Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX).

3600 Background: Patients (pts) with rectal cancer who achieve a clinical complete response (cCR) after neoadjuvant therapy may be safely observed and spared the long-term sequela of total mesorectal excision (TME). We hypothesized that a novel neoadjuvant regimen (short-course radiation with boost and FOLFOXIRI chemotherapy) would achieve higher cCR rates than historical controls. Methods: We conducted a single-arm, phase II study of short-course radiation followed by FOLFOXIRI for pts with >T2N0 or low T2N0M0 rectal adenocarcinoma (NCT04380337). Pts underwent radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Pts were assessed for primary endpoint (cCR) at 8 weeks following chemotherapy. Those who achieved a cCR or near cCR were surveilled. cCR required no tumor on MRI, endoscopy, and if applicable, digital rectal exam. A Simon 2-stage design addressed our primary objective, with interim analyses for futility and toxicity. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, our sample size was 37 pts. Results: Between May 2020 and April 2023, 37 pts enrolled (Table). 25 pts (67.5%) had at least one high risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin [CRM], positive lateral node). All pts completed radiation; 32 pts (86.5%) completed all 8 cycles of chemotherapy. Criteria for futility and safety were met at interim analysis. At primary outcome assessment, 9 (24.3%) pts achieved a cCR and 8 (21.6%) pts achieved a near cCR. 3 pts who initially had a cCR developed local regrowth and underwent TME. Of the pts who had a near cCR, 5 developed local regrowth and underwent TME while 3 pts achieved delayed cCR. Serious adverse events occurred in 5 (13.5%) pts; 1 patient had non-hematologic grade 4 toxicity at least possibly related to treatment. There were no treatment-related deaths. The12-month TME-free survival for all patients was 37.2%, and for patients with T3 and T4 tumors was 44.3% and 12.5%, respectively. Conclusions: Short-course radiation followed by FOLFOXIRI was feasible and safe. In this high-risk cohort of pts with rectal cancer, 24.3% of pts had a cCR at time of primary assessment. Clinical trial information: NCT04380337 . [Table: see text]