Low-dose radiotherapy with pucotenlimab and 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

This trial will try adding a single low dose of radiotherapy to the immunotherapy drug pucotenlimab plus CAPEOX chemotherapy before surgery to see if it improves tumor response in people with pMMR/MSS locally advanced rectal cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Sun Yat-sen University (other)
• Drugs / interventions: pucotenlimab, prednisone, chemotherapy, immunotherapy
• Locations: 1 site (Guangzhou, Guanggong)
• Trial ID: NCT07448142 on ClinicalTrials.gov

What this trial studies

This randomized, open-label phase II trial enrolls patients with pMMR/MSS locally advanced rectal adenocarcinoma and randomizes them 1:1 to receive a single fraction of either 2 Gy or 5 Gy low-dose radiotherapy followed by pucotenlimab 200 mg IV every 3 weeks plus CAPEOX chemotherapy. Treatment response is assessed after two cycles using endoscopy and pelvic MRI to guide whether patients continue systemic therapy, switch to standard chemoradiotherapy, or receive alternative multidisciplinary care. The trial measures safety and tumor response as neoadjuvant outcomes, with subsequent surgical or organ-preserving decisions made according to response. All treatments and follow-up are performed at the sponsoring center with monitoring for adverse events and radiographic/clinical outcomes.

Who should consider this trial

Good fit: Adults 18–75 years with histologically confirmed rectal adenocarcinoma within 10 cm of the anal verge, clinical stage T2N+ or T3–T4a, pMMR/MSS status, no distant metastasis, CRM ≥2 mm on MRI, ECOG 0–1, and adequate organ function are the intended participants.

Not a fit: Patients with distant metastases, mesorectal fascia involvement or CRM <2 mm, poor performance status, prior pelvic radiotherapy, or tumors with deficient MMR (dMMR) are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could increase preoperative tumor response and raise the chance of organ preservation or reduced therapy before surgery.

How similar studies have performed: Preclinical data and early clinical reports suggest low-dose radiotherapy can boost immunotherapy responses and total neoadjuvant therapy with immunotherapy has improved pCR rates in some series, but the specific 2 Gy versus 5 Gy sensitization strategy for pMMR rectal cancer is novel and not yet proven.

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).
* 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.

Where this trial is running

Guangzhou, Guanggong

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

Study contacts

• Principal investigator: Pei-Rong Ding — Sun Yat-Sen University Cancer Center
• Study coordinator: Wu Jiang

Conditions: Colorectal Cancer, Colorectal cancer, Neoadjuvant therapy, Low-dose radiotherapy, Immunotherapy, Pucotenlimab, CAPEOX, Total neoadjuvant therapy