Low-Dose Radiotherapy to Sensitize Pucotenlimab Plus CAPEOX for pMMR Locally Advanced Rectal Cancer

Summary

This is a prospective, open-label, randomized, parallel-group phase II trial evaluating the efficacy and safety of a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX as neoadjuvant therapy in patients with pMMR/MSS locally advanced rectal adenocarcinoma. Participants will be randomized 1:1 to receive either 2 Gy or 5 Gy low-dose radiotherapy. Low-dose radiotherapy is delivered as a single fraction of 2 Gy (Arm A) or 5 Gy (Arm B). On the day after radiotherapy, participants will start pucotenlimab 200 mg IV Q3W (administered on Day 2 of each 21-day cycle) plus CAPEOX chemotherapy. Early response will be assessed after 2 cycles using endoscopy and pelvic MRI to guide subsequent treatment: participants with partial response may discontinue radiotherapy and continue neoadjuvant systemic therapy; participants with stable disease may switch to standard chemoradiotherapy; participants with progressive disease will receive multidisciplinary-team-guided salvage therapy. After 4 cycles, participants with clinical complete response may adopt a watch-and-wait strategy; otherwise, they will undergo radical surgery 2-4 weeks after completion of neoadjuvant therapy. Long-term follow-up will include recurrence and survival outcomes and quality of life.

Eligibility

Inclusion Criteria

* Written informed consent provided prior to any study-specific procedures.
* Age 18 to 75 years at the time of enrollment.
* Histologically confirmed rectal adenocarcinoma.
* Tumor located within 10 cm from the anal verge, as assessed by endoscopy or imaging.
* Locally advanced disease, defined as clinical stage T2N+ or T3-T4a (any N) based on pelvic magnetic resonance imaging (MRI).
* Proficient mismatch repair (pMMR) or microsatellite-stable (MSS) tumor status confirmed by immunohistochemistry or molecular testing.
* No evidence of distant metastasis on preoperative imaging, including chest, abdominal, and pelvic computed tomography (CT).
* Circumferential resection margin (CRM) ≥2 mm and no involvement of the mesorectal fascia on baseline MRI.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Adequate organ function as defined by:
* Absolute neutrophil count ≥1.5 × 10⁹/L
* Platelet count ≥100 × 10⁹/L
* Hemoglobin ≥90 g/L
* Total bilirubin ≤1.5 × upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN
* Creatinine clearance ≥50 mL/min
* Thyroid-stimulating hormone (TSH) within normal limits
* Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for a protocol-defined period after the last dose.
* Men with partners of childbearing potential must agree to use effective contraception during the study and for a protocol-defined period after the last dose.

Exclusion Criteria

* Clinical T4b disease, defined as tumor invasion into adjacent organs or structures on baseline imaging.
* Circumferential resection margin (CRM) \<2 mm or definite involvement of the mesorectal fascia on baseline MRI.
* Evidence of distant metastasis outside the pelvis.
* Prior pelvic or abdominal radiotherapy.
* Prior treatment with immune checkpoint inhibitors or other systemic anticancer therapy for rectal cancer.
* Active or history of autoimmune disease requiring systemic treatment, except for conditions considered low risk for recurrence (e.g., vitiligo, resolved childhood asthma).
* Ongoing use of systemic immunosuppressive therapy, including corticosteroids equivalent to \>10 mg/day of prednisone, within 2 weeks prior to enrollment.
* Known human immunodeficiency virus (HIV) infection.
* Active hepatitis B virus infection with positive hepatitis B surface antigen and high viral load, or hepatitis C virus infection requiring treatment.
* Uncontrolled active infection or other serious medical condition that, in the investigator's judgment, would compromise patient safety or study compliance.
* History of another malignancy within 5 years, except for adequately treated basal cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies with negligible risk of recurrence.
* Known hypersensitivity or allergy to pucotenlimab, oxaliplatin, capecitabine, or any of their excipients.
* Pregnant or breastfeeding women.
* Any condition that, in the investigator's opinion, makes the participant unsuitable for study participation.

Conditions2

Interventions2

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