EVESOR the first model-based multi-parameter phase 1 trial meant

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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.

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