EVESOR the first model-based multi-parameter phase 1 trial meant
Transcription
EVESOR the first model-based multi-parameter phase 1 trial meant
Abstract 465P EVESOR the first model-based multi-parameter phase 1 trial meant to optimize the benefit/toxicity ratio of EVErolimus and SORafenib association: preliminary PD outcomes. Mévidette El-Madani 1,2; Emilie Hénin 1; Thibaud Lefort 1,5; Michel Tod 1; Claire Rodriguez-Lafrasse 1,4; Pierre-Jean Valette 1,5; Philippe Cassier 6 ; Juliette Hommel-Fontaine 1,7; Jerome Guitton 1,8; Khemaies Slimane 9; Benoit You 1,3. 1.Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL3738 ; Lyon ; France 2.National Research Centre,Pharmacology Department,Cairo, Egypt, 3.Medical Oncology ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, 4.Biochemistry and molecular biology department; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, 5.Radiology Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France; 6.Phase 1 trial Unit, Centre Léon Bérard, Lyon, France; 7.Pathology Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France,8.Pharmacokinetic Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France,9.Novartis Pharma S.A.S , Medical Oncology, France Study Design and Methods • Everolimus and sorafenib block 2 complementary signaling pathways: RAF-RAFERK and PI3K-AKT-mTor • Traditional phase 1 trials of the combination showed promising activity but significant toxicity What are the optimal doses and dosing schedules of both drugs ? • EVESOR study is a non-randomized, open-labeled phase I study of everolimus and sorafenib given according to 4 different administration schedules (A,B,C,D) in patients with advanced solid tumors. Pharmacodynamic biomarkers outcome of everolimus and sorafenib combination EVE SOR EVE SOR SOR EVE • The optimized doses and dosing schedules of everolimus and sorafenib, associated with the maximal benefit/toxicity ratio, may be determined using mathematical modeling. EVE SOR SOR EVE Pharmacodynamic interactions ? Anti-angiogeneic effects • Induced by EVE, and reversed by addition of SOR • by addition of EVE to SOR Effects on ERK and AKT pathways • Lack of effect of EVE reversed by addition of SOR Toxicity Most of adverse events: - Grade 1-2: 50% fatigue; weight loss; diarrhea and anorexia; 25% were rhinorrhea; hyperbilirubinemia and hypocalcemia. - Grade 3 toxicities: hypophosphatemia (50%); fatigue (25%); transaminase elevation (25%); lymphopenia (25%); fatigue (25%); hypokalemia (25%). 1 SUSAR : Grade 3 hemolytic anemia in a patient on sorafenib alone (arm B). Conclusion The on-going EVESOR trial suggests there may be strong PD interactions between SOR and EVE regarding inhibition of AKT & ERK signaling pathways and anti-angiogenic effects, with influence by the respective dosing schedules.