This is a Phase Ib/II seamless, open-label, randomized controlled trial evaluating the safety and efficacy of a serine/glycine-restricted diet combined with neoadjuvant chemoradiotherapy and immunotherapy in patients with locally advanced rectal cancer (LARC). The study consists of two phases. Phase Ib is a non-randomized, single-arm safety run-in phase enrolling 6 patients, all of whom will receive the experimental regimen (serine/glycine-restricted diet plus CAPOX chemotherapy, PD-1 inhibitor, and short-course radiotherapy). The primary objective of Phase Ib is to assess safety, tolerability, and dietary compliance. If the safety criteria are met (≥3 grade diet-related adverse event rate ≤20% and compliance rate ≥70%), the study will proceed to Phase II. Phase II is a randomized, open-label, parallel-controlled phase in which 134 additional patients will be randomized in a 1:1 ratio to either the experimental group (serine/glycine-restricted diet plus standard neoadjuvant chemoradiotherapy and immunotherapy) or the control group (standard neoadjuvant chemoradiotherapy and immunotherapy alone). The total enrollment is 140 patients (6 in Phase Ib + 134 in Phase II). The primary endpoint is the complete response rate (pCR + cCR). Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, mrTRG regression grade, event-free survival (EFS), progression-free survival (PFS), overall survival (OS), adverse event profile, changes in serum amino acid levels, quality of life (EORTC QLQ-C30), and nutritional status. Exploratory endpoints include gut microbiome diversity and tumor immune microenvironment changes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
140
A specialized liquid nutritional powder free of serine and glycine, supplemented with a list of permitted low-serine/glycine foods. Patients receive 30 kcal/kg/day energy and 1.5 g/kg/day protein for 4 weeks during the neoadjuvant treatment period.
Oxaliplatin 130 mg/m² IV on day 1 of each 3-week cycle, plus capecitabine 1000 mg/m² orally twice daily on days 1-14 of each cycle, for a total of 6 cycles.
PD-1 inhibitor administered intravenously every 3 weeks in combination with CAPOX chemotherapy as part of the neoadjuvant regimen.
25 Gy delivered in 5 fractions (5 Gy/fraction) over 1 week, administered during the second week of Cycle 1 (C2, Week 1), concurrent with capecitabine.
West China Hospital, Sichuan University
Chengdu, Sichuan, China
Complete Response Rate (pCR + cCR)
Time frame: At the time of surgery, approximately 6-8 weeks after completion of all 6 cycles of neoadjuvant chemoradiotherapy and immunotherapy
Major Pathological Response (MPR) Rate
Time frame: At the time of radical surgery, approximately 24 weeks after initiation of neoadjuvant treatment.
R0 Resection Rate
Time frame: At the time of radical surgery, approximately 24 weeks after initiation of neoadjuvant treatment.
mrTRG Regression Grade
Time frame: Up to approximately 24 weeks after initiation of neoadjuvant treatment (at the time of pre-surgery imaging assessment).
Event-Free Survival (EFS)
Time frame: Up to 5 years after randomization.
Progression-Free Survival (PFS)
Time frame: Up to 5 years after randomization.
Overall Survival (OS)
Time frame: Up to 5 years after randomization.
Incidence of Adverse Events
Time frame: From the start of study treatment through 30 days after the last dose of study treatment (approximately up to 22 weeks for the active treatment phase).
Changes in Serum Amino Acid Levels
Time frame: Baseline and at cycles 1, 2, and 3 (weeks 3, 6, and 9) during the intervention phase.
Quality of Life (EORTC QLQ-C30)
Time frame: Baseline, at cycles 1, 2, 3, 4, 5, 6 (weeks 3, 6, 9, 12, 15, 18), and at 30-day safety follow-up.
Nutritional Status
Time frame: Baseline, at cycles 1, 2, and 3 (weeks 3, 6, and 9), and at surgery.
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