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Protocol/Amendment No.: 252-10 a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK-3475) in Combin

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Protocol/Amendment No.: 252-10 a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK-3475) in Combin Product: MK-3475 (SCH 900475), INCB024360 1 Protocol/Amendment No.: 252-10 (INCB 24360-301-10) / NCT02752074 THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. This study is co-funded by Incyte and MSD. Execution of Trial: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. One Merck Drive P.O. Box 100 Whitehouse Station, New Jersey, 08889-0100, U.S.A. Protocol-specific Contact information can be found in the Investigator Trial File Binder (or equivalent). Global Sponsor of the Study: Incyte Corporation (Referenced herein as Sponsor) 1801 Augustine Cut-Off Wilmington, Delaware, 19803, U.S.A TITLE: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK- 3475) in Combination With Epacadostat or Placebo in Subjects with Unresectable or Metastatic Melanoma (KEYNOTE-252 / ECHO-301) IND NUMBER: 121,704 EudraCT NUMBER: 2015-004991-31 MK-3475-252-10 (INCB 24360-301-10) Final Protocol 18-May-2018 Confidential 04XN7M Product: MK-3475 (SCH 900475), INCB024360 2 Protocol/Amendment No.: 252-10 (INCB 24360-301-10) TABLE OF CONTENTS SUMMARY OF CHANGES.................................................................................................14 1.0 TRIAL SUMMARY...................................................................................................29 2.0 TRIAL DESIGN.........................................................................................................30 2.1 Trial Design ............................................................................................................30 2.2 Trial Diagram.........................................................................................................31 3.0 OBJECTIVE(S) & HYPOTHESIS(ES)...................................................................32 3.1 Primary Objective(s) & Hypothesis(es) ...............................................................32 3.2 Secondary Objective(s) & Hypothesis(es)............................................................32 33 4.0 BACKGROUND & RATIONALE...........................................................................34 4.1 Background ............................................................................................................34 4.1.1 Pharmaceutical and Therapeutic Background .....................................................34 4.1.1.1 Inhibition of PD-1 as a Target for Cancer ....................................................35 4.1.1.2 Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer ............35 4.1.1.3 Combined Immune Checkpoint Inhibition ...................................................37 4.1.1.4 Overview of Metastatic Melanoma...............................................................38 4.1.1.5 Treatment for Advanced or Metastatic Melanoma .......................................39 4.1.2 Pre-clinical and Clinical Trials ............................................................................41 4.1.3 Ongoing Clinical Trials........................................................................................41 4.2 Rationale.................................................................................................................41 4.2.1 Rationale for the Trial and Selected Subject Population .....................................41 4.2.1.1 Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor in Melanoma .....................................................................................................41 MK-3475-252-10 (INCB 24360-301-10) Final Protocol 18-May-2018 Confidential 04XN7M Product: MK-3475 (SCH 900475), INCB024360 3 Protocol/Amendment No.: 252-10 (INCB 24360-301-10) 4.2.2 Rationale for Dose Selection/Regimen/Modification ..........................................42 4.2.2.1 Justification for Treatment Regimen ............................................................42 4.2.2.2 Rationale for a Fixed Dose of Pembrolizumab.............................................43 4.2.3 Rationale for Endpoints .......................................................................................44 4.2.3.1 Efficacy Endpoints........................................................................................44 4.2.3.1.1 Primary Efficacy Endpoints...................................................................44 4.2.3.1.2 Secondary Efficacy Endpoints...............................................................44 45 4.2.3.2 Immune-related RECIST (irRECIST) ..........................................................45 4.2.3.3 Patient Reported Outcomes...........................................................................46 4.2.3.4 Safety Endpoints ...........................................................................................46 4.2.3.5 Pharmacokinetic Endpoints ..........................................................................46 4.2.3.6 Pharmacodynamic Endpoints........................................................................46 46 47 47 47 48 48 49 4.3 Benefit/Risk ............................................................................................................49 4.3.1 Risks from Epacadostat........................................................................................49 4.3.2 Risks from Pembrolizumab..................................................................................51 4.3.3 Risks for the Combination of Pembrolizumab and Epacadostat..........................51 MK-3475-252-10 (INCB 24360-301-10) Final Protocol 18-May-2018 Confidential 04XN7M Product: MK-3475 (SCH 900475), INCB024360 4 Protocol/Amendment No.: 252-10 (INCB 24360-301-10) 5.0 METHODOLOGY ....................................................................................................52 5.1 Entry Criteria.........................................................................................................52 5.1.1 Diagnosis/Condition for Entry into the Trial .......................................................52 5.1.2 Subject Inclusion Criteria.....................................................................................52 5.1.3 Subject Exclusion Criteria ...................................................................................55 5.2 Trial Treatment(s) .................................................................................................58 5.2.1 Dose Selection/Modification ...............................................................................58 5.2.1.1 Dose Selection (Preparation) ........................................................................58 5.2.1.2 Dose Modification (Escalation/Titration/Other)...........................................58 5.2.1.3 Dose Modification and Toxicity Management of Infusion-reactions Related to Pembrolizumab............................................................................63 5.2.1.4 Procedures for Subjects Exhibiting Serotonin Syndrome (SS).....................65 5.2.1.5 Dose Interruptions Unrelated to Adverse Events..........................................66 5.2.2 Timing of Dose Administration ...........................................................................66 5.2.2.1 Timing of Dose Administration of Pembrolizumab .....................................66 5.2.3 Trial Blinding.......................................................................................................67 5.3 Randomization or Treatment Allocation.............................................................67 5.4 Stratification...........................................................................................................67 5.5 Concomitant Medications/Vaccinations (Allowed & Prohibited) .....................68 5.5.1 Acceptable Concomitant Medications .................................................................68 5.5.2 Prohibited Medications and Measures .................................................................68 5.6 Rescue Medications & Supportive Care ..............................................................69 5.6.1 Supportive Care Guidelines for Pembrolizumab .................................................69 5.7 Diet/Activity/Other Considerations......................................................................70 5.7.1 Diet.......................................................................................................................70 MK-3475-252-10 (INCB 24360-301-10) Final Protocol 18-May-2018 Confidential 04XN7M Product: MK-3475 (SCH 900475), INCB024360 5 Protocol/Amendment No.: 252-10 (INCB 24360-301-10) 5.7.2 Contraception.......................................................................................................70 5.7.3 Pregnancy.............................................................................................................72 5.7.4 Use in Nursing Women........................................................................................73 5.8 Subject Withdrawal/Discontinuation Criteria ....................................................73 5.8.1 Discontinuation of Treatment ..............................................................................73 5.8.2 Withdrawal from the Trial ...................................................................................75 5.9 Subject Replacement Strategy..............................................................................75 5.10 Beginning and End of the Trial ............................................................................75
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