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], 198 9); Institutional Review Board/Independent Ethics Committee (IRB/IEC) Guidelines; and applicable local legal and regulatory requirements. Treos Bio ZRT OBERTO -101 Amendment 3 Product: PolyPEPI 1018 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 C olorectal 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 Treos Bio ZRT OBERTO -101 Amendment 3 Product: PolyPEPI 1018 Colorectal Cancer Vaccine Page 3 of 81 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 Ap ril 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: PolyPEPI 1018 Colorectal Cancer Vaccine Page 4 of 81 CONFIDENTIAL SYNOPSIS Name of Sponsor/C ompany: Treos Bio ZRT Name of P roduct: PolyPEPI 1018 CRC Vaccine (PolyPEPI1018) Title of Study: A Phase 1, Multiple doses, Multicenter, Open -label Study t o Evaluate Safety, Tolerability, Immunogenicity and Efficacy of Subcutaneous Injections of PolyPEPI 1018 Vaccine as an Add -on Immunotherapy to the Standard-of- Care Maintenance Therapy in Subjects with Metastatic C olorectal Cancer (OBERTO) Phase of Developm ent: Phase 1; First -in-Human Planned Study Period: Initiation: Second quarter of 2018 (first subject first visit) Primary Completion: Third quarter of 201 9 (last subject Week 12 assessment) Study Objective(s): Primary Objective: • To evaluate the safety and tolerability of multiple doses of PolyPEPI 1018 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 PolyPEPI 1018 in each study subject • To evaluate the immunogenicity of PolyPEPI 1018 by measuring both effector and memory T cell responses • To evaluate initial efficacy of PolyPEPI 1018 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) injection s of PolyPEPI 1018 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) .