Locally Advanced Rectal Cancer (LARC), Mismatch Repair-Proficient (pMMR) Rectal Cancer, Non-metastatic Rectal Cancer
Conditions
Brief summary
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.
Interventions
DRUGDrug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT)
QL1706 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
Sponsors
Sun Yat-sen University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Age 18-75 years, male or female. Histologically confirmed rectal adenocarcinoma. Locally advanced disease (cT3-4 and/or N+, M0) based on pelvic MRI and/or CT. Tumor located within 12 cm from the anal verge. Proven microsatellite stability (MSS) or proficient mismatch repair (pMMR) status. ECOG performance status 0-1. Adequate organ function: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelet count ≥ 100 × 10⁹/L Hemoglobin ≥ 90 g/L ALT/AST ≤ 2.5 × ULN Total bilirubin ≤ 1.5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min No prior pelvic radiotherapy, chemotherapy, immunotherapy, or targeted therapy for rectal cancer. Signed written informed consent
Exclusion criteria
Evidence of distant metastasis. Previous or concurrent malignant tumor (except cured basal cell carcinoma of skin or cervical carcinoma in situ). Active autoimmune disease requiring systemic immunosuppressive therapy. Active infection including hepatitis B, hepatitis C, HIV, or tuberculosis. Known allergy or hypersensitivity to study drugs or excipients. Uncontrolled cardiovascular disease (e.g., recent myocardial infarction, unstable angina, congestive heart failure, arrhythmia). Pregnant or breastfeeding women. Any condition judged by investigators to make the patient unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response (pCR) Rate | At the time of surgery following completion of total neoadjuvant therapy (approximately 16-24 weeks after enrollment). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response (cCR) Rate | At response evaluation after neoadjuvant therapy and before surgery (approximately 12-20 weeks after enrollment). | 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 | At the time of surgery following neoadjuvant therapy. | The proportion of patients with ≤10% residual viable tumor cells in the resected specimen. |
| R0 Resection Rate | At the time of surgery | The proportion of patients who undergo curative resection with negative microscopic margins (R0). |
| Overall Survival (OS) | Up to 3 years after treatment. | Time from enrollment to death from any cause. |
| Disease-Free Survival (DFS) | Up to 3 years after treatment. | Time from surgery (or start of treatment for patients managed non-operatively) to first documented recurrence, progression, or death from any cause. |
Contacts
Primary ContactZhenhai Lu, MD
Outcome results
None listed