Low-dose radiotherapy: 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: 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: 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.
Study 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
Sex
ALL
Min age
18 Years
Max age
75 Years
Healthy volunteers
No
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.
Primary outcome measure(s)
Complete Response Rate (CR) — From the start of neoadjuvant therapy until the completion of pre-operative assessment (approximately 12 weeks) and the time of surgery (approximately 14-16 weeks). The Combined CR rate is defined as the percentage of participants achieving either Clinical Complete Response (cCR) or Pathologic Complete Response (pCR). cCR is assessed via pelvic MRI, digital rectal examination (DRE), and endoscopy following the completion of 4 cycles of neoadjuvant therapy (each cycle is 21 days). For patients who do not achieve cCR and subsequently undergo radical surgery (scheduled 2-4 weeks after the last dose of neoadjuvant therapy), pCR is assessed by pathological examination of the resected surgical specimen (Tumor Regression Grading, TRG 0) according to the AJCC/College of American Pathologists (CAP) guidelines.
Trial sites (1)
Facility
City
Region
Status
Dept. of Colorectal Surgery, Sun Yat-sen University Cancer Center. Yuexiu District, Dongfeng East Road 651
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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