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Confidential CONFIDENTIAL PROTOCOL TITLE: Combination immunotherapy with Herceptin and the HER2 vaccine E75 in low and intermediate HER2- expressing breast cancer patients to prevent recurrence STUDY DRUGS: HERCEPTIN® (Trastuzumab) E75 peptide (KIFGSLAFL, HER2/neu, 369-377) GM-CSF (Leukine®, Berlex) SPONSORS: Genentech, Inc. Galena Biopharma, Inc. IND NUMBER: BB-IND#14919 IND SPONSOR/INVESTIGATOR George E. Peoples, MD, FACS PROGRAM DIRECTOR: Cancer Insight, LLC 110 E. Houston Street, Floor 7 San Antonio, TX 78205 210-557-4291 [email protected] MEDICAL MONITOR: Cancer Insight, LLC PROTOCOL VERSION/DATE: 3.1/ 05 March 2017 SPONSOR STUDY NUMBER: ML25749 CONFIDENTIAL Page 2 of 102 TABLE OF CONTENTS Page 1. INTRODUCTION ............................................................................................ 5 1.1 Disease Background ........................................................................... 5 1.2 HER2 and Breast Cancer .................................................................... 6 1.3 Herceptin Clinical Experience ............................................................. 7 1.4 Safety .................................................................................................. 8 1.5 Clinical Pharmacokinetics of Trastuzumab ......................................... 9 1.6 E75 Background .................................................................................. 10 1.7 HER2-Directed Therapies in HER2 Low-Expressing Tumors ............. 12 1.8 Combined HER2-Directed Therapy ..................................................... 13 2. OBJECTIVES .................................................................................................. 14 2.1 Primary Objectives .............................................................................. 14 2.2 Secondary Objectives ......................................................................... 14 3. STUDY DESIGN ............................................................................................. 15 3.1 Description of the Study ...................................................................... 15 3.2 Rationale for Study Design .................................................................. 16 3.3 Outcome Measures ............................................................................. 16 3.3.1 Primary Outcome Measure .................................................. 16 3.3.2 Secondary Outcome Measures ............................................ 17 3.3.3 Ancillary Safety Outcome Measures .................................... 17 3.4 Safety Plan .......................................................................................... 17 3.4.1 Cardiac Dysfunction ............................................................. 17 3.4.2 Management of Cardiac Safety ............................................ 18 3.4.2.1 Adjuvant Breast Cancer Protocols ...................... 18 3.5 Dose Reductions of Vaccine Component ............................................ 21 3.6 Compliance with Laws and Regulations ............................................. 21 4. MATERIALS AND METHODS ........................................................................ 22 4.1 Subjects .............................................................................................. 22 4.1.1 Subject Selection .................................................................. 22 4.1.2 Inclusion Criteria ................................................................... 23 4.1.3 Exclusion Criteria ................................................................. 23 4.2 Method of Treatment Assignment ....................................................... 24 4.3 Study Treatment .................................................................................. 24 4.3.1 Herceptin Formulation .......................................................... 25 4.3.2 Herceptin Dosage, Preparation, Administration, and Storage 25 4.3.3 Herceptin Dosage Modification ............................................. 27 4.3.4 Herceptin Overdosage ......................................................... 27 4.3.5 Vaccine ................................................................................. 27 4.3.6 Inoculation Series - Administration ....................................... 29 4.3.7 Booster Inoculations ............................................................. 29 4.4 Study Assessments ............................................................................ 29 4.4.1 Assessments during Treatment ............................................ 30 4.4.2 Follow-Up Assessments ....................................................... 31 4.4.3 Human Biological Specimens ............................................... 31 4.4.4 Specimen Processing ........................................................... 32 4.4.5 HLA-A2/A3/A24/A26 Testing ................................................ 33 4.4.6 Dimer Assay ......................................................................... 33 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 CONFIDENTIAL Page 3 of 102 4.4.7 ELISPOT Assay ................................................................... 33 4.4.8 Local Reaction ...................................................................... 33 4.4.9 DTH Reaction ....................................................................... 34 4.5 Discontinuation of Protocol-Specified Therapy ................................... 34 4.6 Subject Discontinuation ....................................................................... 35 4.7 Study Discontinuation ......................................................................... 36 4.8 Statistical Methods .............................................................................. 36 4.8.1 Analysis of the Conduct of the Study .................................... 36 4.8.2 Analysis of Treatment Group Comparability ......................... 37 4.8.3 Efficacy Analysis .................................................................. 37 4.8.4 Safety Analysis ..................................................................... 39 4.8.5 Planned Analyses ................................................................. 40 4.8.6 Missing Data ......................................................................... 41 4.8.7 Determination of Sample Size ……………………………….. 41 4.9 Data Quality Assurance ...................................................................... 42 5. REPORTING OF ADVERSE EVENTS ........................................................... 42 5.1 Adverse Event and Reporting Definitions ........................................... 42 5.2 Reporting of Serious Adverse Events Associated with this Study ....... 43 5.2.1 MedWatch 3500A Reporting Guidelines .............................. 44 5.3 Reporting Requirements for IND Holders ............................................ 45 6. INVESTIGATOR REQUIREMENTS ............................................................... 46 6.1 Study Initiation ..................................................................................... 46 6.2 Study Completion ................................................................................ 46 6.3 Informed Consent ................................................................................ 46 6.4 Institutional Review Board or Ethics Committee Approval .................. 46 6.5 Study Monitoring Requirements .......................................................... 48 6.6 Data Collection .................................................................................... 48 6.7 Study Medication Accountability ......................................................... 49 6.8 Disclosure of Data ............................................................................... 49 6.9 Retention of Records .......................................................................... 49 6.10 Publications ......................................................................................... 49 6.11 Changes to the Protocol ...................................................................... 50 REFERENCES ........................................................................................................ 51 TABLES Table 1: Herceptin Infusion Time and Post-Infusion Observation Period ......... 26 TRIAL APPENDICES Appendix A: Herceptin and Vaccination Timeline Appendix B: NCI Common Terminology Criteria for Adverse Events, v4.03 Appendix C.1: Study Flowchart Appendix C.2: Patient Visit Chart Appendix D: HFSA Guidelines for CHF Treatment Appendix E: NCCN Guidelines for Adjuvant Breast Cancer Treatment Appendix F: Study Randomization and Stratification Schema Appendix G: E75 + GM-CSF and DTH Formulation Plan Appendix H: Leukine Package Insert Appendix I: Performance Status Criteria Appendix J: Case Report Forms (Free standing electronic documents) Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 CONFIDENTIAL Page 4 of 102 Appendix K: Data Safety Monitoring Plan (Free standing document) Appendix L: Adverse Event Reporting Algorithm Appendix M: FDA Medwatch 3500A Form Link Appendix N: Genentech Drug Safety – Reporting instructions for IND Sponsor Appendix O: PI Agreement and Signature Page Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 CONFIDENTIAL Page 5 of 102 1. INTRODUCTION 1.1 DISEASE BACKGROUND Breast cancer is, by far, the most commonly diagnosed malignancy in women (excluding cancers of the skin), and it is the second leading cause of cancer mortality among women. The American
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