PD-1 + FOLFOXIRI vs CAPOX as Total Neoadjuvant Therapy for pMMR Low Rectal Cancer

A Multicenter, Prospective, Phase III Randomized Controlled Trial of PD-1 Antibody Plus FOLFOXIRI Combined With Radiotherapy Versus CAPOX Combined With Radiotherapy as Total Neoadjuvant Therapy for pMMR Locally Advanced Low Rectal Cancer

The goal of this clinical trial is to find out if adding a PD-1 antibody (serplulimab) to FOLFOXIRI chemotherapy and radiotherapy works better than CAPOX chemotherapy with radiotherapy as total neoadjuvant therapy for adults with pMMR locally advanced low rectal cancer. It will also look at the safety of these treatments and how they affect long-term outcomes such as organ preservation and survival.

The main questions it aims to answer are:

Does PD-1 antibody plus FOLFOXIRI with radiotherapy improve 3-year event-free survival compared with CAPOX with radiotherapy?

Does this treatment increase the chance of clinical complete response and avoiding a permanent stoma (sphincter-preserving or non-surgical "watch-and-wait" management)?

What side effects and medical problems occur during and after these treatments?

Researchers will compare:

Group A (experimental group): PD-1 antibody (serplulimab) plus FOLFOXIRI chemotherapy combined with long-course radiotherapy as total neoadjuvant therapy.

Group B (control group): CAPOX chemotherapy combined with long-course radiotherapy as total neoadjuvant therapy.

Participants will:

Sign an informed consent form and have screening tests (physical exam, blood tests, ECG, imaging such as MRI/CT, endoscopy) to confirm they can join the trial.

Be randomly assigned (like drawing lots) to Group A or Group B. Receive several cycles of chemotherapy together with a 5-week course of pelvic radiotherapy before surgery; the experimental group will also receive PD-1 antibody during part of the chemotherapy and radiotherapy period.

Have regular clinic visits for checkups, blood tests, and assessment of side effects during treatment.

After neoadjuvant therapy, have MRI/CT and endoscopy to assess tumor response. Depending on the response, they may:

Receive surgery to remove the rectal tumor, or

If a clinical complete response is achieved and both doctor and patient agree, enter a "watch-and-wait" program instead of immediate surgery.

Provide blood samples and allow tumor tissue to be collected (for example, from biopsy and surgery) for future research (such as building PDX models and testing blood markers).

Be followed regularly for at least 5 years with clinic visits, blood tests (including CEA), imaging, and colonoscopy to check for tumor recurrence, side effects, and quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Low Rectal Adenocarcinoma; pMMR (Microsatellite Stable Rectal Cancer)
• Intervention / Treatment: Drug: Serplulimab; Drug: FOLFOXIRI chemotherapy; Radiation: Long-course pelvic radiotherapy; Drug: CAPOX chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 382
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Junzhong Lin, MD; Phone Number: +862087343124; Email: linjzh@sysucc.org.cn

Study Locations

• China
  • None Selected
    • Guangzhou, None Selected, China, 510060
      • Sun Yat-sen University Cancer Center
      • Contact: Junzhong Lin; Phone Number: 02087343124; Email: linjzh@sysucc.org.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed rectal adenocarcinoma.
• pMMR status documented by immunohistochemistry (MSH1, MSH2, MSH6 and PMS2 all positive) or by MSI testing showing MSS or MSI-L.
• Primary tumor located within 5 cm from the anal verge on pelvic MRI.
• Clinical stage cT3-4bN0M0 or cTxN+M0, with or without positive mesorectal fascia (MRF) and/or extramural vascular invasion (EMVI), and assessed by the multidisciplinary team as resectable with the potential for R0 resection.
• No clinical or radiologic evidence of bowel obstruction.
• No prior colorectal surgery.
• No prior chemotherapy or radiotherapy.
• No prior treatment with biologic agents (e.g., monoclonal antibodies), immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4), or other investigational drugs.
• Age 18 to 75 years (inclusive).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Estimated life expectancy > 2 years.
• Adequate bone marrow function: WBC > 3.5 × 10^9/L; platelets > 100 × 10^9/L; hemoglobin > 80 g/L.
• Adequate liver function: ALT and AST ≤ 1.5 × upper limit of normal (ULN); total bilirubin < 23.0 μmol/L.
• Adequate renal function: eGFR ≥ 60 mL/min/1.73 m² (CKD-EPI) or creatinine clearance (Ccr) ≥ 60 mL/min.
• Ability to understand and willingness to sign a written informed consent form.

Exclusion Criteria:

• Evidence of inguinal or lateral pelvic lymph node metastasis (lymph node short-axis diameter ≥ 7 mm or MRI features typical for metastatic lymph nodes).
• Clinically significant cardiac disease, including arrhythmias requiring anti-arrhythmic treatment (except β-blockers or digoxin), symptomatic coronary artery disease or myocardial ischemia (myocardial infarction within the last 6 months), or congestive heart failure > NYHA class II.
• Uncontrolled severe hypertension.
• History of HIV infection or active chronic hepatitis B (HBV DNA > 2 × 10^3 IU/mL) or hepatitis C (HCV RNA > 1 × 10^3 IU/mL).
• Active pulmonary tuberculosis under treatment or having received anti-tuberculosis therapy within 1 year before screening.
• Other active severe infections (as defined by NCI-CTCAE v5.0).
• Evidence of distant metastasis outside the pelvis before treatment.
• Cachexia or decompensated organ dysfunction.
• Prior pelvic or abdominal radiotherapy.
• Multiple primary colorectal cancers.
• History of seizures requiring ongoing treatment (e.g., corticosteroids or anti-epileptic drugs).
• History of another malignancy within the past 5 years, except adequately treated cervical carcinoma in situ or basal cell carcinoma of the skin.
• Drug or alcohol abuse, or any medical, psychological, or social condition that, in the investigator's judgment, could interfere with study participation or the evaluation of study results.
• Any active autoimmune disease or history of autoimmune disease (including but not limited to interstitial pneumonia, uveitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, or hypothyroidism).
• Receipt of any prophylactic vaccine against infectious diseases (e.g., influenza, varicella) within 4 weeks before enrollment.
• Requirement for long-term immunosuppressive therapy or systemic/local corticosteroids at immunosuppressive doses (equivalent to > 10 mg/day of prednisone or other corticosteroids).
• Known or suspected allergy or hypersensitivity to any study drug or to any component of the study treatments.
• Any unstable condition or other circumstance that may, in the opinion of the investigator, compromise patient safety or study compliance.
• Pregnant or breastfeeding women, or women of childbearing potential who are unwilling or unable to use adequate contraception during the study.
• Refusal or inability to provide written informed consent.

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: Experimental: Serplulimab + FOLFOXIRI + Radiotherapy; Participants in this arm will receive a PD-1 antibody (serplulimab) in combination with FOLFOXIRI chemotherapy and long-course pelvic radiotherapy as total neoadjuvant therapy before surgery. Treatment will be given according to the study protocol, with regular safety monitoring and response assessments.	Drug: Serplulimab; Serplulimab will be administered intravenously in combination with FOLFOXIRI chemotherapy and long-course pelvic radiotherapy as part of total neoadjuvant therapy in the experimental arm.; Other Names: PD-1 antibody; Drug: FOLFOXIRI chemotherapy; The FOLFOXIRI chemotherapy regimen (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) will be administered according to the study protocol as part of total neoadjuvant therapy in the experimental arm, in combination with serplulimab and long-course pelvic radiotherapy.; Other Names: 5-fluorouracil, leucovorin, oxaliplatin, irinotecan; Radiation: Long-course pelvic radiotherapy; Long-course pelvic external beam radiotherapy will be delivered according to institutional standards as part of total neoadjuvant therapy in both study arms, in combination with chemotherapy (FOLFOXIRI plus serplulimab in the experimental arm or CAPOX in the active comparator arm).; Other Names: External beam radiotherapy; Pelvic radiotherapy
Active Comparator: Active Comparator: CAPOX + Radiotherapy; Participants in this arm will receive CAPOX chemotherapy and long-course pelvic radiotherapy as total neoadjuvant therapy before surgery. Treatment will be given according to the study protocol, with regular safety monitoring and response assessments.	Radiation: Long-course pelvic radiotherapy; Long-course pelvic external beam radiotherapy will be delivered according to institutional standards as part of total neoadjuvant therapy in both study arms, in combination with chemotherapy (FOLFOXIRI plus serplulimab in the experimental arm or CAPOX in the active comparator arm).; Other Names: External beam radiotherapy; Pelvic radiotherapy; Drug: CAPOX chemotherapy; The CAPOX chemotherapy regimen (capecitabine plus oxaliplatin) will be administered according to the study protocol as part of total neoadjuvant therapy in the active comparator arm, in combination with long-course pelvic radiotherapy.; Other Names: Capecitabine plus oxaliplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Event-Free Survival (EFS)	Event-free survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: (1) locoregional failure, including unresectable primary tumor after completion of total neoadjuvant therapy, R2 resection (macroscopic residual tumor), or local bed recurrence after R0-R1 resection; (2) distant metastasis; (3) new invasive primary colorectal cancer; or (4) death from any cause. Patients without an event at the time of analysis will be censored at the date of the last tumor assessment.	Up to 3 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Complete Response (cCR) Rate	Proportion of participants achieving clinical complete response (cCR) after completion of total neoadjuvant therapy. cCR will be assessed by digital rectal examination, endoscopy, pelvic MRI and serum CEA according to predefined criteria (no palpable tumor, endoscopic whitening or telangiectasia only, fibrotic signal on MRI without residual tumor or nodes, and normal CEA).	At 10-14 weeks after completion of radiotherapy (response assessment prior to definitive management)
Anal Sphincter Preservation Rate	Proportion of participants who achieve anal sphincter preservation, defined as undergoing sphincter-preserving surgery (e.g., low anterior resection, intersphincteric resection) or managed with a watch-and-wait strategy without permanent stoma at last follow-up.	From randomization to definitive management (surgery or decision for watch-and-wait) and last follow-up, up to approximately 1 year after randomization
Incidence of Treatment-related Adverse Events During Total Neoadjuvant Therapy	Number and proportion of participants experiencing treatment-related adverse events during total neoadjuvant therapy, graded according to NCI-CTCAE version 5.0. Both overall adverse events and grade 3-5 toxicities related to chemotherapy, immunotherapy, or radiotherapy will be summarized.	From first dose of study treatment until 30-90 days after completion of chemotherapy/radiotherapy or surgery, up to approximately 1 year after randomization

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): December 29, 2025
• Primary Completion (Estimated): December 29, 2028
• Study Completion (Estimated): December 29, 2028

Study Registration Dates

• First Submitted: November 30, 2025
• First Submitted That Met QC Criteria: November 30, 2025
• First Posted (Actual): December 11, 2025

Study Record Updates

• Last Update Posted (Actual): December 11, 2025
• Last Update Submitted That Met QC Criteria: November 30, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: PD-1 antibody; serplulimab; total neoadjuvant therapy; watch-and-wait; pMMR locally advanced rectal cancer
• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Camptothecin; Alkaloids; Enzymes and Coenzymes; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Deoxyribonucleosides; Capecitabine; Oxaliplatin; Irinotecan; Fluorouracil; Leucovorin; spartalizumab
• Other Study ID Numbers: 2025-FXY-302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No