This is a prospective, multicenter, open-label, single-arm Phase II study designed to evaluate the efficacy and safety of total neoadjuvant mFOLFOX6 combined with suvemcitug and enlonstobart in patients with MRI（Magnetic Resonance Imaging）-defined high-risk, mid-rectal, locally advanced rectal adenocarcinoma with pMMR/MSS status.
All enrolled participants will receive 6 cycles of mFOLFOX6 plus suvemcitug and enlonstobart every 2 weeks. After 6 cycles, participants will undergo reassessment with pelvic MRI and systemic imaging. Participants who achieve at least 20% tumor regression on MRI without new high-risk radiologic features will continue with 2 additional cycles of mFOLFOX6 followed by radical total mesorectal excision surgery, without routine pelvic radiotherapy. Participants who do not meet the predefined regression threshold or show disease progression will receive long-course chemoradiotherapy with concurrent capecitabine, followed by 3 cycles of mFOLFOX6 and radical surgery.
Age 18 to 75 years, male or female.
Histologically confirmed rectal adenocarcinoma.
pMMR or MSS status confirmed by genetic testing or immunohistochemistry.
Tumor lower margin located 5-12 cm from the anal verge, based on colonoscopy or MRI, consistent with mid-rectal cancer.
Imaging evidence of cT4 disease, mesorectal fascia positivity, or lateral lymph node metastasis.
Prior pelvic radiotherapy or prior systemic antitumor treatment for the current disease, including chemotherapy, targeted therapy, or immunotherapy.
Special histologic subtypes, including mucinous adenocarcinoma, signet-ring cell carcinoma, undifferentiated carcinoma, or other special histologic types.
Known allergy or contraindication to any component of the study drugs, including oxaliplatin, 5-fluorouracil, suvemcitug, or enlonstobart.
Single group
mFOLFOX6
DrugOxaliplatin 85 mg/m2 IV over 2 hours on Day 1; leucovorin calcium 400 mg/m2 IV over 2 hours on Day 1; 5-fluorouracil 400 mg/m2 IV bolus on Day 1; 5-fluorouracil 2400 mg/m2 continuous IV infusion over 46-48 hours;every 2 weeks, for 6 cycles during the initial total neoadjuvant treatment phase. Participants meeting the predefined MRI regression criterion will receive 2 additional cycles of mFOLFOX6 before surgery. Participants requiring chemoradiotherapy will receive 3 additional cycles of mFOLFOX6 after long-course chemoradiotherapy before surgery.
Suvemcitug
DrugSuvemcitug 2 mg/kg IV infusion on Day 1 of each 14-day cycle, every 2 weeks, for 6 doses during the initial total neoadjuvant treatment phase.
Enlonstobart
DrugEnlonstobart 240 mg IV infusion on Day 1 of each 14-day cycle, every 2 weeks, for 6 doses during the initial total neoadjuvant treatment phase.
Pelvic Chemoradiotherapy
RadiationUsed selectively for participants who do not achieve the predefined interim MRI regression threshold or who show disease progression. 45-50.4 Gy in 25-28 fractions. Oral capecitabine during radiotherapy.
Total Mesorectal Excision
Procedure/SurgeryFor participants omitting radiotherapy: approximately 2-4 weeks after completion of total neoadjuvant systemic therapy. For participants receiving chemoradiotherapy: after long-course chemoradiotherapy and subsequent mFOLFOX6 treatment, according to investigator assessment.
Pathologic Complete Response Rate
R0 Resection Rate
Circumferential Resection Margin Negative Rate
Major Pathologic Response Rate
Proportion of Participants Receiving Pelvic Radiotherapy
Correlation between changes in plasma cell-free RNA (cfRNA) signature scores and tumor regression.
The correlation between longitudinal changes in plasma cell-free RNA (cfRNA) signature scores and rumor regression will be assessed. Plasma cfRNA will be measured by high-throughput RNA sequencing using the SLiPiR-seq (Splint Ligation and Phosphate-independent RNA Sequencing) method. Normalized cfRNA expression data will be used to calculate predefined or exploratory transcriptomic signature scores, including tumor-related and immune-related signature scores. The change in each cfRNA signature score from baseline (T1, before initiation of neoadjuvant treatment) to the preoperative assessment (T2, after completion of neoadjuvant treatment) will be calculated as the absolute and/or relative change in normalized signature score. The strength of the relationship between the change in cfRNA signature score and tumor regression will be quantified using the Spearman rank correlation coefficient.
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