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

Sponsor: Sun Yat-sen University • ClinicalTrials.gov ID: NCT07448142

Registry updated: 2026-10-15

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Description

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. Tumor response will be assessed after two cycles using endoscopy and pelvic magnetic resonance imaging (MRI). Participants with non-progressive disease, defined as partial response (PR) or stable disease (SD), will receive no further low-dose radiotherapy and will continue pucotenlimab plus CAPEOX for cycles 3 and 4. Participants with local progressive disease, defined as enlargement of the rectal tumor, will receive salvage chemoradiotherapy according to the center's standard operating procedures. Participants who develop distant metastases will receive further treatment determined by a multidisciplinary team (MDT). After four cycles, participants who achieve a clinical complete response (cCR) may enter a watch-and-wait strategy. Participants without cCR and without progressive disease will undergo radical surgery according to total mesorectal excision (TME) principles. Participants with progressive disease will receive individualized treatment determined by the MDT.

Interventions

Low-dose radiotherapy (Radiation)
Low-dose radiotherapy is delivered to the primary rectal tumor and regional lymphatic drainage areas using IMRT or 3D-CRT. Participants receive one fraction at the start of each of the first two 21-day cycles: 2 Gy per fraction in Arm A (planned total dose 4 Gy) or 5 Gy per fraction in Arm B (planned total dose 10 Gy), excluding any salvage radiotherapy. No further low-dose radiotherapy is administered during cycles 3 and 4 in participants with PR or SD at the two-cycle assessment. Local progressive disease is managed with salvage chemoradiotherapy according to the center's SOP.
Pucotenlimab (Drug)
Pucotenlimab is a programmed cell death protein 1 (PD-1) monoclonal antibody. It is administered at a fixed dose of 200 mg by intravenous infusion on Day 2 of each 21-day cycle, every 3 weeks (Q3W), during the neoadjuvant treatment phase.
CAPEOX/XELOX (Drug)
CAPEOX chemotherapy consists of oxaliplatin 130 mg/m² administered intravenously on Day 1 and capecitabine 1000-1250 mg/m² administered orally twice daily on Days 1-14 of each 21-day cycle during neoadjuvant therapy.

Eligibility criteria

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). * 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. * 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.

Conditions

Colorectal Cancer (CRC)

Locations

Dept. of Colorectal Surgery, Sun Yat-sen University Cancer Center. Yuexiu District, Dongfeng East Road 651 — Guangzhou, Guanggong, China

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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

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