This is a multicenter, prospective, phase II study evaluating total neoadjuvant therapy (TNT) consisting of short-course radiotherapy (SCRT; 5×5 Gy) followed by QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, code name only) plus mFOLFOX6 chemotherapy in patients with locally advanced rectal cancer (LARC) with proficient mismatch repair/microsatellite-stable (pMMR/MSS) biology. Patients with pMMR/MSS disease derive limited benefit from immune checkpoint inhibition alone. Preclinical and clinical evidence suggests that SCRT and oxaliplatin-based chemotherapy can enhance antitumor immunity (e.g., antigen release, T-cell infiltration), providing a biological rationale for combining QL1706 with SCRT-primed TNT.
Eligible adults with cT3-4 and/or N+ mid-to-low rectal adenocarcinoma (without distant metastasis), confirmed pMMR/MSS, and ECOG 0-1 will receive: SCRT (total 25 Gy over 5 fractions), then several cycles of QL1706 plus mFOLFOX6 as neoadjuvant systemic therapy. Definitive total mesorectal excision (TME) is planned per multidisciplinary assessment; a watch-and-wait approach may be considered for patients achieving a stringent clinical complete response per institutional criteria. Standard perioperative care and postoperative follow-up will be performed.
Primary endpoint is pathologic complete response (pCR, ypT0N0) rate at surgery. Key secondary endpoints include: clinical complete response (cCR) rate, major pathologic response rate, R0 resection rate, tumor downstaging, radiologic response, disease-free survival (DFS), overall survival (OS), organ preservation rate (for patients managed non-operatively), surgical morbidity, and safety/tolerability (CTCAE v5.0). Exploratory endpoints include correlations between efficacy and baseline clinicopathologic features; optional translational analyses may investigate immune-inflammation markers related to response and resistance.
This trial aims to determine whether SCRT-primed QL1706 plus mFOLFOX6 TNT can improve tumor eradication and organ preservation while maintaining acceptable safety in pMMR/MSS LARC-a population with unmet need for effective immunotherapy-based strategies.
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Single group
Drug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT)
DrugQL1706 is an investigational bifunctional MabPair antibody that simultaneously targets PD-1 (IgG4) and CTLA-4 (IgG1). It is administered intravenously according to the study protocol during the neoadjuvant chemotherapy cycles. The use of QL1706 aims to enhance antitumor immunity in the pMMR/MSS rectal cancer setting, a population typically unresponsive to immune checkpoint blockade alone. mFOLFOX6 is a standard oxaliplatin-based chemotherapy regimen composed of oxaliplatin, leucovorin, and 5-fluorouracil. It is administered in combination with QL1706 during the neoadjuvant phase as part of total neoadjuvant therapy (TNT). The regimen is modified to optimize tolerability while maintaining efficacy in locally advanced rectal cancer. Short-course radiotherapy consists of a total dose of 25 Gy delivered in 5 fractions over one week to the pelvis. This approach is designed to rapidly downstage tumors, release tumor antigens, and prime the immune microenvironment for subsequent immunotherapy
Pathologic Complete Response (pCR) Rate
The proportion of patients who achieve pathologic complete response, defined as the absence of viable tumor cells in both the resected primary rectal specimen and the resected lymph nodes (ypT0N0), as assessed by central pathology review.
Clinical Complete Response (cCR) Rate
The proportion of patients achieving clinical complete response, defined by endoscopy, pelvic MRI, and digital rectal examination showing no evidence of residual tumor, based on institutional criteria.
Major Pathologic Response (MPR) Rate
The proportion of patients with ≤10% residual viable tumor cells in the resected specimen.
R0 Resection Rate
The proportion of patients who undergo curative resection with negative microscopic margins (R0).
Overall Survival (OS)
Time from enrollment to death from any cause.
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Sun Yat-sen University
Lead sponsor
Sun Yat-Sen University Cancer Center
Sponsor institution
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