16-Hour Fasting Plus Serplulimab and CAPEOX as Neoadjuvant Therapy in pMMR/MSS Advanced Mid-to-Low Rectal Cancer

Neoadjuvant 16-Hour Fasting Combined With Serplulimab and CAPEOX for pMMR/MSS Locally Advanced Mid-to-Low Rectal Cancer: A Prospective, Single-Arm, Phase II Trial.

Although standard neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) effectively reduces local recurrence, radiotherapy-related toxicities and surgical complications severely impair patients' quality of life, making a radiotherapy-free strategy urgently needed. However, chemotherapy alone yields a pathological complete response (pCR) rate of only 6.6%-15%, which is far from satisfactory.

The pMMR/MSS subtype, accounting for 90% of rectal cancers, is "immune-cold" and shows almost no response to PD-1 monotherapy; nonetheless, chemotherapy can reshape the tumor immune microenvironment, and multiple studies have demonstrated that combining chemotherapy with PD-1 inhibitors (without radiotherapy) can elevate pCR rates to 26.8%-42.9%, yet further improvement remains desirable. A recent mechanistic study published in Cell Metabolism (2026) revealed that a single 16-hour fasting episode before treatment promotes isoleucine accumulation in the tumor microenvironment, which enhances CD8+T-cell cytotoxic function and reduces exhaustion through acetyl-CoA metabolism and epigenetic reprogramming, thereby significantly sensitizing PD-1 inhibitors-and this intervention is non-invasive, low-cost, and easily adoptable by patients.

Based on the above evidence, we hypothesize that the neoadjuvant triple-combination regimen of "16-hour fasting + chemotherapy + PD-1 inhibitor" (radiotherapy-free) in pMMR/MSS locally advanced mid-to-low rectal cancer may further increase pCR rates and tumor regression, offering a novel, highly effective, and low-toxicity therapeutic option for LARC patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Fasting, Intermittent; Locally Advanced Rectal Carcinoma; pMMR/MSS
• Intervention / Treatment: Behavioral: 16-Hour Fasting; Drug: Serplulimab + chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 51
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: feng Ke Ding; Phone Number: +86 13588425440; Email: dingkefeng@zju.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Male or female subjects ≧ 18 years ≦ 75 of age.
3. Histological or cytological documentation of adenocarcinoma of the rectum.
4. No previous any systemic anticancer therapy for rectal cancer disease.
5. The primary rectal tumor is assessed as likely to be R0 resectable by a multidisciplinary colorectal cancer collaborative team, comprising at least 2 gastrointestinal surgeons and 1 radiologist.
6. The lower margin of the tumor is less than 10cm from the anus verge.
7. cT2N1-2M0, cT3N0-2M0, cT4N0-1M0 MSS with MRF(-) assessed by MRI.
8. Primary tumor can be detected by CT or MRI.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Eligible tumor tissues were identified for MSI/MMR assays.
11. Hepatitis B Surface Antigen (HBsAg) (-).
12. If HBsAg (+) , HBV-DNA must be less than 2500 copies/mL or 500 IU/mL to be enrolled.
13. Patients with HCV antibody (-) or HCV-RNA negative can be enrolled. Aspartate aminotransferase (AST) must be ≤ 3 x ULN for the lab. If HCV-RNA is positive, patients with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) performed ≤3×ULN could be enrolled. Patients infected with both hepatitis B virus and hepatitis C virus should be excluded (positive for HBsAg or HBcAb and positive for HCV antibodies).

Exclusion Criteria:

1. Patients with recurrent rectal cancer or a history of pelvic radiotherapy.
2. Patients with a history of inflammatory bowel disease.
3. Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease (HIV1 antibody, HIV2 antibody, HTLV1 antibody positive) should be excluded.
4. Patients who are preparing for or have previously received an organ or bone marrow transplant.
5. History of myocardial infarction, poorly controlled arrhythmias (including QTc interval ≥470 ms in women) in the 6 months prior to enrollment (QTc interval calculated by Fridericia formula).
6. According to New York College of Cardiology (NYHA) standards for Grade III-IV cardiac insufficiency or cardiac color ultrasound: left ventricular ejection fraction (LVEF) <50%.Poor hypertension control (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg), a past hypertensive crisis or hypertensive encephalopathy.
7. Poor hypertension control (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg), a past hypertensive crisis or hypertensive encephalopathy.
8. Patients had undergone major surgery within 28 days prior to enrollment. Patients with tumor biopsy or lymph node dissection biopsy were admitted. Patients undergoing enterostomy due to intestinal obstruction were admitted.
9. The patients had previously been treated with other antibodies/drugs that target immune checkpoints, such as PD-1, PD-L1, and cytotoxic T lymphocyte-associated Antigen 4 (CTLA-4).
10. Patients are participating in other clinical studies, or plan to start this study treatment less than 14 days from the end of the previous clinical study.
11. Uncontrolled tumor-related pain.
12. A known history of severe allergy to any monoclonal antibody.
13. Known to be allergic or intolerance to any oxaliplatin and capecitabine ingredients.
14. Pregnant or lactating women.
15. The investigators determined that the patient had other factors that might have led to the early termination of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 16-Hour Fasting + Serplulimab + CAPEOX; Patients enrolled in the study are required to fast for 16 hours prior to the administration of serplulimab in combination with CAPEOX. Serplulimab: 300 mg, IV, d1, q3w. CAPEOX regimen: Oxaliplatin(130mg/m2) on day 1 of each cycle and Capecitabine, 1000mg/m2, PO, BID, day1-14, q3w. Treatment repeats every 3 weeks for 4 cycles followed by surgery (total mesorectal excision, TME).

Behavioral: 16-Hour Fasting; Patients begin fasting at 20:00 on the day prior to immunotherapy (only plain water is allowed) and continue until 10:00 the next morning, when serplulimab is administered. Fasting is maintained until 12:00 noon, after which normal diet may be resumed.; Drug: Serplulimab + chemotherapy; Serplulimab is an innovative monoclonal antibody targeting PD-1, developed by Shanghai Henlius Biotech, Inc. 300 mg, IV, d1, q3w. CAPEOX regimen: Oxaliplatin(130mg/m2) on day 1 of each cycle and Capecitabine, 1000mg/m2, PO, BID, day1-14, q3w. 4 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rates	Proportion of participants achieving pathological complete response (pCR) after neoadjuvant therapy.	10 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of clinical complete response rate(cCR)	Proportion of participants achieving clinical complete response (cCR) after neoadjuvant therapy.	1 year
R0 resection rates	Proportion of patients achieved a complete resection with negative margin	10 days after surgery
Disease Free Survival	Defined as the interval from enrollment to locoregional or metastatic recurrence or the appearance or a secondary colorectal cancer or death, whichever occurs first	3 years
Event free survival	Defined as the time from enrollment to the first occurrence of any of the following events: tumor disease progression on imaging as assessed by RECIST 1.1; tumor recurrence, including local recurrence or distant recurrence, as assessed on imaging or tissue biopsy transfer; death from any cause.	3 years
Overall survival (OS)	Defined as the time between the date of enrollment and death from any cause.	3 years
Treatment-related adverse events	Assessed by evaluation of treatment-related adverse events.	1 year
Single-Cell RNA Sequencing (scRNA-seq) of Tumor Microenvironment	Use single cell sequence to describe changes in the microenvironment of rectal cancer before and after treatment.	1 year
Spatial Transcriptomics Profiling of Tumor and Stroma	Explore spatial organization of gene expression within the tumor microenvironment and its association with treatment response using spatial transcriptomics.	1 year

Collaborators and Investigators

• Sponsor: Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: August 18, 2026
• First Submitted That Met QC Criteria: August 18, 2026
• First Posted (Actual): August 21, 2026

Study Record Updates

• Last Update Posted (Actual): September 8, 2026
• Last Update Submitted That Met QC Criteria: September 4, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Rectal cancer; neoadjuvant therapy; Serplulimab; CAPEOX; 16-hour fasting
• 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; Behavior; Feeding Behavior; Fasting; Rectal Neoplasms; Intermittent Fasting; Therapeutics; Drug Therapy
• Other Study ID Numbers: SCAR2

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