465P - EVESOR the first model-based multi-parameter phase 1 trial meant to optimize the benefit/toxicity ratio of everolimus and sorafenib association: Pr...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
Translational Research
Clinical research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological therapy
Presenter Mevidette Mohamed
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors M.A. Mohamed1, E. Henin2, G. Freyer3, M. Tod4, C. Rodriguez-Lafrasse5, P. Valette6, P. Cassier7, J.H. Hommel-Fontaine8, J. Guitton9, K. Slimane10, B. You3
  • 1Emr 3738, Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL 3738 ; Lyon ; France, BP1269921 - Lyon/FR
  • 2Emr3738, Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL 3738 ; Lyon ; France, 69000 - Lyon/FR
  • 3Medical Oncology, Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL 3738 ; Lyon ; France Medical Oncology ; CITOHL; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, BP1269921 - Lyon/FR
  • 4Modeling, Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL 3738 ; Lyon ; France, BP1269921 - Lyon/FR
  • 5Biology, Biochemistry and molecular biology department; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, BP1269921 - Lyon/FR
  • 6Radiology, Radiology Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, BP1269921 - Lyon/FR
  • 7Medecine, Centre Léon Bérard, 69008 - Lyon/FR
  • 8Pathology, Pathology Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, BP1269921 - Lyon/FR
  • 9Pharmacokinetics, Université de Lyon ; Université Claude Bernard Lyon 1 ; Faculté de médecine Lyon-Sud ; EMR UCBL/HCL 3738 ; Lyon ; France; 8. Pharmacokinetic Department ; Hospices Civils de Lyon ; Centre Hospitalier Lyon-Sud ; Lyon ; France, BP1269921 - Lyon/FR
  • 10Medical Oncology, SAS Novartis Pharma, Lyon/FR

Abstract

Aim

The best doses and dosing schedules of everolimus (EVE) and sorafenib (SOR) which enable maximization of benefit/toxicity ratio may be searched using mathematical modeling of data derived from an adequately designed multi-parameter phase 1 trial.

Methods

This academic study is composed of 4 arms (A; B; C & D) with different dosing schedules and doses of EVE and SOR. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies & repetitive PBMC assays; kinetics of circulating tumor DNA kinetics & VEGF angiogenesis markers; tumor angiogenesis changes using repeated DCE-ultrasounds; and radiological/clinical effects. The optimal doses and dosing schedules of EVE and SOR will be searched using simulations and then tested. The protocol was approved by ethic committee in 2012.

Results

8 patients with different metastatic tumor types (CRC: 3; pancreas: 2; breast: 1; HCC: 1; endom: 1) have been enrolled in 2 arms out of 4 (A: EVE 5mg qd 2 weeks and then SOR 200 mg bid + EVE; or B: SOR 200 mg bid 2 weeks and then SOR + EVE 5 mg qd). 4 patients were assessable for response: 2 SD (for more than 4 months) and 2 PD. Most of side effects were grade 1-2. Grade 3 toxicities were transaminase elevation, hypokalemia and fatigue. A SUSAR was observed: confirmed blood grade 3 hemolytic anemia in a patient on SOR alone (arm B). Longitudinal measurements of ERK, AKT & pAKT signals in PBMCs; VEGF & VEGFR2 in serum and DCE-US angiogenesis suggest that the anti-angiogenic effect induced by run-in EVE (41% reduction) would be reversed by combination to SOR (431% increase). Addition of EVE to run-in SOR would increase the anti-angiogenic effects. However the lack of effect on AKT and ERK pathways induced by EVE (150% increase) might be reversed by the combination to SOR (21% decrease).

Conclusions

The on-going EVESOR trial suggests there may be strong PD interactions between everolimus and sorafenib regarding inhibition of AKT & ERK signaling pathways and anti-angiogenic effects, with large impact by the respective drug dosing schedules. The intermittent arms C and D will bring more data on these PD interactions. EVESOR trial aims at optimizing the doses and dosing schedules of the 2 drugs.

Disclosure

All authors have declared no conflicts of interest.