591P - A Phase Ib Study of Everolimus, 5-Fluorouracil (5-Fu) and Pelvic Radiotherapy (Rt) As Neo-Adjuvant Treatment for Locally Advanced Rectal Cancer (Larc)

Abstract

ABSTRACT Aim: The addition of 5FU to preoperative RT increases clinical downsizing and pathological downstaging and optimizes local control but has no significant effect on survival (OS). New cytotoxic drugs (irinotecan and oxaliplatin, i.e.) and targeted agents (bevacizumab and cetuximab, i.e.) have been tested in combination with 5FU and RT, but with no benefit on pathological complete response (pCR) and OS. Primary aim of the present phase Ib study is to establish the maximum tolerated dose (MTD) of everolimus in combination with 5FU and RT in LARC. Secondary: Tumor regression grade (Dworak score); rates of pCR; evaluation of biological parameters of inhibition of target (tissue expression of phosphorilated S6 and mTOR) before, after 2 weeks of treatment (before concomitant treatment) and on surgical specimen. Methods: Between march 2011 and december 2013 12 patients with histologically confirmed diagnosis of LARC (T3-T4; N0-1; within 15 cm from anal rhyma) were enrolled at University Hospital of Modena. Pts have been sequentially assigned to one of the following 4 cohorts and have been administered with the following dose levels: everolimus at 2,5 mg; 5 mg; 7,5 mg; 10 mg daily per os starting from 14 days before 5FU and RT and for all the duration of the concomitant treatment. DLT was defined as every reported toxicity (haematological and non haematological) ≥ grade 3, as defined by CTC criteria 3.0. Grade 2 pneumonitis lasting more than 7 days or recurrent on the same cycle or grade > 3 of any duration. Results: Twelve pts have been treated and no DLT (as defined above) was recorded. The reported toxicities were: skin rash (observed in 3 cases: 2 G1 and 1 G2), asthenia (observed in 4 cases, G1), diarrhea (observed in 6 cases: 5 G1 and 1 G2), mucositis (observed in 1 case, G1) and urinary disfunction (observed in 4 cases, G1; probably related to pelvic radiotherapy). Only one pt underwent Miles surgical resection (8%). Dworak TRG was as follows: TRG 0-1-2 = 10/12 (83%); TRG 4 (pathological complete response) = 2/10 (17%). No TRG3 was recorded. Conclusions: Combination of everolimus, 5FU and RT is feasible. We observed ≥15% of patients with TRG 3-4; the combination will be considered for a phase II trial. Biological parameters evaluation is still ongoing. Disclosure: All authors have declared no conflicts of interest.