The TEEL Study: A Phase I Trial of Tamoxifen with Ribociclib (LEE011) in Adult Patients with Advanced ER+ (HER2 Negative) Breast Cancer NCT02586675 Version 12.0 September 14, 2016 TEEL Protocol- Tamoxifen +Ribociclib Page 1 TITLE PAGE The TEEL Study: A Phase I trial of Tamoxifen with Ribociclib (LEE011) in adult patients with advanced ER+ (HER2 negative) breast cancer. Protocol: MCC 18332 Chesapeake IRB Pro00015228 Principal Investigator: Co-Investigators: Statistician: Experimental Therapeutics Program H. Lee Moffitt Cancer Center 12902 Magnolia Drive Tampa, FL 33612 & Comprehensive Breast Program Moffitt McKinley Outpatient Center 10920 N. McKinley Dr. Tampa, FL 33612 Study Site Contact: Protocol Version 12 Date: September 14, 2016 TEEL Protocol- Tamoxifen +Ribociclib Page 2 TITLE PAGE .............................................................................................................................................. 1 SYNOPSIS ................................................................................................................................................... 5 Patient Population ................................................................................................................................. 5 Type of Study ......................................................................................................................................... 5 Prior Therapy......................................................................................................................................... 5 Rationale for Study ................................................................................................................................ 5 Rationale for the combination of CDK4/6 inhibitors with Tamoxifen plus goserelin ................ 6 Type of Study: ........................................................................................................................................ 7 Phase I ............................................................................................................................................... 7 Phase Ib dose expansion ................................................................................................................... 7 Phase I Study drugs (ribociclib dose may change depending on results of phase I) .................. 8 Safety Evaluation ................................................................................................................................... 8 Dose and Treatment Schedule .............................................................................................................. 8 Prohibited Medications: ........................................................................................................................ 9 Statistical Considerations ...................................................................................................................... 9 Efficacy Evaluation .............................................................................................................................. 10 DEFINITIONS: ......................................................................................................................................... 11 1 BACKGROUND AND RATIONALE ....................................................................................... 12 1.1 Introduction ............................................................................................................................ 12 1.2 Tamoxifen ................................................................................................................................ 13 1.3 CDK Inhibitors ....................................................................................................................... 13 1.4 Role of the CDK4/6 pathway in breast cancer ..................................................................... 14 2 INTRODUCTION TO INVESTIGATIONAL TREATMENT(S) AND OTHER STUDY TREATMENT(S) ......................................................................................................................... 15 2.1 Overview of RIBOCICLIB .................................................................................................... 15 2.1.1 Nonclinical pharmacokinetics and metabolism ............................................................. 16 2.1.2 Clinical experience of RIBOCICLIB .............................................................................. 17 2.1.3 Clinical safety of RIBOCICLIB ...................................................................................... 17 2.1.4 Clinical efficacy of RIBOCICLIB ........................................................................................ 21 2.1.5 Clinical pharmacokinetics of RIBOCICLIB .................................................................. 21 2.2 Overview of Tamoxifen .......................................................................................................... 21 2.3 Potential for a drug-drug interaction between ribociclib and Tamoxifen ......................... 22 2.4 Overview of goserelin ............................................................................................................. 23 2.4.1 Very Low potential for drug-drug interactions with goserelin ..................................... 24 2.5 Rationale for the combination of CDK4/6 inhibitors with Tamoxifen plus goserelin ...... 24 3 OBJECTIVES .............................................................................................................................. 25 3.1 Primary Objective .................................................................................................................. 25 3.2 Secondary Objectives: ............................................................................................................ 25 4 INCLUSION CRITERIA ............................................................................................................ 25 5 EXCLUSION CRITERIA ........................................................................................................... 27 6 PATIENT REGISTRATION: .................................................................................................... 28 7 TREATMENT PLAN:................................................................................................................. 29 7.1 Dose Modifications.................................................................................................................. 30 7.2 Ribociclib dose adjustment and management recommendation for all other adverse reactions ................................................................................................................................... 36 7.3 Adjustment of Starting Dose in Special Populations ........................................................... 38 7.4 Follow-up for toxicities ........................................................................................................... 38 TEEL Protocol- Tamoxifen +Ribociclib Page 3 7.5 Concomitant Medications ...................................................................................................... 38 7.6 Permitted concomitant therapy requiring caution .............................................................. 39 7.7 Prohibited concomitant therapy ............................................................................................ 39 7.8 Packaging and labeling........................................................................................................... 41 7.9 Drug Supply and Storage ....................................................................................................... 41 7.10 Study Drug Compliance and Accountability ........................................................................ 42 8 TREATMENT PLAN .................................................................................................................. 42 8.1 Study Design: .......................................................................................................................... 43 8.2 Dosing regimen ....................................................................................................................... 44 8.3 General dosing guidelines ...................................................................................................... 44 8.4 Safety Evaluation .................................................................................................................... 45 8.5 STUDY CALENDAR ............................................................................................................. 46 8.6 Efficacy Evaluation for Dose I Expansion Cohorts: ............................................................ 49 8.7 Treatment Duration................................................................................................................ 50 9 PHARMACOKINETICS ............................................................................................................ 50 10 STATISTICAL CONSIDERATIONS ....................................................................................... 51 10.1 Statistical Considerations for Phase I escalation Study ..................................................... 51 10.2 Statistical Considerations for Phase Ib Dose expansion Study ........................................... 52 10.3 Statistical Considerations for Safety ..................................................................................... 52 11 CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE .......................................