Official Protocol Title: Carcinoma (KEYNOTE-240) 21
Official Protocol Title:A Phase III Study of Pembrolizumab (MK-3475) vs. BestSupportive Care as Second-Line Therapy in Subjects withPreviously Systemically Treated Advanced HepatocellularCarcinoma (KEYNOTE-240)NCT number:Document Date:NCT0270240121-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-031THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATINGTO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCKSHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC.,WHITEHOUSE STATION, NJ, U.S.A.SPONSOR:Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.(hereafter referred to as the Sponsor or Merck)One Merck DriveP.O. Box 100Whitehouse Station, New Jersey, 08889-0100, U.S.A.Protocol-specific Sponsor Contact information can be found in the Investigator Trial FileBinder (or equivalent).TITLE:A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-LineTherapy in Subjects with Previously Systemically Treated Advanced HepatocellularCarcinoma (KEYNOTE-240)IND NUMBER: 123,482EudraCT NUMBER: 2015-004567-36MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-032TABLE OF CONTENTSSUMMARY OF CHANGES . 111.0TRIAL SUMMARY. 262.0TRIAL DESIGN. 272.1Trial Design . 272.2Trial Diagram. 293.0OBJECTIVE(S) & HYPOTHESIS(ES). 293.1Primary Objective(s) & Hypothesis(es) . 293.2Secondary Objective(s) & Hypothesis(es). 303.3Exploratory Objectives. 304.0BACKGROUND & RATIONALE. 314.1Background . 314.1.1Pharmaceutical and Therapeutic Background . 314.1.2Pre-clinical and Clinical Trials . 334.1.3Ongoing Clinical Trials. 334.1.4Information on Other Trial-related Therapy . 334.2Rationale . 344.2.1Rationale for the Trial and Selected Subject Population . 344.2.2Rationale for Dose Selection/Regimen . 344.2.3Rationale for the Use of Comparator/Placebo . 354.2.4Rationale for Endpoints . 364.2.4.1Efficacy Endpoints. 364.2.4.1.1Primary Efficacy Endpoint . 364.2.4.1.2Secondary Efficacy Endpoint . 364.2.4.1.3Exploratory Efficacy Endpoint . 364.2.4.2Immune-Related RECIST . 364.2.4.3Patient Reported Outcomes. 374.2.4.4Safety Endpoints . 384.2.4.5Biomarker Research. 394.2.4.6Future Biomedical Research . 40MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-034.35.03Benefit/Risk . 41METHODOLOGY . 41Entry Criteria. 415.15.1.1Diagnosis/Condition for Entry into the Trial . 415.1.2Subject Inclusion Criteria. 415.1.3Subject Exclusion Criteria . 445.2Trial Treatment(s) . 465.2.1Dose Selection/Modification . 475.2.1.1Dose Selection (Preparation) . 475.2.1.2Dose Interval Modification for Non-Hepatic Drug-Related AdverseEvents. 475.2.1.3Guidance for Diagnosis and Management of Hepatic Events of ClinicalInterest (ECIs). 515.2.2Timing of Dose Administration . 565.2.3Trial Blinding. 565.3Randomization . 565.4Stratification. 575.5Concomitant Medications/Vaccinations (Allowed & Prohibited) . 575.5.1Acceptable Concomitant Medications . 575.5.2Prohibited Concomitant Medications. 585.6Rescue Medications & Supportive Care . 595.6.1Rescue Medications . 595.6.2Supportive Care Guidelines . 595.7Diet/Activity/Other Considerations. 625.7.1Diet. 625.7.2Contraception . 625.7.3Use in Pregnancy . 655.7.4Use in Nursing Women. 655.8Subject Withdrawal/Discontinuation Criteria . 655.8.1Discontinuation of Treatment . 655.8.1.1Discontinuation from Study Therapy after Complete Response . 665.8.2Withdrawal from the Trial . 665.8.3Lost to Follow Up . 67MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-0345.9Beginning and End of the Trial . 675.10Clinical Criteria for Early Trial Termination . 676.0TRIAL FLOW CHART . 686.1Initial Treatment with Study Drug . 686.2Second Course Treatment. 747.0TRIAL PROCEDURES . 777.1Trial Procedures . 777.1.1Administrative Procedures . 777.1.1.1Informed Consent. 777.1.1.1.1General Informed Consent. 777.1.1.1.2Consent and Collection of Specimens for Future BiomedicalResearch. 787.1.1.2Inclusion/Exclusion Criteria . 787.1.1.3Subject Identification Card . 787.1.1.4Medical History . 787.1.1.5Disease Details. 787.1.1.6Prior and Concomitant Medications Review . 787.1.1.6.1Prior Medications. 787.1.1.6.1.1 Prior Treatment Details for HCC . 797.1.1.6.2Concomitant Medications . 797.1.1.7Subsequent Anti-Cancer Status. 797.1.1.8Assignment of Screening Number . 797.1.1.9Assignment of Treatment/Randomization Number . 797.1.1.10 Trial Compliance (Medication/Diet/Activity/Other) . 807.1.2 Clinical Procedures/Assessments. 807.1.2.1Adverse Event Monitoring. 807.1.2.2Physical Exam. 807.1.2.2.1Full Physical Exam . 807.1.2.2.2Directed Physical Exam . 807.1.2.3Height, Weight, and Vital Signs . 817.1.2.412-Lead Electrocardiogram . 817.1.2.5Eastern Cooperative Oncology Group Performance Status. 81MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-0357.1.2.6Child-Pugh Score . 817.1.2.7Patient Reported Outcomes (PROs). 817.1.3Laboratory Procedures/Assessments . 827.1.3.1Laboratory Safety Evaluations (Hematology, Chemistry, andUrinalysis). 827.1.3.2Pregnancy Tests . 837.1.3.3Central Laboratory Assessments. 837.1.3.4Pharmacokinetic (PK) /Pharmacodynamic Evaluations . 837.1.3.4.1Blood Collection for PK . 837.1.3.4.2Blood Collection for Anti-pembrolizumab Antibodies . 837.1.3.5Blood Samples for RNA Analysis, and Biomarker Studies . 847.1.3.6Tumor Tissue . 847.1.3.7Planned Genetic Analysis Sample Collection. 847.1.3.8Future Biomedical Research Sample Collection . 847.1.4 Efficacy Measurements. 857.1.4.17.1.5Tumor Imaging and Assessment of Disease . 857.1.4.1.1Initial Tumor Imaging. 857.1.4.1.2Tumor Imaging During the Trial . 857.1.4.1.3End of Treatment and Follow-up Tumor Imaging. 867.1.4.1.4Second Course (Retreatment) Tumor Imaging . 867.1.4.1.5RECIST 1.1 Assessment of Disease . 877.1.4.1.6Modified RECIST (mRECIST) Assessment of Disease. 877.1.4.1.7irRECIST Assessment of Disease. 88Other Procedures. 917.1.5.1Withdrawal/Discontinuation . 917.1.5.1.1Withdrawal From Future Biomedical Research . 927.1.5.2Blinding/Unblinding . 927.1.5.3Calibration of Equipment. 937.1.6Visit Requirements. 937.1.6.1Screening. 937.1.6.2Treatment Period. 947.1.6.3Post-Treatment Visits. 957.1.6.3.1Safety Follow-up Visits . 95MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-037.1.6.3.2Follow-up Visits . 957.1.6.3.3Survival Follow-up . 967.1.6.47.26Survival Status . 96Assessing and Recording Adverse Events . 967.2.1Definition of an Overdose for This Protocol and Reporting of Overdose tothe Sponsor. 977.2.2Reporting of Pregnancy and Lactation to the Sponsor . 977.2.3Immediate Reporting of Adverse Events to the Sponsor . 987.2.3.1Serious Adverse Events . 987.2.3.2Events of Clinical Interest. 997.2.3.3Protocol-Specific Exceptions to Serious Adverse Event Reporting . 1007.2.4Evaluating Adverse Events . 1007.2.5Sponsor Responsibility for Reporting Adverse Events . 1037.3Trial Governance and Oversight. 1037.3.1Scientific Advisory Committee. 1037.3.2Executive Oversight Committee . 1037.3.3Data Monitoring Committee . 1038.0STATISTICAL ANALYSIS PLAN . 1048.1Statistical Analysis Plan Summary . 1048.2Responsibility for Analyses/In-House Blinding . 1068.3Hypotheses/Estimation . 1068.4Analysis Endpoints . 1078.4.1Efficacy Endpoints . 1078.4.1.1Primary. 1078.4.1.2Secondary. 1078.4.28.5Safety Endpoints . 107Analysis Populations. 1078.5.1Efficacy Analysis Populations . 1078.5.2Safety Analysis Populations . 1088.6Statistical Methods. 1088.6.1Statistical Methods for Efficacy Analyses . 1088.6.1.1Progression-free Survival. 108MK-3475-240-03 Final Protocol04TC56Confidential21-Dec-2017
Product: MK-3475Protocol/Amendment No.: 240-0378.6.1.2Overall Survival . 1108.6.1.3Objective Response Rate . 1118.6.1.4Disease Control Rate. 1118.6.1.5Time to Progression . 1118.6.1.6Duration of Response. 1128.6.2Statistical Methods for Safety Analyses . 1138.6.3Summaries of Demographic and Baseline Characteristics . 1158.7Interim Analyses . 1158.7.1Efficacy Interim Analyses.
Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-240) Product: MK3475 - 1 Protocol/Amendment No.: 240-03 MK-3475-240-03 FinalProtocol 21-Dec-2017 Confidential THIS PROTOCOL AMENDMENTAND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK
17 Sebaceous carcinoma. 18 Lipid-rich carcinoma. 19 Glycogen-rich clear cell carcinoma. 20 Acinic cell carcinoma. Special h. istological types of breast carcinoma Tubular carcinoma. Mucinous carcinoma. M. etaplastic carcinoma. Invasive lobular carcinoma. Strict diagnostic criteria must be used to.
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tumors, squamous cell carcinoma, granulomatous tumors [6], sebaceous gland carcinoma, Merkel cell carcinoma, and metastatic adenocarcinoma. In order to differentiate PCMC from metastasis of mucinous carcinoma, a thorough clinical and imaging assessment must be completed; however, some features that may suggest a primary cutaneous origin include
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Department of Pathology & Laboratory Medicine University of Pennsylvania, Perelman School of Medicine . Specify if Hurthle cell (oncocytic) type e. Suspicious for Malignancy i. Suspicious for papillary carcinoma . Squamous cell carcinoma vi. Carcinoma with mixed features (specify) vii. Metastatic carcinoma viii. Non-Hodgkin lymphoma
such as adenocarcinoma (1 case) or hepatoid carcinoma (5 cases) coexisted with the neuroendocrine neoplasm in all these 7 cases except the present case. In our case, there were no histopathological features and patterns of immunoreactiv-ity typically usually seen in carcinoma arising from pancreatic ducts, acinar cell, or hepatoid carcinoma.
In Abrasive Jet Machining (AJM), abrasive particles are made to impinge on the work material at a high velocity. The jet of abrasive particles is carried by carrier gas or air. The high velocity stream of abrasive is generated by converting the pressure energy of the carrier gas or air to its kinetic energy and hence high velocity jet. The nozzle directs the abrasive jet in a controlled manner .
