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Study Protocol and Statistical Analysis Plan Confidential Clinical study protocol number: J1228 Page 1 Version Date: May 7, 2018 IRB study Number: NA_00067315 A Trial of maintenance Rituximab with mTor inhibition after High-dose Consolidative Therapy in CD20+, B-cell Lymphomas, Gray Zone Lymphoma, and Hodgkin’s Lymphoma Principal Investigator: Douglas E. Gladstone, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 1650 Orleans Street, CRBI-287 Baltimore, MD 21287 Phone: 410-955-8781 Fax: 410-614-1005 Email: [email protected] IRB Protocol Number: NA_00067315 Study Number: J1228 IND Number: EXEMPT Novartis Protocol Number: CRAD001NUS157T Version: May 7, 2018 Co-Investigators: Jonathan Powell 1650 Orleans Street, CRBI-443 Phone: 410-502-7887 Fax: 443-287-4653 Email: [email protected] Richard Jones 1650 Orleans Street, CRBI-244 Phone: 410-955-2006 Fax: 410-614-7279 Email: [email protected] Confidential Clinical study protocol number: J1228 Page 2 Version Date: May 7, 2018 IRB study Number: NA_00067315 Satish Shanbhag Johns Hopkins Bayview Medical Center 301 Building, Suite 4500 4940 Eastern Ave Phone: 410-550-4061 Fax: 410-550-5445 Email: [email protected] Statisticians: Gary Rosner Phone: 410-955-4884 Email: [email protected] Marianna Zahurak Phone: 410-955-4219 Email: [email protected] Confidential Clinical study protocol number: J1228 Page 3 Version Date: May 7, 2018 IRB study Number: NA_00067315 Table of contents Table of contents ......................................................................................................................... 3 List of abbreviations ................................................................................................................... 5 Schema ........................................................................................................................................ 7 1 Introduction ................................................................................................................... 8 1.1 Everolimus ...................................................................................................................... 8 1.1.1.....mTOR pathway and mechanism of action ......................................................... 8 1.1.2….Preclinical studies ............................................................................................ 12 1.1.3….Clinical experience with Everolimus ............................................................... 15 1.2 Hopkins Experience of High-dose consolidative therapy for low grade B cell and Hodgkin's lymphoma .................................................................................................... 16 2 PrimaryStudy Objective ............................................................................................. 17 2.1 Secondary Objectives .................................................................................................... 17 3 Investigational plan ..................................................................................................... 18 3.1 Overall study design ..................................................................................................... 18 3.2 Study population ........................................................................................................... 18 3.2.1....Patient population ............................................................................................. 19 3.2.2....Inclusion and exclusion criteria ........................................................................ 19 3.2.3....Study Interruption or Study Withdrawal ........................................................... 20 3.2.4....Monitoring of everolimus suspected toxicities ................................................. 20 3.2.5....Known Undesirable Side Effects of everolimus ............................................... 20 3.3 Treatments..................................................................................................................... 22 3.3.1....Everolimus Administration ............................................................................... 22 3.3.2....Concomitant therapy ......................................................................................... 23 3.3.3....Treatment compliance ....................................................................................... 23 3.4 Visit schedule and assessments ..................................................................................... 24 3.4.1....Visit schedule: Examination and Laboratory Evaluations ............................... 24 3.4.2...Study Calendar...................................................................................................24 3.4.3...Efficacy assessments .......................................................................................... 28 3.4.4....Safety assessments ............................................................................................ 29 3.4.4.1....Adverse Events .................................................................................. 29 3.4.4.2....Serious Adverse Events ..................................................................... 30 3.4.5....Novartis instructions for rapid notification of serious adverse events .............. 32 3.4.6....Pregnancy Risks for Everolimus ....................................................................... 32 4 Protocol amendments, or changes in study conduct ................................................ 33 Confidential Clinical study protocol number: J1228 Page 4 Version Date: May 7, 2018 IRB study Number: NA_00067315 5 Data management ....................................................................................................... 33 5.1 Data collection .............................................................................................................. 33 5.2 Data Safety and Monitoring Plan .................................................................................. 33 6 Statistical Considerations ........................................................................................... 34 7 References .................................................................................................................... 38 Addendum 1: Inhibitors of CYP3A4 and/or PgP ..................................................................... 41 Addendum 2: Inducers of CYP3A4 and/or PgP ....................................................................... 42 Addendum 3: Clinically relevant drug interactions .................................................................. 43 Addendum 4: Dose Modifications ........................................................................................... 46 Addendum 5: Management of stomatitis .................................................................................. 47 Addendum 6: Management of hyperlipidemia and hyperglycemia .......................................... 48 Addendum 7: Management of non-infectious pneumonitis ...................................................... 49 Addendum 8: Action to be taken for positive baseline hepatitis B results............................. .. 50 Addendum 9: Guidelines for management of hepatitis B...................................................... ... 51 Confidential Clinical study protocol number: J1228 Page 5 Version Date: May 7, 2018 IRB study Number: NA_00067315 List of abbreviations 4E-BP1 4E-binding protein Ab Antibodies ADR Adverse Drug Reaction AE adverse event ALT/SGPT 1 alanine aminotransferase/glutamic pyruvic transaminase/Serum glutamic-pyruvic transaminase AST/SGOT aspartate aminotransferase/glutamic oxaloacetic transaminase/Serum glutamic-oxaloacetic transaminase ATC Anatomical Therapeutic Chemical classification system AUC Area under the plasma-concentration time curve BAC Bronchoalveolar carcinoma Cmax Maximum plasma concentration CR Clinical research CRF Case report/Record form CRO Contract Research Organization CT Computer tomography CTC Common toxicity criteria CV Coefficient of Variation CYP3A4 CytochromeP450 3A4 isoenzyme DNA Deoxyribonucleic Acid DLT Dose limiting toxicity ECG Electrocardiogram EGF Epidermal growth factor EGFR Epidermal growth factor receptor eIF-4E Eucariotic Initiation Factor 4E EPR Early progression rate FDG-PET Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission Tomography FKBP-12 FK506-binding protein 12 GF Growth factor HBV hepatitis B virus HBcAb hepatitis B core antibodies HBs Ab hepatitis B surface antibodies HbsAg hepatitis B surface antigen HCV hepatitis C virus INR International Normalized Ratio Confidential Clinical study protocol number: J1228 Page 6 Version Date: May 7, 2018 IRB study Number: NA_00067315 LDL Low-density lypoproteins LFTs liver function tests LLOQ Lower limit of quantification MAPK Mitogen Activated Protein Kinase mRNA messenger Ribonucleic acid mTOR mammalian Target of Rapamycin NIH/NCI National Institutes of Health/National Cancer Institute nM nano-molar NSCLC Non-small cell lung cancer OS overall survival P-AKT phosphor-AKT PCR Polymerase Chain Reaction PD Pharmacodynamics PET Proton emission tomography PFS progression free survival P-gp P-glycoprotein PI3K Phosphoinositide 3-kinase PK Pharmacokinetics PK/PD Pharmacokinetic/pharmacodynamic PT/PTT prothrombin time PTEN Phosphatase and Tensin homolog deleted on chromosome 10 QOD Every other day RBC red blood cell count REB Research Ethics Board RNA Ribonucleic acid RR response rate S6K1 S6 kinase 1 SAE serious adverse event SCLC Small cell lung cancer STAT3 Signal Transducer and Activator of Transcription 3 TK Tyrosine
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