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A Phase IB Dose Exploration Trial with MK-8628, a Small Official Protocol Title: A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors NCT number: NCT02698176 Document Date: 21-Nov-2016 Product: MK-8628 1 Protocol/Amendment No.: 006-02 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. SPONSOR: Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp. (hereafter referred to as the Sponsor or Merck) Weystrasse 20 6000 Lucerne Switzerland Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). TITLE: A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors IND NUMBER: 123,715 EudraCT NUMBER: 2015-005488-18 MK-8628-006-02 Final Protocol 21-Nov-2016 Confidential Product: MK-8628 2 Protocol/Amendment No.: 006-02 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 11 1.0 TRIAL SUMMARY.................................................................................................. 13 2.0 TRIAL DESIGN........................................................................................................ 14 2.1 Trial Design ........................................................................................................... 14 2.2 Trial Diagram........................................................................................................ 15 3.0 OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16 3.1 Primary Objective(s) & Hypothesis(es) .............................................................. 16 3.2 Secondary Objective(s) & Hypothesis(es)........................................................... 16 3.3 Other Objectives (Exploratory)........................................................................... 17 4.0 BACKGROUND & RATIONALE.......................................................................... 17 4.1 Background ........................................................................................................... 17 4.1.1 Pharmaceutical and Therapeutic Background .................................................... 17 4.1.1.1 NUT Midline Carcinoma ............................................................................. 18 4.1.1.2 Non-Small Cell Lung Cancer....................................................................... 19 4.1.1.3 Triple-Negative Breast Cancer .................................................................... 20 4.1.1.4 Castration-Resistant Prostate Adenocarcinoma........................................... 21 4.1.2 MK-8628 Metabolism – Cytochrome P450 Interactions.................................... 22 4.1.3 MK-8628 – Ongoing Clinical Trials in Advanced Solid Tumors....................... 22 4.2 Rationale................................................................................................................ 23 4.2.1 Rationale for the Trial and Selected Subject Population .................................... 23 4.2.2 Rationale for Dose Selection/Regimen/Escalation ............................................. 25 4.2.2.1 Starting Dose for This Trial ......................................................................... 26 4.2.2.2 Maximum Dose/Exposure for This Trial ..................................................... 28 4.2.2.3 Rationale for Dose Interval and Trial Design .............................................. 28 4.2.3 Rationale for Endpoints ...................................................................................... 28 4.2.3.1 Safety Endpoints .......................................................................................... 28 4.2.3.1.1 Primary Safety Endpoint:...................................................................... 28 4.2.3.1.2 Secondary Safety Endpoints ................................................................. 28 4.2.3.2 Pharmacokinetic Endpoints ......................................................................... 28 MK-8628-006-02 Final Protocol 21-Nov-2016 Confidential Product: MK-8628 3 Protocol/Amendment No.: 006-02 4.2.3.3 Pharmacodynamic Endpoints....................................................................... 29 4.2.3.4 Efficacy Endpoints....................................................................................... 30 4.2.3.4.1 Secondary Efficacy Endpoints: RECIST or PCWG -based Response Rate....................................................................................... 30 4.2.3.4.2 Exploratory Efficacy Endpoints............................................................ 30 4.2.3.5 Planned Exploratory Biomarker Research................................................... 30 4.2.3.6 Future Biomedical Research ........................................................................ 30 4.3 Benefit/Risk ........................................................................................................... 31 5.0 METHODOLOGY ................................................................................................... 31 5.1 Entry Criteria........................................................................................................ 31 5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 31 5.1.2 Subject Inclusion Criteria.................................................................................... 31 5.1.3 Subject Exclusion Criteria .................................................................................. 33 5.2 Trial Treatment(s) ................................................................................................ 34 5.2.1 Dose Selection/Modification .............................................................................. 35 5.2.1.1 Dose Selection (Preparation) ....................................................................... 35 5.2.1.2 Dose Escalation (Part A).............................................................................. 35 5.2.1.3 NMC Cohort (Part B)................................................................................... 37 5.2.1.4 Dose Limiting Toxicity................................................................................ 37 5.2.1.5 Recommended Phase II Dose ...................................................................... 39 5.2.1.6 Dose Adaptation........................................................................................... 39 5.2.2 Timing of Dose Administration .......................................................................... 41 5.2.2.1 Premedication .............................................................................................. 41 5.2.3 Trial Blinding...................................................................................................... 41 5.3 Randomization or Treatment Allocation............................................................ 42 5.4 Stratification.......................................................................................................... 42 5.5 Concomitant Medications/Vaccinations (Allowed & Prohibited) .................... 42 5.5.1 Medications......................................................................................................... 42 5.6 Rescue Medications & Supportive Care ............................................................. 43 5.6.1 Supportive Care Guidelines ................................................................................ 43 5.6.1.1 General Guidelines for Clinically Significant Toxicities............................. 43 5.6.1.2 Hepatic Laboratory Abnormalities .............................................................. 44 MK-8628-006-02 Final Protocol 21-Nov-2016 Confidential Product: MK-8628 4 Protocol/Amendment No.: 006-02 5.7 Diet/Activity/Other Considerations..................................................................... 44 5.7.1 Diet...................................................................................................................... 44 5.7.2 Potential Phototoxicity........................................................................................ 44 5.7.3 Contraception...................................................................................................... 44 5.7.4 Use in Pregnancy ................................................................................................ 47 5.7.5 Use in Nursing Women....................................................................................... 47 5.8 Subject Withdrawal/Discontinuation Criteria ................................................... 47 5.9 Subject Replacement Strategy............................................................................. 48 5.10 Beginning and End of the Trial ........................................................................... 48 5.11 Clinical Criteria for Early Trial Termination ................................................... 48 6.0 TRIAL FLOW CHART ........................................................................................... 49 7.0 TRIAL PROCEDURES ........................................................................................... 52 7.1 Trial Procedures ..................................................................................................
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