood samples will be collected to evaluate tumor biomarkers, including carcinoembryonic 
antigen (CEA) and cancer antigen (CA 19-9). 

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6.7.8.3 
Assessment of Laboratory Values 
6.7.8.3.1 
Assessment of Abnormal Laboratory Values  
The investigator’s assessment of each laboratory value will be recorded on the CRF. For each 
abnormal laboratory value, the investigator will determine whether the value is considered 
clinically significant or not. For clinically significant values, the investigator will indicate if 
the value constitutes a new AE (see definition in Section 8.1.1, and record the sign, symptom, 
or medical diagnosis on the AE CRF), is a symptom or related to a previously recorded AE, 
is due to a pre-existing disease (described in Section 8.2.2), or is due to another issue that 
will be specified. If the abnormal value was not clinically significant, the investigator will 
indicate the reason, i.e., because it is due to a preexisting disease, due to a lab error, or due to 
another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an AE 
should be obtained when clinically indicated. Any abnormal value that persists should be 
followed at the discretion of the investigator. The investigator will communicate the AE to 
the safety review team for final evaluation. 
6.7.9 
Patient Diary 
A subject diary will be distributed to subjects on Day 1 (Visit 2), Day 92 ±2 (Visit 7) and 
Day 183 ±2 (Visit 12) to collect local signs related to the injection sites, physical fatigue, and 
body temperature during the first two weeks after the injection. Temperature should be 
consistently measured at the same location (e.g. underarm, ear, mouth etc.). 
6.8 
Procedures for Monitoring Subject Compliance 
All study procedures are to be performed under the direct supervision of the investigator/a 
licensed healthcare professional at the study site, and thus, no separate procedures will be 
used to monitor subject compliance. 

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7 
ASSESSMENTS AND PROCEDURES BY STUDY VISIT 
The timing of the study assessments and procedures are summarized in the SoA 
(Appendix A). Note: At the end of the follow up period (that is 12 weeks after each 
vaccination), ideally one week rest period should be observed before the next vaccination, as 
described in the SoA. However, up to 1 month rest period is allowed. 
7.1 
Screening Period (Visit 1 - Days -21 to Day -1 – Weeks -3 to -1) 
The following procedures will be performed at the Screening Visit:  
• Informed consent 
• Inclusion/exclusion criteria 
• ECOG performance status 
• Medical history 
• Medication history 
• Complete physical exam  
• Evaluation of response to first-line therapy 
• Cancer biopsy for TIL analysis 
• CT and RECIST assessment 
• Hematology and blood chemistries 
• Tumor biomarkers 
• Urinalysis 
• Urine pregnancy test 
• Blood collection for immunogenicity assays 
7.2 
PolyPEPI1018 Administration (Visit 2 – Day 1 - Week 0), (Visit 7 – Day 92 ±2 - 
Week 13) and (Visit 12 – Day 183 ±2 - Week 26), 
The following procedures will be performed at Visits 2, 7 and 12:  
• Concomitant medications 
• Complete physical exam  
• Vaccine site evaluation 
• Buccal swab 
• Vaccine administration and 1-hour post-vaccination observation 

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• Distribute diary 
• Hematology and blood chemistries (not on Visits 7 and 12) 
• Tumor biomarkers (not on Visits 7 and 12) 
• Urinalysis (not on Visits 7 and 12) 
• Urine Pregnancy Test (not on Visits 7 and 12) 
• Blood Collection for Immunogenicity Assays (not on Visits 7 and 12) 
7.3 
Follow-Up Period  
7.3.1 
Visit 3 (Day 22 - Week 3), Visit 5 (Day 64 - Week 9), Visit 8 (Day 113 ±2 - 
Week 16), Visit 10 (Day 155 ±2 - Week 22), Visit 13 (Day 204 ±2 - Week 29) 
and Visit 15 (Day 246 ±2 - Week 35) 
The following procedures will be performed at Visits 3, 5, 8, 10, 13 and 15:  
• Concomitant medications 
• Targeted physical exam  
• Vaccine site evaluation 
• Collect diary 
• Blood collection for immunogenicity assays 
7.3.2 
Visit 4 (Day 43 - Week 6), Visit 6 (Day 85 - Week 12), Visit 9 (Day 134 ±2 - 
Week 19), Visit 11 (Day 176 ±2 - Week 25), Visit 14 (Day 225 ±2 - Week 32) 
and Visit 16 (Day 267 ±2 - Week 38) 
The following procedures will be performed at Visits 4, 6, 9, 11, 14 and 16:  
• Concomitant medications 
• Complete physical exam  
• Vaccine site evaluation 
• Collect diary 
• CT and RECIST assessment (irRECIST assessment for subjects suspected of 
progression diseases at Visit 4) 
• Hematology and blood chemistries 
• Tumor biomarkers 
• Urinalysis 
• Urine pregnancy test 

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• Blood collection for immunogenicity assays 
• Cancer biopsy for TIL analysis (only at Visit 6) 
7.4 
Last Visit 
Every effort will be made to have discontinued, withdrawn, and terminated subjects complete 
the assessments described for Visit 16 (see Section 7.3.2). If the Last Visit is performed as an 
unscheduled visit, the assessment results will be recorded with the Last Visit. If a subject 
terminates participation in the study and does not return for the Visit 16 assessments, their 
last recorded assessments shall remain recorded with their last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation will 
be used in the analysis and included in the clinical study report. If additional assessments are 
required, the assessments shall be recorded separately.  
In the event of subject discontinuation due to an AE, clinical and/or laboratory investigations 
that are beyond the scope of the required study observations/assessments may be performed 
as part of the evaluation of the event. These investigations will take place under the direction 
of the investigator in consultation with the sponsor, and the details of the outcome may be 
reported to the appropriate regulatory authorities by the sponsor. 

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8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Timely collection and assessment of SAE reports are critical for protecting the safety of 
patients. SAE reporting is a regulatory responsibility of the Sponsor under the Code of 
Federal Regulations (Title 21, Sub-Part B, section 312.32). 
8.1 
Definitions 
8.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered an IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom (e.g., 
rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, etc.), or 
outcome of death temporally associated with the use of an IP, whether considered causally 
related to the IP.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the treatments or any event already present that worsens in either intensity or 
frequency following exposure to the treatments. 
8.1.2 
Serious Adverse Event  
An SAE is defined as an untoward medical occurrence that at any dose meets 1 or more of 
the following criteria: 
1. Outcome is fatal/results in death (including fetal death). 
2. Is life-threatening – defined as an event in which the subject was, in the judgment of 
the safety review team, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe. 
3. Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, regardless 
of length of stay. 
4. Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions). 
5. Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above.  

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8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any suspected adverse reaction to study treatment (i.e., including active comparators) that is 
both serious and unexpected.  
The event(s) must meet all the following: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to study treatment 
Once determined to meet the criteria for a SUSAR, an SAE should be submitted to regulatory 
agencies expeditiously.  
8.1.4 
Non-Serious Adverse Event 
A non-serious AE is an AE that does not meet the criteria of an SAE. 
8.1.5 
Unexpected Adverse Events 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (RSI). “Unexpected” also refers to the AEs that are mentioned in the 
Investigator’s Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the product, but are not specifically mentioned as occurring 
with the product under investigation. The expectedness of AEs will be determined by the 
sponsor using the Investigator’s Brochure as the RSI. This determination will include 
considerations such as the number of AEs previously observed, but not on the basis of what 
might be anticipated form the pharmacological properties of a product. 
8.1.6 
Preexisting Diseases 
Preexisting diseases that are present before entry in to the study are described in the medical 
history, and those that manifest with the same severity, frequency, or duration after IP 
exposure, will not be recorded as AEs. However, when there is an increase in the severity, 
duration, or frequency of a preexisting disease, the event must be described on the AE CRF. 

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8.2 
Assessment of Adverse Events 
Each AE from the IP exposure until study completion/discontinuation date will be described 
on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be 
established at the time of reporting the AE, a symptom or sign, in standard medical 
terminology to avoid the use of vague, ambiguous, or colloquial expressions (see definition 
in Section 8.1). Each AE will be evaluated by the safety review team for: 
1. Seriousness as defined in Section 8.1.2 
2. Severity as defined in Section 8.2.1 
3. Causal relationship to IP exposure or study procedure as defined in Section 8.2.2 
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, recovered/resolved 
with sequelae, not recovered/not resolved, fatal, unknown) and if applicable (e.g. for 
maintenance therapy drugs) action taken (i.e., dose increased, dose not changed, dose 
reduced, drug interrupted, drug withdrawn, not applicable, or unknown) will also be recorded 
on the AE CRF. AEs attribution must be clearly specified, whether it is attributed to the 
vaccine or to maintenance drugs or any other concomitant medication. Recovering/resolving 
AEs will be followed until resolution, medically stabilized, or 30 days after the study 
completion, whichever comes first). If the severity rating for an ongoing AE changes before 
the event resolves, the original AE report will be revised (i.e., the event will not be reported 
as separate AE). During the course of any AE, the highest severity rating will be reported. 
Deviations from the protocol-specified dosage (including overdosing, under dosing, abuse, 
and withdrawal), treatment errors (including incorrect route of administration, use of an 
incorrect product, and deviations from the protocol-defined dosing schedule), failures of 
expected pharmacological actions, and unexpected therapeutic or clinical benefits will be 
followed with regard to occurrence of AEs, lack of efficacy, and/or other observations 
because these events may be reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP to a female subject or to a male subject 
whose partner gets pregnant during the study period will be reported on a Pregnancy Report 
Form and followed-up at estimated date of delivery. 

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If an investigator becomes aware of an SAE occurring in a subject after study completion, the 
SAE must be reported on the provided SAE Report Form within 24 hours after awareness; no 
additional reporting on CRFs is necessary.  
8.2.1 
Severity 
The safety review team will assess the severity of each AE using his/her clinical expertise 
and judgment based on the most appropriate description below (according to CTCAE 
Version 4.0): 
1. Mild (Grade 1) 
o Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
2. Moderate (Grade 2) 
o Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) 
3. Severe (Grade 3) 
o Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL  
4. Life threatening (Grade 4) 
o Life-threatening consequences; urgent intervention indicated  
5. Death related to AE (Grade 5) 
o Grade 5 is not appropriate for some AEs and therefore is not an option  
These severity definitions will also be used to assess the severity of an AE with a 
study-related procedure(s), if necessary. 
8.2.2 
Causality 
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association (or 
lack of association) with underlying disease, presence (or absence) of a more likely cause, 
and physiological plausibility. For each AE, the safety review team will assess the causal 

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relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE: 
1. Not related (both circumstances must be met) 
o Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs 
o Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology).  
2. Unlikely related (either 1 or both circumstances are met) 
o Has little or no temporal relationship to the IP  
o A more likely alternative etiology exists 
3. Possibly related (both circumstances must be met) 
o Follows a reasonable temporal relationship to the administration of IP 
o An alternative etiology is equally or less likely compared to the potential 
relationship to the IP 
4. Probably related (both circumstances must be met) 
o Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following:  
– Reappearance of a similar reaction upon re-administration (positive 
rechallenge) 
– Positive results in a drug sensitivity test (skin test, etc.) 
– Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid 
o Another etiology is unlikely or significantly less likely 
5. Definitely related 
o There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
These causality definitions will also be used to assess the relationship of an AE with a 
study-related procedure(s), if necessary. 

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9 
STATISTICS 
9.1 
Analysis Populations 
The Safety Analysis Set (SAS) will include all subjects who receive at least 1 dose of the IP. 
This population will be the primary analysis set for safety outcomes. 
9.2 
Replacement of Subjects 
Any subject who withdraws from the study prematurely, or who discontinues study 
vaccination prematurely without experiencing a primary safety endpoint (Section 9.4) before 
the Day 85 (Week 12, Visit 6) evaluation, and whose reasons for withdrawing from the 
study, or discontinuing study vaccination administration, are unrelated to any real or 
perceived effect of the study vaccination or its administration, will be replaced with another 
subject. If possible, all subjects who discontinue study treatment prematurely will be 
followed for 12 weeks for all study evaluations. A maximum of 5 subjects will be replaced 
without asking the sponsor’s permission. If more than 5 subjects need to be replaced, then the 
study team may, for this reason, ask the sponsor for approval. 
9.3 
Handling of Missing, Unused, and Spurious Data 
9.3.1 
Missing Data Resulting from Study Withdrawal  
Only data collected from the visits by subjects will be included in the statistical analysis. No 
imputation will be carried out on missing values. 
9.3.2 
Intermediate Missing Data 
Only data collected from the visits by subjects will be included in the statistical analysis. No 
imputation will be carried out on missing values. 
9.4 
Primary Endpoint 
The primary endpoint is the occurrence of at least 1 ≥Grade 4 local AE or 1 ≥Grade 3 
systemic AE and/or signs/symptoms, lab toxicities, and/or clinical events that is probably or 
definitely related to study treatment (as judged by the safety review team, including site 
clinicians on the team) any time from Day 1 (Visit 2) until 21 days after administration of the 
vaccine (Visit 3). 

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9.5 
Statistical Analyses 
9.5.1 
Safety Analysis 
Major components for the safety analysis will include:  
• AEs solicited at every study visit, recorded, and coded according to the version of the 
Medical Dictionary for Regulatory Activities (MedDRA) that is current on the date of 
study initiation 
• SAEs 
• Vital signs and physical examination findings 
• Laboratory parameters 
All safety assessments will be summarized in a descriptive manner similar to the analysis 
described in Section 9.5.1.1.  
Data reported by the subjects in Patient Diary, including local signs related to the injection 
sites, physical fatigue, and body temperature, will be summarized in a descriptive manner.  
9.5.1.1 
Analysis of Adverse Events 
All AEs will be analyzed in terms of descriptive statistics and qualitative analysis. Adverse 
events will be listed for each subject and summarized by system organ class (SOC) and 
preferred term according to the latest version of MedDRA. In addition, summaries of AEs by 
severity and relationship to IP will be presented. All safety and tolerability data recorded 
during the study will be listed and summarized over time, as appropriate. For the purpose of 
summaries and listings, the durations of AEs will be calculated as follows: (stop [day] – start 
[day]) + 1 day, which yields the number of days on which the AE was present. 
Treatment emergent AEs are defined as AEs that first occurred or worsened in severity after 
the first administration of the IP. Adverse event summaries will include incidence of TEAEs, 
SAEs including deaths, AEs that led to IP discontinuation, AEs by maximum severity and 
relationship to IP, and temporally infusion related AEs. The version of the MedDRA that is 
current on the date of study initiation will be used throughout conduct and data analysis. All 
summaries will be presented by MedDRA SOC and preferred term for each treatment group. 
Safety/tolerability and AE data will be presented in individual listings. 

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9.5.2 
PEPI and Immunogenicity Analyses 
Each of the 6 peptides in PolyPEPI1018 contain 2 epitopes (for a total of 12 epitopes) 
selected to elicit a T cell response in a high portion of subjects. The PEPI Test identifies 
which epitope represents a PEPI (that is capable of inducing a T cell response) in each 
subject. A PEPI is unique and is based on the subject’s HLA genotype. Therefore, a selected 
epitope encoded in PolyPEPI1018 might be a PEPI for 1 individual and not for others, and 
vice versa. A subject may have more than 1 PEPI, or no PEPI. The PEPI Test (described in 
Section 6.6.1) will be performed in each subject who is enrolled in the study from the results 
of the HLA genotyping.  
The ELISPOT assay (described in Section 6.6.2) and the PHPC assay (described in 
Section 6.6.3) measure effector and memory responses, respectively. These assays will be 
performed in each subject from blood samples collected during a time course from Baseline 
until the Last Visit. Based on the results of the PEPI Test and the immunogenicity tests 
(ELISPOT and PHPC) the secondary outcome measures will be analyzed as described in 
Section 3.2.2.  
Immunogenicity analyses may be performed at any time during the trial, however, the results 
of the PEPI Test will be obtained before the results of the corresponding immunogenicity 
tests are available. Final analysis will be based on all data up to Day 85 (Week 12, 
Visit 6) for all study subjects (data from the start of study treatment of the last accrued 
subject through Day 85 [Week 12, Visit 6]). 
9.5.3 
Efficacy Analyses  
Efficacy will be evaluated as Objective Response Rate (ORR) measured by CT scan at 
Screening Visit (Week -3 to -1), and at 6-, and 12 weeks after administration of each dose of 
the vaccine. RECIST and irRECIST criteria will be used. 
Primary and secondary analyses will be summarized in a descriptive manner.  
 

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9.5.4 
Exploratory Analyses  
• Pearson correlation coefficients will be calculated to measure correlations. The 
significance of the correlations will be tested using standard method of estimating 
significance of correlations (𝑟𝑟ට
𝑛𝑛−2
1−𝑟𝑟2 follows the t distribution with degree of freedom 
n-2, where r is the Pearson correlation and n is the number of measurements) 
• Correlated data points will be plotted and trend lines will be obtained using 
perpendicular (orthogonal) regression, since both axes contain measurements and/or 
predicted values (PEPIs predicted by the PEPI Test)  
• The significance of the changes will be tested by non-parametric tests (Wilcoxon 
signed-rank test). Non-parametric test is preferred due to the small sample size and 
the questionable normality of the data 
9.6 
Determination of Sample Size 
Approximately 10 subjects will be enrolled in the study to receive three vaccinations. The 
study is not statistically powered to assess the primary or secondary outcomes measures. 
Assuming that the HLA sets from the subjects follow the distribution observed in the HLA 
sets from the in-house database, at least 39 positive immune responses are expected from 
10 subjects. The distribution of the expected number of positive tests is displayed in Figure 4, 
which is generated from 10,000 simulations. The x-axis shows the number of positive tests, 
and the y-axis shows the probabilities. 

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Figure 4. Distribution of the Expected Number of Positive Tests 
 
Based on the simulation, at least 7 subjects are expected to have an immune response against 
2 or more cancer antigens with at least 97.5% probability. The expected distribution of 
probabilities having a given number of subjects with positive immune response for 2 or more 
antigens is displayed in Figure 5, the x-axis shows the number of subjects with a given 
probability and the y-axis shows the probability. 
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0
10
20
30
40
50
60
70
80

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Figure 5. Expected Distribution of Probabilities Having a Given Number of Subjects 
with Positive Immune Response for Two or More Antigens 
 
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0
1
2
3
4
5
6
7
8
9
10

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10 
ETHICAL AND LEGAL CONSIDERATIONS 
10.1 
Compliance Statement 
This study will be conducted in accordance with the protocol and with ICH GCP guidelines, 
as well as all applicable country and regional legal and regulatory requirements. The 
investigator is responsible for ensuring that this protocol, the site’s ICF, and any other 
information that will be presented to potential subjects are reviewed and approved by the 
appropriate IRB or IEC prior to the enrollment of any study subjects. 
10.2 
Ethics Committee and Regulatory Authorities 
Before patients participate in this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information will be reviewed and 
approved/given favorable opinion by the Ethics Committee (EC) and applicable regulatory 
authorities. The Investigator’s Brochure will be provided for review. The EC’s composition 
or a statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of approval/favorable 
opinion from the EC and, if required, upon the sponsor’s notification of applicable regulatory 
authority(s) approval, as described in the Clinical Trial Agreement.  
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities, where applicable. The protocol amendment will only be implemented 
upon the sponsor’s receipt of approval and, if required, upon the sponsor’s notification of 
applicable regulatory authority(s) approval. 
10.3 
Informed Consent and Human Subject Protection 
Investigators will choose patients for participation while considering the study eligibility 
criteria. The investigator will exercise no selectivity so that no bias is introduced from this 
source.  
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. An assent form may be provided and should be signed by 

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patients less than 18 years of age. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(s), where applicable, (see 
Section 10.2). The informed consent form will include a comprehensive explanation of the 
proposed treatment without any exculpatory statements, in accordance with the elements 
required by ICH GCP and applicable national and local regulatory requirements. Patients or 
their legally authorized representative(s) will be allowed sufficient time to consider 
participation in the study. By signing the informed consent form, patients/healthy volunteers 
or their legally authorized representative(s) agree that they will complete all evaluations 
required by the study, unless they withdraw voluntarily or are terminated from the study for 
any reason. 
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed consent 
will be updated, if necessary. This new information and/or revised informed consent form, 
which has been approved by the applicable EC and regulatory authorities, where applicable, 
will be provided by the investigator to the subjects who consented to participate in the study. 
Four out of ten subjects have already been accrued under the original single-dose Study 
Design, the first one being accrued in May 2017. These subjects will be asked to sign a new 
informed consent for multiple dosing. 
10.4 
Confidentiality 
The investigator will comply with the confidentiality policy as described in the Clinical Trial 
Agreement. 

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11 
ADMINISTRATIVE CONSIDERATION 
11.1 
Investigator’s Responsibilities 
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements as 
described in the Clinical Trial Agreement. The investigator is ultimately responsible for the 
conduct of all aspects of the study at the study site and verifies by signature the integrity of 
all data transmitted to the sponsor. The term “investigator” as used in this protocol as well as 
in other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other authorized 
study personnel are eligible to sign for the investigator, except where the investigator’s 
signature is specifically required. 
The coordinating investigator will be selected before study start. The coordinating 
investigator will sign the clinical study report.  
11.2 
Study Training 
The sponsor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, at 
the study site, and/or by instruction manuals. In addition, the sponsor will be available for 
consultation with the investigator and will serve as the liaison between the study site and the 
sponsor. 
11.3 
Study Monitoring 
The study monitor is responsible for ensuring and verifying that each study site conducts the 
study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study site 
at appropriate intervals, as described in the Clinical Trial Agreement. Monitoring processes 
specific to the study will be described in the clinical monitoring plan. 

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11.4 
Safety Monitoring 
Accrual, withdrawals from treatment, all toxicities, and AEs will be monitored during the 
study. Reports should be reviewed every 2 weeks by the safety review team from one week 
after the study opens until it closes.  
If 2 subjects experience a primary safety endpoint (Section 9.4), or 1 subject experiences a 
≥Grade 4 AE that is probably or definitely related to study treatment, enrollment will be 
suspended. Depending on the severity of the AE, study treatment administration to subjects 
may be terminated, pending a subsequent decision by the study team on how to proceed.  
When the last subject reaches Week 12, the safety review team will review all available 
safety data, including hematology, chemistries, tumor biomarkers, viral load data, and all 
clinical events.  
11.5 
Audits 
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study conduct 
and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the Clinical Trial Agreement. Auditing processes specific to the study will be 
described in the audit plan. 
11.6 
Documentation 
11.6.1 
Case Report Forms and Study Records 
The investigator will maintain complete and accurate paper format study documentation in a 
separate file. Study documentation may include information defined as “source data” (see 
Section 11.6.3), records detailing the progress of the study for each subject, signed informed 
consent forms, correspondence with the EC and the study monitor/sponsor, screening 
information, CRFs, SAE reports (SAERs), laboratory reports (if applicable), and data 
clarifications requested by the sponsor.  

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The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry will 
be crossed out entirely, remaining legible; and 2) each correction must be dated and initialed 
by the person correcting the entry; the use of correction fluid and erasing are prohibited. 
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form.  
Only authorized study site personnel will record or change data on the CRFs. If data is not 
entered on the CRFs during the study visit, the data will be recorded on paper, and this 
documentation will be considered source documentation. Changes to a CRF will require 
documentation of the reason for each change. An identical (electronic/paper) version of the 
complete set of CRFs for each subject will remain in the investigator file at the study site in 
accordance with the data retention policy (see Section 11.6.4). 
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the sponsor. 
Data management and control processes specific to the study will be described in the data 
management plan. 
11.6.2 
Direct Access to Source Data, Source Documents, and Study Records 
The investigator/study site will cooperate and provide direct access to study documents and 
data, including source documentation for monitoring by the study monitor, audits by the 
sponsor or sponsor’s representatives, review by the IEC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement. If contacted by an 
applicable regulatory authority, the investigator will notify the sponsor of contact, cooperate 
with the authority, provide the sponsor with copies of all documents received from the 
authority, and allow the sponsor to comment on any responses, as described in the Clinical 
Trial Agreement. 
11.6.3 
Source Data 
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 

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trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in paper 
and/or electronic format. Source data for this study comprise the following: hospital records, 
medical records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or 
evaluation checklists, outcomes reported by subjects, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories and at medico-technical 
departments involved in the clinical study. 
No data will be entered directly onto the CRF.  
For additional information on study documentation and CRFs, see Section 11.6.1. 
11.6.4 
Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the Clinical Trial Agreement. 
11.7 
Non-Compliance with the Protocol 
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor will also ensure the responsible EC and relevant competent 
authority is notified of the urgent measures taken in such cases according to local regulations. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will notify 
the EC and applicable regulatory authorities of any investigator termination. 

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11.8 
Financing and Insurance 
The investigator will comply with investigator financing, investigator/sponsor insurance, and 
subject compensation policies, if applicable, as described in the Clinical Trial Agreement. 
11.9 
Publication Policy 
The investigator will comply with the publication policy as described in the Clinical Trial 
Agreement. 

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12 
REFERENCES 
Bever KM and Le DT. An Expanding Role for Immunotherapy in Colorectal Cancer. J Natl 
Compr Canc Netw. 2017;15(3):401-410. 
Calarota SA, Foli A, Maserati R, et al. HIV-1-specific T cell precursors with high 
proliferative capacity correlate with low viremia and high CD4 counts in untreated 
individuals. J Immunol. 2008;180(9):5907-5915. 
Cassidy S and Syed BA. Colorectal cancer drugs market. Nat Rev Drug Discov. 2017; 
16(8):525-526. 
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 
2013;39(1):1-10. 
Cox L, Larenas-Linnemann D, Lockey RF, et al. Speaking the same language: The World 
Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. 
Allergy Clin Immunol. 2010;125(3):569-74. 
Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus 
FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal 
cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 
TRIBE study. Lancet Oncol. 2015;16(13):1306-15. 
DeNardo DG and Coussens LM. Inflammation and breast cancer. Balancing immune 
response: crosstalk between adaptive and innate immune cells during breast cancer 
progression. Breast Cancer Res. 2007;9(4):212. 
Emens LA and Middleton G. The interplay of immunotherapy and chemotherapy: harnessing 
potential synergies. Cancer Immunol Res. 2015;3(5):436-43. 
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-
86. 
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus 
FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal 
cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-
75. 
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, 
placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–312. 
Klintrup K, Makinen JM, Kauppila S, et al. Inflammation and prognosis in colorectal cancer. 
Eur J Cancer. 2005;41(17):2645-2654. 
Loupakis F, Cremolini C, Masi G, et al. Initial Therapy with FOLFOXIRI and Bevacizumab 
for Metastatic Colorectal Cancer. N Engl J Med. 2014;371(17):1609-18.  

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Mansfield AS, Nevala WK, Lieser EAT, et al. The immunomodulatory effects of 
bevacizumab on systemic immunity in patients with metastatic melanoma. 
Oncoimmunology. 2013;2(5):e24436. 
Mariotto AB, Yabroff KR, Shao, et al. Projections of the cost of cancer care in the United 
States: 2010-2020. Journal of the National Cancer Institute. 2011;103(2):117–128.  
Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients 
with melanoma. Nature. 2017;547:217–221. 
Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize 
poly-specific therapeutic immunity against cancer. Nature. 2017;547:222–226. 
Saltz LB. Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based 
chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III 
study. J Clin Oncol. 2008;26(12):2013-9. 
Schmidt M, Bohm D, von Torne C, et al. The humoral immune system has a key prognostic 
impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13. 
Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan 
alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer 
(PICCOLO): a prospectively stratified randomised trial. The Lancet Oncology. 
2013;14(8):749–759. 
Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR Pathway Blockade Inhibits 
Tumor-Induced Regulatory T-cell Proliferation in Colorectal Cancer. Cancer Res. 2013; 
72(2):539-49. 
Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of First-Line Chemotherapy Combined 
With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type 
Advanced or Metastatic Colorectal Cancer. JAMA. 2017;317(23):2392-2401. 
Walter S, Weinschenk T, Stenzi A, Zdrojowy R. Multipeptide immune response to cancer 
vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. 
Nat Med. 2012;18(8):1254-61. 
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vaccination for advanced cancer patients: Analysis of 500 cases. Oncol Rep. 2011;25(1):57-
62. 

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APPENDIX A. 
SCHEDULE OF STUDY ASSESSMENTS   
Assessment 
Period 
Screening 
Vaccination and Evaluation 
Visit Number 
1 
2 
3 
4 
5 
6 
End of Week 
-3 to -1 
0 
3 
6 
9 
12 
Day 
-21 to -1 
1 
22 ±2 
43 ±2 
64±2 
85±2 
Informed Consent  
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
Complete Physical Exam  
X 
X 
 
X 
 
X 
Targeted Physical Exam  
 
 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
Vaccine Site Evaluation 
 
X 
X 
X 
X 
X 
Evaluation of Response to First-line Therapy 
X 
 
 
 
 
 
Buccal Swab 
 
X 
 
 
 
 
Vaccine Administration/ 1-hour Observation 
 
X 
 
 
 
 
Distribute Diary1 
 
X 
 
 
 
 
Collect Diary 
 
 
X 
 
 
 
Cancer Biopsy/ Tumor Infiltrating Lymphocytes 
Analysis 
X 
 
 
 
 
X 
CT and RECIST (irRECIST) Assessment 
X 
 
 
X 
 
X 
Hematology & Blood Chemistries 
X 
X 
 
X 
 
X 
Tumor Biomarkers 
X 
X 
 
X 
 
X 
Urinalysis 
X 
X 
 
X 
 
X 
Urine Pregnancy Test 
X 
X 
 
X 
 
X 
Blood Collection for PBMC and Immunogenicity 
Assays (ELISpot and PHPC) 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; CT = computerized tomography 
1. The Patient Diary will be used to collect local signs related to the injection sites, physical fatigue, and body temperature 

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Assessment 
Period 
Vaccination and Evaluation 
Visit Number 
7 
8 
9 
10 
11 
End of Week 
13 
16 
19 
22 
25 
Day 
92 ±2 
113 ±2 
134 ±2 
155 ±2 
176 ±2 
Informed Consent for additional vaccinations2 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
Complete Physical Exam  
X 
 
X 
 
X 
Targeted Physical Exam  
 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
Vaccine Site Evaluation 
X 
X 
X 
X 
X 
Vaccine Administration/ 1-hour Observation 
X 
 
 
 
 
Distribute Diary1 
X 
 
 
 
 
Collect Diary 
 
X 
 
 
 
Cancer Biopsy/ Tumor Infiltrating Lymphocytes 
Analysis 
 
 
 
 
X 
CT and RECIST (irRECIST) Assessment 
 
 
X 
 
X 
Hematology & Blood Chemistries 
 
 
X 
 
X 
Tumor Biomarkers 
 
 
X 
 
X 
Urinalysis 
 
 
X 
 
X 
Urine Pregnancy Test 
 
 
X 
 
X 
Blood Collection for PBMC and Immunogenicity 
Assays (ELISpot and PHPC) 
 
X 
X 
X 
X 
Abbreviations: CT = computerized tomography 
1. The Patient Diary will be used to collect local signs related to the injection sites, physical fatigue, and body temperature  
2. Only for those subjects who had originally signed an Informed Consent Form for a single vaccination 
 
 
 
 

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Assessment 
Period 
Vaccination and Evaluation 
Visit Number 
12 
13 
14 
15 
16 
End of Week 
26 
29 
32 
35 
38 
Day 
183 ±2 
204 ±2 
225 ±2 
246 ±2 
 267 ±2 
Concomitant Medications 
X 
X 
X 
X 
X 
Complete Physical Exam  
X 
 
X 
 
X 
Targeted Physical Exam  
 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
Vaccine Site Evaluation 
X 
X 
X 
X 
X 
Vaccine Administration/ 1-hour Observation 
X 
 
 
 
 
Distribute Diary1 
X 
 
 
 
 
Collect Diary 
 
X 
 
 
 
Cancer Biopsy/ Tumor Infiltrating Lymphocytes 
Analysis 
 
 
 
 
X 
CT and RECIST (irRECIST) Assessment 
 
 
X 
 
X 
Hematology & Blood Chemistries 
 
 
X 
 
X 
Tumor Biomarkers 
 
 
X 
 
X 
Urinalysis 
 
 
X 
 
X 
Urine Pregnancy Test 
 
 
X 
 
X 
Blood Collection for PBMC and Immunogenicity 
Assays (ELISpot and PHPC) 
 
X 
X 
X 
X 
Abbreviations: CT = computerized tomography 
1. The Patient Diary will be used to collect local signs related to the injection sites, physical fatigue, and body temperature 
Note: At the end of the follow up period (that is 12 weeks after each vaccination), ideally one week rest period should be observed 
before the next vaccination, as described in the above SoA. However, up to 1 month rest period is allowed. 
 
 
 
 

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APPENDIX B. 
THE WORLD ALLERGY ORGANIZATION SUBCUTANEOUS IMMUNOTHERAPY SYSTEMIC 
REACTION GRADING SYSTEM 
 
See attached Article (13 pages) by Cox L. et al