Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT)
Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT): A Single-arm, Exploratory, Phase II Trial
Shandong Cancer Hospital and Institute
54 participants
May 30, 2025
INTERVENTIONAL
Conditions
Summary
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.
Eligibility
Inclusion Criteria7
- 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 1.
- 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.
Exclusion Criteria11
- 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
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Interventions
1. Radiotherapy: Radiotherapy location: primary site and the corresponding draining lymph node. Radiotherapy techniques: IMRT/VMRT. Radiotherapy dose and fractionation pattern: conventional external irradiation, 50Gy/25 fx/5 weeks or 25Gy/5fx/1 week. 2. Chemotherapy: Long-course radiotherapy concurrent with chemotherapy: capecitabine 825mg/m2, bid, d1-5/week. Short-course radiotherapy without concurrent chemotherapy. Consolidation chemotherapy and immunotherapy: QL1706 (iparomlimab and tuvonralimab 5mg/kg, d1) and CAPOX (Oxaliplatin 130mg/m2, d1 + capecitabine 1000mg/m2, bid, d1-14), repeated on a 21-day cycle, for 6 cycles. 3. Surgery or watch-and-wait Total mesorectal excision (TME), or watch-and-wait (for patients with clinical complete response).
Locations(1)
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NCT07026422