Abstract LB-302: A comprehensive study of translational research and safety exploration of the vascular disrupting agent (VDA) AVE8062 in combination with cisplatin administered every 3 weeks to patients with advanced solid tumors
Authors: Soria Jean-Charles , Sessa Christina , Perotti A , Massard Christophe , Armand jean-pierre , Lassau Nathalie , farace francoise , Borghi Elsa , Gianni Luca 
Published: May 2019

Abstract
AVE8062 is an analog of Combretastatin A4 against tumor-vasculature. Its property of destroying endothelium and causing shutdown of blood perfusion in animals has been confirmed in a trial with AVE8062 given as a single agent to patients with solid tumors. Synergy observed with AVE8062 and cisplatin in preclinical models prompted the exploration of this combination in advanced stage solid tumors.
Objectives: The primary objective of the study was to determine the recommended dose (RD) of the combination and to define a better understanding of the dynamic of vascular response. Secondary objectives were the assessment of the overall safety profile, the tolerability of the schedule, the pharmacokinetic (PK) profile and the anti-tumor activity. Vascular assessment was performed at each cycle. A pharmacodynamic study included the assessment of tumor blood flow by DCE-US, and the evaluation of changes in mature Circulating Endothelial Cells (CEC) and Progenitors (CEP) levels during treatment in a subset of patients.
Methods: AVE8062 was given over a 30 min intravenous infusion immediately followed by a cisplatin (CDDP) infusion. Cohorts of 3 or 6 pts were treated at 11.5, 15.5, 20, 25 and 30 mg/m² of AVE8062 in combination with a fixed dose of 75 mg/m² of CDDP. Ten additional patients were treated at the RD. PK sampling was performed at Cycle 1, DCE-US at Cycles 1 & 2 and every other cycle, and CEC & CEP at Cycle 1.
Results: Thirty seven patients were treated. DLTs were: tumor haemorrhage, thrombocytopenia, neutropenic complications and ALT/AST elevation. No cardiovascular adverse event occurred. The overall safety profile was mainly related to the chemotherapy. The RD was defined at AVE8062 25mg/m² and CDDP at 75 mg/m². Antitumor activity was observed in different tumor types at different AVE8062 doses. PK of AVE8062 and its main metabolite RPR258063 were similar to those of the drug administered as a single agent. Total and ultrafilterable CDDP exposure was similar to that observed with CDDP as single agent. DCE-US imaging showed a significant decline of tumor perfusion at 6 and 24 hours after the AVE8062-CDDP administration. A 2 fold increase in CEC levels was observed on Day 2 compared to baseline (p&lt;0.02) followed by a drop on Day 7. A dramatic increase from 1.9 to 30.9% of CEP values on Day 3 or 7 was observed.
Conclusions: AVE8062 in combination with CDDP was well tolerated. The RD was defined at 25mg/m² of AVE8062 and 75 mg/m² of CDDP. DCE-US imaging showed a significant decline of tumor perfusion at 6 and 24 hours after AVE8062-CDDP administration. CEC and CEP hold promise as biomarkers of VDA activity. VDA leads to a burst in CEC followed by an acute mobilization of CEP that provides a mechanistic rationale to combine VDA with other anti-cancer agents and notably anti-angiogenic compounds.