599TiP - A randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare)

Abstract

Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m2 for four times, regardless of the genetype of UGT1A1, which has been regarded in favor of predicting toxicities. In our previous phase I trial, the weekly dose of irinotecan was escalated to 65mg/m2 and 80mg/m2 guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Trial design: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m2 twice daily from first day of radiotherapy and given 5 days per week during radiotherapy in control group. In the other group, capecitabine dose is 625mg/m2 twice daily and additional weekly irinotecan dose is 80mg/m2 or 65mg/m2 guided by UGT1A1*28 6/6 or 6/7 genetypes (total of five times). Stratification was performed by center, UGT1A1*28 genetype (6/6, 6/7), T stage (cT3, cT4), and distance from anal verge (<= 5cm, >5cm). Surgery is schedule 8 weeks after the end of CRT, then, five cycles of XELOX are recommended during the course of adjuvant chemotherapy. The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial identification: NCT02605265, released on December 24, 2015 Legal entity responsible for the study: Fudan University Shanghai Cancer Center