Short-course RT Followed by NALIRIFOX Plus Pucotenlimab as Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer With MSS/pMMR

A Phase II Clinical Study of Short-course Radiotherapy Followed by NALIRIFOX Plus Pemolivimab as Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer With MSS/pMMR

The goal of this clinical trial is conducted to evaluate the neoadjuvant regimen of short-course radiotherapy (SCRT) followed by NALIRIFOX chemotherapy plus Pucotenlimab immunotherapy for high-risk locally advanced rectal cancer.

The main questions it aims to answer are:

1. Does this regimen increase the complete response rate ?
2. What medical problems (adverse events) do participants have when receiving this treatment? Researchers will evaluate this regimen compared to historical standard neoadjuvant chemoradiotherapy to see if it achieves a higher complete response rate and improves sphincter preservation.

Participants will:

1. Receive short-course radiotherapy (25Gy/5f) over 5 consecutive days.
2. Then receive NALIRIFOX chemotherapy every 2 weeks for 9 cycles and Pucotenlimab immunotherapy every 3 weeks for 6 cycles (total treatment duration approximately 6 months).
3. Regular checkups and tests during treatment.
4. Keep a diary of their symptoms and the number of times they use a rescue inhaler.

Inclusion Criteria:

1. Age: 18-70 years;
2. ECOG PS score: 0-1;
3. Pathologically confirmed rectal adenocarcinoma with immunohistochemistry and/or genetic testing showing MSS/pMMR status;
4. Lesion located ≤10 cm from the anal verge, confirmed by colonoscopy or digital rectal examination;
5. According to the 8th edition of the 2018 AJCC Cancer Staging Manual and the 2008 ESMO staging criteria for lower rectal cancer: patients with stage II/III rectal cancer staged by MRI or endorectal ultrasound, who have at least one of the following high-risk factors: cT4a with more than half the circumference of the bowel invaded (measured by MRI), cT4b (resectable), cT3 with tumor penetration ≥5 mm beyond the muscularis propria (T3c/d) and positive extramural venous invasion (EMVI+) (for mid-upper rectal tumors), cN2, MRF+ (≤2 mm); for lower rectal tumors located on the anterior wall, additional criteria include T3 stage and tumor occupying >50% of the bowel circumference; for tumors primarily located on the lateral-posterior wall in the lower rectum, tumor penetration through the bowel wall (internal anal sphincter) ≥5 mm; for tumors invading the external anal sphincter or levator ani muscle (staged as stage IV). Preoperative T staging is based on endorectal ultrasound and rectal MRI; N staging on abdominal CT; M staging on abdominal and chest CT. If symptoms are present, appropriate imaging studies (brain MRI or whole-body bone scan) should be performed. Patients with MRI contraindications may be cautiously included based on CT and endorectal ultrasound staging. All patient staging must be reviewed and confirmed by a multidisciplinary team (MDT).
6. No evidence of distant metastasis confirmed by comprehensive evaluation;
7. Primary rectal cancer patients who have not received prior surgery (except palliative stoma formation), radiotherapy, systemic chemotherapy, or other anti-tumor treatments before enrollment;
8. Normal organ function, meeting the following laboratory criteria: Hemoglobin (HB) ≥9 g/dL, white blood cell count (WBC) ≥3.5×10⁹/L, neutrophil count ≥1.5×10⁹/L, platelet count (PLT) ≥100×10⁹/L. Biochemical tests must meet the following standards: creatinine (Crea) and bilirubin (BIL) ≤1.0×ULN, ALT and AST ≤2.5×ULN, alkaline phosphatase (ALP) ≤2.5×ULN, total bilirubin (Tbil) ≤1.5×ULN;
9. No history of hypersensitivity to 5-FU class drugs or platinum-based agents;
10. No prior radiation therapy to the planned irradiation site;
11. Female participants of childbearing potential must undergo a pregnancy test (serum or urine) within 7 days prior to enrollment, with a negative result, and agree to use an effective method of contraception during the study and for 8 weeks after the last dose. Male participants must agree to use an effective method of contraception during the study and for 8 weeks after the last dose;
12. Participants must voluntarily enroll in the study, sign informed consent, demonstrate good compliance, and cooperate with follow-up visits.

Exclusion Criteria:

1. Prior pelvic radiotherapy;
2. Active or progressive infection requiring systemic treatment, such as active tuberculosis or active hepatitis;
3. Presence of uncontrolled systemic diseases, as determined by the investigator, including diabetes, hypertension, cirrhosis, rheumatological or autoimmune disorders, and severe pulmonary disease;
4. Clinically significant thyroid dysfunction (based on serum thyroid hormone levels TT4, TT3, FT3, FT4, and serum thyrotropin TSH), deemed unsuitable for study participation by the investigator. (5) History of hemorrhagic or thromboembolic events within the past 6 months, such as cerebrovascular accidents (including transient ischemic attacks), pulmonary embolism, or spontaneous major bleeding from tumors;

(6) Prior or concurrent diagnosis of other malignancies (including synchronous colorectal cancer), except for cured cases of cutaneous basal cell carcinoma and cervical carcinoma in situ; (7) Presence of any other disease, metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, raises concern about the patient's unsuitability for the investigational drug, may interfere with interpretation of study results, or places the patient at high risk; (8) Estimated insufficient compliance of the patient to participate in this clinical study; (9) History of gastrointestinal fistula, perforation, bleeding, severe peptic ulcer disease, or other serious gastrointestinal disorders; (10) Patients who have undergone solid organ or bone marrow transplantation, or those who have had an active autoimmune disease requiring systemic treatment within 2 years prior to the first dose.