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
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 66
- 主要终点
- Pathologic Complete Response (pCR) Rate
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Drug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT) (Drug)
结局指标
主要结局
Pathologic Complete Response (pCR) Rate
时间窗: 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.
次要结局
- 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.)
研究者
Zhen-Hai Lu
Prof
Sun Yat-sen University