Oncology Clinical Development Ribociclib (LEE011) Protocol CLEE011XUS29 / NCT02732119 TRINITI-1: A Phase I/II, single arm, open-label study of Ribociclib in Combination with Everolimus + Exemestane in the Treatment of Men and Postmenopausal Women with HR+, HER2- Locally Advanced or Metastatic Breast Cancer Following Progression on a CDK 4/6 Inhibitor Triplet with Ribociclib, AfINitor® and AI posT CDK 4/6 Inhibitor Authors Document type Amended Protocol Version Version number 03 (Clean) Development phase I/II Document status Final Release date 15-Feb-2019 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Novartis Confidential Page 2 Amended Protocol v03 (clean) CLEE011XUS29 Table of contents Table of contents..................................................................................................................................... 2 List of tables............................................................................................................................................ 8 List of figures........................................................................................................................................ 10 List of abbreviations ............................................................................................................................. 11 Glossary of terms .................................................................................................................................. 14 Amendment 3........................................................................................................................................ 16 Amendment 2........................................................................................................................................ 18 Amendment 1........................................................................................................................................ 21 Synopsis................................................................................................................................................ 24 1 Background........................................................................................................................................... 35 1.1 Overview of current treatment................................................................................................. 35 1.1.1 Epidemiology of breast cancer ............................................................................. 35 1.1.2 Treatment options for hormone receptor positive advanced breast cancer........... 35 1.2 Introduction to investigational treatment(s) and other study treatment(s)............................... 39 1.2.1 Overview of ribociclib (LEE011)......................................................................... 39 1.2.2 Summary of results from patients treated with the combination of ribociclib 600 mg and letrozole 2.5 mg daily from study CLEE011A2301 (MONALEESA-2)................................................................................................ 45 1.2.3 Overview of everolimus (RAD001/ Afinitor®) .................................................... 49 1.2.4 Overview of exemestane....................................................................................... 52 1.2.5 Ribociclib in combination with everolimus.......................................................... 53 2 Rationale............................................................................................................................................... 59 2.1 Study rationale and purpose .................................................................................................... 59 2.1.1 Rationale for Continuous Dosing- Phase I-Dose Escalation ................................ 60 2.1.2 Rational for stomatitis prevention mouthwash ..................................................... 62 2.2 Risks and benefits.................................................................................................................... 62 2.2.1 Potential benefits to clinical trial participation ..................................................... 63 2.2.2 Potential risks to clinical trial participants............................................................ 63 3 Study objectives and endpoints............................................................................................................. 63 3.1 Objectives and related endpoints-Phase I................................................................................ 63 3.2 Objectives and related endpoints-phase II............................................................................... 64 4 Study design.......................................................................................................................................... 66 4.1 Description of study design..................................................................................................... 66 4.1.1 Screening phase (Phase I and II) .......................................................................... 68 4.1.2 Treatment phase.................................................................................................... 69 4.1.3 Treatment discontinuation .................................................................................... 69 4.1.4 Safety follow-up ................................................................................................... 69 Novartis Confidential Page 3 Amended Protocol v03 (clean) CLEE011XUS29 4.2 Timing of interim analyses...................................................................................................... 69 4.3 Definition of end of study........................................................................................................ 70 4.4 Early study termination ........................................................................................................... 70 5 Population............................................................................................................................................. 70 5.1 Patient population.................................................................................................................... 70 5.1.1 Screening for Hepatitis B...................................................................................... 71 5.1.2 Screening for Hepatitis C...................................................................................... 71 5.2 Inclusion criteria...................................................................................................................... 72 5.3 Exclusion criteria..................................................................................................................... 74 6 Treatment.............................................................................................................................................. 77 6.1 Study treatment........................................................................................................................ 77 6.1.1 Dosing regimen..................................................................................................... 77 6.2 Dose escalation and de-escalation guidelines: Phase I Safety Run-in..................................... 78 6.2.1 Criteria for dose escalation and determination of MTD(s)/RP2D ........................ 79 6.2.2 Definitions of dose limiting toxicities (DLTs) ..................................................... 80 6.2.3 Follow up for dose limiting toxicities................................................................... 81 6.2.4 Doses for Phase II................................................................................................. 82 6.3 Overview of Dexamethasone oral solution ............................................................................. 83 6.4 Dose modification ................................................................................................................... 84 6.4.1 Dose cohort modification ..................................................................................... 84 6.4.2 Anticipated Risks and safety considerations of the study drug combination........ 87 6.4.3 Dose modifications for ribociclib+everolimus+exemestane combination............ 87 6.4.4 Dose modification and management for everolimus specific toxicities ............... 95 6.4.5 Recommended actions to be taken for positive baseline hepatitis B test.............. 99 6.4.6 Guidance for all other adverse reactions............................................................. 100 6.5 Concomitant medications ...................................................................................................... 101 6.5.1 Permitted concomitant therapy for all treatment groups..................................... 101 6.5.2 Prohibited concomitant therapy during combined ribociclib + everolimus + exemestane.......................................................................................................... 102 6.5.3 Permitted concomitant therapy requiring caution and/or action while on study ................................................................................................................... 103 6.5.4 Drugs with QTc prolongation............................................................................. 103 6.6 Patient numbering, treatment assignment or randomization ................................................. 104 6.6.1 Patient numbering..............................................................................................