Clinical Development Osilodrostat (LCI699) Oncology Clinical Trial Protocol CLCI699C1201 / NCT02468193 A Phase II, open-label, dose titration, multi-center study to assess the safety/tolerability and efficacy of osilodrostat in patients with all types of endogenous Cushing’s syndrome except Cushing’s disease Document type Amended protocol version EUDRACT number Not applicable Version number 04 (Clean) Development phase II Document status Final Release date 31-Jul-2018 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Template version 6-Apr-2017 Novartis Confidential Page 2 Amended Protocol Version 04 (Clean) Protocol No. CLCI699C1201 Table of contents Table of contents .................................................................................................................2 List of tables ........................................................................................................................5 List of figures ......................................................................................................................6 List of abbreviations ............................................................................................................7 Amendment 4 (31-Jul-2018) ...............................................................................................9 Summary of previous amendments ...................................................................................10 Amendment 3 (07-Aug-2017) ...........................................................................................10 Amendment 2 (11-Nov-2016) ...........................................................................................11 Amendment 1 (29-Feb-2016)............................................................................................14 Protocol summary:.............................................................................................................16 1 Background........................................................................................................................18 1.1 Overview of disease pathogenesis, epidemiology and current treatment..............18 1.1.1 Epidemiology and pathogenesis of Cushing’s syndrome (CS).............18 1.1.2 Current treatment modalities.................................................................18 1.2 Introduction to investigational treatment(s) and other study treatment(s).............19 1.2.1 Overview of osilodrostat (LCI699).......................................................19 2 Rationale............................................................................................................................25 2.1 Study rationale and purpose...................................................................................25 2.2 Rationale for the study design ...............................................................................25 2.3 Rationale for dose and regimen selection..............................................................26 2.4 Rationale for choice of combination drugs............................................................27 2.5 Rationale for choice of comparators drugs............................................................27 2.6 Benefit-Risk Assessment of osilodrostat in study population ...............................27 28 3 Objectives and endpoints...................................................................................................29 4 Study design ......................................................................................................................32 4.1 Description of study design ...................................................................................32 4.2 Timing of interim analyses and design adaptations...............................................33 4.3 Definition of end of the study................................................................................33 4.4 Early study termination..........................................................................................33 5 Population..........................................................................................................................34 5.1 Patient population ..................................................................................................34 5.2 Inclusion criteria ....................................................................................................34 5.3 Exclusion criteria...................................................................................................36 6 Treatment...........................................................................................................................38 6.1 Study treatment......................................................................................................38 Novartis Confidential Page 3 Amended Protocol Version 04 (Clean) Protocol No. CLCI699C1201 6.1.1 Dosing regimen .....................................................................................38 6.1.2 Ancillary treatments..............................................................................39 6.1.3 Rescue medication ................................................................................39 6.1.4 Guidelines for continuation of treatment ..............................................39 6.1.5 Treatment duration................................................................................39 6.2 Dose escalation guidelines.....................................................................................40 6.3 Dose modifications ................................................................................................40 6.3.1 Dose modification and dose delay ........................................................40 6.3.2 Follow-up for toxicities.........................................................................44 6.3.3 Anticipated risks and safety concerns of the study drug.......................45 6.4 Concomitant medications ......................................................................................45 6.4.1 Permitted concomitant therapy .............................................................45 6.4.2 Prohibited concomitant therapy ............................................................46 6.5 Patient numbering..................................................................................................47 6.6 Study drug preparation and dispensation...............................................................47 6.6.1 Study drug packaging and labeling.......................................................48 6.6.2 Drug supply and storage........................................................................48 6.6.3 Study drug compliance and accountability ...........................................48 6.6.4 Disposal and destruction .......................................................................49 7 Visit schedule and assessments .........................................................................................49 7.1 Study flow and visit schedule................................................................................49 7.1.1 Screening...............................................................................................58 7.1.2 Run-in period ........................................................................................59 7.1.3 Treatment period ...................................................................................59 7.1.4 Discontinuation of study treatment .......................................................59 7.1.5 Follow up for safety evaluations...........................................................61 7.1.6 Lost to follow-up...................................................................................61 7.2 Assessment types ...................................................................................................61 7.2.1 Efficacy assessments.............................................................................61 7.2.2 Safety and tolerability assessments.......................................................62 7.2.3 Pharmacokinetics ..................................................................................70 71 7.2.5 Resource utilization...............................................................................72 7.2.6 Patient reported outcomes.....................................................................72 8 Safety monitoring and reporting........................................................................................73 8.1 Adverse events.......................................................................................................73 8.1.1 Definitions and reporting ......................................................................73 Novartis Confidential Page 4 Amended Protocol Version 04 (Clean) Protocol No. CLCI699C1201 8.1.2 Laboratory test abnormalities................................................................74 8.1.3 Adverse events of special interest.........................................................75 8.2 Serious adverse events...........................................................................................76 8.2.1 Definitions.............................................................................................76 8.2.2 Reporting...............................................................................................76 8.3 Pregnancies ............................................................................................................77