A Multicenter, Prospective, Phase II Clinical Trial of Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6 as Total Neoadjuvant Therapy for Patients With pMMR/MSS Locally Advanced Rectal Cancer
Trial Snapshot
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Enrollment
- 66
- Primary Endpoint
- Pathologic Complete Response (pCR) Rate
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts 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-
- •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.
Arms & Interventions
Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6
Participants will receive short-course radiotherapy (SCRT, 25 Gy in 5 fractions over one week) followed by total neoadjuvant therapy (TNT) consisting of QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, investigational code name only) in combination with mFOLFOX6 chemotherapy for several cycles. After completion of neoadjuvant therapy, patients will undergo total mesorectal excision (TME) when operable, or may be managed with a watch-and-wait strategy if a strict clinical complete response (cCR) is achieved per institutional criteria. Standard perioperative care and follow-up will be provided.
Intervention: Drug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT) (Drug)
Outcomes
Primary Outcomes
Pathologic Complete Response (pCR) Rate
Time Frame: 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 Outcomes
- Clinical Complete Response (cCR) Rate(At response evaluation after neoadjuvant therapy and before surgery (approximately 12-20 weeks after enrollment).)
- Major Pathologic Response (MPR) Rate(At the time of surgery following neoadjuvant therapy.)
- R0 Resection Rate(At the time of surgery)
- Overall Survival (OS)(Up to 3 years after treatment.)
- Disease-Free Survival (DFS)(Up to 3 years after treatment.)
Investigators
Zhen-Hai Lu
Prof
Sun Yat-sen University