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.

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: mFOLFOX6; Drug: Serplulimab

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tingyu Wu, Ph.D.; Phone Number: +86-021-25077855; Email: wutingyu@xinhuamed.com.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mFOLFOX6+Serplulimab; Preoperative treatment with mFOLFOX6 chemotherapy combined with Serplulimab (3mg/kg) every 2 weeks, for a total of 6 cycles before surgery.	Drug: mFOLFOX6; Oxaliplatin 85 mg/m², intravenous infusion on Day 1; Fluorouracil 400 mg/m², intravenous infusion on Day 1; Fluorouracil 2400 mg/m², continuous infusion via chemotherapy pump for 46-48 hours; Leucovorin calcium 400 mg/m², intravenous infusion on Day 1 (or Levoleucovorin 200 mg/m², intravenous infusion).; Drug: Serplulimab; 3 mg/kg, intravenous infusion, Day 1.
Active Comparator: mFOLFOX6; Preoperative treatment with mFOLFOX6 chemotherapy every 2 weeks, for a total of 6 cycles before surgery.	Drug: mFOLFOX6; Oxaliplatin 85 mg/m², intravenous infusion on Day 1; Fluorouracil 400 mg/m², intravenous infusion on Day 1; Fluorouracil 2400 mg/m², continuous infusion via chemotherapy pump for 46-48 hours; Leucovorin calcium 400 mg/m², intravenous infusion on Day 1 (or Levoleucovorin 200 mg/m², intravenous infusion).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pathological Complete Response Rate (pCR)	Day 7 after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor regression grade		Day 7 after surgery
Major Pathological Response (MPR)		Day 7 after surgery
Objective Response Rate		Pre-neoadjuvant therapy, Post-neoadjuvant therapy.
R0 resection rate		Day 7 after surgery
Sphincter preservation rate		Surgical date
Overall Survival		Five years after surgery
Recurrence-Free Survival		Five years after surgery
Disease-Free Survival		Five years after surgery
Treatment-Related Adverse Events		Adverse events are evaluated the day before each chemotherapy cycle, up to 90 days after the last neoadjuvant treatment.
Surgical-related complications		Within 1 month post-surgery
Neoadjuvant rectal score	The Neoadjuvant Rectal Score (NAR) ranges from 0 to 100, with lower scores indicating better neoadjuvant efficacy.	Day 7 after surgery

Collaborators and Investigators

• Sponsor: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: January 25, 2026
• First Submitted That Met QC Criteria: January 25, 2026
• First Posted (Actual): February 2, 2026

Study Record Updates

• Last Update Posted (Actual): February 3, 2026
• Last Update Submitted That Met QC Criteria: January 30, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: rectal cancer; neoadjuvant therapy; PD1 inhibitor; microsatellite stable; pMMR
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms
• Other Study ID Numbers: XHEC-C-2025-300-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In this study personal information and data such as patient history, physical examination results, surgical records, and study questionnaire data will be collected. These data will be used to evaluate the efficacy and safety of the therapeutic regimen and for academic publication. The researcher will treat the personal data of patients confidentially and anonymize the data and information in any public release of the results of the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No