NCT06911684

Radiotherapy Plus Iparomlimab and Tuvonralimab (QL1706), Regorafenib, and CAPOX as Neoadjuvant Therapy for pMMR/MSS LARC.

Short-Term Radiotherapy Combined With Iparomlimab and Tuvonralimab (QL1706), Regorafenib, and CAPOX Neoadjuvant Therapy for Locally Advanced Rectal Cancer：A Multicenter, Prospective, Randomized, Phase II Clinical Trial

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 88 (estimated)
• Sponsor: Sun Yat-sen University · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

This study is a multicenter, prospective, randomized, double-arm, Phase II clinical trial designed to evaluate the efficacy of short-term radiotherapy combined with Iparomlimab and Tuvonralimab (QL1706), Regorafenib, and CAPOX as neoadjuvant therapy for locally advanced rectal cancer. Additionally, the study seeks to explore the relationship between biomarkers in blood, urine, feces, and tumor tissue and treatment efficacy. Eligible participants (pMMR/MSS locally advanced rectal cancer) were randomly assigned in a 1:1 ratio to two groups, with randomization stratified by MRF (+ vs. -). Participants will: * Group A patients received two cycles of QL1706, regorafenib, and CAPOX induction therapy, followed by sequential short-course radiotherapy, and then continued with four cycles of QL1706, regorafenib, and CAPOX consolidation therapy. * Group B patients received short-course radiotherapy followed by six cycles of QL1706, regorafenib, and CAPOX consolidation therapy. After two cycles of neoadjuvant therapy in Group A and six cycles in Group B, efficacy was evaluated and decisions regarding surgery or watchful waiting were made based on efficacy.

Detailed description

Colorectal cancer (CRC) is the third most common malignancy worldwide. 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%. Iparomlimab and Tuvonralimab (QL1706) is a bispecific antibody targeting PD-1 and CTLA-4, enhancing T cell activation and anti-tumor response through synergistic effects. In September 2024, QL1706 was approved for the treatment of recurrent or metastatic cervical cancer. Based on existing studies, short-term radiotherapy combined with immunotherapy (PD-1 antibody, CTLA-4 antibody), regorafenib, and CAPOX chemotherapy may significantly improve efficacy in pMMR/MSS LARC patients, warranting further exploration of its safety and effectiveness. Eligible participants (pMMR/MSS locally advanced rectal cancer) were randomly assigned in a 1:1 ratio to two groups, with randomization stratified by MRF (+ vs. -). Group A patients received two cycles of QL1706, regorafenib, and CAPOX induction therapy, followed by sequential short-course radiotherapy, and then continued with four cycles of QL1706, regorafenib, and CAPOX consolidation therapy. Group B patients received short-course radiotherapy followed by six cycles of QL1706, regorafenib, and CAPOX consolidation therapy. After two cycles of neoadjuvant therapy in Group A and six cycles in Group B, efficacy was evaluated and decisions regarding surgery or watchful waiting were made based on efficacy. Postoperative need for adjuvant therapy was determined by the investigator. Efficacy assessment: Patients achieving clinical complete response (cCR) could undergo a watch-and-wait strategy; patients with near cCR could undergo transanal local excision; patients with partial response (PR) or stable disease (SD) would undergo radical surgery. The need for postoperative adjuvant therapy was determined by the investigator. Patients with local progressive disease (PD) or distant metastasis were treated according to current guidelines.

Conditions

• Rectal Cancer Patients

Interventions

Type	Name	Description
COMBINATION_PRODUCT	lparomlimab and Tuvonralimab Injection and regorafenib and CPAOX and short-course radiotherapy	Group A patients received two cycles of QL1706, regorafenib, and CAPOX induction therapy, followed by sequential short-course radiotherapy, and then continued with four cycles of QL1706, regorafenib, and CAPOX consolidation therapy. lparomlimab and Tuvonralimab Injection(QL1706): 5 mg/kg, intravenous (IV), on Day 1, every 3 weeks (q3w) during the neoadjuvant treatment phase. Regorafenib:80 mg, oral (PO), once daily (qd), Days 1-14, every 3 weeks (q3w) during the neoadjuvant treatment phase. CAPOX: Oxaliplatin( 130 mg/m², IV over 2 hours, Day 1, every 3 weeks (q3w))+ Capecitabine( 1000 mg/m², PO, twice daily (bid), Days 1-14, every 3 weeks (q3w)). Short-course radiotherapy:The total dosage was 25Gy consisted of 5 fractions of 5 Gy to clinical target volume without a boost dose.
COMBINATION_PRODUCT	lparomlimab and Tuvonralimab Injection and regorafenib and CPAOX and short-course radiotherapy	Group B patients received short-course radiotherapy followed by six cycles of QL1706, regorafenib, and CAPOX consolidation therapy. lparomlimab and Tuvonralimab Injection(QL1706): 5 mg/kg, intravenous (IV), on Day 1, every 3 weeks (q3w) during the neoadjuvant treatment phase. Regorafenib:80 mg, oral (PO), once daily (qd), Days 1-14, every 3 weeks (q3w) during the neoadjuvant treatment phase. CAPOX: Oxaliplatin( 130 mg/m², IV over 2 hours, Day 1, every 3 weeks (q3w))+ Capecitabine( 1000 mg/m², PO, twice daily (bid), Days 1-14, every 3 weeks (q3w)). Short-course radiotherapy:The total dosage was 25Gy consisted of 5 fractions of 5 Gy to clinical target volume without a boost dose.

Timeline

• Start date: 2025-04-30
• Primary completion: 2026-04-30
• Completion: 2031-12-31
• First posted: 2025-04-04
• Last updated: 2025-04-23

Locations

1 site across 1 country: China