Arginine-Restricted Diet Combined With Chemoradiotherapy in Neoadjuvant Rectal Cancer: A Phase Ib/II Trial

This is a Phase Ib/II clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of an arginine-restricted diet combined with standard neoadjuvant chemoradiotherapy in patients with locally advanced middle/high rectal cancer. Background: Standard neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer to shrink tumors before surgery. However, the rate of complete tumor disappearance (pathological complete response) with standard treatment remains relatively low (around 10-20%). Arginine is an amino acid that supports tumor growth and immune escape. Preclinical studies and our previous Phase I trial (NCT07038044) suggest that restricting arginine in the diet can alter tumor metabolism and enhance the body's anti-tumor immune response. Study Design: The study consists of two phases. Phase Ib is a single-arm safety run-in, where 6 patients will receive the arginine-restricted diet plus standard chemoradiotherapy. Phase II is a randomized, open-label, controlled phase. Approximately 120 patients will be randomly assigned in a 1:1 ratio to either the experimental group or the control group. Neither the patient nor the doctor can choose the group. Interventions: Standard Treatment: All participants will receive standard CAPOX chemotherapy (oxaliplatin and capecitabine) and long-course radiotherapy. Arginine-Restricted Diet: Patients in the experimental group will consume a specially formulated, nutritionally complete, arginine-restricted nutritional powder combined with specific low-arginine foods for 7-8 weeks during the radiotherapy period, replacing their normal diet. Patients in the control group will maintain a normal diet. Objectives: The primary objective is to evaluate whether this dietary intervention can improve the complete response rate (including pathological complete response \[pCR\] and clinical complete response \[cCR\]) compared to standard treatment alone. Secondary objectives include assessing safety (adverse events), surgical outcomes (R0 resection rate), survival outcomes (event-free survival, progression-free survival, overall survival), and changes in nutritional and immune status.

Inclusion Criteria: * Signed written informed consent prior to any study-related procedures. * Male or female, aged 18 to 80 years. * Histologically or radiologically confirmed locally advanced middle/high rectal cancer (cT3, cT4, or lymph node positive) assessed by pelvic MRI. The distance from the lower edge of the tumor to the anal verge must be \>5 cm and ≤15 cm. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Nutritional Risk Screening (NRS-2002) score \< 3. * Body mass index (BMI) ≥ 18.5 kg/m² (may be relaxed to ≥ 17.0 kg/m² due to tumor hypermetabolism). * Ability to take oral food or enteral nutrition via a feeding tube, and able to tolerate enteral nutrition. * Adequate organ function, defined as: Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count ≥ 100 × 10\^9/L; Hemoglobin ≥ 9 g/dL; Serum albumin ≥ 3.0 g/dL; Total bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN; Creatinine clearance ≥ 50 mL/min or serum creatinine ≤ 1.5 × ULN; INR ≤ 1.5 × ULN, PT and APTT ≤ 1.5 × ULN; Urine protein \< 2+ (if ≥ 2+, 24-hour urine protein must be \< 2.0 g); Normal myocardial enzyme profile. * Women of childbearing potential must have a negative serum HCG test within 3 days prior to treatment, must not be lactating, and must agree to use effective contraception. * All subjects (male and female) with reproductive potential must agree to use highly effective contraception during the study and for at least 120 days (or 180 days after the last chemotherapy dose) after the last dose of study treatment. Exclusion Criteria: * Stage I or Stage IV rectal cancer. * Cognitive impairment or psychiatric illness preventing the patient from understanding the study content. * Central nervous system or meningeal metastases. * Clinically symptomatic moderate or severe ascites (requiring therapeutic paracentesis within 2 weeks before study treatment). * Uncontrolled, moderate, or severe pleural effusion and pericardial effusion. * Severe diarrhea, intractable vomiting, severe malabsorption syndrome, paralytic or mechanical ileus; tracheoesophageal fistula, gastrointestinal perforation or fistula, or intra-abdominal abscess; gastrointestinal bleeding (CTCAE Grade 3 or higher within 6 months, or Grade 2 or higher within 3 months prior to study treatment). * Other factors that may affect study results or lead to forced termination (e.g., alcoholism, drug abuse, severe concurrent diseases requiring combined treatment, significantly abnormal laboratory values, or social/family factors). * Known allergy to the active ingredients or excipients of the study drugs or nutritional powder. * Poorly controlled diabetes mellitus. * Severe cardiovascular and cerebrovascular diseases (e.g., cerebrovascular accident, transient ischemic attack, myocardial infarction within 6 months; unstable angina; NYHA Class II or higher heart failure; left ventricular ejection fraction \< 50%; or severe arrhythmia uncontrolled by medication). * Pregnant or lactating women. * Any other conditions deemed unsuitable for enrollment by the investigator.