Clinical Development BGJ398 Protocol CBGJ398X2201 / NCT01975701 A Phase 2, multicenter, open-label study of BGJ398 in patients with recurrent resectable or unresectable Glioblastoma Authors Document type Amended Protocol Version EUDRACT number 2013-002200-13 Version number 02 (Clean) Development phase II Document status Final Release date 01-Apr-2015 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Template version 15-Feb-2012 Novartis Confidential Page 2 Amended Protocol Version 02 (Clean) Protocol No. CBGJ398X2201 Table of contents Table of contents ................................................................................................................. 2 List of figures ...................................................................................................................... 6 List of tables ........................................................................................................................ 6 List of abbreviations ............................................................................................................ 7 Glossary of terms ............................................................................................................... 10 Amendment 2 ........................................................................................................................... 11 IRB/IEC/HA ...................................................................................................................... 12 Amendment 1 .................................................................................................................... 13 Protocol summary .............................................................................................................. 15 1 Background ........................................................................................................................ 19 1.1 Overview of disease pathogenesis, epidemiology and current treatment .............. 19 1.2 Introduction to investigational treatment(s) and other study treatment(s) ............. 20 1.2.1 Overview of BGJ398 ............................................................................. 20 2 Rationale ............................................................................................................................ 24 2.1 Study rationale and purpose ................................................................................... 24 2.2 Rationale for the study design ............................................................................... 24 2.3 Rationale for dose and regimen selection .............................................................. 25 3 Objectives and endpoints ................................................................................................... 26 4 Study design ...................................................................................................................... 28 4.1 Description of study design ................................................................................... 28 4.2 Timing of interim analyses and design adaptations ............................................... 31 4.3 Definition of end of the study ................................................................................ 31 4.4 Early study termination .......................................................................................... 31 5 Population .......................................................................................................................... 31 5.1 Patient population .................................................................................................. 31 5.2 Inclusion criteria .................................................................................................... 32 5.3 Exclusion criteria ................................................................................................... 33 6 Treatment ........................................................................................................................... 36 6.1 Study treatment ...................................................................................................... 36 6.1.1 Dosing regimen ..................................................................................... 36 6.1.2 Ancillary treatments .............................................................................. 38 6.1.3 Supportive treatment needed for GBM ................................................. 38 6.1.4 Treatment duration ................................................................................ 38 6.2 Dose modifications ................................................................................................ 38 6.2.1 Dose modification and dose delay ........................................................ 38 Novartis Confidential Page 3 Amended Protocol Version 02 (Clean) Protocol No. CBGJ398X2201 6.2.2 Follow-up for toxicities ......................................................................... 47 6.2.3 Anticipated risks and safety concerns of the study drug ....................... 47 6.3 Concomitant medications ...................................................................................... 47 6.3.1 Permitted concomitant therapy ............................................................. 47 6.3.2 Permitted concomitant therapy requiring caution and/or action ........... 48 6.3.3 Prohibited concomitant therapy ............................................................ 50 6.4 Patient numbering, treatment assignment or randomization ................................. 51 6.4.1 Patient numbering ................................................................................. 51 6.4.2 Treatment assignment or randomization ............................................... 51 6.5 Study drug preparation and dispensation ............................................................... 51 6.5.1 Study drug packaging and labeling ....................................................... 51 6.5.2 Drug supply and storage ........................................................................ 51 6.5.3 Study drug compliance and accountability ........................................... 52 6.5.4 Disposal and destruction ....................................................................... 52 7 Visit schedule and assessments ......................................................................................... 52 7.1 Study flow and visit schedule ................................................................................ 52 7.1.1 Molecular pre-screening ........................................................................ 58 7.1.2 Clinical Screening ................................................................................. 58 7.1.3 Treatment period ................................................................................... 60 7.1.4 End of treatment visit including study completion and premature withdrawal ............................................................................................. 60 7.1.5 Follow up period ................................................................................... 61 7.2 Assessment types ................................................................................................... 62 7.2.1 Efficacy assessments ............................................................................. 62 7.2.2 Safety and tolerability assessments ....................................................... 62 66 69 8 Safety monitoring and reporting ........................................................................................ 71 8.1 Adverse events ....................................................................................................... 71 8.1.1 Definitions and reporting ...................................................................... 71 8.1.2 Laboratory test abnormalities ................................................................ 72 8.2 Serious adverse events ........................................................................................... 73 8.2.1 Definitions ............................................................................................. 73 8.2.2 Reporting ............................................................................................... 73 8.3 Emergency unblinding of treatment assignment ................................................... 74 8.4 Pregnancies ............................................................................................................ 74 Novartis Confidential Page 4 Amended Protocol Version 02 (Clean) Protocol No. CBGJ398X2201 8.5 Warnings and precautions ...................................................................................... 75 8.6 Data Monitoring Committee .................................................................................. 75 8.7 Steering Committee ............................................................................................... 75 9 Data collection and management ....................................................................................... 75 9.1 Data confidentiality ............................................................................................... 75 9.2 Site monitoring ...................................................................................................... 76 9.3 Data collection 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