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 Anti-Cancer Agents & Biologic Therapy
Pharmacology
Translational Research
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.