Abstract CT148: Clinical results of the multiparameter phase 1 trial EVESOR meant to optimize the doses and dosing schedules of the combination EVErolimus and SORafenib in solid tumors
Authors: You Benoit , Tod Michel , Payen Lea , Lopez Jonathan , Guitton Jerome , Rousset Pascal , Fontaine Juliette , Peron Julien , Maillet Denis , Tartas Sophie , Bonnin Nathalie , Trillet-Lenoir Veronique , Colomban Olivier , Augu-Denechere Diane , Freyer Gilles , Puszkiel Alicja 
Published: September 2020

Abstract
Objectives: Defining the optimal doses & dosing schedules of combined targeted drugs is a challenge. Blocking both the PI3K-AKT-mTor and RAS-RAF-ERK pathways is a rationale therapeutic strategy in solid tumors. However, the phase 1 trials of everolimus (EVE) and sorafenib (SOR) failed to define the recommended phase II trial doses (RP2D) of both drugs, due to the toxicity when given continuously; and the combination was abandoned. The academic multi-parameter EVESOR trial (NCT01932177) was designed to assess alternative doses & dosing schedules of EVE & SOR, and to provide data that would be used to define the optimal doses & dosing schedules of both drugs associated with the best efficacy/toxicity ratio by modeling/simulation. Methods: EVESOR is an open dose-escalation phase 1 trial assessing the combination of EVE and SOR in patients with multi-treated advanced solid tumors. Enrolled patients were allocated to 1 of the 4 arms: A) EVE 5 mg QD for 2 weeks followed by continuous EVE + SOR 200 mg BID; B) SOR 200 mg BID for 2 weeks followed by continuous EVE 5 mg QD + SOR; C) alternating EVE 5-10 mg QD with SOR 200-400 mg BID every week; D) continuous EVE 5-10 mg QD + SOR 200-400 mg BID for 3 days on-4 days off. Multiple tumor & blood pharmacokinetic (PK) and pharmacodynamic (PD) parameters were sampled at baseline and during treatment (Nanostring panels). The 1st endpoint was the RP2D of both drugs in each arm A+B; C; and D. Results: 43 patients were included from 2013 to 2019: arm A n= 7; arm B n= 7; arm C n= 16; arm D n = 13. Most of them had gynecological (25.6%), cholangiocarcinomas (23.2%), colorectal (14%), and breast cancers (11.6%). Dose escalations to EVE 10 mg QD and SOR 400 mg BID were possible in both arms C and D. Five dose-limiting toxicities (DLTs) were observed (1; 3; and 1 in arms B, C and D respectively). Dose reductions were needed in 40% patients, stabilizing at EVE 5 mg and SOR 200 mg BID for the majority of them (58%). The overall response rate was 7%, and the disease control rate (DCR) was 73%. No relationships between dose levels and efficacy were found. However, the intermittent dosing schedules (arms C and D) were associated with better DCR. The median progression-free survival (PFS) was 3.6 months (2.7; 6.3; 2.7; and 3.6 months in arms A, B, C and D). Longer PFS were observed with cholangiocarcinomas (9.8 months) and gynecological cancers (3.7 months). Baseline activation of RAS-RAF-ERK was associated with higher non-progression rates at 4 months (50% vs 10%, P=0.12) and longer PFS (4.2 vs 2.1 months, P = 0.016). Decreases in S6K and AKT phosphorylations were observed in 89% and 70% of patients, respectively, with no significant impact on efficacy. Conclusions: EVE 5 mg QD and SOR 200 mg BID combination is the RP2D in solid tumor patients, in both intermittent arms C & D. Intermittent dosing was associated with higher efficacy. Long responses were found in cholangiocarcinomas. Adequately designed multi-schedules phase 1 trials can help for drug development, and avoid abandon of effective targeted drug combinations. Modeling/simulation will be used to optimize dose & dosing schedules of EVE and SOR based on collected data, and then tested.
Citation Format: Benoit You, Michel Tod, Lea Payen, Jonathan Lopez, Jerome Guitton, Pascal Rousset, Juliette Fontaine, Julien Peron, Denis Maillet, Sophie Tartas, Nathalie Bonnin, Veronique Trillet-Lenoir, Olivier Colomban, Diane Augu-Denechere, Gilles Freyer, Alicja Puszkiel. Clinical results of the multiparameter phase 1 trial EVESOR meant to optimize the doses and dosing schedules of the combination EVErolimus and SORafenib in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT148.