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Study Protocol and Statistical Analysis Plan 7487 FRED HUTCHINSON CANCER RESEARCH CENTER UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE Previous version: 05/05/2015 Current version: 03/02/2016 Title of Protocol: The Effect of Antiangiogenic Therapy with Pazopanib Prior to Preoperative Chemotherapy for Subjects with Extremity Soft Tissue Sarcomas: A Randomized Study to Evaluate Response by Imaging Investigator List: Principal Investigator Professional Title Phone Number Darin Davidson, MD Assistant Professor of Orthopedics and Sports Medicine, (206) 543-3690 University of Washington Co-Principal Investigator Robin Jones, MD Affiliate Professor of Medicine, University of Washington (206) 288-7439 Affiliate Member, Fred Hutchinson Cancer Research Center Eve Rodler, MD Affiliate Assistant Professor of Medicine, University of (206)-288-7438 Washington Affiliate Assistant Member, Fred Hutchinson Cancer Co-Investigators Research Center Andrew Shields, MD Clinical Assistant Professor, University of Washington Elizabeth Loggers, Assistant Professor of Medicine, University of Washington (206) 288-6975 MD, PhD Assistant Member, Fred Hutchinson Cancer Research Center Lee Cranmer, MD, Associate Professor, University of Washington (206) 288-7439 PhD Associate Member, Fred Hutchinson Cancer Research Center Gabrielle Kane, MD Associate Professor, Radiation Oncology, University of (206)-598-7362 Washington Rosa Yeh, Pharm. D. Director, Pharmacokinetics Lab SCCA Affiliate Investigator, FHCRC (206)288-7396 Seth Pollack, M.D. Assistant Professor, University of Washington Assistant Member, Fred Hutchinson Cancer Research Center (206)-667-6629 Biostatistician: Brenda F. Kurland Associate Member, Fred Hutchinson Cancer Research Center (206)-667-2804 Research Staff: Phase I Program (206) 288-7551 Emergency Contact: Operator at UWMC (206) 598-6190 Version 8.0 02Mar2016 Page 1 of 71 7487 Table of Contents 1.0 INTRODUCTION .............................................................................................................................. 4 2.0 BACKGROUND ............................................................................................................................... 4 2.1 Soft Tissue Sarcoma Adjuvant and Neoadjuvant Chemotherapy ........................................... 4 2.2 Antiangiogenic Therapy in Sarcoma ....................................................................................... 6 2.3 Pazopanib in Sarcoma ............................................................................................................. 6 2.4 Study Agent – Pazopanib ........................................................................................................ 7 2.5 Dose Rationale ....................................................................................................................... 11 2.6 Chemotherapy ........................................................................................................................ 11 2.7 Imaging Studies to Determine Early Response to Therapy in Soft Tissue Sarcoma ............ 11 2.8 Risks/Benefits ........................................................................................................................ 12 3.0 STUDY OBJECTIVES ..................................................................................................................... 12 3.1 Primary Objectives ................................................................................................................ 12 3.2 Secondary Objectives ............................................................................................................ 13 4.0 STUDY DESIGN .............................................................................................................................. 13 4.1 Description of Study .............................................................................................................. 13 4.2 Endpoints ............................................................................................................................... 13 4.3 Study Procedures ................................................................................................................... 13 5.0 SUBJECT SELECTION ................................................................................................................... 16 5.1 Inclusion Criteria ................................................................................................................... 16 5.2 Exclusion Criteria .................................................................................................................. 17 6.0 SUBJECT REGISTRATION ............................................................................................................ 20 7.0 TREATMENT PLAN ....................................................................................................................... 20 7.1 Agent Administration ............................................................................................................ 21 7.2 Radiation Therapy ................................................................................................................. 25 7.3 Surgery .................................................................................................................................. 26 7.4 Concomitant Medication and Supportive Care Guidelines ................................................... 26 7.5 Duration of Therapy ..............................................................................................................28 7.6 Duration of Follow Up .......................................................................................................... 28 7.7 Dosing Delays/Dose Modifications ...................................................................................... 29 7.8 Criteria for Evaluability and Removal/Withdrawal from Study ........................................... 33 8.0 GUIDELINES FOR ADVERSE EVENT REPORTING ................................................................. 34 8.1 Adverse Event Reporting/Institutional Policy ....................................................................... 34 8.2 Study-Specific Adverse Event Capture ................................................................................. 37 9.0 DATA AND SAFETY MONITORING PLAN .............................................................................. 37 9.1 Data Monitoring ……………………………………………………………………………..37 9.2 Safety Monitoring …………………………………………………………………………...38 9.3 Auditing ……………………………………………………………………………………..38 Version 8.0 02Mar2016 Page 2 of 71 7487 9.4 Quality Assurance Review …………………………………………………………………..38 10.0 STUDY AGENT INFORMATION .................................................................................................38 10.1 Pazopanib ................................................................................................................ ………..38 10.2 Ifosfamide .............................................................................................................................. 43 10.3 Doxorubicin ........................................................................................................................... 44 10.4 Mesna .............................................................................................................................. 47 10.5 Pegfilgrastim.......................................................................................................................... 48 11.0 ASSESSMENT OF EFFICACY .....................................................................................................49 11.1 Pharmacodynamic Studies .....................................................................................................49 11.2 Pharmacokinetic Studies........................................................................................................ 50 11.3 Efficacy Variables ................................................................................................................. 51 11.4 Determining Response to Pazopanib for Continuation on Maintenance ...............................53 12.0 DATA MANAGEMENT/CONFIDENTIALITY ........................................................................... 53 13.0 CORRELATIVE STUDIES ............................................................................................................ 54 14.0 STATISTICAL CONSIDERATIONS .............................................................................................54 14.1 Analysis Plan .......................................................................................................................... 54 14.2 Sample Size Justification ........................................................................................................ 55 14.3 Protocol Enrollment and Special Considerations .................................................................... 55 15.0 RECORDS 15.1 Source Documentation ..............................................................................................................56 15.2 Access........................................................................................................................................56 16.0 TERMINATION OF STUDY ......................................................................................................... 57 REFERENCES ........................................................................................................................................ 57 APPENDICES APPENDIX A: Study Activities and Treatment Calendar APPENDIX
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