12 1.2 Short title: ............................................................................................................................. 12 1.3 Clinical trial objectives and endpoints: ................................................................................. 12 1.4 Trial Design: ......................................................................................................................... 12 1.5 Trial treatment: ..................................................................................................................... 12 1.6 Patient Population: ............................................................................................................... 13 2 INTRODUCTION ................................................................................................................. 14 2.1 Background .......................................................................................................................... 14 2.1.1 Background on non- small cell lung cancer .......................................................................... 14 2.2 Investigational medicinal product ......................................................................................... 14 2.2.1 Structure of AST -VAC2 ....................................................................................................... 14 2.2.2 Mechanism of action of AST -VAC2 ..................................................................................... 15 2.3 Safety considerations for the trial ......................................................................................... 15 2.3.1 Non- clinical pharmacology .................................................................................................. 15 2.3.2 Pharmacokinetics ................................................................................................................ 16 2.3.3 Toxicology ............................................................................................................................ 16 2.4 Clinical experience (other compounds in the same class) ................................................... 17 2.5 Rationale for the trial ............................................................................................................ 17 2.5.1 Justification for dose and schedule ..................................................................................... 17 3 TRIAL DESIGN ................................................................................................................... 19 3.1 Clinical trial objectives and endpoints .................................................................................. 19 3.1.1 Primary objectives and endpoints ....................................................................................... 19 3.1.2 Secondary objectives and endpoints ................................................................................... 19 3.1.3 Tertiary objectives and endpoints ........................................................................................ 20 3.2 Design of the clinical trial ..................................................................................................... 20 3.3 Safety Review ...................................................................................................................... 22 3.3.1 Safety considerations .......................................................................................................... 22 3.3.2 Safety Evaluation ................................................................................................................. 22 3.3.2.1 Data to be discussed at safety review meetings. ............................................................ 23 3.3.3 Stopping rule criteria. ........................................................................................................... 23 3.4 Patient evaluability ............................................................................................................... 24 3.4.1 Response ............................................................................................................................. 24 3.4.2 Safety ................................................................................................................................... 24 3.4.3 Immunogenicity ................................................................................................................... 24 4 PATIENT SELECTION ........................................................................................................ 25 4.1 Eligibility criteria ................................................................................................................... 25 4.1.1 Inclusion criteria ................................................................................................................... 25 4.1.2 Exclusion criteria ................................................................................................................. 25 4.2 Patient enrolment ................................................................................................................. 27 5 TREATMENT ...................................................................................................................... 28 5.1 Selection of the Phase I clinical dose and schedule ............................................................ 28 5.2 Dosing schedule/treatment schedule ................................................................................... 28 5.3 Enrolment ............................................................................................................................. 28 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 4 of 72 EudraCT number : 2016 -002577 -35 Cancer Research UK 5.3.1 Dose reductions ................................................................................................................... 28 5.3.2 Dose delays & interruptions .................................................................................................