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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR, Rabin Medical Center

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Mar 2026 → ongoing

Decision date (initial)

2026-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BeOne Switzerland GmbH.

External identifiers

EU CT number

2025-522120-28-00

ClinicalTrials.gov

NCT06940388

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To compare the 3-year TME-free survival of the investigational and the standard regimens

Secondary objectives 4

1. • To compare the efficacy of the investigational and standard regimens, in terms of downstaging, cCR, disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) rates.
2. • To define the safety and toxicity profile of the addition of tislelizumab to the chemotherapy phase of TNT.
3. • To measure patient-reported functional outcomes and quality of life (QoL).
4. • To evaluate the prognostic and predictive roles of various blood and tissue biomarkers, including CPS (PD-L1 combined positive score), tumor-immune distance, MMR (mismatch repair), ctDNA (circulating tumor DNA), peripheral blood mononuclear cells (PBMCs) subpopulations, microbiome, cytokines and growths factors.

Conditions and MedDRA coding

Locally Advanced Rectal Cancer (LARC) stage II (T3-4N0M0) or stage III (TxN1-2M0)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. • Subjects with histologically confirmed primary (non-recurrent) LARC (tumor ≤<12 cm from the anal verge, as assessed by rigid proctoscopy), stage II (T3-4 N0 M0) or stage III (TX N1-2 M0) according to base-line pelvic MRI and PET-CT.
2. • Patients who are planned for TNT (total neoadjuvant treatment) and are surgical candidates as determined by the treating physician.
3. • No prior chemotherapy, immunotherapy, radiotherapy or surgery for rectal cancer.
4. • No prior radiotherapy to the pelvis, for any reason.
5. • Able to provide the FFPE block or 10 unstained slides from the colonoscopy for confirmation of the diagnosis, CPS (PD-L1 combined positive score) status and for investigational purposes.
6. • Age ≥ > 18 years.
7. • Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2.
8. • Screening laboratory values must meet the following criteria (using CTCAE v5.0): i) WBC ≥ 2000/µL ii) Neutrophils ≥ 1500/ µL iii) Platelets ≥ 100 x 10^3 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)
9. • Ability to swallow tablets.
10. • 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.
11. • 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.
12. • Women must not be breastfeeding.
13. • 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 12

1. • 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.
2. Patients with mismatch repair deficient (MMRd) / microsatellite instability- high (MSI-H) tumors.
3. Any evidence of interstitial lung disease or active, noninfectious pneumonitis
4. • Medical history of vasculitis.
5. • Prior organ transplant, including allogenic bone marrow transplantation.
6. • Grade > 1 peripheral sensory neuropathy.
7. • 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.
8. • 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).
9. • 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.
10. • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
11. • 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.
12. Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the 3-year TME-free survival rates (intention to treat, ITT)

Secondary endpoints 7

1. ­ 3-year TME-free survival (CPS≥1%)
2. ­ cCR
3. ­ DFS
4. ­ PFS
5. ­ OS rates
6. ­ safety and toxicity profile
7. ­ patient-reported functional outcomes and QoL (quality of life) with EORTC QLQ-C30 and CR-29

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Sponsor organisation

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Address

Langenbeckstrasse 1, Oberstadt Oberstadt

City

Mainz

Postcode

55131

Country

Germany

Scientific contact point

Organisation

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Contact name

Sponsor contact point clinical trials

Public contact point

Organisation

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Contact name

Sponsor contact point clinical trials

Rabin Medical Center

Sponsor organisation

Rabin Medical Center

Address

39 Zeev Jabotinsky Street

City

Petah Tikva

Postcode

4941492

Country

Israel

Sponsor responsibilities

Article 77 compliance

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Contact point sponsor

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Article 77 implementation

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications