Clinical Development INC424 (ruxolitinib) Protocol CINC424A2401 / NCT01493414 An open-label, multicenter, expanded access study of INC424 for patients with primary myelofibrosis (PMF) or post polycythemia myelofibrosis (PPV MF) or post- essential thrombocythemia myelofibrosis (PET-MF) Authors Document type Amended Protocol Version EUDRACT number 2010-024473-39 Version number 05 (Clean) Development phase IIIB Document status Final Release date 21-Mar-2016 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 05 (Clean) Protocol No. CINC424A2401 Table of contents Table of contents .................................................................................................................2 List of figures ......................................................................................................................6 List of tables ........................................................................................................................6 List of abbreviations ............................................................................................................7 Glossary of terms...............................................................................................................10 Amendment 5 ....................................................................................................................11 Oncology clinical study protocol synopsis........................................................................39 1 Background........................................................................................................................51 1.1 Overview of myelofibrosis and myeloproliferative neoplasms and current treatment options ...................................................................................................51 1.2 Inhibition of Janus Kinases (JAK) in MPN...........................................................55 1.3 Overview of INC424 .............................................................................................56 1.3.1 INC424 pharmacokinetics.....................................................................57 1.3.2 INC424 preclinical safety .....................................................................58 1.3.3 INC424 clinical safety in healthy volunteers ........................................59 1.3.4 INC424 clinical safety and efficacy in phase I/II trials.........................59 1.3.5 Phase III INC424 clinical trials (controlled MF study with oral JAK inhibitor treatment [COMFORT; (INCB 18424-351 and CINC424A2352)]) ................................................................................65 2 Rationale............................................................................................................................69 2.1 Study rationale and purpose...................................................................................69 2.2 Rationale for dose and regimen selected ...............................................................70 3 Objectives and endpoints...................................................................................................70 3.1 Primary objectives .................................................................................................70 3.2 Secondary objectives .............................................................................................70 3.3 Study endpoints .....................................................................................................70 3.3.1 Safety.....................................................................................................70 3.3.2 Efficacy .................................................................................................71 3.3.3 Quality of Life.......................................................................................71 3.3.4 Medical resource utilization (MRU) .....................................................71 4 Study design ......................................................................................................................71 4.1 Description of study design ...................................................................................71 4.2 Early study termination..........................................................................................73 5 Population..........................................................................................................................74 5.1 Patient population ..................................................................................................74 Novartis Confidential Page 3 Amended Protocol Version 05 (Clean) Protocol No. CINC424A2401 5.2 Inclusion criteria ....................................................................................................74 5.3 Exclusion criteria...................................................................................................75 6 Treatment...........................................................................................................................77 6.1 Investigational treatment, other study treatment, supportive treatment ................77 6.1.1 Study drug dosing .................................................................................77 6.2 Dose modifications ................................................................................................78 6.2.1 Dose increases of INC424.....................................................................78 6.2.2 Dose interruption or dose reduction......................................................81 6.2.3 Restarting or reinstituting previous dose...............................................83 6.2.4 Dose reductions for concomitant CYP inhibitor usage.........................84 6.2.5 Optional dose tapering strategy in the event of study drug discontinuation ......................................................................................84 6.2.6 Dose interruption and discontinuation of study drug............................85 6.2.7 Treatment of investigational drug overdose..........................................86 6.3 Concomitant medications ......................................................................................86 6.3.1 Permitted concomitant therapy .............................................................87 6.3.2 Permitted concomitant therapy requiring caution and/or action...........87 6.3.3 Prohibited concomitant therapy ............................................................88 6.4 Patient numbering, treatment assignment and randomization...............................88 6.4.1 Patient numbering .................................................................................88 6.4.2 Treatment assignment and randomization ............................................89 6.4.3 Treatment blinding................................................................................89 6.5 Study drug supply..................................................................................................89 6.5.1 Study drug preparation and dispensation ..............................................89 6.5.2 Study drug packaging and labeling.......................................................89 6.5.3 Drug supply and storage........................................................................89 6.5.4 Study drug compliance and accountability ...........................................90 7 Visit schedule and assessments .........................................................................................91 7.1 Study flow and visit schedule................................................................................91 7.2 Study evaluations...................................................................................................96 7.2.1 Efficacy .................................................................................................96 7.2.2 Safety and tolerability ...........................................................................96 7.3 Screening ...............................................................................................................96 7.3.1 Information to be collected on screening failures.................................98 7.4 Baseline evaluations (Day -7 to Day -1)................................................................98 7.4.1 Combining Screening and Baseline Visits into 1 Visit.........................99 Novartis Confidential Page 4 Amended Protocol Version 05 (Clean) Protocol No. CINC424A2401 7.5 On treatment evaluations .......................................................................................99 7.5.1 On treatment evaluation requirements ................................................100 7.6 End of treatment visit, including premature withdrawal and study discontinuation visit.............................................................................................107 7.6.1 Criteria for premature withdrawal.......................................................107 7.6.2 End of treatment evaluations...............................................................109 7.6.3 Follow-up period.................................................................................109 8 Study assessments ...........................................................................................................110 8.1 Demographic and other pretreatment assessments..............................................110 8.2 Safety