Neoadjuvant mFOLFOX6 Chemotherapy Combined With Anti-PD-1 Therapy in MSS/pMMR Locally Advanced Rectal Cancer (FIRM02 Study)

A Multicenter, Randomized Controlled Clinical Study of Neoadjuvant mFOLFOX6 Chemotherapy Combined With Anti-PD-1 Therapy in MSS/pMMR Locally Advanced Rectal Cancer (FIRM02 Study)

This multicenter, randomized controlled clinical trial (FIRM02 Study) aims to evaluate the effectiveness and safety of neoadjuvant mFOLFOX6 chemotherapy combined with PD-1 inhibitor (Serplulimab) in patients with MSS/pMMR locally advanced rectal cancer (LARC). A total of 128 patients with non-metastatic, untreated, locally advanced rectal cancer will be randomly assigned in a 1:1 ratio to either the experimental group (64 patients) or the control group (64 patients). The experimental group will receive 6 cycles of mFOLFOX6 chemotherapy combined with 3 mg/kg of Serplulimab every 2 weeks prior to surgery. The control group will receive 6 cycles of mFOLFOX6 chemotherapy alone. The primary endpoint is the pathological complete response (pCR), and secondary endpoints include major pathological response (MPR), tumor regression grade (TRG), overall response rate (ORR), and survival outcomes (DFS, RFS, and OS). Safety will be assessed based on adverse events and post-operative complications.

Inclusion Criteria:

1. Rectal cancer patients with MRI showing the lower edge of the tumor within 15 cm of the anal verge, cT3-4 N any or cT any N1/2;
2. Pathologically confirmed adenocarcinoma, with pMMR (MLH1, MSH2, MSH6, and PMS2) positivity for all four proteins, or gene testing indicating microsatellite stability;
3. No complete bowel obstruction, or proximal colostomy relieving bowel obstruction;
4. Aged 18 to 75 years, regardless of gender;
5. ECOG performance status: 0-1;
6. Expected survival time ≥2 years;
7. No previous chemotherapy, radiotherapy, targeted therapy, or immunotherapy;
8. Laboratory test results meeting the following criteria during screening:Hematology: Neutrophil count ≥1.5×10⁹/L, platelet count ≥75×10⁹/L, hemoglobin ≥80 g/L; Liver function: AST and ALT ≤2.5× upper limit of normal (ULN); total bilirubin ≤1.5×ULN; Kidney function: Serum creatinine ≤1.5×ULN; Coagulation function: APTT ≤1.5×ULN, INR ≤1.5, PT ≤1.5×ULN; Urine protein: Urine protein ≤1+ (if ≥2+, 24-hour urine protein test required, and if result <1g, inclusion is allowed); Cardiac left ventricular ejection fraction ≥50%;
9. Female participants must not be breastfeeding, and pregnancy test results must be negative;
10. Voluntary signing of the informed consent form, with the ability to understand and comply with the study requirements.

Exclusion Criteria:

1. Local invasion of surrounding organs by rectal tumor: Imaging tests suggest the tumor directly invades adjacent organs or structures, i.e., tumors with clinical stage cT4 below the peritoneal reflection or cT4b above the peritoneal reflection;
2. Patients with distant metastasis;
3. Previous treatment with any chemotherapy, radiotherapy, targeted therapy, or immunotherapy;
4. Active autoimmune diseases requiring systemic treatment (e.g., corticosteroids or immunosuppressants) within the past 2 years prior to enrollment;
5. History of HIV infection, or active chronic hepatitis B or C (high viral DNA load);
6. Currently receiving tuberculosis treatment or having received tuberculosis treatment in the past year prior to screening for active tuberculosis;
7. Known or suspected allergy to the study drugs or any drug related to the study;
8. Severe cardiovascular or cerebrovascular diseases;
9. Severe active infection or uncontrollable infection requiring systemic treatment, or unexplained fever >38.5°C within 14 days before the first dose;
10. Systemic corticosteroid treatment or other immunosuppressants within 14 days before the first dose, or immunostimulants within 4 weeks prior to the first dose;
11. Clear history of neurological or psychiatric disorders, including epilepsy or dementia;
12. Subjects who, for any other reason, may not be able to complete the study, or the investigator deems them unsuitable for inclusion;
13. Refusal to sign the informed consent form.