2 TABLE OF CONTENTS ............................................................................................................................ 3 CLINICAL STUDY SYNOPSIS ................................................................................................................... 6 ABBREVIATIONS ................................................................................................................................. 13 1.0 GENERAL INFORMATION ..................................................................................................... 16 1.1 Protocol Number and Title of the Study .................................................................................... 16 1.2 Sponsor ...................................................................................................................................... 16 1.3 Medical Monitor ........................................................................................................................ 16 1.4 Signature Authorization ............................................................................................................. 16 1.5 Investigator and Institution ....................................................................................................... 16 2.0 BACKGROUND INFORMATION ............................................................................................. 16 2.1 Introduction ............................................................................................................................... 16 2.2 The Investigational Product ....................................................................................................... 18 2.2.1 HS-130 .......................................................................................................................... 18 2.2.2 HS-110 .......................................................................................................................... 19 2.3 Preclinical Studies ...................................................................................................................... 19 2.3.1 Pharmacodynamics studies .......................................................................................... 19 2.3.2 Immuno -toxicity Studies .............................................................................................. 20 2.3.3 Dose Range Finding Studies to Support Clinical Dosing ............................................... 21 2.4 Previous Clinical Studies ............................................................................................................ 22 2.5 Rationale for Starting Dose and Dosing Schedule ..................................................................... 22 2.6 Potential Risks and Benefits ...................................................................................................... 23 2.7 Characteristics of a Well -Conducted Trial ................................................................................. 23 2.8 Patient Population ..................................................................................................................... 24 3.0 TRIAL OBJECTIVES AND PURPOSE ........................................................................................ 24 4.0 TRIAL DESIGN ...................................................................................................................... 24 4.1 Overview of Trial Design ............................................................................................................ 24 4.2 End of Study ............................................................................................................................... 25 4.3 Drug Product .............................................................................................................................. 25 4.4 Duration of Therapy .................................................................................................................. 26 4.5 Trial Discontinuation ................................................................................................................. 26 4.6 Investigational Product Accountability/Disposition of Clinical Trial Supplies ........................... 26 5.0 SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................................... 26 5.1 Inclusion Criteria ........................................................................................................................ 26 5.2 Exclusion Criteria ....................................................................................................................... 27 5.3 Inclusion of Women, Minorities and Children ........................................................................... 28 5.4 Withdrawal Criteria ................................................................................................................... 29 5.4.1 With drawn Subjects ..................................................................................................... 29 5.4.2 Replacement of Subjects .............................................................................................. 29 5.5 Study Stopping Criteria .............................................................................................................. 29 5.6 Noncompliance .......................................................................................................................... 30 HS130- 001 4 of 60 Version 2.0 - 11 Feb 2020 Confidential - Entire Page 6.0 TREATMENT OF SUBJECTS ................................................................................................... 30 6.1 Drug Preparation and Administration ....................................................................................... 30 6.1.1 Dose Escalation Scheme ............................................................................................... 31 6.1.2 Dose -Limiting Toxicity .................................................................................................. 33 6.1.3 Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) .............. 34 6.2 Dose Interruptions/Withh olding ............................................................................................... 34 6.3 Dose Modification ..................................................................................................................... 34 6.4 Concomitant Treatment ............................................................................................................ 34 6.5 Monitoring Subject Compliance ................................................................................................ 35 7.0 STUDY EVALUATIONS .......................................................................................................... 35 7.1 Schedule of Study Evaluations ................................................................................................... 35 7.2 Pre-treatment ............................................................................................................................ 38 7.3 During Treatment ...................................................................................................................... 38 7.3.1 Cycle 1 .......................................................................................................................... 38 7.3.2 Cycle 2 .......................................................................................................................... 39 7.3.3 Cycle 3 and Beyond (Day 1± 2 days) ............................................................................ 39 7.4 30-Day Safety Follow up Visit from Last Dose ( ±3 days) ........................................................... 40 7.5 Post -treatment Follow -up ( ± 1 week) ....................................................................................... 40 7.6 Survival Follow -up ( ± 2 weeks) .................................................................................................. 40 8.0 STUDY ASSESSMENTS .......................................................................................................... 41 8.1 Safety Assessments ................................................................................................................... 41 8.1.1 Safety Analysis .............................................................................................................. 41 8.1.2 Reporting of Adverse Events ........................................................................................ 41 8.2 Efficacy Assessments ................................................................................................................. 44 8.2.1 RECIST 1.1 Criteria ........................................................................................................ 44 8.3 Best Overall Response ............................................................................................................... 50 8.4 Overall Survival (OS) .................................................................................................................. 50 8.5 Progression -free Survival (PFS) .................................................................................................. 50 8.6 Analysis of Immune Response ................................................................................................... 50 8.6.1 Analysis of Immunological Effect ................................................................................. 51 8.6.2 Immune Reactivation Response ................................................................................... 51 8.7 Analysis of Pro -inflammatory Cytokines and Chemokines ........................................................ 51 8.8 Bioinformatics Analysis of CTAs and Shared Antigen Expression .............................................. 51 8.9 Exploratory Biomarkers ............................................................................................................. 51 9.0 STATISTICS .......................................................................................................................... 52 9.1 Analysis Popul ations .................................................................................................................. 52 9.2 Endpoints ................................................................................................................................... 52 9.2.1 Primary ......................................................................................................................... 52 9.2.2 Secondary ..................................................................................................................... 52 9.2.3 Exploratory ................................................................................................................... 52 9.3 Safety ......................................................................................................................................... 53 9.4 Efficacy ....................................................................................................................................... 53 9.5 Exploratory/Other Studies ......................................................................................................... 53 9.6 Sample Size ................................................................................................................................ 53 10.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES .............................................. 53 10.1 Monitoring of the Study and Regulatory Compliance ............................................................... 53 HS130- 001 5 of 60 Version 2.0 - 11 Feb 2020 Confidential - Entire Page 10.2 Curricula Vitae and Financial Disclosure of Investigators.......................................................... 54 10.3 Protocol Modifications ..............................................................................................................