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

NCT06940388 | Recruiting Phase 2 DMC

• 1 other identifier: TOTAL
• Study Type: interventional
• Target: 134
• Locations: 2 countries
• Sites: 2

Brief 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.

Conditions

Locally Advanced Rectal Cancer (LARC)

Keywords

rectal cancer; locally advanced rectal cancer; total neoadjuvant treatment; immunotherapy

Outcome Measures

Primary Outcomes (1)

• 3-year total mesorectal excision (TME) free survival rates

  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 Outcomes (5)

• 3 year TME-free survival rates of the CPS positive population

  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 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 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)

  The time interval between the day of registration and the date of death of any cause, assessed up 60 months.

• Progression-free survival (PFS)

  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

Study Arms (2)

TNT with Immunotherapy

EXPERIMENTAL

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

TNT

OTHER

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)

Interventions

Tislelizumab DRUG

During ChemoImmunotherapy: Patients in the investigational arm will receive 8 cycles of tislelizumab 150 mg IV on Day 1, followed by mFOLFOX6 (Q2W).

TNT with Immunotherapy

Total neoadjuvant therapy (TNT) DRUG

Patients will be treated with 6 weeks of capecitabine-based CRT followed 4 weeks later by 16 weeks of chemotherapy with mFOLFOX6, Q2W.

TNT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• brenner baruch: lead
• Johannes Gutenberg University Mainz: collaborator

Study Sites (2)

Johannes Gutenberg-University Clinic, Mainz, Germany 1.Dept. Medicine, Prof. Peter R. Galle

Mainz, Germany

NOT YET RECRUITING

Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital

Petah Tikva, Israel

RECRUITING

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MeSH Terms

Conditions

Rectal Neoplasms

Interventions

tislelizumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Central Study Contacts

Baruch Brenner, M.D

CONTACT

+972-50-4065452; brennerb@clalit.org.il

Ayelet Rosenberg Ayal, M.D

CONTACT

+972-54-4499333; shayeletro@clalit.org.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head, Department of Oncology, Davidoff Cancer Center Rabin Medical Center, Beilinson Hospital Petach Tikva, Israel

Model Details: 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.

Study Record Dates

• First Submitted: April 1, 2025
• First Posted: April 23, 2025
• Study Start: July 23, 2025
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2030
• Last Updated: July 24, 2025

Record last verified: 2025-07

Locations

DE (1); IL (1)