PROTOCOL UMCC 2016.013 Pilot Study of Pazopanib with Low Fat Meal (PALM) in advanced renal cell carcinoma Principal Investigator: Ajjai Alva, MD University of Michigan 7316 Cancer Center 1500 E. Medical Center Drive Ann Arbor, MI 48109 Phone: (734) 936-0091 Fax: (734) 615-2719 Email: [email protected] Sub-Investigator(s): Maryann Shango, MD Hematology/Oncology University of Michigan Bruce Redman, DO Hematology/Oncology University of Michigan Sarah Yentz, MD Hematology/Oncology University of Michigan Shawna Kraft, Pharmacist Pharmacy University of Michigan Research Staff: Danielle Karsies, MS, RD, CSO Lead Dietitian Senior C435 Med Inn Building, Box 5843 Phone: (734) 232-1643 Research Staff: Bo Wen, Manager Pharmacokinetics Core, College of Pharmacy University of Michigan Room 3400 of Building 520, North Campus Research Complex 1600 Huron Parkway Ann Arbor, MI 48109. Phone: (734) 615-3470 Biostatistician: Stephanie Daignault, MS Statistician Senior Center for Cancer Biostatistics M2180 SPH II, University of Michigan Ann Arbor MI 48109-2029 Phone: (734) 647-3271 Email: [email protected] Study Drug: Pazopanib, sold under the brand name Votrient i. Protocol UMCC 2016.013 Initial version: 7/16/15 Amendment One version: 6/10/16 Amendment Two version 8/16/16 Amendment Three version 10/3/16 IND: Exempt Funding Support: CTRAC Drug Supply: Commercially Available Page ii of v Protocol UMCC 2016.013 TABLE OF CONTENTS ABBREVIATIONS ........................................................................................................................... 1 STUDY SYNOPSIS .......................................................................................................................... 3 1.0 BACKGROUND AND RATIONALE ...................................................................................... 5 1.1 Disease Background........................................................................................................ 5 1.2 Rationale .......................................................................................................................... 6 1.3 Schema ............................................................................................................................ 7 2.0 STUDY OBJECTIVES ........................................................................................................... 8 2.1 Primary Objectives ........................................................................................................... 8 2.2 Secondary Objectives ...................................................................................................... 8 2.4 Endpoints ......................................................................................................................... 8 3.0 PATIENT ELIGIBILITY .......................................................................................................... 8 3.1 Inclusion Criteria .............................................................................................................. 8 3.2 Exclusion Criteria ............................................................................................................. 9 4.0 SUBJECT SCREENING AND REGISTRATION PROCEDURES ........................................ 9 5.0 TREATMENT PLAN ............................................................................................................ 10 5.1 Treatment Dosage and Administration .......................................................................... 10 5.2 Toxicities and Dosing Delays/Dose Modifications ......................................................... 10 5.3 Concomitant Medications/Treatments ........................................................................... 13 5.4 Duration of Therapy ....................................................................................................... 13 5.5 Off Treatment Criteria .................................................................................................... 13 5.6 Duration of Follow-Up .................................................................................................... 13 5.7 Off Study Criteria ........................................................................................................... 14 5.8 Patient Replacement ..................................................................................................... 15 6.0 STUDY PROCEDURES ....................................................................................................... 15 Page iii of v Protocol UMCC 2016.013 6.1 Pharmacokinetic assesment …………………………………………………………………15 6.2 Screning/Baseline Procedures ...................................................................................... 15 6.3 Procedures During Treatment ....................................................................................... 16 6.4 Time and Events Table/Study Calendar ........................................................................ 17 7.0 MEASUREMENT OF EFFECT ............................................................................................ 19 7.1 Antitumor Effect- Solid Tumors ...................................................................................... 19 7.2 Safety/Tolerability .......................................................................................................... 23 8.0 ADVERSE EVENTS ............................................................................................................. 23 8.1 Experimental Therapy.................................................................................................... 23 8.2 Adverse Event Reporting Requirements ....................................................................... 23 8.3 Definitions ...................................................................................................................... 24 8.4 Adverse Event Characteristics ...................................................................................... 25 8.5 Serious Adverse Event Reporting Guidelines ............................................................... 26 8.6 Routine Reporting .......................................................................................................... 26 8.7 Reporting of Unanticipated Problems ............................................................................ 26 8.9 Stopping Rules .............................................................................................................. 27 9.0 DRUG INFORMATION ........................................................................................................ 27 9.1 Agent Pazopanib .......................................................................................................... 27 10.0 CORRELATIVES/SPECIAL STUDIES ................................................................................ 29 11.0 STATISTICAL CONSIDERATIONS .................................................................................. 30 11.1 Study Design/Study Endpoints ...................................................................................... 30 11.2 Sample Size and Accrual .............................................................................................. 30 12.0 DATA AND SAFETY MONITORING ................................................................................... 31 13.0 REFERENCES ................................................................................................................... 31 Page iv of v Protocol UMCC 2016.013 APPENDICES .................................................................................................................... 32 Page ii of v Protocol UMCC 2016.013 ABBREVIATIONS: AE Adverse Event ALT Alanine Aminotransferase ANC Absolute Neutrophil Count AST Aspartate Aminotransferase BP Blood Pressure BUN Blood Urea Nitrogen CBC Complete Blood Count CMP Comprehensive Metabolic Panel CR Complete Response CT Computed Tomography CTCAE Common Terminology Criteria for Adverse Events CTO Clinical Trials Office DLT Dose Limiting Toxicity DSMB Data and Safety Monitoring Board ECG Electrocardiogram EF Ejection fraction H&P History & Physical Exam HRPP Human Research Protections Program HTN Hypertension IND Investigational New Drug IRB Institutional Review Board IV (or iv) Intravenously LFTs Aspartate aminotransferase, alanine aminotransferase and total bilirubin MTD Maximum Tolerated Dose NCI National Cancer Institute ORR Overall Response Rate OS Overall Survival RCC Renal Cell Carcinoma PD Progressive Disease PFS Progression Free Survival PI Principal Investigator PO per os/by mouth/orally PR Partial Response PRC Protocol Review Committee PPI Proton Pump Inhibitor SAE Serious Adverse Event SD Stable Disease TTE Transthoracic echocardiogram UaP Unanticipated Problem ULN Upper Limit Normal UMCCC University of Michigan Comprehensive Cancer Center Page 1 of 34 Protocol UMCC 2016.013 UPC Urine protein to creatinine VEGF/VEGFR Vascular endothelial growth factor/vascular endothelial growth factor receptor WBC White Blood Cells STUDY SYNOPSIS Pilot Study of PAzopanib with Low Fat Meal (PALM) in advanced renal Title cell carcinoma. Phase Feasibility pilot study Methodology Open-label Study Duration 1 year of accrual. Study Center(s) Single-center Primary Objectives • To determine the safety and feasibility of pazopanib given with a low fat meal for therapy of metastatic renal cell carcinoma. Secondary Objectives Objectives • To determine the overall response rate to pazopanib given with a low fat diet in first-line therapy of metastatic