Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT): A Single-arm, Exploratory, Phase II Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Overall complete response (CR) rate
研究概览
简要总结
In colorectal cancer (CRC), ICIs show strong therapeutic associations with microsatellite instability-high (MSI-H) status, while patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors exhibit poor responses. Dual immunotherapy may represent a promising strategy for MSS populations. The Dutch NICHE trial reported a 27% pathological response rate (4/15) in MSS CRC patients with clinical stage I-III disease treated with neoadjuvant ipilimumab plus nivolumab. In advanced or metastatic CRC, a study by Jin Li et al. demonstrated that iparomlimab/tuvonralimab combined with bevacizumab and the XELOX regimen achieved an objective response rate of 70.6% (95% CI: 56.2%-82.5%).
Radiotherapy may synergize with ICIs through multiple immunomodulatory mechanisms. For pMMR/MSS LARC, combining CRT with ICIs holds promise to overcome the "immune-cold" tumor microenvironment and improve therapeutic efficacy. In this clinical trial, the investigators aim to evaluate the efficacy and safety of integrating immunotherapy with CRT as a novel total neoadjuvant therapy for pMMR/MSS rectal cancer.
详细描述
The "sandwich" approach, combining preoperative concurrent chemoradiotherapy (CRT) with total mesorectal excision (TME) and postoperative adjuvant chemotherapy, has been shown to improve pathological complete response (pCR) rates, local control rates (LCR), and sphincter preservation rates in patients with locally advanced rectal cancer (LARC). However, this strategy does not significantly enhance overall survival (OS) or distant metastasis-free survival (DMFS). Total neoadjuvant therapy (TNT), a novel treatment paradigm, involves administering chemotherapy either before neoadjuvant CRT (induction TNT) or after neoadjuvant CRT (consolidation TNT). This approach improves treatment compliance, reduces chemotherapy-related toxicity, and increases pCR rates. Patients achieving pCR following TNT exhibit lower risks of local tumor recurrence and improved survival outcomes.
Immune checkpoint inhibitors (ICIs) have become a cornerstone of cancer therapy. Antibodies targeting negative immune regulators-such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1)-have demonstrated efficacy across multiple solid tumors. In colorectal cancer (CRC), ICIs show strong therapeutic associations with microsatellite instability-high (MSI-H) status, while patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors exhibit poor responses. Dual immunotherapy may represent a promising strategy for MSS populations. The Dutch NICHE trial reported a 27% pathological response rate (4/15) in MSS CRC patients with clinical stage I-III disease treated with neoadjuvant ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1), including 3 major pathological responses and 1 partial response. In advanced or metastatic CRC, a study by Jin Li et al. demonstrated that iparomlimab/tuvonralimab combined with bevacizumab and the XELOX regimen achieved an objective response rate of 70.6% (95% CI: 56.2%-82.5%).
Radiotherapy may synergize with ICIs through multiple immunomodulatory mechanisms, including enhanced tumor antigen release, activation of innate immune pathways, increased T-cell infiltration, improved antigen presentation, and modulation of immunosuppressive cells. For pMMR/MSS LARC, combining CRT with ICIs holds promise to overcome the "immune-cold" tumor microenvironment and improve therapeutic efficacy. In this clinical trial, the investigators aim to evaluate the efficacy and safety of integrating immunotherapy with CRT as a novel total neoadjuvant therapy for pMMR/MSS rectal cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 old, male and female
- •Histologically confirmed pMMR/MSS rectal adenocarcinoma, defined by MRI as clinical stage II (T3-4, N-) or stage III (any T, N+)
- •Tumor within 12 cm of the anal verge with at least one of the following high-risk factors: cT4, cN2, extramural vascular invasion [EMVI+], mesorectal fascia involved [MRF+], lateral lymph node [LN+], tumor deposit, or low rectal cancer (≤5 cm from the anal verge)
- •Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or
- •No evidence of distant metastases based on chest and abdominal CT or whole body PET-CT examinations
- •No other rectal cancer (e.g., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, neuroendocrine carcinoma, etc.) or synchronous colon cancer
- •Presence of measurable lesions that meet RECIST v1.1 criteria for evaluation.
排除标准
- •dMMR or MSI-H patients
- •Myelosuppression without obvious causes
- •Locally advanced rectal cancer without high-risk factors
- •Prior or concurrent other malignancies (except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix)
- •Severe allergic reaction to other monoclonal antibodies
- •Uncontrolled cardiac clinical symptoms or disease
- •Active autoimmune disease or immunodefciencies, known history of organ transplantation or systematic use of immunosuppressive agents
- •Abnormal coagulation (INR>1.5 or PT>16s), bleeding tendency or on thrombolytic or anticoagulant therapy
- •Known history and current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonitis, or severely impaired lung function
- •Known history of prior antitumor therapy, including radiotherapy, chemotherapy, immune checkpoint inhibitors, T-cell related therapy, etc.
- •Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1-2 antibody-positive), active syphilis infection, active tuberculosis infection, or active hepatitis B virus or hepatitis C virus infection at screening
研究组 & 干预措施
Dual immunotherapy group
Total neoadjuvant therapy integrating iparomlimab/tuvonralimab with chemoradiotherapy
干预措施: Total neoadjuvant therapy integrating iparomlimab/tuvonralimab with chemoradiotherapy (Combination Product)
结局指标
主要结局
Overall complete response (CR) rate
时间窗: 1 year
Overall complete response (CR) rate, meaning the rates of pathological complete response (pCR) plus clinical complete response (cCR).
次要结局
- The incidence and grade of adverse events(1 year)
- 3 year local recurrence free survival (LRFS) rate(3 year)
- Organ preservation rate(1 year)
- 3 year disease free survival (DFS) rate(3 year)
- Overall survival (OS)(3 year)
- Rate of surgical complications(1 year)
研究者
Jinbo Yue
Director of Radiation Oncology Department
Shandong Cancer Hospital and Institute