NCT07528209

Neoadjuvant CAPOX With or Without Pucotenlimab Plus Selective Radiotherapy for Locally Advanced Rectal Cancer

Neoadjuvant CAPOX Plus Pucotenlimab Combined With Selective Radiotherapy Versus CAPOX Combined With Selective Radiotherapy in Patients With Locally Advanced Rectal Cancer：A Multicenter, Phase III, Randomized Clinical Trial

• Status: Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 556 (estimated)
• Sponsor: Sun Yat-sen University · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

This is a multicenter, phase III, randomized controlled trial. Eligible patients with pMMR/MSS locally advanced rectal cancer will be randomized in a 1:1 ratio to either the experimental group or the control group using stratified randomization, with mesorectal fascia (MRF) status as the stratification factor. Patients in the experimental group will receive four cycles of CAPOX plus pucotenlimab. Patients in the control group will receive four cycles of CAPOX alone. Tumor response will then be assessed. Patients with tumor shrinkage ≥20% and no persistent tumor involvement of the mesorectal fascia will proceed directly to surgery. Patients with tumor shrinkage \<20% or persistent MRF-positive disease will receive short-course radiotherapy, followed by two additional cycles of CAPOX plus pucotenlimab in the experimental group or CAPOX alone in the control group. After completion of neoadjuvant treatment, efficacy will be reassessed, and the timing of surgery will be determined according to treatment response. Postoperative adjuvant therapy will be decided by the investigator.

Detailed description

Colorectal cancer (CRC) is the third most common malignancy worldwide. Rectal cancer accounts for more than half of CRC cases in many regions, making it a major clinical challenge. The standard treatment for locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy, total mesorectal excision (TME), and postoperative adjuvant chemotherapy. However, distant metastasis and postoperative complications remain major challenges. Total neoadjuvant therapy (TNT), by advancing adjuvant chemotherapy to the neoadjuvant phase, has significantly improved patient compliance and tumor response rates. The MSKCC study demonstrated a tumor response rate of up to 90% under the TNT regimen, with 30% of patients achieving pathological or clinical complete response (pCR or cCR). The TIMING trial further confirmed that TNT significantly increased the pCR rate without increasing side effects or surgical complications. Immunotherapy has shown significant efficacy in dMMR/MSI-H CRC. The NICHE study demonstrated that dual immunotherapy achieved 100% pathological response in dMMR colorectal cancer patients. However, pMMR/MSS CRC is not sensitive to immunotherapy, but some patients may still benefit from combined anti-angiogenesis agents (such as regorafenib) or CTLA-4 antibodies. The REGONIVO study showed an objective response rate (ORR) of 36.0% in pMMR/MSS CRC patients, while the RIN study further increased the ORR to 27.6%. Radiotherapy combined with immunotherapy has emerged as a new treatment modality for LARC. The UNION study found that short-term radiotherapy followed by sequential PD-1 antibody and CAPOX chemotherapy increased the pCR rate to 39.8%. The TORCH study explored the effectiveness of short-term radiotherapy combined with PD-1 antibody and CAPOX chemotherapy, achieving a CR rate of over 50%. The REGINA study went further, using short-term radiotherapy combined with regorafenib and nivolumab, achieving a CR rate of 44.4%. Although radiotherapy improves local control, it may cause significant short- and long-term toxicities, such as radiation enteritis, cystitis, and impaired anorectal, urinary, and sexual function. It may also increase surgical complexity and reduce postoperative quality of life. These concerns have driven growing interest in radiotherapy decline or even omission in selected patients. Neoadjuvant chemotherapy alone has therefore been investigated as an alternative approach. Studies such as PROSPECT, FOWARC, and the CONVERT study from our center suggest that neoadjuvant chemotherapy alone does not increase local recurrence or distant metastasis in selected patients, while substantially reducing radiation-related toxicity. In particular, the CONVERT study demonstrated that among patients with high-resolution MRI-defined negative circumferential resection margin risk, neoadjuvant chemotherapy was not inferior to conventional chemoradiotherapy. These findings provide proof of concept for a selective radiotherapy strategy. Based on this background, we propose the CONVERT-2 study, a multicenter phase III trial designed to evaluate neoadjuvant CAPOX plus pucotenlimab with selective radiotherapy versus CAPOX with selective radiotherapy in patients with pMMR/MSS locally advanced rectal cancer. We hypothesize that the addition of pucotenlimab will further increase tumor response, reduce the proportion of patients requiring radiotherapy, and maintain favorable safety and oncologic outcomes. If successful, this study may establish a more individualized neoadjuvant strategy for pMMR/MSS LARC, balancing treatment efficacy, toxicity reduction, and organ preservation.

Conditions

• Rectal Cancer
• pMMR (Microsatellite Stable Rectal Cancer)

Interventions

Type	Name	Description
DRUG	Pucotenlimab combine with CAPOX	Pucotenlimab will be administered at 200 mg intravenously on Day 1 every 3 weeks. Oxaliplatin will be administered at 130 mg/m² intravenously over more than 2 hours on Day 1 every 3 weeks. Capecitabine will be administered orally at 1000 mg/m² twice daily on Days 1 through 14 every 3 weeks. Patients in the experimental group will receive four cycles of CAPOX plus pucotenlimab. Tumor response will then be assessed. Patients with tumor shrinkage ≥20% and no persistent tumor involvement of the mesorectal fascia will proceed directly to surgery. Patients with tumor shrinkage \<20% or persistent MRF-positive disease will receive short-course radiotherapy, followed by two additional cycles of CAPOX plus pucotenlimab in the experimental group . After completion of neoadjuvant treatment, efficacy will be reassessed, and the timing of surgery will be determined according to treatment response. Postoperative adjuvant therapy will be decided by the investigator.
DRUG	CAPOX	Oxaliplatin will be administered at 130 mg/m² intravenously over more than 2 hours on Day 1 every 3 weeks. Capecitabine will be administered orally at 1000 mg/m² twice daily on Days 1 through 14 every 3 weeks. Patients in the control group will receive four cycles of CAPOX alone. Tumor response will then be assessed. Patients with tumor shrinkage ≥20% and no persistent tumor involvement of the mesorectal fascia will proceed directly to surgery. Patients with tumor shrinkage \<20% or persistent MRF-positive disease will receive short-course radiotherapy, followed by two additional cycles of CAPOX alone in the control group. After completion of neoadjuvant treatment, efficacy will be reassessed, and the timing of surgery will be determined according to treatment response. Postoperative adjuvant therapy will be decided by the investigator.

Timeline

• Start date: 2026-04-20
• Primary completion: 2032-04-20
• Completion: 2034-04-20
• First posted: 2026-04-14
• Last updated: 2026-04-14

Locations

1 site across 1 country: China