Table 3.

Clinical endpoints of the ACO/ARO/AIO-21 trial.

Primary Endpoint

Analysis of safety and identification of the maximum tolerated dose (MTD) of capecitabine, administered concomitantly with standard radiotherapy in combination with Anakinra at a fixed dose of 100 mg s.c., will be the primary objective. A 3 + 3 design will be used. MTD is defined as the highest dose of capecitabine at which 0 of 3, or no more than 1 of 6 evaluable patients experience a dose-limiting toxicity (DLT) per NCI CTCAE V5.0. At least 3 patients will be enrolled per dose level of capecitabine (500 mg/m2 bid, 650 mg/m2 bid and 825 mg/m2 bid, respectively). The following will be considered DLT of capecitabine if they occur at any point whilst the patient is on study: Grade 4 neutropenia Grade 3 thrombocytopenia Grade 4 vomiting Grade 3 diarrhea lasting greater than 96 h despite adequate treatment and/or requiring CRT interruption of more than 5 days Grade 3 stomatitis Grade 3 hand-foot syndrome Grade 3 hepatic toxicity Grade 3 peripheral neuropathy

Secondary Endpoints

•Postoperative complications of (salvage) surgery Late toxicity assessment according to NCI CTCAE V.5.0 Rate of W&W with or without local regrowth Cumulative incidence of locoregional regrowth after cCR Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth Cumulative incidence of local recurrence after (salvage) surgery Cumulative incidence of distant recurrences Disease-free survival Overall survival Pathological TNM-staging R0 resection rate; negative circumferential resection rate Tumor regression grading according to Dworak Quality of TME according to MERCURY Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation Translational / biomarker studies