2. approval signatures
4. table of contents

| 1.    | ADDRESSES, RESPONSIBILITIES AND SIGNATURES 9                                     |
|-------|----------------------------------------------------------------------------------|
| 2.    | APPROVAL SIGNATURES 11                                                           |
| 3.    | PROTOCOL SYNOPSIS 12                                                             |
| 4.    | TABLE OF CONTENTS 32                                                             |
| 5.    | LIST OF ABBREVIATIONS 37                                                         |
| 6.    | INTRODUCTION 43                                                                  |
| 6.1   | Neoadjuvant chemotherapy in breast cancer 43                                     |
| 6.1.1 | Pathological complete response is a prognostic marker for survival 43            |
| 6.1.2 | Extend of residual disease after neoadjuvant chemotherapy 43                     |
| 6.1.3 | New concepts for post-neoadjuvant systemic treatment 45                          |
| 6.2   | The role of cyclin-dependent kinases in breast cancer 46                         |
| 6.2.1 | Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer  Cells 46 |
| 6.2.2 | Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer 47        |
| 6.3   | INVESTIGATIONAL PRODUCT 47                                                       |
| 6.3.1 | Overview of palbociclib 47                                                       |
| 6.3.2 | Preclinical Data 47                                                              |
| 6.3.3 | Human Pharmacokinetic (PK) Data 50                                               |
| 6.3.4 | QTc Evaluation Data 54                                                           |
| 6.3.5 | Palbociclib Dose Rationale 55                                                    |
| 6.3.6 | Phase I/II Data in Combination with Letrozole in Advanced Breast Cancer 55       |
| 6.3.7 | Combination with other endocrine agents 57                                       |
| 6.3.8 | Long Term toxicity data 58                                                       |
| 7.    | RATIONALE OF THE STUDY 59                                                        |
| 8.    | DISCUSSION OF THE STUDY DESIGN 60                                                |
| 8.1   | Control Treatments 60                                                            |
| 8.2   | Washout Periods and carry over Effects 60                                        |
| 8.3   | Selection of Study Population 60                                                 |  
| 8.4                                                                                                                                     | Rationale for Biomarker Assessment ......................................................................................................61   |
|-----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|
| Removal of Patients from Therapy or Assessment .                                                                                        |                                                                                                                                               |
| 8.5                                                                                                                                     |                                                                                                                                               |
| 8.6                                                                                                                                     | Blinding .                                                                                                                                    |
| Rationale for the duration of treatment .............................................................................................64 |                                                                                                                                               |
| 8.7                                                                                                                                     |                                                                                                                                               |
| 8.8                                                                                                                                     | Treatment Compliance .                                                                                                                        |
| 8.9                                                                                                                                     | Appropriateness of the Primary Efficacy Variable .............................................................64                              |
| 8.10                                                                                                                                    | Risk-benefit Analysis for the Participants                                                                                                    |
| Interpretation of Potential Study Results                                                                                               |                                                                                                                                               |
| 8.11                                                                                                                                    |                                                                                                                                               |
| 9.                                                                                                                                      | STUDY OBJECTIVES .                                                                                                                            |
| Primary Objectives                                                                                                                      |                                                                                                                                               |
| 9.1                                                                                                                                     |                                                                                                                                               |
| 9.2                                                                                                                                     | Secondary Objectives .                                                                                                                        |
| STUDY DESIGN .                                                                                                                          |                                                                                                                                               |
| 10.                                                                                                                                     |                                                                                                                                               |
| 1.                                                                                                                                      | STUDY POPULATION                                                                                                                              |
| Number of patients .                                                                                                                    |                                                                                                                                               |
| 11.1                                                                                                                                    |                                                                                                                                               |
| 1.2                                                                                                                                     | Inclusion Criteria .                                                                                                                          |
| 1.3                                                                                                                                     | Exclusion Criteria .                                                                                                                          |
| 1.4                                                                                                                                     | Removal of Patients from Study                                                                                                                |
| D Drop-outs without treatment                                                                                                           |                                                                                                                                               |
| 11.4.1                                                                                                                                  |                                                                                                                                               |
| 1.4.2                                                                                                                                   | Premature Treatment Discontinuation                                                                                                           |
| STUDY TREATMENT                                                                                                                         |                                                                                                                                               |
| 12.                                                                                                                                     |                                                                                                                                               |
| 12.1                                                                                                                                    | Method of assigning patients to treatment group                                                                                               |
| Breaking the Blind by Investigator                                                                                                      |                                                                                                                                               |
| 12.2                                                                                                                                    |                                                                                                                                               |
| 12.2.1                                                                                                                                  | D During treatment with IMP                                                                                                                   |
| After IMP treatment discontinuation .                                                                                                   |                                                                                                                                               |
| 12.2.2                                                                                                                                  |                                                                                                                                               |
| 12.3                                                                                                                                    | Investigational Product                                                                                                                       |
| 12.3.1                                                                                                                                  | Formulation and Packaging                                                                                                                     |
| 12.3.2                                                                                                                                  | Preparation and Dispensing                                                                                                                    |
| Administration .                                                                                                                        |                                                                                                                                               |
| 12.3.3                                                                                                                                  |                                                                                                                                               |
| 12.3.4                                                                                                                                  | Premedication and supportive treatment .                                                                                                      |
| Recommended Dose Modification                                                                                                           |                                                                                                                                               |
| 12.3.5                                                                                                                                  |                                                                                                                                               |  
| 12.3.6                                                                                                                                                     | Dosing Interruptions .                                                                                                                           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| Retreatment                                                                                                                                                |                                                                                                                                                  |
| 12.3.7                                                                                                                                                     |                                                                                                                                                  |
| 12.3.8                                                                                                                                                     | Dose Reductions                                                                                                                                  |
| QTc prolongation management                                                                                                                                |                                                                                                                                                  |
| 12.3.9                                                                                                                                                     |                                                                                                                                                  |
| 12.3.10  Medication Errors and Overdose                                                                                                                    |                                                                                                                                                  |
| 12.3.11 Compliance .....................................................................................................................................81 |                                                                                                                                                  |
| 12.4                                                                                                                                                       | Drug Storage and Drug Accountability .........................................................................................81                 |
| Concomitant Medications ....................................................................................................................82             |                                                                                                                                                  |
| 12.5                                                                                                                                                       |                                                                                                                                                  |
| 12.5.1                                                                                                                                                     | Prohibited Medications ................................................................................................................82        |
| Medications Not Recommended ................................................................................................... 83                         |                                                                                                                                                  |
| 12.5.2                                                                                                                                                     |                                                                                                                                                  |
| 12.5.3                                                                                                                                                     | Permitted Medications ........................................................................................................................83 |
| Concomitant Radiotherapy or Surgery                                                                                                                        |                                                                                                                                                  |
| 12.6                                                                                                                                                       |                                                                                                                                                  |
| 12.7                                                                                                                                                       | Pregnancy and Lactation ..................................................................................................................84     |
| Non-investigational Products ..........................................................................................................85                  |                                                                                                                                                  |
| 12.8                                                                                                                                                       |                                                                                                                                                  |
| 12.8.1                                                                                                                                                     | Description, Formulation, and Handling of the non-investigational                                                                                |
| products                                                                                                                                                   |                                                                                                                                                  |
| Post-study Treatment ..........................................................................................................................85          |                                                                                                                                                  |
| 12.9                                                                                                                                                       |                                                                                                                                                  |
| 13.                                                                                                                                                        | STUDY PROCEDURE - ASSESSMENTS AND SCHEDULE                                                                                                       |
| 13.1                                                                                                                                                       | Study Procedures at Screening                                                                                                                    |
| 13.2                                                                                                                                                       | Evaluation during active treatment with palbociclib/placebo ................................... 90                                               |
| Pharmacokinetic measurements                                                                                                                               |                                                                                                                                                  |
| 13.3                                                                                                                                                       |                                                                                                                                                  |
| 13.4                                                                                                                                                       | Patient Reported Outcomes (PRO) and health economics ............................................96                                              |
| EORTC QLQ-C30, EORTC QLQ-FA13, QLQ-BR23 ................................................................97                                                 |                                                                                                                                                  |
| 13.4.1                                                                                                                                                     |                                                                                                                                                  |
| 13.4.2                                                                                                                                                     | EQ-5D                                                                                                                                            |
| General Anxiety Disorder-7 (GAD-7) ...................................................................................... 98                               |                                                                                                                                                  |
| 13.4.3                                                                                                                                                     |                                                                                                                                                  |
| 13.5                                                                                                                                                       | Collection of Biomaterials .                                                                                                                     |
| 13.6                                                                                                                                                       | Biomarker analysis                                                                                                                               |
| 13.7                                                                                                                                                       | End of Treatment (EOT) .                                                                                                                         |
| Follow-up Period                                                                                                                                           |                                                                                                                                                  |
| 13.8                                                                                                                                                       |                                                                                                                                                  |
| 13.9                                                                                                                                                       | Treatment Discontinuation of Individual Patient                                                                                                  |  
| 13.10                                                                                                                                             | End of Study (EOS) 102                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| 13.10.1 Regular End of Study 102 13.10.2 Premature Termination of Study 102 13.10.3 Premature Termination of Study at a Particular Study Site 102 |                                                          |
| 14.                                                                                                                                               | DATA QUALITY ASSURANCE 103                               |
| 14.1                                                                                                                                              | Data Management and Documentation 103                    |
| 14.2                                                                                                                                              | Monitoring and Source Data Verification 104              |
| 14.3                                                                                                                                              | Computer Systems 104                                     |
| 15.                                                                                                                                               | STATISTICS 105                                           |
| 15.1                                                                                                                                              | Disposition of patient 105                               |
| 15.2                                                                                                                                              | Analysis populations 105                                 |
| 15.3                                                                                                                                              | Sample Size Determination 106                            |
| 15.4                                                                                                                                              | Treatment Stratification 107                             |
| 15.5                                                                                                                                              | Statistical Analyses 107                                 |
| 15.5.1                                                                                                                                            | Analyses of primary and secondary endpoints 107          |
| 15.5.2                                                                                                                                            | Extent of study treatment exposure and compliance 109    |
| 15.5.3                                                                                                                                            | Extent of investigational medicinal product exposure 109 |
| 15.5.4                                                                                                                                            | Analysis of Adverse Events 110                           |
| 15.5.5                                                                                                                                            | Analyses of laboratory variables 110                     |
| 15.5.6                                                                                                                                            | Translational research analyses 111                      |
| 15.5.7                                                                                                                                            | Interim Analysis for Safety 111                          |
| 15.5.8                                                                                                                                            | Interim Analysis for Efficacy 112                        |
| 15.5.9                                                                                                                                            | Further Analysis after the End of the Study 113          |
| 16.                                                                                                                                               | INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 113         |
| 16.1                                                                                                                                              | IDMC Members and Mission 113                             |
| 16.2                                                                                                                                              | Recommendations of the IDMC 114                          |
| 16.3                                                                                                                                              | Early Termination of the Trial 114                       |
| 17.                                                                                                                                               | ADVERSE EVENTS 114                                       |
| 17.1                                                                                                                                              | Adverse Event 114                                        |
| 17.2                                                                                                                                              | Adverse Reaction 115                                     |  
| 17.3                                                                                                                  | Serious Adverse Event/Serious Adverse Reaction ............................................................ 115   |
|-----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| Suspected Unexpected Serious Adverse Reactions .                                                                      |                                                                                                                   |
| 17.4                                                                                                                  |                                                                                                                   |
| 17.5                                                                                                                  | Adverse Events of Special Interest .                                                                              |
| Pregnancy: .                                                                                                          |                                                                                                                   |
| 17.5.1                                                                                                                |                                                                                                                   |
| 17.5.2                                                                                                                | Relevant overdose with IMP:.                                                                                      |
| Potential Cases of Drug-Induced Liver Injury .................................................................... 117 |                                                                                                                   |
| 17.5.3                                                                                                                |                                                                                                                   |
| 17.6                                                                                                                  | D DEATH ON STUDY .                                                                                                |
| SAE and AESI Reporting .                                                                                              |                                                                                                                   |
| 17.7                                                                                                                  |                                                                                                                   |
| 17.8                                                                                                                  | SUSAR Reporting                                                                                                   |
| ADMINISTRATIVE EXECUTION .                                                                                            |                                                                                                                   |
| 18.                                                                                                                   |                                                                                                                   |
| 18.1                                                                                                                  | MONITORING .                                                                                                      |
| Sponsor's Responsibilities .                                                                                          |                                                                                                                   |
| 18.2                                                                                                                  |                                                                                                                   |
| 18.3                                                                                                                  | Investigator's Responsibilities                                                                                   |
| Patient Informed Consent .                                                                                            |                                                                                                                   |
| 18.4                                                                                                                  |                                                                                                                   |
| 18.5                                                                                                                  | Confidential Follow-up .                                                                                          |
| Ethics and Regulatory Considerations .                                                                                |                                                                                                                   |
| 18.6                                                                                                                  |                                                                                                                   |
| 18.7                                                                                                                  | Declaration of Helsinki                                                                                           |
| Study Documents                                                                                                       |                                                                                                                   |
| 18.8                                                                                                                  |                                                                                                                   |
| 18.9                                                                                                                  | Case Report Forms                                                                                                 |
| GCP Documents                                                                                                         |                                                                                                                   |
| 18.10                                                                                                                 |                                                                                                                   |
| 18.11                                                                                                                 | Archiving                                                                                                         |
| Use of Information and Publication .                                                                                  |                                                                                                                   |
| 18.12                                                                                                                 |                                                                                                                   |
| 18.13                                                                                                                 | Finance and Insurance                                                                                             |
| SUBSTUDIES                                                                                                            |                                                                                                                   |
| 19.                                                                                                                   |                                                                                                                   |
| 19.1                                                                                                                  | TBD.                                                                                                              |
| INVESTIGATOR'S AGREEMENT .                                                                                            |                                                                                                                   |
| APPENDICES                                                                                                            |                                                                                                                   |
| 21.1                                                                                                                  | Appendix 1:  CPS-EG Score / AJCC Breast Cancer Staging ............................................126            |
| 21.2                                                                                                                  | Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance                                                 |
| STATUS                                                                                                                |                                                                                                                   |  
18. 19.  
20.  
21.  
| 21.3   | Appendix 3: List of foods and drugs known to be CYP3A4 inhibitors or  inducers: 127                                |
|--------|--------------------------------------------------------------------------------------------------------------------|
| 21.4   | Appendix 4: List with examples of Drugs Known to Predispose to Torsade de  Pointes 128                             |
| 21.5   | Appendix 5a and Appendix5b:EORTC OLQ-30 to be used in combination with  Cancer Related Fatigue: EORTC QLQ-FA13 129 |
| 21.6   | Appendix 6 EORTC QLQ BR-23 131                                                                                     |
| 21.7   | Appendix 7 GAD7 133                                                                                                |
| 21.8   | Appendix 8 EQ5D 134                                                                                                |
| 21.9   | Appendix 9: RECIST (Response Evaluation Criteria In Solid Tumors) version  1.1 Guidelines 137                      |
| 21.10  | Appendix 10: Declaration of Helsinki 142                                                                           |
| 21.11  | Appendix 11: National Cancer Institute Common Terminology Criteria for  Adverse Events NCI CTCAE version 4.0 148   |
| 21.12  | Appendix 12: Assessment of response to neoadjuvant chemotherapy 148                                                |
| 21.13  | Appendix 13 Administrative Letter 1 149                                                                            |
| 21.14  | Appendix 14 Administrative Letter 2 150                                                                            |
| 21.15  | Appendix 15 Administrative Letter 3 151                                                                            |
| 21.16  | Appendix 16 Administrative Letter 4 152                                                                            |
| 21.17  | Appendix 17 Administrative Letter 5 153                                                                            |
| 22.    | REFERENCES 154                                                                                                     |
| 5.     | LIST OF ABBREVIATIONS                                                                                              |
| ABC    | Advanced Breast Cancer                                                                                             |
| ASCO   | American Society of Clinical Oncology                                                                              |
| AE     | Adverse Event                                                                                                      |
| AESi   | Adverse Event of special Interest                                                                                  |
| ALT    | Alanine Aminotransferases                                                                                          |
| AI     | Aromatase Inhibitor                                                                                                |
| ANC    | Absolute Neutrophil Count                                                                                          |
| AST    | Aspartate Aminotransferases                                                                                        |
| AUC    | Area Under the Curve                                                                                               |  
| BC               | Breast Cancer                                                                     |
|------------------|-----------------------------------------------------------------------------------|
| CAP              | Chest, Abdomen, Pelvis OR College of American Pathologists  depending on context. |
| CCND1            | Cyclin D1                                                                         |
| CDK              | Cyclin-Dependent Kinase                                                           |
| CDKN2A, p16Ink4A | Cyclin-Dependent Kinase Inhibitor 2A                                              |
| CI               | Confidence Interval                                                               |
| CISH             | Chromogenic In Situ Hybridization                                                 |
| CLIA             | Clinical Laboratory Improvement Amendments                                        |
| Cmax             | Maximum Plasma Concentration                                                      |
| CNS              | Central Nervous System                                                            |
| cCR              | Clinical Complete Response                                                        |
| CR               | Complete Response                                                                 |
| CRF              | Case Report Form                                                                  |
| CSA              | Clinical Study Agreement                                                          |
| CSF              | Colony-Stimulating Factors                                                        |
| CT               | Computed Tomography                                                               |
| CTA              | Clinical Trial Application                                                        |
| CTCAE            | Common Terminology Criteria for Adverse Events                                    |
| CYP              | Cytochrome P-450                                                                  |
| DC               | Disease Control                                                                   |
| DCR              | Disease Control Rate                                                              |
| DFI              | Disease Free Interval                                                             |
| DFS              | Disease Free Survival                                                             |
| DLT              | Dose Limiting Toxicity                                                            |
| DNA              | Deoxyribonucleic Acid                                                             |
| DR               | Duration of Response                                                              |
| ECG              | Electrocardiogram                                                                 |
| ECOG             | Eastern Cooperative Oncology Group                                                |  
| EDTA                                                           | Ethylenediaminetetraacetic acid                                                                                                                                      |            |    |               |    |           |
|----------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|----|---------------|----|-----------|
| GnRH                                                           | A gonadotropin-releasing hormone analogue (GnRH analogue or  analog), also known as a luteinizing hormone releasing hormone  agonist (LHRH agonist) or LHRH analogue |            |    |               |    |           |
| eGFR:                                                          | Estimated Glomerular Filtration Rate                                                                                                                                 |            |    |               |    |           |
| EIU                                                            | Exposure In Utero                                                                                                                                                    |            |    |               |    |           |
| EQ-5D                                                          | Dimension Health State EuroQoL Score                                                                                                                                 |            |    |               |    |           |
| ER                                                             | Estrogen Receptor                                                                                                                                                    |            |    |               |    |           |
| FDA                                                            | US Food and Drug Administration                                                                                                                                      |            |    |               |    |           |
| FDA                                                            | US Food and Drug Administration Administration Amendments                                                                                                            |            |    |               |    |           |
| FFPE                                                           | Formalin Fixed Paraffin Embedded                                                                                                                                     |            |    |               |    |           |
| FIH                                                            | First in Human                                                                                                                                                       |            |    |               |    |           |
| FISH                                                           | Fluorescent In Situ hybridization                                                                                                                                    |            |    |               |    |           |
| GCP                                                            | Good Clinical Practice                                                                                                                                               |            |    |               |    |           |
| G-CSF                                                          | Granulocyte Colony Stimulating Factor                                                                                                                                |            |    |               |    |           |
| GM-CSF                                                         | Granulocyte Macrophage Colony Stimulating Factor                                                                                                                     |            |    |               |    |           |
| Hb                                                             | Hemoglobin                                                                                                                                                           |            |    |               |    |           |
| HDPE                                                           | High Density Polyethylene                                                                                                                                            |            |    |               |    |           |
| HER                                                            | Human Epidermal Growth Factor Receptor                                                                                                                               |            |    |               |    |           |
| hERG                                                           | Human Ether-à-Go-Go Related Gene                                                                                                                                     |            |    |               |    |           |
| HR                                                             | Hazard Ratio or Heart Rate depending on context                                                                                                                      |            |    |               |    |           |
| IB                                                             | Investigator's Brochure                                                                                                                                              |            |    |               |    |           |
| IC50                                                           | Concentration of 50% Inhibition                                                                                                                                      |            |    |               |    |           |
| ICH                                                            | International                                                                                                                                                        | Conference | on | Harmonisation | of | Technical |
| Requirements for Registration of Pharmaceuticals for Human Use |                                                                                                                                                                      |            |    |               |    |           |
| IDMC                                                           | Independent Data Monitoring Committee                                                                                                                                |            |    |               |    |           |
| IWRS                                                           | Interactive web response system                                                                                                                                      |            |    |               |    |           |
| IEC                                                            | Independent Ethics Committee                                                                                                                                         |            |    |               |    |           |
| IHC                                                            | Immunohistochemistry                                                                                                                                                 |            |    |               |    |           |  
| INR       | International Normalized Ratio                                                                                                                                       |
|-----------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| IORT      | Intraoperative Radiation Therapy                                                                                                                                     |
| IMPAKT    | Improving Care and Knowledge through Translational Research                                                                                                          |
| IRB       | Institutional Review Board                                                                                                                                           |
| IRT       | Interactive Randomization Technology                                                                                                                                 |
| ITT       | Intent-to-treat                                                                                                                                                      |
| LFT       | Liver Function Test                                                                                                                                                  |
| LHRH      | A gonadotropin-releasing hormone analogue (GnRH analogue or  analog), also known as a luteinizing hormone releasing hormone  agonist (LHRH agonist) or LHRH analogue |
| LPD       | Local Product Document                                                                                                                                               |
| LSLV      | Last Subject Last Visit                                                                                                                                              |
| MedDRA    | Medical Dictionary for Regulatory Activities                                                                                                                         |
| MRI       | Magnetic Resonance Imaging                                                                                                                                           |
| MTD       | Maximum Tolerated Dose                                                                                                                                               |
| NACT      | Neoadjuvant chemotherapy                                                                                                                                             |
| NCI CTCAE | National Cancer Institue Common Terminology Criteria                                                                                                                 |
| NCI       | National Cancer Institute                                                                                                                                            |
| NYHA      | New York Heart Association                                                                                                                                           |
| OBU       | Oncology Business Unit                                                                                                                                               |
| OR        | Objective Response                                                                                                                                                   |
| ORR       | Objective Response Rate                                                                                                                                              |
| OS        | Overall Survival                                                                                                                                                     |
| PCD       | Primary Outcome Completion Date                                                                                                                                      |
| pCR       | pathological Complete Response, pathological Complete Response                                                                                                       |
| PD        | Progressive Disease                                                                                                                                                  |
| PET       | Positron Emission Tomography                                                                                                                                         |
| PFS       | Progression Free Survival                                                                                                                                            |
| pINV      | pathological residual Invasive cancer                                                                                                                                |  
| PK     | Pharmacokinetic                                                                                                                                                                                                |
|--------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PR     | Partial Response or Progesterone Receptor (depending on context)                                                                                                                                               |
| PR     | The PR interval is measured from the beginning of the P wave to the  beginning of the QRS complex.                                                                                                             |
| PS     | Performance Status                                                                                                                                                                                             |
| PRO    | Patient Reported Outcome                                                                                                                                                                                       |
| PT     | Prothrombin Time                                                                                                                                                                                               |
| QD     | Quaque Die (once daily)                                                                                                                                                                                        |
| QRS    | The QRS complex is a name for the combination of three of the  graphical deflections seen on a typical electrocardiogram. The QRS complex reflects the rapid depolarization of the right and  left ventricles. |
| QT     | Time between the start of the Q wave and the end of the T wave in  the heart's electrical cycle                                                                                                                |
| QTc    | QT interval corrected for heart rate                                                                                                                                                                           |
| QTcB   | QT interval corrected for heart rate using Bazett's fomula                                                                                                                                                     |
| QTcF   | QT interval corrected for heart rate using Fridericia's fomula                                                                                                                                                 |
| RANKL  | Receptor Activator of Nuclear Factor Kappa B Ligand                                                                                                                                                            |
| RB/Rb  | Retinoblastoma                                                                                                                                                                                                 |
| RECIST | Response Evaluation Criteria in Solid Tumors                                                                                                                                                                   |
| RNA    | Ribonucleic Acid                                                                                                                                                                                               |
| RP2D   | Recommended Phase 2 Dose                                                                                                                                                                                       |
| RR     | The interval between an R wave and the next R wave                                                                                                                                                             |
| Rac    | Accumulation Ratio                                                                                                                                                                                             |
| SAE    | Serious Adverse Event                                                                                                                                                                                          |
| SAP    | Statistical analysis plan                                                                                                                                                                                      |
| SISH   | Silver in Situ Hybridization                                                                                                                                                                                   |
| SD     | Stable Disease or Standard Deviation (depending on context)                                                                                                                                                    |
| SPC    | Summary of Product Characteristics                                                                                                                                                                             |
| SmPC   | Summary of Product Characteristics                                                                                                                                                                             |  
| t½   | Terminal Elimination Half-life   |
|------|----------------------------------|
| TdP  | Torsade de Pointes               |
| TEAE | treatment emergent adverse event |
| Tmax | Time for Cmax                    |
| ULN  | Upper Limit of Normal            |
| USPI | United States Package Insert     |
| Vz/F | Apparent Volume of Distribution  |
| WBC  | White Blood Cell                 |
2. approval signatures
6. introduction 6.1 neoadjuvant chemotherapy

The concept of moving systemic treatment from after surgery to before surgery was first developed based on a hypothesis that the earlier disseminated single tumor cells are being killed and the development of metastasis at a later stage is therefore less likely. However, trials conducted in the 80's and 90's of the last century have not confirmed this concept but found a similar outcome of patients treated with chemotherapy before or after surgery.10 Thereafter neoadjuvant chemotherapy was mainly used to obtain a better operability of large operable or even inoperable locally advanced tumors. Today this approach is considered as a model to learn not only of the biology of breast cancer in general, but also of the treatment sensitivity of an individual patient's tumor. Tumor tissue obtained by core biopsy before treatment allows biological characterization of the tumor and development of an individual treatment plan. Early assessment after the first couple of cycles allows to test for functional predictors but also to change treatment according to early response. After completing all neoadjuvant treatment, histological examination of the surgically removed breast and axillary tissue allows precise assessment of tumor response and characterization of residual, treatment-resistant disease.
2. approval signatures
6.1.1 pathological complete response is

It has been repeatedly shown that patients with a pathological complete response (pCR) after neoadjuvant chemotherapy have a better outcome than those without a pCR. However, the prognostic value varies for the different breast cancer subtypes.  
11 12 Especially in patients with HR-positive/HER2-normal tumors the association of a pCR with favorable outcome is only modest and in lower risk patients having highly or moderately differentiated tumors this association is even not existing. In fact, in this subgroup survival improvement was demonstrated without any increase in pCR rates.13
2. approval signatures
6.1.2 extend of residual disease

Extent and characterization of residual disease after neoadjuvant chemotherapy raises increasingly more interest especially in patients with HR-positive/HER2-normal disease. The above mentioned meta-analysis 8showed that the extent of residual disease after neoadjuvant chemotherapy in the breast as well in the nodes is associated with survival of patients. Worst prognosis with median survival of around 5 years was observed for patients with post-treatment persisting inflammatory breast cancer as well as significant (>10) involvement of axillary lymph nodes. Further characterization of residual disease included examination of Ki-67 on the residual tumor and, together with patients achieving pCR where Ki-67 was not detectable, analysis of a total of 1150 patients from the GeparTrio study for disease-free and overall survival.14 Patients were subdivided into 4 groups (pCR, Ki-67 0-15%,
Ki-67 15.1-35%, Ki-67 >35%) having significant different disease-free and overall survival. In fact, post-treatment Ki-67 measurements were prognostically more relevant than pretreatment measurements or changes from before to after treatment. When analyzing patients separately according to the hormone-receptor status of their tumor, it became obvious, that in hormone-receptor-positive disease, patients with low or moderate posttreatment Ki-67 levels had a comparable outcome to patients with a pCR and only patients with high Ki-67 levels showed a very high risk of relapse. In hormone-receptor-negative disease, however, patients with a pCR did better than those with low or moderate Ki-67 levels, and again, patients with highly proliferating tumors had a most unfavorable outcome. However, as methodology and cut-offs of Ki-67 is not standardized, prognostic assessment by a clinical score post-neoadjuvant chemotherapy might be more appropriate as a risk selection tool in a global clinical trial. The clinical-pathologic stage - estrogen/grade (CPSEG)1,15combining clinical stage before neoadjuvant treatment, pathological stage after neoadjuvant treatment, grading and estrogen-receptor status can be used to identify these high-risk patients. The score was further validated on 2454 patients with HR-positive/HER2normal tumors from the German neoadjuvant studies' meta-database (F. Marmé, unpublished manuscript). In an updated version of this meta-database (n=2659) patients who have a score of 3 or higher or Score 2 and ypN+ disease show a 3-yrs DFS of 77% despite adjuvant endocrine treatment. The CPS-EG score allows identification of patients at increased risk of early relapse and allows to isolate a population of patients in whom testing of a new agent is indicated. This clinically driven selection approach allows further characterization of the tumors into subsets of molecularly different diseases using prospectively defined markers. This approach is thought to lead to determination of specific population of patients in whom use of palbociclib would be indicated.
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6.1.3 new concepts for post-neoadjuvant

Developing treatment strategies for those patients with unfavorable outcome due to residual disease after neoadjuvant chemotherapy appears a major task for the future. The NATAN
study (NCT00512993) has recruited 693 patients with residual disease after anthracyclinetaxane based chemotherapy and randomized them to 5 years treatment with zoledronic acid or observation. However, as 80% of the patients had hormone-receptor-positive disease and the patients were not otherwise selected for a high relapse-risk, event rate was much lower than expected. Results revealed no effect of zoledronic acid on survival with a median DFS of 73% overall.16. Due to the unfavorable outcome of patients without a pCR after neoadjuvant treatment with chemotherapy and trastuzumab, patients with HER2-positive tumors might be better candidates for such a post-neoadjuvant approach. A registration trial is currently under development with the aim to compare postsurgical treatment with trastuzumab to post-surgical treatment with trastuzumab emtansine (T-DM1), a fusion molecule of trastuzumab and an anti-microtubule agent derived from maytansine (Katherine study). So far no post-neoadjuvant trial has been conducted for patients with high-risk HRpositive/HER2-normal tumors.
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6.2 the role of cyclin-dependent

6.2.1 *Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer Cells* Studies of ER-positive breast cancer cell lines indicate that estrogens17 and antiestrogens18 act on sensitive populations of cells in early to mid-G1 phase. G1/S transition is under the control of CDKs activated by specific complex formation with regulatory cyclins. CDK4 and CDK6 are activated by binding to D-type cyclins and act early in G1 phase.19 20 21 22A primary target of CDK action in G1 phase is the retinoblastoma susceptibility gene product (Rb), which mediates G1 arrest through sequestration of transcriptional factors of the E2F-DP family. Phosphorylation of Rb and other members of the pocket protein family (p107 and p130) by active cyclin-CDK complexes leads to release of E2F and DP transcription factors and transcription of requisite genes for S-phase entry.23 D-type cyclins play an essential role in recognition of extracellular growth stimuli and initiation of G1 transit,24 25 and several lines of evidence have linked estrogen regulation of cellular proliferation to cyclin D1 expression. Estrogen-induced proliferation of normal uterine and breast epithelium *in vivo* is associated with increased expression of cyclin D1 mRNA and protein.26 27 28 29 Expression of cyclin D1 in breast tumor isolates correlates with ER-positive status.30 31 32 MCF-7 breast cancer cells treated with estrogen exhibit increased expression of cyclin D1 mRNA and protein, formation of active cyclin D1-CDK4 complexes, and phosphorylation of Rb leading to G1 /S transition.33 34 35 36 Estrogen-induced S-phase entry in these cells is inhibited by microinjection of antibodies to cyclin D1.37 Anti-estrogen-induced growth arrest of ER-positive breast cancer cells is associated with decreased cyclin D1 expression.38 Collectively, these studies are consistent with a model of estrogen action in which receptor activation induces increased cyclin D1 expression, CDK4 activation, and cell cycle progression. An upstream role for cyclin D1 has been suggested by recent reports describing direct physical interactions between cyclin D1 and the ER, leading to recruitment of steroid receptor co-activators and activation of ER-dependent transcription. This occurs in the absence of hormone and is independent of D-type cyclin association with CDK4.39 40 41 42 Constraint upon CDK activity and G1 progression is provided by the universal CDK inhibitors of the Cip-Kip family, including gp21Cip1 and p27Kip1, and the specific CDK4 and CDK6 inhibitors of the INK4 family, typified by p16INK4a.  
43 44 45 46 47 The CDKN2A gene product inhibits formation of active D-type cyclin-CDK complexes through specific binding interactions with CDK4 or CDK6 that prevent D-type cyclin-CDK association., 48 49 50Over expression of p16INK4a in cells with functional Rb results in inhibition of both CDK4-and CDK6-associated kinase activity and Rb phosphorylation, with subsequent cell cycle arrest.51 52 In addition, inhibition of D-type cyclin-CDK4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-CDK2 activity. 53 54 55 Overexpression of p16INK4a through adenoviral transduction of CDKN2A into MCF-7 cells leads to G1 arrest associated with inhibited CDK activity.56 57 Cell cycle progression induced by estradiol requires action of the steroid through mid-G1, well beyond the point of cyclin D1-CDK4 activation.58 Functional association of cyclin D1-CDK4 is required for estrogen-induced CDK2 activation and G1/S transition and estrogen regulates expression of p21Cip1, p27Kip1, and Cdc25A independent of D-type cyclin-CDK4 function.59 6.2.2 *Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer* Cell cycle related genes and proteins are frequently deregulated in breast cancer. Approximately 15%–20% of human breast cancers exhibit amplification of the cyclin D1 (CCND1) gene,60 61 62 while the majority of human mammary carcinomas over express cyclin D1 protein.63 64 65 Over expression of cyclin D1 is seen early in breast cancer, and it is maintained at all stages of breast cancer progression, including metastatic lesions.66 67 Amplification of the CDK4 gene, located at 12q13-q14, has been shown as an alternative genetic alteration to CDKN2A inactivation in various human tumor including breast cancer.68 69 There is a mounting body of evidence linking a specific CCND1 polymorphism (G/A870) to increased risk of cancer and outcome in a variety of tumor types including breast cancer. This polymorphism results in a splice variant, altered protein structure and enhanced oncogenic activity in experimental models.70 The continued presence of CDK4-associated kinase activity is actually required to maintain breast tumorigenesis.71 Direct analyses of primary tumors have revealed loss of Rb expression in 20–35% of tumors, and loss of heterozygosity or other alterations of the Rb locus in 7-37% of tumors.72 73 74 75 In preclinical models, Rb depletion appears to be associated with resistance to antiestrogen therapy.76 Finally, virtually all ER-positive cell lines harbor loss of p16INK4a 77 78expression, and low expression of CDK inhibitors p21 and p27 and high expression level of cyclin E and D1 have all been associated with resistance to anti-estrogen therapy.
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6.3 investigational product 6.3.1 overview

Palbociclib (Molecular Weight free base: 447.53) is an orally active potent and highly selective reversible inhibitor of CDK4 and CDK6. The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase.  
6.3.2 *Preclinical Data* Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied by the inhibition of specific Rb phosphorylation by CDK4 or CDK6 on residues serine -780 and -795 of Rb. The IC50 values for reduction of Rb phosphorylation at serine -780 and -795 in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 µM, respectively. The IC50 values for reduction of Rb phosphorylation are similar to the IC50 values of inhibition of thymidine incorporation across a range of cultured tumor and normal cells.  
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines. Results from these experiments indicate that those cell lines that are more sensitive to palbociclib (IC50 < 150 nM) have low levels of CDKN2A (p16) and high levels of Rb1, while resistant cell lines show the opposite characteristics. Sensitive cell lines in this panel represent mostly the luminal ER+ subtype.79 The combination of palbociclib and aromatase inhibitors has been tested in preclinical models.80 Additionally, the combination of palbociclib with tamoxifen has been tested in vitro in ER+ human breast cancer cell lines indicating a synergistic interaction81. This provides a biologic rationale for evaluating the combination of palbociclib with anti-hormonal therapy in the clinic.  
Palbociclib has been evaluated in safety pharmacology, genetic toxicity, reproductive and development (fertility and early embryonic development, embryofetal development), and repeat-dose toxicity studies of up to 15-weeks duration in the rat and dog. Based on the nonclinical safety studies conducted with palbociclib, the primary palbociclib-related systemic toxicities were observed in hematolymphopoietic tissues (decreased cellularity, increased iron pigment, decreases in peripheral leukocytes and RBC parameters) and male reproductive organs (degeneration of seminiferous tubules, secondary epididymal hypospermia and increased intratubular cellular debris). Partial to complete reversibility of toxicities was demonstrated following a 4 week recovery period, with the exception of the male reproductive organ findings in the dog. These toxicities occurred in both rats and dogs, and are consistent with the intended pharmacologic effect of palbociclib (i.e., cell cycle inhibition) (Fink et al, 2001; Arguello et al, 1998; Bartkova et al, 2003). Palbociclib was also identified with the potential to cause QT prolongation (Section 6.3.4 Penelope Protocol), developmental effects, and aneugenicity. Developmental effects that were considered adverse included a decrease in fetal body weights in rats and a low incidence of small phalanges on the forepaws in rabbits. A no effect level for aneugenicity was observed at approximately 7-fold higher than unbound systemic AUC24 exposures associated with the human clinical dose of 125 mg QD. Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog repeat-dose toxicity study. (Administrative Letter1, Appendix 13, chapter 21.13) In Administrative Letter 1 we informed you, that Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog repeat-dose toxicity study. Following Data were released by Pfizer on 27th Jan 2014 as Special Safety Concern Report:
The study entitled "27-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with PD0332991 in Rats with a 12-Week Recovery Phase (Study 8282224; Sponsor Reference Number 13LJ036). The identification of cataracts in rats following 27-weeks of intermittent dosing represented a potential new target organ toxicity. In the previous rat and dog repeat-dose toxicity studies up to 15 weeks duration, the primary target organ findings were observed in the hematolymphopoietic and male reproductive tissues. The minimal dose level for cataract formation has not been identified from the 27-week rat toxicity study, based on the histological data (lens degeneration was noted microscopically ). Cataracts were identified from ophthalmic evaluations at the lower examined dose of 30 mg/kg/day in males but at no dose in females. While the impact of this nonclinical finding initially was considered to suggest a potential risk to human subjects, the overall benefit-risk for palbociclib remains favorable. (Administrative Letter 3, Appendix 21.15). Further data were communicated with Administrative Letter 5 (Appendix 21.17) that emerged from this toxicity study showing correlation between altered glucose metabolism and the formation of cataracts/lens degeneration. In dog toxicity studies (15-week and 39-week), no altered glucose levels or cataracts/lens degeneration have been observed (lack of lens degeneration not yet confirmed in the 39-week study; histopathology pending). Hyperglycemia and diabetes mellitus, are currently (July 2014) not considered to be identified clinical risks and are not considered to be adverse drug reactions (ADRs) of palbociclib. According to exclusion Criterion \#10 a severe acute or chronic medical condition that may increase the risk associated with study participation needs to be excluded, which includes uncontrolled diabetes melittus. HbA1C levels need to be controlled while patient is under palbociclib treatment and in case of a signal the patients need to be refered to a diabetologist or a medical advisor to easily control the diabetes. Once daily oral administration of palbociclib was well tolerated in rats at levels of 10 mg/kg/day for males and up to 200 mg/kg/day for females (Sponsor Reference No.  
12LJ025)82.  
Addition of clinical information on glucose and cataracts from Study A5481023 in context of discussion of nonclinical data on glucose metabolism and findings of cataracts has been provided by the manufacturer via the update of the investigators brochue (Palbociclib IB, version December 2015). Given the lack of a signal of hyperglycemia or cataract development from the clinical experience and the fact that the finding of cataracts observed in young rats is most reasonably, based on now available aged rat toxicity studies, interpreted to be secondary to hyperglycemia, the manufacuters Risk Management Committee concluded that it was no longer warranted to include monitoring for hyperglycemia and ophthalmic changes in planned studies of the manufacturer. For the PenelopeB study, ophthalmic assessments have been removed as required study assessment by the sponsor.
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6.3.3 human pharmacokinetic (pk) data

As of 31 August 2016, twenty-seven clinical studies have evaluated the PK of palbociclib. Eight of these trials were conducted in patients with advanced malignant disease. Nineteen Phase 1 clinical pharmacology and biopharmaceutic studies of palbociclib were conducted in healthy subjects. Eleven of these 19 clinical trials were clinical pharmacology studies conducted to investigate the absorption, distribution, metabolism, and excretion of palbociclib as well as examine the potential for DDI with palbociclib. The remaining 8 of the 19 clinical trials were biopharmaceutic studies conducted to examine the bioavailability, bioequivalence, and food effect of the palbociclib formulations. Pharmacokinetic parameters are available from all 74 patients enrolled in Study A5481001 (a first-in-human dose-escalation study in patients with advanced cancer) following multiple-dose administration (Day 8 of Cycle 1) at daily doses ranging from 25 to 225 mg of palbociclib. In addition, PK parameters are also available for nine patients on Day 14 of Cycle 1 (from patients on Schedule 2/1, i.e., 2 weeks on treatment followed by 1 week off treatment) and 4 patients on Day 21 of Cycle 1 (from patients on Schedule 3/1, i.e., 3 weeks on treatment followed by 1 week off treatment). The exposure (AUC(0-10) and Cmax)
increased in a dose proportional manner (i.e. dose linearity) over the dose range of 25 to 225 mg QD following palbociclib administration on Days 1 and 8 of Cycle 1, although some variability (low to moderate) around these doses was observed particularly at the 150 mg QD dose level. Following repeated daily dosing to Day 14 and Day 21 palbociclib was absorbed with a median Tmax of ~4 hours when fasting 2 hours before and after palbociclib administration. The mean palbociclib Vz/F was 3103 L, which is significantly greater than total body water (42 L), indicating that palbociclib extensively penetrates into peripheral tissues. The ability for palbociclib to cross the blood brain barrier in humans is unknown. In rats, palbociclib displayed minimal ability to cross the intact blood brain barrier. Palbociclib was eliminated slowly; the mean t½ was 26.5 hours (ranged 15.8 to 36.2 hours) and the mean CL/F was 86.1 L/hour. Palbociclib accumulated following repeated dosing with a median Rac of 2.4, which is consistent with a half-life of ~27 hours. Pharmacokinetic data from Study A5481002 indicate that palbociclib exposure at steady state in mantle cell lymphoma patients is similar to that observed in solid tumors (Protocol A5481001). Pharmacokinetic analysis of the Phase 1 portion of Study A5481003 (Paloma-1/Trio-18, breast cancer, combination with letrozole) was conducted to evaluate the potential for drug-drug interaction between palbociclib and letrozole. The results indicate lack of a potential for drug-drug interaction between palbociclib and letrozole when administered in combination. See section 6.3.6 for further details. The effect of food on the bioavailability of palbociclib when administered as the commercial free base capsule (the formulation being used in the PENELOPE Study), was investigated in Study A5481021. The administration of the free base formulation of palbociclib with food
(including a high fat or a low fat meal given together with palbociclib, or moderate fat meals given 1 hour before and 2 hours after palbociclib) resulted in more uniform drug absorption and significantly reduced the intersubject variability in drug exposure when compared to the administration of the commercial free base formulation of palbociclib in a fasted state. Because of these findings, patients should be instructed to take palbociclib/placebo with food. This may begin immediately. This change does not significantly affect the study's scope, safety, or scientific quality. (Administrative Letter 2, Appendix 14, chapter 21.14). Comparison of the palbociclib isethionate capsule formulation given under both the overnight and minimal fasting conditions and the palbociclib commercial free base capsule formulation with food was found to be bioequivalent (Study A5481036). The solubility of the palbociclib free base is pH dependent—palbociclib is water soluble at low pH (2.1-4.5), while the solubility dramatically decreases as pH rises above 4.5. Concomitant administration of agents which increase gastric pH can alter the solubility and absorption of palbociclib free base formulations. Study A5481038 evaluated the effects of staggered dosing of the H2-receptor antagonist (H2RA) famotidine, and of the staggered dosing of the local antacid Mi-Acid Maximum Strength Liquid on the PK of a single oral 125 mg palbociclib free base capsule given with food in healthy subjects. The results indicated that administration of palbociclib under fed conditions with staggered famotidine and staggered Mi-Acid Maximum Strength Liquid dosing had no impact on the exposure of palbociclib. Study A5481038 also evaluated the effects the coadministration of a single 125 mg dose of the free base capsule of palbociclib following multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions in healthy volunteers. Concurrent administration of rabeprazole with palbociclib decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease) compared with a single dose of palbociclib administered alone. This 13% reduction in overall exposure is not thought to be clinically relevant. Given the reduced effect on gastric pH of H2RAs and local antacids compared to PPIs, the effect of dosing these classes of acid-reducing agents palbociclib exposure when given simultaneously with palbociclib free base capsules under fed conditions is expected to be minimal 83 84.  
In another DDI study (Study A5481018) in healthy subjects, the coadministration of a single 125 mg dose of the free base capsule of palbociclib with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with a single dose of palbociclib administered alone. This study readout during the conduct of the PENELOPE study, resulting in an administrative letter prohibiting the use of PPIs and recommending the use of alternative treatments (such as H2RAs or local antacids given by staggered dosing) when required (Administrative Letter 3, Appendix 15, chapter 21.15). This study also prompted the design and conduct of another clinical study evaluating the effects of gastric acid-reducing agents on palbociclib PK when palbociclib free base capsules were administered in the fed state (Study A5481038, discussed in the preceding paragraphs). Collectively, these antacid DDI data further support the requirement that the free base capsule of palbociclib should be taken with food. Thus, to decrease inter- and intra-subject variability in palbociclib drug exposure as well as to minimize the DDI potential of concurrent administration of gastric acid-reducing agents, the palbociclib free base capsule formulation should be taken with food. Update to Administrative Letter 3, Appendix 15, chapter 21.15: The results from the recently performed study A5481038, "A Phase 1, Open-Label Fixed-Sequence 2-Period Crossover Study Of Palbociclib In Healthy Subjects To Investigate The Potential Effect Of Antacid Treatment On The Pharmacokinetics Of A Single Oral Dose Administered Under Fasted Conditions" suggest that coadministration of a single 125 mg dose of pablociliclib with multiple doses of the proton pump inhibitors (PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when compared to a single dose of Palbociclib administered alone. Given the reduced effect on gastric pH of H2 receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure.
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as a result of these

Palbociclib is metabolized to multiple metabolites in a qualitatively similar manner in rat, dog and human liver microsomes. In vitro, palbociclib is primarily metabolized by CYP3A4 enzymes. An exploratory evaluation of the circulating metabolites for palbociclib was conducted in plasma samples obtained from patients treated with palbociclib 200 mg QD (Schedule 2/1) in Study A5481001. Assessment of the pooled plasma samples on Day 14 of Cycle 1 indicated that the glucuronide conjugate of palbociclib and the lactam of palbociclib (PF-05089326) were the main metabolites present in plasma. Glucuronide conjugate of palbociclib is unlikely to be active vs the intended target (CDK4/6). Although PF-05089326 showed similar in vitro activity vs CDK4/6 as with palbociclib, the unbound exposure of this metabolite is considerably lower than the parent drug. Therefore, contribution of this metabolite to the pharmacologic activity in humans is anticipated to be low. Other metabolites observed were the glucuronide conjugates of hydroxylated palbociclib and the glucuronide conjugate of reduced palbociclib. PF-05089326 was also observed in the circulation of rats following repeated daily oral administration of palbociclib. Plasma protein binding of palbociclib and PF-05089326 is ~85% and 95%, respectively. The effect of multiple dosing of palbociclib (125 mg QD) on the single-dose PK of a sensitive CYP3A4/5 probe substrate, midazolam (2 mg), was evaluated in 26 healthy fasted women of nonchildbearing potential in Study A5481012. Coadministration of palbociclib and midazolam increased midazolam AUCinf and Cmax by 61% and 37%, respectively, relative to midazolam given alone. The ratios (90% CIs) of the adjusted geometric means for midazolam AUCinf and Cmax were 161% (146% 177%) and 137% (124% 152%), respectively, following administration of midazolam with multiple doses of palbociclib (Test), relative to midazolam administered alone (Reference). These results indicate that palbociclib is a weak timedependent inhibitor of CYP3A. Based on these results, physicians should be aware that the dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with palbociclib.  
The effect of multiple doses of itraconazole (200 mg QD), a strong CYP3A inhibitor, on the single dose PK of palbociclib (125 mg) was evaluated in 12 healthy fed subjects in Study A5481016. Coadministration of itraconazole and palbociclib increased palbociclib AUCinf and Cmax by approximately 87% and 34%, respectively, relative to those when palbociclib dose was given alone. The ratios (90% CIs) of the adjusted geometric means for palbociclib AUCinf and Cmax were 187% (173%-202%) and 134% (126%-143%), respectively, when palbociclib was administered with multiple doses of itraconazole (Test), relative to palbociclib administered alone (Reference). The concomitant use of strong CYP3A inhibitors including, but not limited to, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice should be avoided. The effect of multiple dosing of a strong CYP3A4 inducer, rifampin (600 mg QD), on the single-dose PK of palbociclib (125 mg), was evaluated in 15 healthy fasted subjects in Study A5481017. Coadministration of rifampin and palbociclib decreased palbociclib AUCinf and Cmax by approximately 85% and 70%, respectively, relative to palbociclib given alone. The ratios (90% CIs) of the adjusted geometric means for palbociclib AUCinf and Cmax were 15.5% (12.0% 19.9%) and 30.2% (23.5% 38.7%), respectively, following administration of palbociclib with multiple doses of rifampin (Test), relative to palbociclib administered alone (Reference). The concomitant use of strong CYP3A inducers including, but not limited to, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort should be avoided. The multiple dose PK of palbociclib in patients of the Asian race has been evaluated in Studies A5481008, A5481010, A5481019, and A5481023. While palbociclib geometric mean AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese healthy subjects compared with those in demographic-matched non-Asian healthy subjects, palbociclib steady-state AUC, Cmax, and Ctrough values for Japanese and/or Asian (excluding Japanese) patients with advanced breast cancer were comparable with those in non-Asian patients with advanced breast cancer in some study populations but were higher in others.  
Notwithstanding, the maximum tolerated dose (MTD) of palbociclib that was determined for Japanese advanced cancer patients for both palbociclib monotherapy and in combination with letrozole was identical to the MTD determined in the predominantly Caucasian advanced cancer patients. Likewise, the same dosing regimen had also been demonstrated to be tolerable in Chinese advanced breast cancer patients. Based on analysis of the cumulative PK, safety, and efficacy data, no dose adjustment based on Asian race is necessary.
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6.3.4 qtc evaluation data

A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between palbociclib exposure and ECG variables (RR interval and QTc) was developed using data from postmenopausal women with ER-positive, HER2 negative advanced breast cancer enrolled in the QTc analysis subgroup included in Study A5481008 that was conducted as the definitive QT interval prolongation evaluation for the palbociclib program. A total of 125 patients were enrolled in this subgroup to evaluate the effect of palbociclib on QT interval. Of these 125 patients, 77 were randomized to the palbociclib plus letrozole treatment arm and 48 were randomized to the placebo plus letrozole arm. A total of 2597 recorded individual QT
intervals and 322 palbociclib concentrations obtained from 77 palbociclib plus letrozoletreated patients were included in the analysis dataset. The median (range) age and baseline body weight of patients in the analysis dataset was 62.0 (36-86) years and 72.3 (48.1-157) kg, respectively. Among the 77 patients, 70 patients provided a total of 320 matched PK-ECG pairs to evaluate the relationship between palbociclib exposure and ECG variables (RR interval and QTc). Following administration of a therapeutic regimen of 125mg palbociclib QD in combination with 2.5 mg letrozole QD, the observed plasma concentrations of palbociclib had a median (range) of 88.0 (14.7-210) ng/mL in the PK-ECG matched data. The average heart rate, RR interval, QT interval, QT interval corrected for heart rate according to Bazett (QTcB), QT interval corrected for heart rate according to Fridericia (QTcF), and QTcS (QT interval corrected for heart rate according to a studyspecific correction factor) at baseline for PK-ECG matched data were 76.0 beats per minute, 811 msec, 384 msec, 429 msec, 413 msec, and 415 msec, respectively. The results of the analysis indicated that palbociclib did not appear to have a concentration dependent effect on the heart rate. A slight positive linear relationship was observed between palbociclib concentrations and QTcS; however, at the mean or median steady-state palbociclib Cmax following administration of the recommended clinical dose of Palbociclib (125 mg QD) in patients with cancer, the predicted upper bound of the 1-sided 95% CI for the increase in QTcS was less than 10 msec. Palbociclib, when added to letrozole, did not prolong the QT interval to a clinically relevant extent at the recommended dosing regimen according to the criteria described in the ICH guidance for Industry E14 (ICH E14). Similar results were obtained when QTcF and QTcB were used.
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6.3.5 palbociclib dose rationale

Palbociclib has been tested in a Phase 1 dose escalation Study (A5481001) in 74 patients with advanced cancer. Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on treatment/1 week off treatment) and Schedule 2/1 (2 weeks on treatment/1 week off treatment). All DLTs observed in this study were related to myelosuppression and mainly consisted of Grade 3 neutropenia lasting more than 7 days after the end of the treatment cycle. However, neutropenia was reversible and non-cumulative. Other most common adverse events included fatigue, anemia, diarrhea, constipation, vomiting and dyspnea, all with mild to moderate severity. At the MTD, a greater proportion of patients on the 200 mg QD, 2/1 schedule had treatment-related TEAEs during and after Cycle 1 than patients on the 125 mg QD, 3/1 schedule although the proportion of patients with treatment-related neutropenia was similar with respect to the 2 dosing schedules, both during and after Cycle 1. One partial response was reported in a patient with testicular cancer. A total of 13/37 patients treated with Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients with SD lasting 40 weeks or longer. One of these patients was a woman with ER+ breast cancer who had previously received 7 lines of treatment for her disease. This patient remained on treatment for 80 weeks (7 cycles at 50 mg/d and 13 cycles at 75 mg/d) and eventually discontinued treatment due to disease progression. Based on the relatively improved safety profile of Schedule 3/1, and the efficacy results from this study, the Schedule 3/1 has been selected for further clinical development and the RP2D for this schedule was determined to be 125 mg/d. This schedule and associated RP2D was further explored in combination with letrozole in the Phase I/II study in patients with ABC described below.  
6.3.6 Phase I/II Data *in Combination with Letrozole in Advanced Breast Cancer* Based on the preclinical evidence that palbociclib is highly active in ER(+) cell lines and the encouraging safety and PK profiles observed in the initial clinical studies, a randomized, multicenter active-controlled Phase 1/2 Study (A5481003) was designed to assess the efficacy, safety and pharmacokinetics of letrozole 2.5 mg QD (continuously) in combination with palbociclib 125 mg QD (schedule 3/1) versus single agent letrozole 2.5 mg QD (continuously) for the first-line treatment of ER(+), HER2 (-) advanced breast cancer in postmenopausal women. Letrozole was selected as the active control based on its worldwide approval and use as standard of care for the first-line hormonal treatment of postmenopausal women with ER(+) advanced breast cancer. Study A5481003 was comprised of a limited Phase 1 portion, aimed at confirming the safety and tolerability of the combination and excluding a PK interaction with the combination, and a randomized Phase 2 portion aimed at evaluating the efficacy and safety of letrozole in combination with palbociclib when compared to letrozole alone in the first-line treatment of postmenopausal patients with ER(+), HER2(-) advanced breast cancer. The Phase 2 portion consisted of 2 parts. In Part 1, patient selection was based only on ER/HER2 status. In Part 2, patients were prospectively selected also taking into account tumor CCND1 amplification and/or p16 loss. In May 2012, 177 patients have been enrolled in this study and enrollment is closed. Twelve (12) were enrolled in the Phase 1 portion and 165 (66 and 99 in Part 1 and 2, respectively) were enrolled in the Phase 2 portion.  
Results from the Phase 1 portion,85 indicated no PK interaction between palbociclib and letrozole with mean AUC(0-24) of 2002 and 2043 ng•hr/mL (n=11) for palbociclib in the absence and presence of letrozole, respectively, and 1990 and 1730 ng•hr/mL (n=10) for letrozole in the absence and presence of palbociclib, respectively. The RP2D was determined to be 125 mg QD on Schedule 3/1 (3 weeks continuous treatment followed by 1 week off treatment) in combination with letrozole 2.5 mg QD continuously. Partial responses were reported for 3 (33%) out of 9 patients with measurable disease (3 had bone-only disease). Another 5 patients (42%) had stable disease for ≥ 6 months and the clinical benefit rate (PR + SD ≥ 6 months) was 67%. Eight (8) patients discontinued from the study due to disease progression, including 2 patients with clinical progression, 1 patient withdrew consent and 3 patients are still ongoing. Two (2) interim analyses for the Phase 2 portion of the study have been conducted. The results of the interim analyses showed consistent trend of clinically meaningful improvements in progression-free survival (PFS; primary endpoint). In the first interim analysis (Part 1; N=66), the median PFS for the PD 0332991 plus letrozole arm was 18.2 months versus 5.7 months for the letrozole alone arm (HR=0.35; 95% CI: 0.17, 0.72; p=0.006). The second interim analysis (N=165) continued to demonstrate a statistically significant improvement in PFS (26.1 vs. 7.5 months, respectively; HR=0.37; 95% CI: 0.21, 0.63; p <0.001). The combination of palbociclib plus letrozole was generally well tolerated with safety profile similar to palbociclib as a single agent. The most frequently reported treatment-related adverse events included neutropenia, leukopenia, anemia, and fatigue. There were febrile neutropenia reported to date in this study. Overall, 8 patients in the combination arm were discontinued from the study treatment due to an adverse event, of which 5 were considered treatment-related (grade 3 neutropenia [n=4] and ischemic colitis) and 1 patient from the letrozole alone arm. These results indicate that the combination of palbociclib with letrozole is well tolerated with AEs similar to those seen with either palbociclib or letrozole when administered alone. Additionally, the combination demonstrated antitumor activity which was consistent with the sensitivity of ER(+) breast cancer observed in the preclinical models.
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6.3.7 combination with other endocrine

The potential for a DDI between palbociclib and tamoxifen is considered to be probable. Multiple enzymes are responsible for the metabolism of tamoxifen and its active metabolites including CYP3A4, CYP2C9, and CYP2D6. In vitro evidence suggest that tamoxifen and one of its primary active metabolites, 4-hydroxy-tamoxifen, are inducers of CYP3A4 enzymes. In clinical trials, co-administration of tamoxifen with letrozole and anastrozole (both CYP3A4 substrates) has resulted in decreased exposures (AUC) of each by 37% and 27%, respectively. Palbociclib is aCYP3A4 substrate and CYP3A4 is thought to be the primary route of the oxidative metabolim of pabociclib. Thus, the co-administration of tamoxifen and palbociclib may lead to lower circulating levels of palbociclib and require an upward dose adjustment in palbociclib if these two compounds are used in conjunction. Additionally, time-dependent inhibition of CYP3A4 has been observed in preclinical studies of palbociclib. A fixed-sequence 2-period crossover drug-drug interaction (DDI) study to assess the effect of steady-state levels of tamoxifen and its active metabolites on the pharmacokinetics of single dose palbociclib in healthy volunteers was conducted to rule out a need for palbociclib doseadjustments when used in conjuction with tamoxifen. The effect of multiple dosing of tamoxifen (60 mg QD for 4 days followed by 20 mg QD for 23 days), on the single-dose PK of palbociclib (125 mg), was evaluated in 25 healthy fasted subjects in Study A5481026.  
Administration of palbociclib in the presence of tamoxifen and its metabolites (4-hydroxytamoxifen, N desmethyl tamoxifen, and 4 hydroxy N desmethyl tamoxifen) at steady state showed that palbociclib exposure was comparable with that when palbociclib was given alone. The ratios (90% CIs) of the adjusted geometric means of palbociclib AUCinf and Cmax were 108% (104% 111%) and 116% (105% 129%), respectively, following administration of palbociclib with multiple doses of tamoxifen (Test) relative to palbociclib administered alone (Reference). These results indicate that it is not necessary to adjust palbociclib starting dose when coadministering with tamoxifen.  
Prior to opening the PENELOPEBStudy, the pharmacokinetics of a single oral dose of midazolam, a sensitive CYP3A4 substrate, with and without palbociclib dosed to steady-state will be assessed in a healthy volunteer DDI study (A5481012). The results of this study have been communicated and are detailed in Section 6.3.3.
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palbociclib and anastrozole

The potential for a clinically significant DDI between palbociclib and anastrozole is considered to be low. Anastrozole inhibited CYP1A2, 2C8, 2C9, and 3A4 in vitro with Ki values ~30-fold higher than the steady-state Cmax values observed following a 1mg daily dose.  
In vitro and in vivo assessments of oxidative metabolism have indicated the route of formation of the primary metabolite hydroxyanastrozole is predominantly through CYP3A4. Time dependent inhibition of CYP3A4 has been observed in in vitro studies of palbociclib, thus palbociclib has the potential to inhibit the primary clearance pathway of anastrozole.
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palbociclib and goserelin

The potential for a clinically significant DDI between palbociclib and goserelin is considered to be very low. Goserelin is a synthetic decapeptide analogue of gonadotropin releasing hormone (GnRH) whose primary route of elimination is the cleavage of C-terminal amino acids followed by renal excretion. PK data from Study A5481023 was analyzed to evaluate the potential for DDIs between palbociclib and fulvestrant, as well as between palbociclib and goserelin, at steady-state. These data indicate a lack of any clinically relevant DDIs between palbociclib, fulvestrant, and goserelin when administered in combination. The concurrent administration of goserelin did not have clinically relevant impact on the plasma PK of palbociclib in Study A5481023. Statistical comparisons of the palbociclib withinsubject mean steady-state Ctrough in the presence and absence of goserelin, both ignoring
(ANOVA) and accounting for (ANCOVA) demographic differences between the treatment groups, confirmed the lack of a clinically significant DDI. The adjusted geometric mean ratios ranged from 88.3% to 93.1%, which are not considered clinically relevant. Likewise, the concurrent administration of palbociclib did not have a clinically relevant impact on the plasma PK of goserelin in Study A5481023. Statistical comparisons (ANOVA) of the goserelin within-subject mean steady-state Ctrough in the presence and absence of palbociclib confirmed the lack of a clinically significant DDI. The adjusted geometric mean ratio was 110%, which is not considered clinically relevant. Therefore, there is no clinically relevant DDI between palbociclib and goserelin when the two drugs are coadministered. Further pharmacokinetic data will be collected from the initial cohorts of 24 participants of the PENELOPEBstudy each receiving eitherpalbociclib and tamoxifen, palbociclib and anastrozole, or palbociclib and goserelin and tamoxifen (see Section 13.3 for details). These data will be used to explore the potential for DDIs between antihormonal agentsand palbociclib and the result will be used to inform dose adjustment if necessary at the PK stop.
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6.3.8 long term toxicity data

In order to assess the potential for cumulative toxicity with long term administration of palbociclib, an analysis of commonly reported adverse events (neutropenia, leukopenia, fatigue, anemia, nausea, arthralgia, alopecia, diarrhea, hot flush) using time interval analysis (0-6m, 6-12m, 12-24, and >24m) was performed in Study A5481003 (N=83). This analysis did not show any evidence of cumulative or long-term toxicity with prolonged exposure, since there was an almost universal reduction in reporting frequency for these events as treatment duration increased. An additional analysis was done looking at the cumulative percentage of reports received following one year, two years, and following any duration of dosing. This analysis indicated that for virtually all adverse events examined (alopecia, anemia, arthralgia, asthenia, decreased appetite, diarrhea, dyspnea, epistaxis, fatigue, hot flush, leukopenia, nausea, neuropathy peripheral, neutropenia, pyrexia, stomatitis, thrombocytopenia, URTI, and vomiting), the incremental increase of reported events following the initial year of exposure was marginal. Based on these analyses, there does not appear to be any evidence of cumulative toxicity. Long term administration of palbociclib for 2 years and beyond does not appears to be associated with an increased rate of adverse events.
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7. rationale of the study

About one third of patients with hormone-receptor (HR)-positive, HER2-normal breast cancer and residual disease after neoadjuvant chemotherapy have a substantial risk of relapse. The clinical-pathologic stage - estrogen/grade (CPS-EG) combining clinical stage before neoadjuvant treatment, pathological stage after neoadjuvant treatment, grading and estrogen-receptor status can be used to identify these high-risk patients. The CPS-EG score was additionally validated in 2454 patients with HR-positive/HER2-normal tumors from the German neoadjuvant studies' meta-database. Patients who had a score of 3 or higher or Score 2 and ypN+ disease show a 3-years iDFS of 77% despite adequate local therapy and adjuvant endocrine treatment. Cyclin dependent kinases (CDK), a group of serine/threonine kinases, play a key role in regulating cell cycle progression by interacting with specific cyclin proteins in luminal-type tumors.,
PD-0332991 (palbociclib) is an oral, highly selective inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase through blocking retinoblastoma (Rb) phosphorylation. Preclinical studies identified luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to palbociclib. Final results from a randomized phase II study (Paloma-1/TRIO-18) in 165 postmenopausal, ER+/HER2- metastatic breast cancer patients revealed a progression-free survival of 20.2 months when palbociclib was given in combination with letrozole compared to 10.2 months when letrozole was given alone (HR 0.49 (95% CI 0.32-0.75) (p<0.001). Patients preselected by CCND1 (the gene encoding for cyclin-D1) amplification and/or loss of p16 in the primary tumor did not show different results. Uncomplicated neutropenia (48% grade 3, 6% grade 4), anemia (4% grade 3, 1% grade 4), and fatigue (2% grade 3, 2% grade 4) were the most common grade 3 and 4 adverse events.  
The PENELOPEBstudy is designed to demonstrate that in the background of standard antihormonal therapy palbociclib provides superior invasive disease-free survival (iDFS)
compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be an attractive option with a favourable safety profile for these patients.
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8. discussion of the study

For patients with residual disease after neoadjuvant chemotherapy no specific alternative treatment is recommended except the use of 5-10 years of hormonal agents (tamoxifen, aromatase-inhibitors, LHRH agonists). As patients must have received an adequate cumulative dose and cycles of chemotherapy before surgery (except for those with tumor progression where broad resistance against chemotherapy has to be postulated), no additional post-operative chemotherapy is considered indicated. There are no new agents that are proven to help improve the outcome in this group of high risk patient. It therefore appears reasonable to use a placebo to palbociclib as control treatment.
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8.2 washout periods and carry

Based on the available pharmacokinetic data showing a half-life of 27 hours, palbociclib should be completely washed out within a period of 7 days. Patients should therefore not have elective surgery or new cytotoxic treatment started within this time period after last intake of palbociclib.
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8.3 selection of study population

The study population was initially selected based on the biological subtype of breast cancer as available efficacy data for palbociclib is restricted to patients with HR-positive/HER2normal metastatic breast cancer. For patients with this subtype pathological complete response after neoadjuvant chemotherapy per se does not provide clinically relevant prognostic information. Therefore, a clinical score based on tumor stage before and after neoadjuvant chemotherapy, estrogen-receptor status and grade (CPS-EG score) was chosen as an enrichment strategy to select patients at highest risk for relapse despite continued adjuvant endocrine therapy.1,12 The score was developed and validated by the MD Anderson Hospital, Houston, USA, as a prognostic tool to calculate risk of relapse after neoadjuvant chemotherapy in all types of breast cancer, and was strongly correlated with prognosis in the hormone-receptor-positive subtype as well. However, validation of the score in 2454 patients with only HR-positive, HER2-normal disease from neoadjuvant studies of the German Breast Group/AGO-Breast group86, confirmed the prognostic value in the subset of patients targeted in this trial. The CPS-EG score allows isolation of a population of patients at increased risk of early relapse and allows to isolate a population of patients in whom testing of a new agent is indicated. This clinically driven selection approach allows further characterization of the tumors into subsets of molecularly different diseases using prospectively defined markers. This approach is thought to help to potentially further determine the specific, biomarker defined population of patients in whom use of palbociclib would be indicated.
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8.4 rationale for biomarker assessment

Today neoadjuvant therapy is considered a model to learn not only about the biology of breast cancer and drug effect in general, but also about the treatment sensitivity of an individual patient's tumor. Tumor core biopsy before treatment allows biological characterization of the tumor and development of an individual treatment plan. After completion of neoadjuvant treatment, histological examination of the surgically removed breast and axillary tissue allows precise assessment of tumor response and characterization of residual, likely treatment-resistant disease. It also allows confirmation of the presence of initially diagnosed subset, as it is known that in rare cases a loss of hormone receptor or acquisition of HER2 can be found.8788 The availability of both the initial diagnosis tissue and most importantly the residual tumor tissue for all patients at the time of entry to the PENELOPEBtrial provides an opportunity to confirm the diagnosis before randomization and compare the molecular profile with the tissue from original diagnosis. It also allows prospectively testing of important hypotheses regarding the use of the CDK4/6 inhibitor, palbociclib, in combination with anti-hormonal therapy in the adjuvant setting. It is believed that the large number of markers analyzed in the tissue before entry to the trial will render precious information regarding both antihormonal and palbociclib treatment sensitivity and resistance. The markers will allow for further sub-classification of the disease into luminal A and luminal B as well as RB-positive and RB-negative disease and define amplification and overexpression of genes and proteins relevant to the CDK4/6-related pathway. Further, access to tissue at the time of original diagnosis will allow a reference to a pre-chemotherapy status of the tumor. Based on the data from the metastatic HR+ breast cancer, almost uniform presence of intact Rb in HR+ breast cancer and known CDK4/6 role in estrogen stimulated proliferation of breast cancer, it is hypothesized that all patients in PENELOPEB will derive benefit from addition of palbociclib. Hence the primary endpoint is iDFS in the intent-to-treat (ITT) population. However, data set for assessment of markers of sensitivity is available in the metastatic breast cancer settings only. The data set is small to date and the preclinical studies evaluating the CDK4/6 related pathway are complex. Hence, a definitive prospective selection is not supported by available data and would be premature at this time. Therefore, certain specific secondary hypotheses, prospectively defined in statistical analysis plan, will be conducted to optimize understanding of possible patient subgroups benefit/risk effects based on measurable biological criteria.  
As the population eligible for PENELOPEBtrial is heterogeneous with regard to molecular subtypes of HR+ cancer, these tests will further stratify patients with respect to both biomarkers related to RB pathway alteration and a pre-planned subgroup analysis of luminal B patients (based on a at the time of analysis (which will be around the final efficacy analysis) commercially available CE-marked tests (e.g. PAM50, EndoPredict® or any other newly available test) will be conducted. The prospective hypotheses will be described in detail in the study statistical analysis plan. This approach is expected to lead to determination of specific subpopulation(s) in which palbociclib would demonstrate enhanced efficacy (eg, luminal B as assessed by PAM50), or a specific prognostic group or specific molecular alterations (eg, cyclin D1 overexpression or amplification or others) for whom the benefit/risk of palbociclib would be even greater. It is expected that this enhanced benefit/risk profile in a subpopulation of early breast cancer HR+/HER2 normal patients would be reflected in the indication and/or conveyed in the product labeling. It is understood that during the study conduct, new information might emerge related to important markers in the RB pathway, and these markers will be incorporated prospectively into the statistical analysis plan before unblinding or analyzing this study.  
The prospectively defined hypotheses are important as the understanding of the CDK4/6 driven pathway in breast cancer is currently incomplete. Hence, palbociclib may lead to a significant improvement of iDFS with a moderate toxicity profile, but the treatment effect may be limited to, or predominantly seen in prospectively hypothesized subgroups, both at the time of diagnosis and at study entry. This assumption could support a recommendation that 1-year treatment with palbociclib in combination with endocrine therapy is indicated for patients with HR-positive/HER2-normal disease in the prespecified biomarker subgroups at high relapse risk. Hypotheses to be tested in tumor samples from core biopsy at diagnosis and surgery:
It is hypothesized that tumors with alterations in RB/CDK4/6 pathway are more s**ensitive**
to the combination of anti-hormonal therapy and palbociclib. The molecular alterations are characterized by presence of pRB1 (or total RB1) alone or in combination with one of the following: e.g. overexpression or amplification of cyclinD1 (CCND1), CDK4, CDK6; absence of p16 or loss of CDKN2A
It is also hypothesized that luminal B, higher risk population would achieve largest prolongation of iDFS; hence luminal B tumors or other high risk profile (defined by PAM50, Endopredict® or any other commercially available test at the time of analysis), at the time of diagnosis or after chemotherapy would be predictive of enhanced palbociclib benefit.  
The rationale for the second hypothesis is briefly summarized here: Genetic aberrations leading to hyperactivation of cyclin D1-CDK4/6 are particularly common in ER+ breast cancer, consistent with its critical role in the tumorigenesis of this cancer subtype.89, 90 CCND1 amplification and cyclin D1 overexpression correlates positively with ER+ status 91, 92, 93, 94 and is an independent poor prognostic factor in women with ER+ disease who received adjuvant tamoxifen therapy.95 The recent report from The Cancer Genome Atlas (TCGA) project indicated that poorer prognosis ER+ disease (luminal B) is preferentially enriched with gene amplification of cyclin D1 (luminal A: 29%, luminal B: 58%), and CDK4 gain (luminal A 14%,
luminal B 25%).96 Importantly RB1 (Rb), which is required for the activity of CDK4/6 inhibitors, is wild type in most luminal/ER+ breast cancers (unlike ER- disease), making CDK4/6 inhibitors particularly attractive agents for ER+ breast cancer.  
The TCGA breast cancer study also showed low levels of RB1 mutations in luminal-type breast cancer (∼1%) and frequent amplification of cyclin D1 (40%).97 The cyclin D1/CDK4/6 complex phosphorylates the retinoblastoma (Rb) protein, which leads to cell-cycle activation.98 Results from several studies indicate that CDK4 and CDK6 play an important role in estrogen-stimulated proliferation of breast cancer cells in early to mid G1 phase. 99 100 101 102 103 Thus, CDK4 and CDK6 represent valuable therapeutic targets of ER+ advanced breast cancer104. Consistent with this conclusion, high levels of expression of the Rb-regulated E2F gene family is a frequent feature of endocrine-resistant luminal-type breast cancer. Unlike basal-like breast cancers, in which Rb loss is common 105, inhibition of the critical cell-cycle inhibitory effect of Rb in luminal tumors is achieved primarily through overexpression or amplification of cyclin D1, overexpression or amplification of CDK4, and/or loss of the CDK inhibitors CDKN1B, CDKN2A, and 2B. 106,45 Luminal tumors are therefore likely to prove sensitive to CDK4/6 inhibitors as randomized Phase 2 trials are under way
(NCT00721409), 107and a preliminary report of a randomized trial of letrozole versus letrozole plus palbociclib at the 2012 IMPAKT meeting in Brussels and San Antonio Breast Cancer meeting in December 2012 108showed significant improvement in progression-free survival.109 Interestingly, mantle cell lymphoma, another chemotherapy-refractory cyclin D–
driven malignancy, is also sensitive to CDK4/6 inhibition. 110Basal-like tumors, and occasional luminal B tumors, harbor loss or mutation in Rb and are therefore highly unlikely to be responsive to these agents; thus, determination of the mode of Rb pathway inactivation will be critical to the success of CDK 4/6 inhibitors in breast cancer.111
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8.5 removal of patients from

Patients with progressive disease, medical or subjective intolerability of toxicity, or lack of compliance will be removed from the treatment with palbociclib or placebo. However, the investigators are asked to continue medical treatment as closely as possible to the guidelines given by the protocol. These patients will be followed up for relapse and toxicity as long as the patient does not withdraw her consent.
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8.6 blinding

The allocation of patients to either palbociclib or placebo will be blinded to patients and investigators. Neither the Investigator nor the Sponsor will have access to the individual data for the primary efficacy parameter obtained after the baseline visit in each patient. However, the Independent Data Monitoring Committee (IDMC) will review the blinded data for the safety and primary efficacy parameter in overall descriptive statistics during data review meetings. The descriptive statistics for use in any data review meeting will be generated by the GBG statistician/programmer. Only at the reasonable request of the IDMC, unblinded safety and/or efficacy results will be presented. The analysis will be conducted by an independent GBG statistician, who is not involved in the study operation and execution. The DDI assessment will be conducted by Pfizer and supplied to the IDMC. The procedure for unblinding data to use for analysis of DDI assessment by the core laboratory will be described in the PK unblinding plan.
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8.7 rationale for the duration

Duration of treatment was determined by the time considered acceptable for patients having received neoadjuvant chemotherapy based on the available safety profile and experience with palbociclib. As the annual risk of relapse appeared to be stable over at least 5 years, an optimal duration of treatment could not be identified based on the relapse profile and a year of treatment was chosen arbitrarily.
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8.8 treatment compliance

Compliance is monitored by a patients' diary recording date and time of capsules intake as well by counting the number of capsules brought back by the patient before starting the next cycle. This information will be documented in a summarized form in the electronic data capturing system (e-CRF). No laboratory tests for compliance will be used.
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8.9 appropriateness of the primary

The primary endpoint of this protocol, iDFS, is defined according to a recent position / paper of Hudis C et al.112 In this paper it is stated that: "Overall survival has been recognized as the least ambiguous and most clinically relevant clinical end point in clinical trials of cancer therapy. However, in evaluating postoperative treatment for stage I, II, and IIIA breast cancer where all identifiable tumor has been resected, disease-free survival is frequently employed as a surrogate."
Nevertheless, follow up of patients will continue for further 3 years after the required events for the final iDFS analysis has been observed as this will allow to adequately determining the effect of palbociclib on overall survival. As the final efficacy analysis will be conducted after the last patient stopped treatment with palbociclib, cross-over is not expected to occur. However, during the conduct of the study, palbociclib has received market approval for the treatment of metastatic breast cancer in some countries, therefore some patients in the control arm as well as in the palbociclib arm) might be (re-)treated with palbociclib after relapse.
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8.10 risk-benefit analysis for the

All study participants must have received a standard taxane-containing neoadjuvant chemotherapy using regimes comparable to those currently used as adjuvant treatment, adequate surgery, as well as radiotherapy, if indicated. All patients will also receive adjuvant endocrine treatment according to institutional standards. It is not expected that toxicity of palbociclib will reduce compliance with endocrine treatment. As currently no other kind of treatment is recommended for this subtype of breast cancer, under-treatment of study participants can be excluded. Data of a large randomized phase II metastatic breast cancer trial (A5481003) showed a prolongation of median progression-free survival by palbociclib of 10.0 months corresponding to a hazard risk ratio of 0.49. Median progression free survival increased from 10.2 months for patient treated with letrozole alone to 20.2 months for patients treated with the combination of letrozole, The toxicity profile of palbociclib at the dose and schedule similar to the one that will be used in the PENELOPEBstudy, was moderate with neutropenia being the most frequent treatment related adverse event. The clinical picture of neutropenia seen with the palbociclib/letrozole combination in A5481003 is notable for being quickly reversible, noncumulative and uncomplicated and managed without the use of growth stimulating factors. In fact, the majority of patients have discontinued from this randomized 165 patient study due to disease progression rather than from adverse events. While the neutropenia seen in the A5481003 advanced breast cancer setting has been managed using dose modifications, this has resulted in a high rate of dose interruptions (70%). In the early breast cancer setting to help mitigate this on target toxicity, a more aggressive dose reduction algorithm will be employed. Data on cumulative toxicities seen with 1 year of palbociclib treatment as well as late toxicities after treatment discontinuation is available on >300 patients, and further data is being collected in a large clinical trial program in parallel to this study. As described before, there are no obvious differences in the clinical and laboratory safety profile between patients taking palbociclib for less than 12 months compared to those taking the compound for 12 months or longer based on data collected in clinical studies to date. It is concluded that the data available do not identify any safety concerns associated with long term administration of palbociclib. In addition, participating patients in the current trial will have marginal additional burden due to investigations required for study participation (e.g. additional visits at the site, additional blood tests, additional ECGs, and completion of questionnaires). However, the option to receive a treatment potentially significantly improving iDFS in this high-risk population is considered to balance uncertainties of the toxicity profile of palbociclib and the additional burden related to study investigations.
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8.11 interpretation of potential study

Four scenarios of results can be envisaged which will lead to the following conclusions:
Palbociclib will lead to a significant improvement of iDFS with a moderate toxicity profile allowing the majority of patients to receive treatment at planned dose and schedule. This will support a recommendation that one year treatment with palbociclib in combination with endocrine therapy is indicated for patients with HRpositive/HER2-normal disease at high relapse risk.  
Palbociclib will lead to a significant improvement of iDFS, but compliance with treatment is significantly impaired by toxicities. This might support a recommendation that one year treatment with palbociclib should be considered for selected group of patients with HR-positive/HER2-normal disease (e.g. at very high relapse risk, or based on predictive markers investigated in this study). Other doses and schedules will likely need to be explored.  
Palbociclib will lead to an overall significant improvement of iDFS with a moderate toxicity profile, but the treatment effect is limited to or predominantly seen only in prospectively hypothesized subgroups in which palbociclib is at planned dose and schedule. This will support a recommendation that one year treatment with palbociclib in combination with endocrine therapy is indicated for patients with HRpositive/HER2-normal disease in the relevant subgroups at high relapse risk.  
Palbociclib does not significantly improve iDFS in the study population. No recommendation will then be made to use this compound in this setting outside of clinical trials.
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9. study objectives 9.1 primary

To compare invasive disease free survival (iDFS) for palbociclib vs. placebo in patients with residual invasive breast cancer and high CPS-EG score - after neoadjuvant chemotherapy receiving standard adjuvant endocrine therapy for HR-positive/HER2-normal primary breast cancer.
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9.2 secondary objectives secondary objectives

To compare between the two arms:
iDFS excluding second primary of non-breast cancers overall survival (OS)
distant disease free survival (DDFS) locoregional recurrences-free (LRRFS) survival iDFS per treatment group in patients with luminal-B tumors (as determined by e.g.  
PAM50 or any other commercially available test at the time of analysis)
compliance and safety according to NCI-CTCAE Version 4.0 patients reported outcomes health economic outcomes to explore drug-drug interaction (DDI) potential for each palbociclib - endocrine combination therapy in a subset of this patient population to explore correlations between exposure and efficacy and/or safety findings; Other objectives: Scores and markers for their prognostic value in this specific trial setting and their predictive information on the efficacy and/or safety of palbociclib:
pRB immunoreactive score in residual tumor after neoadjuvant treatment Cyclin D immunoreactive score in residual tumor after neoadjuvant treatment residual cancer burden (RCB)
clinical response to neoadjuvant chemotherapy (assessed according to chapter 21.1)
incidence and alterations in genes, proteins, and RNAs relevant to the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug targets (eg, CDK 4/6), and tumor sensitivity and/or resistance (Ki67, pRb, tRB, cyclin E, pi3k, p16, and other markers, measured by optimal test available at the time of analysis) in tumor tissues and/or peripheral blood.  
Low and high risk groups (defined by Endopredict®, ROR or other any other available test at the time of analysis)
low and high risk groups defined by a standardized image analysis system for Ki67 circulating tumor DNA (ctDNA)
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10. study design

This is a prospective, international, multicenter, randomized, double-blinded, placebocontrolled, parallel-group Phase III study comparing the efficacy and the safety of thirteen cycles (1 year) adjuvant treatment with palbociclib versus placebo in high risk (CPS-EG score 3-6 or CPS-EG score 2 and ypN+) patients without pathological complete response after neoadjuvant chemotherapy for hormone-receptor-positive / HER2-normal primary breast cancer. Patient will receive standard adjuvant endocrine treatment after completion of adequate local surgical and radiotherapeutic treatment. Prior endocrine treatment as part of neoadjuvant treatment is acceptable. Adjuvant endocrine treatment might have been started before randomization can be started anytime post-surgery.  
The study has an adaptive design with two interim analyses including sample size reestimation and non-binding stopping of the trial due to futility in the first and early stopping of the trial prematurely due to overwhelming efficacy in the second efficacy interim analysis. Due to the adaptive design sample size will be at least 1100 patients. The sample size can be increased to a maximum of 1250 patients depending on the result of the first efficacy interim analysis. Patients will be randomized in a 1:1 ratio to:
Arm A: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles; Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles.  
Randomization will be stratified using block randomization by:
histological lymph node status at surgery (ypN 0-1 vs ypN2-3)
age at first diagnosis (<=50 vs >50 yrs)
centrally measured Ki-67 (>15% vs <=15%) global region of participating site (Asian vs non Asian) risk status (CPS-EG Score >=3 vs CPS-EG Score = 2 and ypN+)
Due to the prognostic impact of the randomization criterion risk status, randomization to the stratum CPS-EG score =2 and ypN+ will be limited to 50% of the patients. Palbociclib/Placebo will be given for thirteen 28-day cycles or until diagnosis of invasive local, regional or distant recurrence, diagnosis of secondary malignancy, unacceptable toxicity, or withdrawal of consent of the patient or study termination by the Sponsor, whichever occurs first. Patients in both arms shall receive standard endocrine treatment for at least 5 years.
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11. study population 11.1 number

Due to the adaptive design sample size will be at least 1100 patients. The sample size can be increased to a maximum of 1250 patients depending on the result of the first efficacy interim analysis.
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11.2 inclusion criteria

Patients will be eligible for study participation only if they comply with the following criteria:
1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.  
2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue block or a partial block from surgery after neoadjuvant chemotherapy and from corebiopsy before start of neoadjuvant chemotherapy, which will be used for centralized retrospective confirmation of hormone- and HER2-status and to evaluate correlation between genes, proteins, and mRNAs relevant to the endocrine and cell cycle pathways and sensitivity/resistance to the investigational agents. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.  
3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast. 4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.  
5. Centrally confirmed hormone-receptor-positive (≥1% ER and/or PR positive stained cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast, or if no other tissue is available the residual tumor of the lymphnode can be assessed.  
6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on postneoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.  
7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This period must include 6 weeks of a a taxane -containing neoadjuvant therapy (Exception:
Patients with progressive disease that occurred after at least 6 weeks of taxanecontaining neoadjuvant treatment , a total treatment period of less than 16 weeks is also eligible).  
8. Adequate surgical treatment including resection of all clinically evident disease and ipsilateral axillary lymphnode dissection. Histologically complete resection (R0) of the invasive and ductal in situ tumor is required in case of breast conserving surgery as the final treatment. No evidence of gross residual disease (R2) is required after total mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic)) or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.  
9. Less than 16 weeks interval since the date of final surgery and date of randomization or less than 10 weeks from completing radiotherapy (whichever occurs last) at date of randomization.  
10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO
Mamma, NCCN) is strongly recommended. If radiotherapy is not performed the reason for this needs to be documented in the eCRF.  
11. No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion.  
12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3, or score 2 if nodal status at surgery is ypN+, calculated using local ER and grade assessed on either core biopsies taken before start of neoadjuvant treatment or surgical specimen (see chapter 21.1).  
13. Age at diagnosis at least 18 years. 14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see 0). 15. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).  
16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.  
17. The patient must be accessible for scheduled visits, treatment and follow-up. Patients registered on this trial must be treated at the participating center which could be the Principal or a Co- investigator's site.
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11.3 exclusion criteria

1. Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.  
2. Inadequate organ function prior to randomization including: Hemoglobin <10g/dL
(100g/L) ANC < 2000/mm³ (< 2.0 x 109/L); Platelets <100,000/mm³ (< 100 x 109/L); AST or ALT >1.5 x upper limit of normal (ULN); alkaline phosphatase > 2.5 x ULN, total serum bilirubin > 1.25 x ULN; serum creatinine >1.25 x ULN or estimated creatinine clearance < 60 mL/min as calculated using the method standard for the institution; severe and relevant co-morbidity that would interact with the participation in the study 3. Evidence for infection including wound infections, Human Immunodeficiency Virus (HIV)
or any type of Hepatitis 4. QTc >480. 5. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomagnesemia). 6. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.  
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.  
8. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years prior to randomization, except curatively treated basal cell carcinoma of the skin and carcinoma in situ of the cervix.  
9. Current severe acute or uncontrolled chronic systemic disease (e.g. diabetes mellitus) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.  
10. Recent (within the past year) or active suicidal behavior. 11. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.  
12. Major surgery within 2 weeks prior to randomization. 13. 10 weeks or more have passed since completion of radiotherapy at day of randomization and 16 weeks interval since the date of final surgery have passed.  
14. Prior treatment with any CDK4/6 inhibitor.  
15. Patients treated within the last 7 days prior to randomization and/or concurrent use of drugs known to be CYP3A4 inhibitors or inducers (see appendix 21.3).  
16. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to randomization.  
17. Male patients.
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11.4 removal of patients from

This study is conducted according to the principle of intent-to treat. Drop-outs without treatment are defined as those patients who have been randomized in the study but withdrew their consent or are withdrawn by the investigator from the study immediately thereafter but prior to first application of study medication. The reasons are collected and reported in the Consort Statement. Such patients are to be included in the intent-to-treat analysis and will not be replaced.
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11.4.2 premature treatment discontinuation

Patients who have been randomized and have received study medication and, for whatever reason, did not participate throughout the entire study are classified as premature treatment discontinuation. Patients may discontinue study treatment at any time. Reasons for discontinuation must be documented in the case report form (eCRF) and in the patient's medical records. Investigators must attempt to contact patients who fail to attend scheduled visits by telephone, letter, visit, etc., to exclude the possibility of an adverse event being the cause. Should this be the case, the adverse event must be documented, reported and followed-up as described in Section 17. A final examination should be performed if possible on each discontinuation. Patients should receive off study treatment as close as possible to the protocol. Treatment and outcome should be documented on the CRFs. In case a patient withdraws her consent for future data collection the CRFs have to be completed until the date of withdrawal.
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12. study treatment 12.1 method

After a patient has completed the necessary screening visit procedures, the corresponding baseline CRFs have to be completed using the electronic data capturing MedCODES® application. Central histologic assessment has to confirm an eligible tumor subtype (HR+/HER2-) as well to provide results of the biological stratification factors in a MEDCODES®
interface. Eligibility of the patient will be checked and approved by GBG staff before randomization. Patients will be randomly assigned to one of the two arms (palbociclib or Placebo) in a 1:1 ratio using a computerized system. Assignment will be stratified by the predetermined factors (see Section 10) using block randomization created by an independent GBG statistician not involved in the study conduct. Details of the computerized system procedure will be provided in the computerized system Site Manual. All data are collected and stored using the MedCODES® application. Randomization should occur no more than 6 business days before administration of the first dose of investigational product. The site will receive confirmation of randomization and drug supply is ordered automatically via IWRS system.
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12.2 breaking the blind by

At the initiation of the trial, the trial site will be instructed on the method for breaking the blind. The method will be an electronic process in MedCODES®. Blinding codes should only be broken in emergency situations for reasons of patient's safety.. When the blinding code is broken, the date and reason for unblinding must be fully documented in source documents and entered on the case report form. However, every effort should be made by the site staff to ensure that the treatment arm in which the unblinded patient is assigned is not communicated to any sponsor personnel or designee involved in the conduct of the trial.
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12.2.2 after imp treatment discontinuation

Blinding codes may also be broken after a patient discontinues treatment due to disease relapse, as determined by the treating investigator using RECIST v.1.1 criteria or diagnosis of a second primary malignancy, but only if deemed essential to allow the investigator to select the patient's next treatment regimen and after discussion and agreement with GBG staff. Code should not be broken in the absence of relapse of disease as per RECIST v.1.1 (e.g., in case of clinical deterioration, increase in tumor markers or any other evidence suggestive a relapse but in the absence of RECIST-defined new evidence of disease). In case of unblinding after treatment discontinuation, the "end of treatment" and "relapse form" have to be submitted via MedCODES® . The investigator can then send an unblinding request to the GBG unblinded statistician specifying the reason for unblinding. The unblinded information will then be shared as password protected file via email. Every effort should be made by the site staff to ensure that the treatment arm in which the unblinded patient is assigned is not communicated to any sponsor personnel or designee involved in the conduct of the trial.
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12.3 investigational product 12.3.1 formulation

Palbociclib
Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base. Capsules will be supplied in HDPE bottles containing 23 capsules. The capsules can be differentiated by their size and color (see below).  
| Dosage   | Capsule color               | Capsule size   |
|----------|-----------------------------|----------------|
| 75 mg    | Sunset Yellow/Sunset Yellow | 2              |
| 100 mg   | Caramel/Sunset Yellow       | 1              |
| 125 mg   | Caramel/Caramel             | 0              |
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placebo of palbociclib

Placebo will be indistinguishable from the palbociclib capsules and will be supplied as capsules matching in size and color the various palbociclib formulations (see Table 1). Placebo capsules will be supplied in HDPE bottles containing 23 capsules.  
12.3.2 *Preparation and Dispensing* Palbociclib/Placebo will be provided in non-patient-specific bottles. The patient number should be recorded on the bottle label in the spaces provided by site personnel at the time of assignment to patient. Site personnel must ensure that patients clearly understand the directions for self-medication. Patients should be given a sufficient supply to last until their next study visit. Unused drug and/or empty bottles should be returned to the site at the next study visit. Returned unused medication MUST NOT be re-dispensed to a patient. Palbociclib/placebo is an agent that must be handled and administered with care. Patients should be instructed to keep their medication in the bottles provided and not transfer it to any other container. Due to possible unknown hazards associated with topical and environmental exposure to experimental agents, capsules must not be opened and/or emptied into any vehicle for oral ingestion; capsules must be swallowed intact. Only one capsule strength will be dispensed to the patient at each dispensing visit. In the event of dose modification, request should be made of the patient to return all previously dispensed medication to the clinic and new capsules will be dispensed.
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12.3.3 administration

Palbociclib/placebo at a dose of 125 mg will be administered orally once a day at the same day time for 21 days followed by 7 days off treatment of every 28-day cycle, a delay of up to 3 days due to administrative reason is acceptable. A total of thirteen 28-day cycles should be administered palbociclib/placebo capsules will be administered together with endocrine treatment.). Patients should take Palbociclib /placebo with food. Patients should be instructed to swallow palbociclib/Placebo capsules whole and not to chew them prior to swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. Patients should be encouraged to take their dose at approximately the same time each day. Patients should be instructed to record daily administration of the study drugs in a patient diary. Patients experiencing investigational product related toxicity may have their dose modified according to Section. 12.3.5. General Rules:
Patients who miss a day's dose entirely (latest intake 18:00 of a day) must be instructed NOT to "make it up" the next day.  
Patients who vomit any time after taking a dose must be instructed NOT to "make it up," and to resume treatment the next day as prescribed.  
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next day's dose. Also refer to Section 12.3.10 for further details on medication errors and overdose.
12.3.4 *Premedication and supportive treatment* No premedication or prophylactic supportive treatment is recommended.
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12.3.5 recommended dose modification

Every effort should be made to administer study treatment on the planned dose and schedule. However, in the event of significant treatment-related toxicity, administration of investigational product palbociclib/placebo may need to be adjusted as described in the following sections. Depending on the nature of the toxicity observed, dosing adjustment may be required for just one or both study drugs in the combination. In the event of significant treatment-related toxicity, palbociclib/placebo dosing may be interrupted or delayed and/or reduced as described below. In the event of multiple toxicities, dose modification should be based on the worst toxicity observed. Patients are to be instructed to notify Investigators at the first occurrence of any adverse sign or symptom. Dose modifications may occur in three ways:
Within a cycle: dosing interruption until adequate recovery and dose reduction, if required, during a given treatment cycle; Between cycles: next cycle administration may be delayed due to persisting toxicity when a new cycle is due to start; In the next cycle: dose reduction may be required in a subsequent cycle based on toxicity experienced in the previous cycle.
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12.3.6 dosing interruptions

Patients experiencing the following adverse events should have their treatment with palbociclib or palbociclib/placebo interrupted/delayed until criteria for retreatments are met (see 12.3.7):  
Uncomplicated Grade 3 or 4 neutropenia (ANC<1000/mm3); Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection or febrile neutropenia (fever 38.5C with or without infection);
Grade 3 or Grade 4 thrombocytopenia (Platelet count <50,000/mm3);
Non-hematologic toxicity persisting **despite optimal medical treatment** if either Grade 2 lasting more than 3 weeks or Grade 3 (excluding side effects likely related to endocrine treatment (e.g. joint pain of Grade 3) or alopecia ;
Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs). if a patient experiences concurrent > 3xULN ALT and 2xULN bilirubin the dose needs to be held while the cause is investigated.
Appropriate follow up assessments should be done until adequate recovery occurs as assessed by the Investigator. Criteria required before treatment can resume are described in Section 12.3.7. Doses may be held as needed until toxicity resolution. Depending on when the adverse event resolved, a treatment interruption may lead to the patient missing all subsequent planned doses within that same cycle or even to delay the initiation of the subsequent cycle. If the adverse event that led to the treatment interruption recovers within the same cycle, then re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the same cycle. The need for a dose reduction at the time of treatment resumption should be based on the criteria defined in Section 12.3.8 unless expressly agreed otherwise following discussion between the investigator and GBG staff. If a dose reduction is applied in the same cycle, the patient will need to return to the clinic to receive new drug supply. In the event of a treatment interruption **for reasons other than treatment related toxicity**
(eg, non-cancer related surgery) lasting ≥3 weeks, treatment resumption will be decided in consultation with GBG medical staff.
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12.3.7 retreatment

Retreatment following treatment interruption for treatment related toxicity or at the start of any new cycle may not occur until all of the following parameters have been met:
Platelet count  50,000/mm3; ANC  1000/mm3and no fever; G-CSF is not generally recommended as secondary prophylaxis Grade 3 or higher treatment-related non-hematologic AEs considered related to palbociclib (including, nausea, vomiting, diarrhea, and hypertension **only** if persisting despite optimal medical treatment; not including alopecia) have recovered to Grade ≤ 1 or baseline (or, at the investigator's discretion, Grade ≤ 2 if not considered a safety risk for the patient).  
QTc ≤500msec and potential reversible causes (eg, electrolyte imbalance, concomitant medications known to prolong QTc) corrected. If QTc remains above 480 msec, a cardiologist should be consulted and ECG should be monitored more frequently until QTc ≤480 msec.  
If a treatment delay results from decline in hematologic parameters, the frequency of blood count assessments should be adjusted as clinically indicated. If the retreatment parameters are met within 3 weeks of treatment interruption or cycle delay, palbociclib/Placebo may be resumed. Please refer to Table 3 and 4 for adverse events requiring dose reduction at the time of treatment resumption. If these parameters have not been met after 3 weeks of dose interruption (including the scheduled 1 week off treatment) or 3 weeks of cycle delay, permanent discontinuation of palbociclib/Placebo treatment should be considered. Treatment resumption for patients recovering from treatment-related toxicity after >3 weeks of treatment interruption or cycle delay but deemed to be suitable to continue with a lower dose per the investigator's best medical judgment is recommended but left at the investigator's discretion.
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12.3.8 dose reductions

Following dose interruption or cycle delay for palbociclib/placebo toxicity, a 2 step dose reduction schedule is recommended, when treatment is resumed. No specific dose adjustments are recommended for Grade 1 or short lasting Grade 2 treatment related toxicity. However, investigators should always manage their patients according to their medical judgment based on the particular clinical circumstances.  
In case of a history of a grade 2 toxicity lasting for >3 weeks or grade 3 toxicity (both assessed in the presence of maximum supportive care, and as judged by investigator to be associated with palbociclib/placebo and to achieve easily manageable safety profile) a dose reduction is recommended in subsequent cycle (except for neutropenia, alopecia). For details please refer to Table 3 and 4. Dose reduction of palbociclib/placebo by 1 and, if needed, by 2 dose levels (Table 2) is recommended depending on the type and severity of toxicity encountered. In addition a break on day 10-12 or a prolonged holiday of up to 2 weeks after 2 weeks of treatment are further options to modify dose according to tolerability (if in investigator judgment such schedule is manageable and preferred). Taking palbociclib according to recommendation (with food) needs to be reinforced and checked. Alternatively patient will be discontinued from the study and entered into the follow-up phase of the study. All dose modifications/adjustments must be clearly documented in the patient's source notes and Investigational product administration CRF. Once a dose has been reduced for a given patient, all subsequent cycles should be administered at that same reduced dose level, unless further dose reduction is required. Dose re-escalation is not allowed.  
| Dose Level                                                   | palbociclib/placebo for 3 out of 4  weeks (3/1 schedule)   |
|--------------------------------------------------------------|------------------------------------------------------------|
| Starting dose                                                | 125 mg/d                                                   |
| -1                                                           | 100 mg/d                                                   |
| -2                                                           | 75 mg/d*                                                   |
| Discontinue Study Treatment or consider 75mg/d 2/2  schedule |                                                            |
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table 2 available dose levels

* Palbociclib/placebo dose de-escalation below 75 mg/d is not allowed **the schedule may move to 75mg/day**
two weeks on followed by two weeks  
Table 3: Palbociclib/placebo Dose Modifications for Treatment Related Toxicities  
Requiring Treatment Interruption/Delay or Persisting Despite Optimal Medical Treatment.  
| Requiring Treatment Interruption/Delay or Persisting Despite Optimal Medical Treatment. nd episode Subsequent  Toxicity 1 st episode 2 episodes Uncomplicated Grade 3 neutropenia (ANC 500 to <1000/mm3 ) with recovery  to ≤ Grade 2 until planned D1 of next  cycle Same dose  level (DL) Same DL Same DL Uncomplicated Grade 3 or 4  neutropenia without recovery to  ≤ Grade 2 at planned D1 of next cycle DL-2 and break from day 10-12 Next episode  stop or continue  with 2 weeks treatment and 2  weeks holiday Reduce to  Dose Level-1  (DL-1) DL-1 and  break from  day 10-12  Uncomplicated grade 4 neutropenia  (ANC <500/mm3) with recovery to  ≤ Grade 2 until planned D1 of next cycle Neutropenia grade 3 or 4 associated  with a documented infection ; DL -1 and  either break  from day 10-12  or 2 week drug  holiday DL -2 and  either break  from day 10- 12 or 2 week  drug holiday Stop Febrile neutropenia Thrombocytopenia grade 3 or 4 Any grade 2 toxicities for more than 3  weeks (except for neutropenia or  DL-1 DL-2 Stopalopecia)   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Non-hematologic toxicity grade 3 or 4 (including, nausea, vomiting, diarrhea,  and hypertension only if persisting  despite optimal medical treatment; nonincluding alopecia)                                                                        | DL-1                                                                     | DL-2   | Stop   |
|------------------------------------------------------------------------|--------------------------------------------------------------------------|--------|--------|
| Consider break  from day 10-12                                         | Consider  break from  day 10-12                                          |        |        |
| Consider DL-2  for 2 weeks or 2 weeks holiday if  recovery is  delayed | Consider DL-2  for 2 weeks  or 2 weeks  holiday if  recovery is  delayed |        |        |
| QT interval changes see table 4                                        |                                                                          |        |        |
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12.3.9 qtc prolongation management

In the event of QTc prolongation of **>480-500 msec**, possible alternative reversible causes such as serum electrolytes abnormalities, or usage of concomitant medications with the potential to prolong the QTc interval should be evaluated. If such reversible causes are identified, then they should be corrected accordingly (ie, correction of electrolyte abnormalities with supplements to within normal limits and/or discontinuation (if possible) of concomitant medications known to prolong the QT interval). Recommended dose modifications in the event of QTc prolongation are provided in Table 4.  
| Toxicity (NCI CTC Grade, Version 4.0)                                                                          | Grade 4 QTc  prolongation                                                                                                                                                                           |
|----------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (>=501 msec or >60 ms  change from baseline  and life-threatening  signs incl. Torsade de  points)             |                                                                                                                                                                                                     |
| Grade 2 QTc  prolongation                                                                                      |                                                                                                                                                                                                     |
| QTc 481 - 500 ms                                                                                               | Grade 3 QTc  prolongation (>=501 msec)                                                                                                                                                              |
| Treat reversible cause                                                                                         |                                                                                                                                                                                                     |
| Treat reversible cause                                                                                         | Withhold treatment until  QTc<500 msec                                                                                                                                                              |
| Initiate more frequent  ECG monitoring according  to investigator's best  medical judgment until  QTc≤480 msec | Resume treatment at the  same dose level.                                                                                                                                                           |
| Reversible  cause  identified                                                                                  | Permanently  discontinue                                                                                                                                                                            |
| Monitor ECG more  frequently as per  investigator's best  medical judgment until  QTc≤480 msec.                |                                                                                                                                                                                                     |
| Continue at the same  dose level (1)                                                                           | Consult cardiologist.                                                                                                                                                                               |
| Consult cardiologist and  initiate more frequent  ECG monitoring until  QTc≤480 msec                           | Withhold treatment until  QTc<500 msec                                                                                                                                                              |
| No                                                                                                             |                                                                                                                                                                                                     |
| reversible  cause  identified                                                                                  | Permanently  discontinue                                                                                                                                                                            |
| Resume treatment at the  next lower dose level (2)                                                             |                                                                                                                                                                                                     |
| Continue at the same  dose level (1)                                                                           | Monitor ECG more  frequently as until  QTc≤480 msec.                                                                                                                                                |
| (1)                                                                                                            | If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the  absence of other alternative causes or despite correction of alternative causes, dose adjustment |
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table 4 palbociclib/placebo dose modifications

(1) If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of other alternative causes or despite correction of alternative causes, dose adjustment and/or discontinuation should be considered in consultation with a cardiologist and the study medical monitor, taking into account the emerging safety data from palbociclib **trials and the**
investigator's best medical judgment.  
(2) **If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment**
and/or discontinuation should be discussed with study medical monitor in consultation with a cardiologist, taking into consideration the emerging safety data from palbociclib **trials and the** investigator's best medical judgment.
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12.3.10 medication errors and overdose

Medication errors may result in this study from the administration or consumption of the wrong drug, by the wrong patient, or at the wrong dosage. Such medication errors are to be captured irrespective of the presence of an associated toxic event like an SAE on the SAE form. In the event of medication dosing error, GBG should be notified immediately.
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12.3.11 compliance

Patients will be required to return all bottles of palbociclib/placebo as well as the completed patient diary at the beginning of each cycle for drug accountability. Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle. The number of remaining capsules will be documented and recorded. To be considered compliant, each study patient must have received at least 80% of the prescribed number of doses of palbociclib/placebo based on the number of days of actual dose administration. Dose adjustments must follow instructions provided in Section 12.3.4 - 12.3.8.
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12.4 drug storage and drug

Palbociclib/placebo capsules should be stored at controlled room temperature (15-30C,
59-86F) in their original container.  
Medication should be kept in a secured locked area at the study site in accordance with applicable regulatory requirements. Returned medication should be stored separately from medication that needs to be dispensed. To ensure adequate records, palbociclib/placebo capsules will be accounted for as instructed by GBG. Patients are requested to return previously dispensed containers as well as their completed patient diary to the clinic at each visit for accountability purposes even if they will not be issued with new medication at that visit. Storage conditions stated in this protocol or in the Investigator's Brochure (IB), United States Package Insert (USPI), Summary of Product Characteristics (SPC), or Local Product Document (LPD) may be superseded by the label storage. Investigators and site staff are reminded to continuously monitor room storage temperatures and ensure that thermometers are working correctly as required for proper storage of investigational products. These include thermometers for the room storage. Any temperature excursions must be reported immediately to GBG and documented. Once a deviation is identified, palbociclib/placebo MUST be quarantined and not used until GBG provides documentation of permission to use the investigational product. At the end of the trial, GBG will provide instructions as to disposition of any unused investigational product. If GBG authorizes destruction at the trial site, the investigator must ensure that the materials are destroyed in compliance with applicable environmental regulations, institutional policy, and any special instructions provided by GBG. Destruction must be adequately documented.
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12.5 concomitant medications

Patients must be instructed not to take any additional medications (including over-the-counter (OTC) or other products) during the study without prior consultation with the investigator as some herbal supplements or OTC can impact pharmacokinetics of palbociclib/placebo and are in the list on prohibited medications. Any medications including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior to the start of study treatment and up to 28 days following the last dose of investigational product and the reason for their administration must be recorded on the CRF. Routine postoperative care, such as dressing changes, suture removal, drain removal, or venous access (central or peripheral), does not need to be recorded. Anesthetics used for any surgical procedures performed during the patient's participation in the study can be recorded as "unspecified anesthesia" on the concomitant treatment records; it is not necessary to list the specific anesthetics. Supportive care for cancer-related symptoms should be offered to all patients in this study.
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12.5.1 prohibited medications

The following treatments are prohibited throughout the duration of the active treatment phase:
**Anticancer agents:** No additional investigational or commercial anticancer agents such as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy (other than tamoxifen, LHRH analogues or aromatase inhibitors) will be permitted during the active treatment phase. In general, any drugs containing "for the treatment of breast cancer" on the product insert are not permitted on study.  
**Strong CYP3A inhibitors/inducers:** palbociclib is metabolized to multiple metabolites in a qualitatively similar manner in rat, dog and human liver microsomes. In vitro, palbociclib is primarily metabolized by CYP3A4 enzymes. Co-administration with drugs that are CYP3A inhibitors and inducers may change the plasma concentrations of palbociclib in humans (see Section 6.3.3 for details). The concurrent use of CYP3A inhibitors, including amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in the study. The concurrent use of CYP3A inducers, including carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort, are not allowed in the study (see also Appendix 21.3)
**Hormone replacement therapy**, topical estrogens (including any intra-vaginal preparations), **megestrol acetate** and **selective estrogen-receptor modulators** (eg, raloxifene) are prohibited during the active treatment phase.
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12.5.2 medications not recommended

The following treatments are not recommended throughout the duration of the active treatment phase. Alternative therapies should be considered whenever possible. If usage of the following treatments is deemed necessary, consultation and agreement with GBG is required prior to treatment initiation.  
**Moderate CYP3A Inducers:** The concurrent use of moderate CYP3A inducers such as dexamethasone or modafinil is not recommended.  
**Sensitive CYP3A Substrates:**, As described in Section 6.3.3, palbociclib is a weak timedependent inhibitor of CYP3A and caution should be exercised in patients receiving palbociclib in combination with drugs that are predominantly metabolized by CYP3A and have a narrow therapeutic window. In particular, co-administration of palbociclib with CYP3A4 sensitive substrates with narrow therapeutic index including, but not limited to alfentanil, aripiprazole, cyclosporine, ergotamine, fentanyl, halofantrine, pimozide, quinidine, sirolimus, tacrolimus, triazolam, astemizole*, cisapride*, and terfenadine* (*withdrawn from U.S. market) are not recommended during the active treatment phase of the trial. Alternative therapies should be used when available, but if use cannot be avoided the treating physician should be aware that dose reductions of the coadministered drug may be required.  
**Chronic immunosuppressive therapies** should be avoided, including systemic corticosteroids. Steroids given for physiological replacement, as anti-emetics or inhaled as well as short course of oral/topical steroids given for allergic reactions or asthma flares are allowed.  
**Erythropoietin** for the supportive treatment of anemia. The use of **herbal medicine** is not recommended during the active treatment phase.  
12.5.3 *Permitted Medications* The following treatments are permitted throughout the duration of the active treatment phase:
**Standard therapies** for pre-existing medical conditions, medical and/or surgical complications. Any medication intended solely for supportive care (eg, analgesics, antidiarrheals, antidepressants) may also be used at the investigator's discretion. All medications should be recorded.
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bisphosphonates and receptor activator of

Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis. The need to initiate or increase the dose of these therapies during the study will not be considered as indicative of disease progression leading to the discontinuation of patient from the active treatment phase unless disease progression can be confirmed by adequate imaging methods.  
**Hematopoietic growth factors** (eg, granulocyte colony stimulating factor [G-CSF],
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic use of granulocyte-colony stimulating factors is not permitted but they may be used to treat treatment-emergent neutropenia as indicated by the current American Society of Clinical Oncology (ASCO) guideline.113 If neutropenic complications are observed in a cycle in which primary prophylaxis with CSFs was not received, secondary prophylaxis may be given at the discretion of the investigator, but only if dose reduction or delay are not considered a reasonable alternative.
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12.6 concomitant radiotherapy or surgery

Any **concurrent radiotherapy is prohibited** throughout the duration of the active treatment phase of the study. Adjuvant radiotherapy should be completed before entering the study. Patients requiring radiotherapy during the active treatment phase will be discontinued from the active treatment phase and will enter the follow-up phase. Caution is advised on theoretical grounds for any surgical procedures during the study. The appropriate interval of time between surgery and palbociclib required to minimize the risk of impaired wound healing and bleeding, if any, has not been determined. Based on the available pharmacokinetic data, stopping palbociclib/placebo is recommended at least 7 days prior to elective surgery. Postoperatively, the decision to reinitiate palbociclib/placebo treatment should be based on a clinical assessment of satisfactory wound healing and recovery from surgery.
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12.7 pregnancy and lactation

Palbociclib/placebo as well as endocrine treatment **must not be administered to pregnant** women, or to women who are breastfeeding. Treatment has to be immediately been stopped as soon as a pregnancy is diagnosed. A negative pregnancy test is required prior to study entry. Highly effective non-hormonal contraceptive methods that result in a low failure rate should be applied, i.e. some IUDs , sexual abstinence or vasectomised partner (CPMP/ICH/286/95). The use of hormonal contraceptives is not allowed during the entire duration of the study. Patients should be advised not to get pregnant or breast feed during the first 3 months after the end of endocrine therapy.  
In case a patient becomes pregnant during study treatment, endocrine therapy or 3 months thereafter, this has to be documented within one working day using the SAE reporting form and outcome of the pregnancy has to be reported on a separate form provided by GBG.
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12.8 non-investigational products

12.8.1 *Description, Formulation, and Handling of the non-investigational products* Current treatment guidelines recommend adjuvant endocrine treatment for 5 to 10 years after surgery for patients with hormone-receptor-positive disease. Adjuvant endocrine treatment might have already started before the patient enters the study. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal patients, concurrent LHRH agonist use is allowable. PK-DDI sampling was done for patients receiving Tamoxifen or Gosereline+Tamoxifen or Anastrozole as endocrine treatment. Treatment should be performed according to institutional guidelines. Patients discontinuing endocrine treatment due to treatment-related toxicity should first be switched to another type of endocrine therapy. If again this treatment is not tolerated, the patient will be discontinued from the active treatment phase of the study and enter the follow-up phase. Patients discontinuing palbociclib/placebo treatment due to treatment-related toxicity preferably continue endocrine treatment as per the investigator's discretion. For all other information refer to the package insert (PI) and/or the summary of product characteristics (SmPC).
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12.9 post-study treatment

After completion of palbociclib/placebo patients will continue with endocrine treatment for a total of 5 to 10 years. No other kind of treatment is recommended.