Neoadjuvant Chemoradiotherapy Plus Tislelizumab With or Without Probio-M9 in pMMR/MSS Locally Advanced Rectal Cancer

Official title

Neoadjuvant Chemoradiotherapy Combined With Tislelizumab With or Without Probio-M9 in pMMR/MSS Locally Advanced Middle and Low Rectal Cancer: A Single-Center, Prospective, Randomized Controlled Trial (NCRIT-PM9 Trial)

Overview

This prospective, single-center, randomized controlled trial aims to assessing the efficacy and safety of neoadjuvant chemoradiation plus Tislelizumab (PD-1 inhibitor) with or without Probio-M9 and subsequent TME surgery, by comparing assorted endpoints between two experiment groups (Experiment group 1: chemoradiation+PD-1 inhibitor+Probio-M9; Experiment group 2: chemoradiation+PD-1 inhibitor+placebo) with a control group (chemoradiation only).

Detailed description

Patients with clinically staged II-III pMMR/MSS locally advanced rectal adenocarcinoma (≤10 cm from anal verge) will receive long-course chemoradiotherapy (50 Gy/25 fractions) with concurrent Capecitabine, followed by two cycles of CapeOX chemotherapy and Tislelizumab (200 mg IV every 3 weeks). Participants will be randomized to receive either daily oral Probio-M9 (2 g) or matched placebo from treatment initiation until surgery.

Interventions

• Combination product CRT+PD-1 inhibitor+Probio-M9
  Chemoradiation with PD-1 inhibitor (tislelizumab), with or without Probio-M9. Probio-M9 is administered orally at a dose of 2 g (one sachet) once daily. Treatment begins at the initiation of neoadjuvant chemoradiotherapy and continues until the day before surgical resection.
• Combination product CRT+PD-1 inhibitor+placebo
  Chemoradiation with PD-1 inhibitor (tislelizumab) with placebo. Placebo is administered orally at a dose of 2 g (one sachet) once daily. Treatment begins at the initiation of neoadjuvant chemoradiotherapy and continues until the day before surgical resection.

Primary outcome measures

• pCR rate [Time frame: within 10 days after surgery]

Secondary outcome measures (8)

• 2-y OS rate [Time frame: 2 year]
• 2-y DFS rate [Time frame: 2 year]
• 3-y OS rate [Time frame: 3 year]
• 3-y DFS rate [Time frame: 3 year]
• 5-y OS rate [Time frame: 5 year]
• 5-y DFS rate [Time frame: 5 year]
• immune-related adverse event rate [Time frame: from commencing of PD-1 inhibition to the 30th day after surgery]
• Changes in Gut Microbiota Composition [Time frame: Stool samples will be collected at baseline (Day 1), Day 25 during treatment, and prior to surgery.]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• ECOG performance status 0-2
• Biopsy-proven rectal adenocarcinoma
• Distal tumor margin within 10 cm of the anal verge
• No distant metastasis
• Clinical stage II or III based on MRI (T4b excluded)
• Maximum diameter of rectal tumor ≥ 10 mm on baseline CT or MRI (measurable lesion according to RECIST 1.1)
• Willing and able to comply with the study protocol
• Willing to provide blood and tissue specimens for research purposes
• No prior anti-tumor treatment (e.g., radiotherapy, chemotherapy, immunotherapy, biological therapy, or herbal therapy)
• No history of immune system disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis, HIV infection, etc.)
• No significant dysfunction of major organs (heart, lung, liver, kidney)
• No jaundice or gastrointestinal obstruction
• No acute or ongoing infection
• Adequate hematologic and biochemical function including:

• Neutrophils ≥ 1.5 × 10\^9/L
• Hemoglobin ≥ 80 g/L
• Platelets ≥ 100 × 10\^9/L
• Serum creatinine ≤ 1.5 × ULN
• Total bilirubin ≤ 1.5 × ULN
• ALT and AST ≤ 2.5 × ULN
• No social or psychiatric disorders that may interfere with study participation
• Women of childbearing potential must have a negative pregnancy test before enrollment and must use effective contraception from study entry until 60 days after the last dose of study drug

Exclusion criteria

• History of multiple primary cancers or concomitant malignant tumors other than rectal cancer
• Receipt of any anti-cancer treatment (e.g., surgery, chemotherapy, radiotherapy, or other systemic therapies) within the past 5 years
• History of recent major surgery
• Conditions that may affect the gastrointestinal absorption of capecitabine (e.g., inability to swallow, persistent nausea or vomiting, chronic diarrhea)
• Uncontrolled or severe concomitant diseases of any kind
• Known allergy or hypersensitivity to any components of the study drugs
• Estimated life expectancy ≤ 5 years due to any cause
• Planned or prior organ or bone marrow transplantation
• Use of immunosuppressive therapy or systemic corticosteroids for immunosuppressive purposes within 1 month prior to enrollment
• History of central nervous system disorders that may impair the ability to provide informed consent or affect compliance with oral medication (investigator discretion)
• Other conditions that may interfere with study results or lead to premature discontinuation of study treatment (e.g., alcoholism or drug abuse)
• Pregnant or breastfeeding women, or women planning to become pregnant during the treatment period

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Seventh Medical Center of Chinese PLA General Hospital — Beijing

Identifiers

NCT: NCT07458529 · S2026-010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗