Clinical Development Alpelisib (BYL719) Protocol CBYL719A2201 / NCT01923168 A phase II randomized, double-blind placebo controlled, study of letrozole with or without BYL719 or buparlisib, for the neoadjuvant treatment of postmenopausal women with hormone receptor-positive HER2-negative breast cancer Authors Document type Amended Protocol Version (Clean) EUDRACT number 2013-001862-41 Version number 07 Development phase II Document status Final Release date 18-Oct-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 07 (Clean) Protocol No. CBYL719A2201 Table of contents Table of contents .................................................................................................................2 List of appendices................................................................................................................7 List of figures ......................................................................................................................7 List of tables ........................................................................................................................8 List of abbreviations ..........................................................................................................10 Glossary of terms...............................................................................................................13 Amendment 7 (18-Oct-2016) ............................................................................................14 Amendment 6 (04-May-2016)...........................................................................................16 Amendment 5 ....................................................................................................................16 Amendment 4 ....................................................................................................................25 Amendment 3 ....................................................................................................................29 Amendment 2 ....................................................................................................................29 Amendment 1 ....................................................................................................................38 Protocol summary:.............................................................................................................44 1 Background........................................................................................................................47 1.1 Overview of disease pathogenesis, epidemiology and current treatment..............47 1.1.1 Hormone receptor-positive breast cancer..............................................47 1.1.2 PI3K Pathway........................................................................................48 1.1.3 PI3K pathway activation in HR+ Breast Cancer...................................49 1.2 Introduction to investigational treatment(s) and other study treatment(s).............50 1.2.1 Overview of BYL719............................................................................50 1.2.2 Overview of buparlisib (BKM120).......................................................59 1.2.3 Overview of letrozole............................................................................66 1.2.4 Overview of BYL719/buparlisib plus letrozole....................................67 2 Rationale............................................................................................................................70 2.1 Study rationale and purpose...................................................................................70 2.2 Rationale for the study design ...............................................................................71 2.2.1 Rationale for study design and inclusion of wild-type patients ............72 2.2.2 Rationale for the stratification factors...................................................72 2.3 Rationale for dose and regimen selection..............................................................73 2.4 Rationale for choice of combination drugs............................................................74 2.5 Rationale for choice of comparators drugs............................................................74 2.6 Risks and Benefits .................................................................................................75 3 Objectives and endpoints...................................................................................................75 4 Study design ......................................................................................................................79 Novartis Confidential Page 3 Amended Protocol Version 07 (Clean) Protocol No. CBYL719A2201 4.1 Description of study design ...................................................................................79 4.2 Timing of interim analyses and design adaptations...............................................82 4.3 Definition of end of the study................................................................................82 4.4 Early study termination..........................................................................................82 5 Population..........................................................................................................................82 5.1 Patient population ..................................................................................................82 5.2 Inclusion criteria ....................................................................................................83 5.3 Exclusion criteria...................................................................................................84 6 Treatment...........................................................................................................................87 6.1 Study treatment......................................................................................................87 6.1.1 Dosing regimen .....................................................................................87 6.1.2 Instructions for administration ..............................................................88 6.1.3 Guidelines for continuation of treatment ..............................................88 6.1.4 Treatment duration................................................................................89 6.2 Dose escalation guidelines.....................................................................................89 6.3 Dose modifications ................................................................................................89 6.3.1 Dose modification and dose delay ........................................................89 6.3.2 Follow-up for toxicities.........................................................................98 6.4 Concomitant medications ....................................................................................104 6.4.1 Permitted concomitant therapy ...........................................................104 6.4.2 Prohibited concomitant therapy ..........................................................108 6.5 Patient numbering, treatment assignment or randomization ...............................109 6.5.1 Patient numbering ...............................................................................109 6.5.2 Treatment assignment or randomization.............................................109 6.5.3 Treatment blinding..............................................................................110 6.6 Study drug preparation and dispensation.............................................................110 6.6.1 Study drug packaging and labeling .....................................................110 6.6.2 Drug supply and storage......................................................................110 6.6.3 Study drug compliance and accountability .........................................111 6.6.4 Disposal and destruction .....................................................................111 7 Visit schedule and assessments .......................................................................................111 7.1 Study flow and visit schedule ..............................................................................111 7.1.1 Molecular pre-screening......................................................................118 7.1.2 Screening.............................................................................................118 7.1.3 Treatment period .................................................................................121 7.1.4 Discontinuation of Study Treatment ...................................................121 Novartis Confidential Page 4 Amended Protocol Version 07 (Clean) Protocol No. CBYL719A2201 7.1.5 Withdrawal of Consent .......................................................................122 7.1.6 Follow up for Safety Evaluations........................................................123 7.1.7 Lost to follow-up.................................................................................123 7.1.8 Breast Cancer Surgery.........................................................................123 7.2 Assessment types .................................................................................................124 7.2.1 Efficacy assessments...........................................................................124 7.2.2 Safety