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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
88
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.
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.
Dept. of Colorectal Surgery, Sun Yat-sen University Cancer Center. Yuexiu District, Dongfeng East Road 651
Guangzhou, Guangdong, China
RECRUITINGComplete response (CR)
Complete response: Pathological complete response and clinical complete response
Time frame: 1 year
Objective response rate (ORR)
The proportion of patients achieving a complete response (CR) or partial response (PR), evaluated according to RECIST v1.1.
Time frame: 1 year
Major Pathological Response (MPR)
The proportion of patients whose primary tumor shows ≤10% residual tumor cells on pathology.
Time frame: 1 year
Tumor Regression Grade (TRG)
Assessed based on the 8th edition of the AJCC staging system to grade the extent of tumor regression
Time frame: 1 year
R0 Resection Rate
The proportion of surgical patients who achieve an R0 resection. R0 resection: All gross disease has been removed, and microscopic examination reveals all surgical margins free of tumor.
Time frame: 1 year
Organ Preservation Rate (OPR)
The 1-year organ preservation rate is the percentage of patients attaining a complete clinical response (cCR) or near-complete clinical response (near-cCR) following neoadjuvant therapy, who then proceeded with non-surgical management or local excision, was monitored under a Watch \& Wait strategy or for 1 year post-local resection without undergoing radical surgery.
Time frame: 1 year
Event-free survival (EFS)
EFS is defined as the time from randomization to the earliest occurrence of any of the following events: Tumor progression by imaging according to RECIST 1.1, Tumor recurrence (local or distant), confirmed by imaging or biopsy, for patients with no residual tumor after surgery, Death from any cause. Note: A second primary malignancy is not considered an EFS event.
Time frame: 2 years
Overall survival (OS)
The time interval between the date of randomization to the date of death. If the patient has been alive, the time until the last follow-up is taken as the overall survival period.
Time frame: 5 years
Incidence of adverse events
Assessed by Common Terminology Criteria for Adverse Events version 4.0. The overall adverse event rates and the immune-related adverse event rates will be compared between treatment arms using Chi-square test or Fisher's exact test, as appropriate.
Time frame: up to 30 days after last treatment
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