Protocol amendment for ENSEMBLE study: A multicenter, randomized, phase III trial to test the superiority of consolidation irinotecan, capecitabine and oxaliplatin vs capecitabine and oxaliplatin following short course radiotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer—Changing the irinotecan dosage.
Authors: Ando Koji , Watanabe Jun , Kagawa Yoshinori , Bando Hideaki , Kotani Daisuke , Suwa Yusuke , Nishizawa Yujiro , Takahashi Yusuke , Matsuhashi Nobuhisa , Suwa Hirokazu , Sugiyama Masahiko , Kanemitsu Yukihide , Oki Eiji , Uemura Mamoru , Yokota Mitsuru , Tsuboyama Takahiro , Oba Koji , Kato Takeshi , Yoshino Takayuki 
Published: August 2024

TPS99 Background: Total neoadjuvant therapy (TNT) presents a promising approach for treating patients (pts) with locally advanced rectal cancer (LARC). TNT not only enhances outcomes for LARC pts but also contributes to improving their quality of life by offering non-operative management (NOM) for patients with complete clinical response (cCR) or near-complete clinical response (nCR). We are currently conducting a phase III trial, the ENSEMBLE study, which was presented at ASCO Breakthrough 2023. At this stage, we have modified the protocol for this study. Additionally, we are conducting translational research (TR) to establish clear criteria for NOM following TNT. Methods: In the ENSEMBLE study, the experimental treatment group received short-course radiotherapy (SCRT) (5×5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1], and irinotecan 200 mg/m2 [intravenously, day 1, every 3 weeks]). The standard-of-care group received SCRT (5×5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1, every 3 weeks]). However, the experimental treatment group experienced a higher rate of adverse events due to the high starting dose of irinotecan. After consulting the data and safety monitoring committee (DSMC), it was recommended to reduce the starting dose of irinotecan. Results: Enrollment for the ENSEMBLE study commenced in November 2022. By August 2023, severe adverse events necessitating emergency reporting had occurred in the experimental treatment group. In response to these adverse events, the DSMC was consulted, leading to the reduction of the starting dose of irinotecan to 150 mg/m2. Following this adjustment, no severe adverse events requiring emergency reporting were observed during the experimental treatment with CAPOXIRI. We are currently continuing the ENSEMBLE study to advance treatment options for LARC pts. The TR component of the ENSEMBLE study involves genomic profiling through whole genome plus RNA sequencing of tissue and blood samples, as well as circulating nucleic acid sequencing (cNAS). Additionally, all imaging data (MRI, CT, and colonoscopy) and clinical information are being collected to develop criteria for NOM. Conclusions: A starting dose of irinotecan at 150 mg/m2 appears to be feasible after SCRT in the ENSEMBLE study. Furthermore, the ENSEMBLE study aims to establish clear NOM criteria through deep learning with TR. Clinical trial information: NCT05646511 / jRCTs031220342 .