An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients with Stage IIIB/IV Non-small Cell Lung Cancer Tumors with EGFR Activating Mutations (SOLAR Study) ISN/Protocol 8273-CL-0302 ClinicalTrials.gov Identifier: NCT02588261 Date of Protocol: Version 2.0, dated 19 Feb 2016 Sponsor: Astellas Pharma Global Development, Inc. (APGD) 1 Astellas Way Northbrook, IL 60062 Sponsor: APGD ISN/Protocol 8273-CL-0302 EudraCT number 2015-002894-39 - CONFIDENTIAL - An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients with Stage IIIB/IV Non-small Cell Lung Cancer Tumors with EGFR Activating Mutations SOLAR Study Protocol for Phase 3 Study of ASP8273 ISN/Protocol 8273-CL-0302 Version 2.0 Incorporating Substantial Amendment 1 [See Attachment 1] 19 February 2016 IND 119,902 EudraCT 2015-002894-39 Sponsor: Astellas Pharma Global Development, Inc. (APGD) 1 Astellas Way Northbrook, IL 60062 Protocol History: Version 1.0 Original [29Jul2015] Investigator: Investigator information is on file at Astellas. This confidential document is the property of the sponsor. No unpublished information contained in this document may be disclosed without prior written approval of the sponsor. 19 Feb 2016 Astellas Page 1 of 131 Version 2.0 Incorporating Substantial Amendment 1 Sponsor: APGD ISN/Protocol 8273-CL-0302 EudraCT number 2015-002894-39 - CONFIDENTIAL - Table of Contents I. SIGNATURES ······················································································ 8 II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························11 III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················13 IV. SYNOPSIS··························································································17 V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ·································28 1 INTRODUCTION·················································································33 1.1 Background ····················································································33 1.2 Nonclinical and Clinical Data ·······························································34 1.2.1 Nonclinical Pharmacology ·····························································34 1.2.2 Nonclinical Pharmacokinetics ·························································34 1.2.3 Nonclinical Toxicology·································································35 1.2.4 Clinical Data ·············································································37 1.3 Summary of Key Safety Information for Study Drugs ···································37 1.3.1 ASP8273··················································································37 1.3.2 Erlotinib ··················································································38 1.3.3 Gefitinib ··················································································38 1.4 Risk-Benefit Assessment·····································································38 2 STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································39 2.1 Study Objectives ··············································································39 2.1.1 Primary Objective ·······································································39 2.1.2 Secondary Objectives ···································································39 2.1.3 Exploratory Objectives ·································································40 2.2 Study Design and Dose Rationale···························································40 2.2.1 Study Design·············································································40 2.2.2 Dose Rationale···········································································41 2.3 Endpoints·······················································································42 2.3.1 Primary Endpoints·······································································42 2.3.2 Secondary Endpoints····································································42 2.3.3 Exploratory Endpoints ··································································42 3 STUDY POPULATION··········································································42 3.1 Selection of Study Population ·······························································42 3.2 Inclusion Criteria··············································································42 19 Feb 2016 Astellas Page 2 of 131 Version 2.0 Incorporating Substantial Amendment 1 Sponsor: APGD ISN/Protocol 8273-CL-0302 EudraCT number 2015-002894-39 - CONFIDENTIAL - 3.3 Exclusion Criteria ·············································································44 4 TREATMENT(S)··················································································46 4.1 Identification of Investigational Product(s) ················································46 4.1.1 Test Drug(s)··············································································46 4.1.2 Comparative Drug(s)····································································46 4.2 Packaging and Labeling ······································································46 4.3 Study Drug Handling ·········································································47 4.4 Blinding ························································································47 4.5 Assignment and Allocation ··································································47 5 TREATMENTS AND EVALUATION························································48 5.1 Dosing and Administration of Study Drug(s) and Other Medication(s)················48 5.1.1 Dose/Dose Regimen and Administration Period ····································48 5.1.2 Increase or Reduction in Dose of the Study Drug(s) ································48 5.1.2.1 ASP8273 Dose Modification·····················································49 5.1.2.2 Erlotinib Dose Modification······················································51 5.1.2.3 Gefitinib Dose Modification ·····················································53 5.1.3 Previous and Concomitant Treatment (Medication and Nonmedication Therapy) ··················································································53 5.1.4 Treatment Compliance··································································55 5.2 Demographics and Baseline Characteristics ···············································55 5.2.1 Demographics············································································55 5.2.2 Medical History··········································································55 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease··············56 5.2.4 Performance Status······································································56 5.3 Efficacy Assessment··········································································56 5.3.1 Evaluation of Target Lesions ··························································57 5.3.1.1 Complete Response (CR) ·························································57 5.3.1.2 Partial Response (PR) ·····························································57 5.3.1.3 Stable Disease (SD) ·······························································57 5.3.1.4 Progressive Disease (PD) ·························································57 5.3.2 Evaluation of Nontarget Lesions ······················································57 5.3.2.1 Complete Response (CR) ·························································58 5.3.2.2 NonCR/NonPD ····································································58 5.3.2.3 Progressive Disease (PD) ·························································58 19 Feb 2016 Astellas Page 3 of 131 Version 2.0 Incorporating Substantial Amendment 1 Sponsor: APGD ISN/Protocol 8273-CL-0302 EudraCT number 2015-002894-39 - CONFIDENTIAL - 5.3.3 Evaluation of Time Point Response···················································58 5.3.4 Disease Control Rate (DCR) ···························································58 5.3.5 Progression-free Survival (PFS) ·······················································58 5.4 Safety Assessment ············································································58 5.4.1 Vital Signs················································································58 5.4.2 Adverse Events ··········································································58 5.4.2.1 Adverse Events of Possible Hepatic Origin ····································59 5.4.3 Laboratory Assessments································································59 5.4.4 Physical Examination ···································································59 5.4.5 Electrocardiogram (ECG) ······························································59 5.5 Adverse Events and Other Safety Aspects ·················································60 5.5.1 Definition of Adverse Events (AEs) ··················································60 5.5.2 Definition of Serious Adverse Events (SAEs) ·······································60 5.5.3 Criteria for Causal Relationship to the Study Drug ·································61 5.5.4 Criteria for Defining the Severity of an Adverse Event ····························62 5.5.5 Reporting of Serious Adverse Events (SAEs) ·······································62