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Statistical Analysis Plan Version 1 I3Y-MC-JPBX Statistical Analysis Plan Version 1 A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy NCT02450539 Approval Date: 09-Jun-2015 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 1 1. Statistical Analysis Plan: I3Y-MC-JPBX: A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy Confidential Information The information contained in this Statistical Analysis Plan is confidential and the information contained within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly and Company or its subsidiaries. This document and its associated attachments or appendices are subject to United States Freedom of Information Act Exemption 4. Abemaciclib (LY2835219) Study JPBX is a multicenter, randomized, open-label, parallel, comparator-controlled, Phase 2 trial in Stage IV squamous non-small cell lung cancer patients who have progressed after platinum-based chemotherapy, evaluating second-line treatment with abemaciclib versus docetaxel. Eli Lilly and Company Indianapolis, Indiana USA 46285 Statistical Analysis Plan electronically signed and approved by Lilly on date provided below. Approval Date: 09-Jun-2015 GMT LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 2 2. Table of Contents Section Page 1. Statistical Analysis Plan: I3Y-MC-JPBX: A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy.......................................................................1 2. Table of Contents................................................................................................................2 3. Revision History .................................................................................................................6 4. Study Objectives .................................................................................................................7 4.1. Primary Objective ..........................................................................................................7 4.2. Secondary Objectives.....................................................................................................7 4.3. Exploratory Objectives...................................................................................................7 5. Study Design.......................................................................................................................8 5.1. Summary of Study Design..............................................................................................8 5.2. Determination of Sample Size ........................................................................................8 6. A Priori Statistical Methods ..............................................................................................10 6.1. General Consideration..................................................................................................10 6.1.1. Populations ..........................................................................................................10 6.1.2. Definitions and Conventions ................................................................................10 6.2. Handling of Dropouts or Missing Data.........................................................................11 6.3. Patient Disposition .......................................................................................................11 6.4. Patient Characteristics ..................................................................................................11 6.4.1. Baseline Demographics and Patient......................................................................11 6.4.2. Historical Illnesses ...............................................................................................11 6.4.3. Prior Therapies.....................................................................................................11 6.4.4. Post Study Treatment Discontinuation Therapies .................................................11 6.5. Treatment Compliance .................................................................................................11 6.6. Concomitant Therapy...................................................................................................12 6.7. Efficacy Analyses ........................................................................................................12 6.7.1. Stratification Factors............................................................................................12 6.7.2. Primary Outcome and Methodology.....................................................................12 6.7.3. Secondary Outcome and Methodology.................................................................13 6.7.4. Sensitivity Analyses.............................................................................................13 6.8. Health Outcomes/Quality-of-Life Analyses..................................................................14 6.9. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................15 6.10. Tailoring Biomarker Analyses......................................................................................15 6.11. Safety Analyses............................................................................................................15 LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 3 6.11.1. Extent of Exposure...............................................................................................15 6.11.2. Adverse Events ....................................................................................................15 6.11.3. Deaths..................................................................................................................16 6.11.4. Clinical Laboratory Evaluation.............................................................................16 6.11.5. Vital Signs and Other Physical Findings...............................................................16 6.11.6. Electrocardiograms ..............................................................................................16 6.11.7. Hospitalizations and Transfusions ........................................................................17 6.12. Subgroup Analysis .......................................................................................................17 6.13. Interim Analysis...........................................................................................................17 6.14. Protocol Violation........................................................................................................17 6.15. Annual Report Analysis ...............................................................................................18 6.16. Clinical Trial Registry Analyses...................................................................................18 7. Unblinding Plan ................................................................................................................19 8. References ........................................................................................................................20 LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 4 Table of Contents Table Page Table JPBX.6.1. Progression-Free Survival Sensitivity Analysis 1 ......................................14 LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 5 Table of Contents Figure Page Figure JPBX.5.1. Illustration of study design..........................................................................8 LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 6 3. Revision History Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit. LY2835219 I3Y-MC-JPBX Statistical Analysis Plan Version 1 Page 7 4. Study Objectives 4.1. Primary Objective The primary objective of this study is to compare treatment with abemaciclib versus docetaxel therapy with respect to investigator-assessed PFS in patients with Stage IV squamous cell carcinoma NSCLC who have relapsed after prior platinum-based therapy for advanced disease. 4.2. Secondary Objectives The secondary objectives of the study are as follows: To evaluate the pharmacokinetic (PK) parameters including abemaciclib and its active metabolites To compare treatment of abemaciclib versus docetaxel with respect to the following: o Overall survival (OS) o Overall response rate (ORR) [complete response (CR) + partial response (PR)] o Disease control rate (DCR) [CR + PR + stable disease (SD)] o Time to worsening of Performance Status (PS) o The safety and tolerability using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.0) o Change from baseline in patient-reported outcomes (PROs), including: 1) the MD Anderson Symptom Inventory Lung Cancer (MDASI-LC) questionnaire pain and disease-related symptoms scores; and 2) the EuroQol Group’s EQ-5D-5L questionnaire index score, derived from the 5-item descriptive system, and visual analog scale (VAS) self-rated health score. 4.3. Exploratory Objectives To explore potential biomarkers related to the cell cycle pathway components, abemaciclib, and/or the pathogenesis of lung cancer, and their
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