Clinical Development Deferasirox (ICL670) Clinical Trial Protocol CICL670A2421 / NCT01868477 An open-label, phase II, randomized, pilot study to assess the effect in term of erythroid improvement of deferasirox combined with erythropoietin compared to erythropoietin alone in patients with low- and int-1-risk myelodysplastic syndrome Authors Document type Amended Protocol Version EUDRACT number 2013-000981-12 Version number 03 (Clean) Development phase II Document status Final Release date 06-Aug-2015 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Novartis Confidential Page 2 Amended Protocol Version 03 (Clean) Protocol No. CICL670A2421 Table of contents Table of contents .................................................................................................................. 2 List of figures ....................................................................................................................... 6 List of tables ........................................................................................................................ 6 List of abbreviations ............................................................................................................ 7 Glossary of terms ................................................................................................................. 9 Amendment 3..................................................................................................................... 10 Summary of previous amendments ................................................................................... 16 Protocol summary .............................................................................................................. 35 1 Background ........................................................................................................................ 38 1.1 Overview of disease pathogenesis, epidemiology and current treatment .............. 38 1.2 Introduction to investigational treatment(s) and other study treatment(s) ............. 41 1.2.1 Overview of Deferasirox (ICL670) ....................................................... 41 1.2.2 Overview of EPO .................................................................................. 44 2 Rationale ............................................................................................................................ 45 2.1 Study rationale and purpose ................................................................................... 45 2.2 Rationale for the study design ................................................................................ 46 2.3 Rationale for dose and regimen selection .............................................................. 47 2.4 Rationale for choice of combination drugs ............................................................ 48 3 Objectives and endpoints ................................................................................................... 48 4 Study design ...................................................................................................................... 51 4.1 Description of study design .................................................................................... 51 4.2 Definition of end of the study ................................................................................ 56 4.3 Early study termination .......................................................................................... 56 5 Population .......................................................................................................................... 56 5.1 Patient population .................................................................................................. 56 5.2 Inclusion criteria .................................................................................................... 57 5.3 Exclusion criteria ................................................................................................... 58 6 Treatment ........................................................................................................................... 59 6.1 Study treatment ...................................................................................................... 59 6.1.1 Dosing regimen ..................................................................................... 59 6.1.2 Ancillary treatments .............................................................................. 63 6.1.3 Guidelines for continuation of treatment ............................................... 63 6.1.4 Treatment duration ................................................................................ 63 6.2 Dose escalation guidelines ..................................................................................... 64 6.3 Dose modifications ................................................................................................ 64 Novartis Confidential Page 3 Amended Protocol Version 03 (Clean) Protocol No. CICL670A2421 6.3.1 Dose modification and dose delay ........................................................ 64 6.3.2 Treatment interruption and treatment discontinuation .......................... 67 6.3.3 Follow-up for toxicities ......................................................................... 67 6.3.4 Anticipated risks and safety concerns of the study drug ....................... 68 6.4 Concomitant medications ...................................................................................... 68 6.4.1 Permitted concomitant therapy .............................................................. 68 6.4.2 Permitted concomitant therapy requiring caution and/or action ............ 68 6.4.3 Prohibited concomitant therapy ............................................................. 69 6.5 Patient numbering, treatment assignment or randomization ................................. 69 6.5.1 Patient numbering ................................................................................. 69 6.5.2 Treatment assignment or randomization ............................................... 69 6.5.3 Treatment blinding ................................................................................ 69 6.6 Study drug preparation and dispensation ............................................................... 70 6.6.1 Study drug packaging and labeling ....................................................... 70 6.6.2 Drug supply and storage ........................................................................ 70 6.6.3 Study drug compliance and accountability ........................................... 70 6.6.4 Disposal and destruction ........................................................................ 71 7 Visit schedule and assessments ......................................................................................... 71 7.1 Study flow and visit schedule ................................................................................ 71 7.1.1 Screening ............................................................................................... 75 7.1.2 Treatment period ................................................................................... 76 7.1.3 End of Treatment Visit including study completion and premature withdrawal ............................................................................................. 76 7.1.4 Follow up period ................................................................................... 77 7.2 Assessment types ....................................................................................................... 77 7.2.1 Efficacy assessments ............................................................................. 77 7.2.2 Safety and tolerability assessments ....................................................... 78 7.2.4 Other assessments .................................................................................. 82 8 Safety monitoring and reporting ........................................................................................ 82 8.1 Adverse events ....................................................................................................... 82 8.1.1 Definitions and reporting ...................................................................... 82 8.1.2 Laboratory test abnormalities ................................................................ 83 8.1.3 Adverse events of special interest ......................................................... 83 8.2 Serious adverse events ........................................................................................... 84 8.2.1 Definitions ............................................................................................. 84 Novartis Confidential Page 4 Amended Protocol Version 03 (Clean) Protocol No. CICL670A2421 8.2.2 Reporting ............................................................................................... 84 8.3 Emergency unblinding of treatment assignment ................................................... 85 8.4 Pregnancies ............................................................................................................ 85 8.5 Warnings and precautions ...................................................................................... 85 8.6 Data Monitoring Committee .................................................................................. 85 8.7 Steering Committee 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