Clinical Development LEE011 (ribociclib) Protocol CLEE011F2301 / NCT02422615 MONALEESA-3: A randomized double-blind, placebo- controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment Authors Document type Amended Protocol Version (Clean) EUDRACT number 2015-000617-43 Version number 02 (Amended Protocol) Development phase III Document status Final Release date 28-Jul-2016 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Template version 17-Nov-2014 Novartis Confidential Page 2 Amended Protocol Version 02 (Clean) Protocol No. CLEE011F2301 Table of contents Table of contents ................................................................................................................. 2 List of figures ...................................................................................................................... 6 List of tables ........................................................................................................................ 6 List of abbreviations ............................................................................................................ 8 Glossary of terms ............................................................................................................... 11 Amendment 2 (28-Jul-2016) ............................................................................................. 13 Amendment 1 .................................................................................................................... 16 Protocol summary: ............................................................................................................. 21 1 Background ........................................................................................................................ 26 1.1 Overview of disease pathogenesis and current treatment ...................................... 26 1.1.1 Epidemiology ........................................................................................ 26 1.1.2 Available therapeutic options in ER+, HER2-negative breast cancer .................................................................................................... 26 1.1.3 Role of the CDK4/6 pathway in breast cancer ...................................... 27 1.2 Introduction to investigational treatment(s) and other study treatment(s) ............. 28 1.2.1 Overview of ribociclib .......................................................................... 28 1.2.2 Overview of fulvestrant ......................................................................... 34 1.2.3 Overview of ribociclib in combination with fulvestrant ....................... 36 2 Rationale ............................................................................................................................ 37 2.1 Study rationale and purpose ................................................................................... 37 2.2 Rationale for the study design ............................................................................... 38 2.3 Rationale for dose and regimen selection .............................................................. 39 2.4 Rationale for choice of combination drugs ............................................................ 39 2.5 Rationale for choice of comparator drugs ............................................................. 40 2.6 Risks and benefits .................................................................................................. 40 2.6.1 Potential benefits to clinical trial participants ....................................... 40 2.6.2 Potential risks to clinical trial participants ............................................ 40 3 Objectives and endpoints ................................................................................................... 41 4 Study design ...................................................................................................................... 44 4.1 Description of study design ................................................................................... 44 4.1.1 Screening phase ..................................................................................... 46 4.1.2 Treatment phase .................................................................................... 46 4.1.3 Safety follow-up .................................................................................... 46 4.1.4 Efficacy follow-up ................................................................................ 47 4.1.5 Survival follow-up ................................................................................ 47 4.2 Timing of interim analyses and design adaptations ............................................... 47 Novartis Confidential Page 3 Amended Protocol Version 02 (Clean) Protocol No. CLEE011F2301 4.3 Definition of end of the study ................................................................................ 47 4.4 Early study termination .......................................................................................... 48 5 Population .......................................................................................................................... 48 5.1 Patient population .................................................................................................. 48 5.2 Inclusion criteria .................................................................................................... 48 5.3 Exclusion criteria ................................................................................................... 50 6 Treatment ........................................................................................................................... 52 6.1 Study treatment ...................................................................................................... 52 6.1.1 Dosing regimen ..................................................................................... 53 6.1.2 Guidelines for continuation of treatment .............................................. 55 6.1.3 Ancillary treatments .............................................................................. 55 6.1.4 Rescue medication ................................................................................ 55 6.1.5 Treatment duration ................................................................................ 55 6.2 Dose escalation guidelines ..................................................................................... 55 6.3 Patient numbering, treatment assignment or randomization ................................. 55 6.3.1 Patient numbering ................................................................................. 55 6.3.2 Treatment assignment or randomization ............................................... 56 6.3.3 Treatment blinding ................................................................................ 56 6.4 Study drug preparation and dispensation ............................................................... 57 6.4.1 Study drug packaging and labeling ....................................................... 57 6.4.2 Drug supply and storage ........................................................................ 58 6.4.3 Study drug compliance and accountability ........................................... 58 6.4.4 Disposal and destruction ....................................................................... 58 6.5 Dose modifications ................................................................................................ 59 6.5.1 Dose modification and dose delay ........................................................ 59 6.5.2 Follow-up for toxicities ......................................................................... 66 6.5.3 Anticipated risks and safety concerns of the study drug ....................... 66 6.6 Concomitant medications ...................................................................................... 66 6.6.1 Permitted concomitant therapy ............................................................. 66 6.6.2 Concomitant therapy requiring caution ................................................. 67 6.6.3 Prohibited concomitant therapy ............................................................ 68 6.6.4 Drugs with QT prolongation ................................................................. 68 7 Visit schedule and assessments ......................................................................................... 68 7.1 Study flow and visit schedule ................................................................................ 68 7.1.1 Screening ............................................................................................... 77 7.1.2 Treatment period ................................................................................... 78 Novartis Confidential Page 4 Amended Protocol Version 02 (Clean) Protocol No. CLEE011F2301 7.1.3 Discontinuation of Study Treatment ..................................................... 78 7.1.4 Withdrawal of Consent ......................................................................... 80 7.1.5 Follow up for Safety Evaluations .......................................................... 80 7.1.6 Efficacy follow-up ................................................................................ 81 7.1.7 Survival