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

July 22, 2025 updated by: brenner baruch

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

134

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Germany
      • Mainz, Germany
        • Not yet recruiting
        • Johannes Gutenberg-University Clinic, Mainz, Germany 1.Dept. Medicine, Prof. Peter R. Galle
  • Israel
      • Petach Tikva, Israel
        • Recruiting
        • Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subjects with histologically confirmed primary (non-recurrent) LARC (tumor 12 cm or less from the anal verge, as assessed by rigid proctoscopy), stage T3-4 N0 or TX N+ according to base-line pelvic MRI and PET-CT.
  • Patients who are planned for TNT and are surgical candidates as determined by the treating physician.
  • No prior chemotherapy, immunotherapy, radiotherapy or surgery for rectal cancer.
  • No prior radiotherapy to the pelvis, for any reason.
  • Able to provide the FFPE block or 10 unstained slides from the colonoscopy for confirmation of the diagnosis, CPS status and for investigational purposes.
  • Age 18 years or more.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2.

  • Screening laboratory values must meet the following criteria (using CTCAEv5.0):

    i) WBC > 2000/µL ii) Neutrophils > 1500/ µL iii) Platelets > 100 x 103/ µL iv) Hemoglobin > 9.0 g/dL v) Serum creatinine < 1.5 x ULN or calculated creatinine clearance > 60 mL/min (using the Cockcroft Gault formula) vi) AST and ALT < 2.5 x ULN. vii) Total bilirubin < 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome).

  • Ability to swallow tablets.
  • Adequate contraception in fertile patients; using a highly effective method of birth control for the duration of the study, and for at least 9 months after the last dose of chemotherapy and 120 days after the last dose of immunotherapy.
  • Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to the start of treatment.
  • Women must not be breastfeeding.
  • Signed written IRB approved informed consent. This must be obtained before the performance of any protocol related procedure that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatments, and laboratory testing.

Exclusion Criteria:

  • Active or background history of an autoimmune disease except for type I diabetes mellitus, hypothyroidism requiring hormone replacement only and skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment.
  • Medical history of vasculitis.
  • Prior organ transplant, including allogenic bone marrow transplantation.
  • Grade > 1 peripheral sensory neuropathy.
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co- stimulation or checkpoint pathways.
  • Any prior active malignancy < 2 years before trial entry except for any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
  • Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • Known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: TNT with Immunotherapy
Patients 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.
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).
Other: TNT
Patients will be treated with 6 weeks of capecitabine-based CRT followed 4 weeks later by 16 weeks of chemotherapy with 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
3-year total mesorectal excision (TME) free survival rates
Time Frame: Time from the date of registration to the date of TME or the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause. Assessed up to 36 months.
3-year TME free survival will be defined as the percentage of patients who are alive and did not undergo total mesorectal excision (TME) surgery, or did not have an event of loco-regional failure, metastatic recurrence or the appearance of a secondary CRC, at 36 months of follow up.
Time from the date of registration to the date of TME or the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause. Assessed up to 36 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
3 year TME-free survival rates of the CPS positive population
Time Frame: Time from the date of registration to the date of TME or the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause. Assessed up to 36 months.
3-year TME free survival will be defined as the percentage of patients with CPS positive tumors (PDL-1 combined positive score >1%), who are alive and did not undergo total mesorectal excision (TME) surgery, or did not have an event of loco-regional failure, metastatic recurrence or the appearance of a secondary CRC, at 36 months of follow up.
Time from the date of registration to the date of TME or the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause. Assessed up to 36 months.
Incidence of Treatment-Emergent Adverse Events (Safety)
Time Frame: Time from screening until the end of study drug administration, Immune-related AEs will be recorded up to 90 days (+7 days) after the last dose of tislelizumab. Assessed up to 11 months.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0"
Time from screening until the end of study drug administration, Immune-related AEs will be recorded up to 90 days (+7 days) after the last dose of tislelizumab. Assessed up to 11 months.
Disease-free survival (DFS)
Time Frame: Time from the date of registration to the date of the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause, assessed up to 36 months
DFS will be censored for patients who are alive and free of progression at the time of last follow-up. DFS rate will be estimated using the Kaplan-Meier method
Time from the date of registration to the date of the first event of loco-regional failure, metastatic recurrence, the appearance of a secondary CRC or death from any cause, assessed up to 36 months
Overall survival (OS)
Time Frame: The time interval between the day of registration and the date of death of any cause, assessed up 60 months.
Patients who are still alive when last traced will be censored at the date of last follow-up. OS rate will be estimated using the Kaplan-Meier method.
The time interval between the day of registration and the date of death of any cause, assessed up 60 months.
Progression-free survival (PFS)
Time Frame: The time from the date of registration to the date of the first objectively documented tumor progression, or death, whichever occurs first, assessed up to 60 months
PFS is defined as the time from the date of registartion to the date of the first objectively documented tumor progression, or death, whichever occurs first.
The time from the date of registration to the date of the first objectively documented tumor progression, or death, whichever occurs first, assessed up to 60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

brenner baruch

Collaborators

Johannes Gutenberg University Mainz

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 23, 2025

Primary Completion (Estimated)

August 1, 2029

Study Completion (Estimated)

August 1, 2030

Study Registration Dates

First Submitted

April 1, 2025

First Submitted That Met QC Criteria

April 15, 2025

First Posted (Actual)

April 23, 2025

Study Record Updates

Last Update Posted (Actual)

July 24, 2025

Last Update Submitted That Met QC Criteria

July 22, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TOTAL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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