Investigational Product (KPT-330) Karyopharm Therapeutics Inc. Clinical Study Protocol: KCP-330-023 17 August 2018 CLINICAL STUDY PROTOCOL KCP-330-023 A PHASE 3 RANDOMIZED, CONTROLLED, OPEN-LABEL STUDY OF SELINEXOR, BORTEZOMIB, AND DEXAMETHASONE (SVD) VERSUS BORTEZOMIB AND DEXAMETHASONE (VD) IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) Study Name: BOSTON: Bortezomib, Selinexor, and Dexamethasone in Patients with Multiple Myeloma Study Number: KCP-330-023 Study Phase: 3 Investigational Product: Selinexor (KPT-330) EudraCT Number: 2016-003957-14 Indication: Relapsed or refractory multiple myeloma (RRMM) Sponsor: Karyopharm Therapeutics Inc. 85 Wells Avenue Newton, MA 02459 USA Tel. + (617) 658-0600 Protocol Date and Version: 18 November 2016, Version 1.0 22 February 2017, Version 2.0 (Amendment 1) 06 April 2017, Version 3.0 (Amendment 2) 17 August 2018, Version 4.0 (Amendment 3) CONDUCT In accordance with the ethical principles that originate from the Declaration of Helsinki and that are consistent with International Council for Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. CONFIDENTIAL INFORMATION This document is the sole property of Karyopharm Therapeutics Inc. (Karyopharm). This document and any and all information contained herein has to be considered and treated as strictly confidential. This document shall be used only for the purpose of the disclosure herein provided. No disclosure or publication shall be made without the prior written consent of Karyopharm. 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Clinical Study Protocol: KCP-330-023 17 August 2018 INVESTIGATOR’S AGREEMENT I have read and understand the contents of this clinical protocol for Study KCP-330-023 dated 17 August 2018 and will adhere to the study requirements as presented, including all statements regarding confidentiality. In addition, I will conduct the Study in accordance with current Good Clinical Practice, ICH E6, and applicable FDA regulatory requirements. Printed Name of Investigator Signature of Investigator Institution Date Confidential Page 3 Version 4.0 Investigational Product (KPT-330) Karyopharm Therapeutics Inc. Clinical Study Protocol: KCP-330-023 17 August 2018 TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................12 2. PROTOCOL SYNOPSIS ...........................................................................................17 3. STUDY SCHEMATICS AND SCHEDULE OF ASSESSMENTS AND DOSING FOR STUDY KCP-330-023 .......................................................................22 3.1. Schedules of Visits for In-clinic Dosing and MM Evaluations ..................................29 3.2. Dose Schedules ...........................................................................................................31 4. INTRODUCTION ......................................................................................................35 4.1. Multiple Myeloma ......................................................................................................35 4.1.1. Disease Background ...................................................................................................35 4.1.2. MM Treatment ............................................................................................................35 4.2. Selinexor .....................................................................................................................35 4.2.1. Selinexor Mechanism of Action .................................................................................35 4.2.2. Selinexor Pharmacodynamics and Dosing Frequency ...............................................36 4.2.3. Selinexor Pharmacokinetics ........................................................................................36 4.2.4. Selinexor Metabolism/Drug-drug Interactions ...........................................................37 4.2.5. Selinexor Nonclinical Combination with Dexamethasone and Proteasome Inhibitors .....................................................................................................................37 4.2.6. Overall Clinical Experience with Selinexor ...............................................................38 4.2.6.1. Study KCP-330-017 (STOMP) ...................................................................................39 4.2.7. Potential Risks of Selinexor ........................................................................................40 4.2.7.1. Reproductive Risks for Selinexor ...............................................................................41 4.3. Bortezomib and Dexamethasone (Vd) ........................................................................41 4.4. Study and Dose Rationale ...........................................................................................41 4.4.1. Study Rationale ...........................................................................................................41 4.4.2. Dose Rationale ............................................................................................................42 4.4.2.1. Bortezomib QW Dose Rationale ................................................................................43 5. STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 5.1. Objectives ...................................................................................................................44 5.1.1. Primary Objective .......................................................................................................44 5.1.2. Secondary Objectives .................................................................................................44 5.1.3. Exploratory Objectives ...............................................................................................44 5.1.4. Pharmacokinetic Objective .........................................................................................45 Confidential Page 4 Version 4.0 Investigational Product (KPT-330) Karyopharm Therapeutics Inc. Clinical Study Protocol: KCP-330-023 17 August 2018 5.2. Endpoints ....................................................................................................................45 5.2.1. Primary Endpoint ........................................................................................................45 5.2.2. Secondary Efficacy Endpoints ....................................................................................45 5.2.2.1. Key Secondary Efficacy Endpoints ............................................................................45 5.2.2.2. Non-Key Secondary Efficacy Endpoints ....................................................................45 5.2.3. Secondary Safety Endpoints .......................................................................................46 5.2.3.1. Key Secondary Safety Endpoint .................................................................................46 5.2.3.2. Non-Key Secondary Safety Endpoints .......................................................................46 5.2.4. Secondary HR-QoL Endpoint .....................................................................................46 5.2.5. Exploratory Endpoints ................................................................................................46 5.2.6. PK Endpoints ..............................................................................................................46 6. INVESTIGATIONAL PLAN .....................................................................................47 6.1. Overall Study Design and Plan ...................................................................................47 6.2. Crossover ....................................................................................................................49 6.3. Data Safety Monitoring Board ....................................................................................50 6.4. Independent Review Committee .................................................................................50 7. STUDY POPULATION SELECTION ......................................................................51 7.1. Study Population .........................................................................................................51 7.2. Inclusion Criteria ........................................................................................................51 7.3. Exclusion Criteria .......................................................................................................52 8. REGISTRATION AND RANDOMIZATION ...........................................................55 8.1. Screening and Registration .........................................................................................55