NCT06940388

Total Neoadjuvant Treatment With or Without Tislelizumab for Locally Advanced Rectal Cancer.

Total Neoadjuvant Treatment With or Without Tislelizumab for Locally Advanced Rectal Cancer: An Open-label Randomized Controlled Phase II Study (The TOTAL Trial)

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 134 (estimated)
• Sponsor: brenner baruch · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This prospective, multi-center, phase II randomized controlled trial will evaluate the actual benefit of adding immunotherapy with tislelizumab to the currently most effective approach against LARC, namely TNT. In this trial, we will harness several elements that may each potentially contribute to an overall high efficacy, at least in local outcomes: nCRT rather than SCRT, full length (8 cycles of mFOLFOX6) of consolidation chemotherapy, CIMT following nCRT (exploiting the upregulation of the immune response induced by the latter) and tislelizumab (with its theoretical advantage over other CPIs). In line with the changing treatment paradigms in LARC, in which high therapeutic efficacy translates into the possibility to avoid TME, the trial will have a novel primary endpoint of long-term unmaintained cCR, i.e. 3 year TME-free survival.

Detailed description

This is a prospective, multi-center, double arm, open-label, phase II randomized (1:1) controlled trial aimed to determine the efficacy and safety of TNT with or without tislelizumab in patients with primary, histologically proven LARC. All subjects will undergo a screening process, based on the inclusion and exclusion criteria listed below. All subjects confirmed to be eligible will be randomized (1:1) into one of the two study arms, using an eCRF software. Patients in the investigational arm will be treated with 6 weeks of capecitabine-based CRT followed 4 weeks later by 16 weeks of CIMT with tislelizumab and mFOLFOX6, both given Q2W. Patients in the control arm will be treated with 6 weeks of capecitabine-based CRT followed 4 weeks later by 16 weeks of chemotherapy with mFOLFOX6, without tislelizumab, Q2W. Patients in both arms will be re-staged 8 weeks (+/-14 days) after the completion of therapy. Patients who will achieve cCR/near cCR will be closely followed by WW, and will undergo TME at any sign of local tumor regrowth. Patients in both arms with residual tumor, will undergo immediate TME. All patients will be followed according to current NCCN guidelines.The primary aim of the trial is to demonstrate that an approach of adding tislelizumab to the chemotherapy phase of the neoadjuvant treatment will increase the 3 year TME-free survival rate by \>20%, from 50% (based on the 53% 3 year TME-free survival rate in the OPRA trial) to 70% in patients with LARC.

Conditions

• Locally Advanced Rectal Cancer (LARC)

Interventions

Type	Name	Description
DRUG	Tislelizumab	During ChemoImmunotherapy: Patients in the investigational arm will receive 8 cycles of tislelizumab 150 mg IV on Day 1, followed by mFOLFOX6 (Q2W).
DRUG	Total neoadjuvant therapy (TNT)	Patients will be treated with 6 weeks of capecitabine-based CRT followed 4 weeks later by 16 weeks of chemotherapy with mFOLFOX6, Q2W.

Timeline

• Start date: 2025-07-23
• Primary completion: 2029-08-01
• Completion: 2030-08-01
• First posted: 2025-04-23
• Last updated: 2025-07-24

Locations

2 sites across 2 countries: Germany, Israel