Low-Dose Radiotherapy to Sensitize Pucotenlimab Plus CAPEOX for pMMR Locally Advanced Rectal Cancer
A Randomized, Two-Arm, Open-Label Phase II Trial of Low-Dose Radiotherapy Sensitization Combined With Pucotenlimab and CAPEOX as Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Adenocarcinoma
Sun Yat-sen University
50 participants
Mar 15, 2026
INTERVENTIONAL
Conditions
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 Criteria19
- 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 Criteria14
- 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.
Interventions
Low-dose radiotherapy delivered by linear accelerator to the primary rectal tumor and regional lymphatic drainage areas using IMRT or 3D-CRT techniques. Participants receive either 2 Gy or 5 Gy according to randomized assignment, administered prior to initiation of systemic neoadjuvant therapy.
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 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.
Locations(1)
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NCT07448142