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RECRUITING

NCT07026422

PHASE2

Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT)

Sponsor: Shandong Cancer Hospital and Institute

View on ClinicalTrials.gov

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.

Official title: Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT): A Single-arm, Exploratory, Phase II Trial

Key Details

Gender

All

Age Range

18 Years - 75 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2025-05-30

Completion Date

2028-05-30

Last Updated

2025-06-18

Healthy Volunteers

Conditions

Rectal Malignant Neoplasms

Interventions

COMBINATION_PRODUCT

Total neoadjuvant therapy integrating iparomlimab/tuvonralimab with chemoradiotherapy

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).

Inclusion Criteria: 1. Age 18-75 years old, male and female 2. Histologically confirmed pMMR/MSS rectal adenocarcinoma, defined by MRI as clinical stage II (T3-4, N-) or stage III (any T, N+) 3. 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) 4. Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. 5. No evidence of distant metastases based on chest and abdominal CT or whole body PET-CT examinations 6. No other rectal cancer (e.g., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, neuroendocrine carcinoma, etc.) or synchronous colon cancer 7. Presence of measurable lesions that meet RECIST v1.1 criteria for evaluation. Exclusion Criteria: 1. dMMR or MSI-H patients 2. Myelosuppression without obvious causes 3. Locally advanced rectal cancer without high-risk factors 4. Prior or concurrent other malignancies (except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix) 5. Severe allergic reaction to other monoclonal antibodies 6. Uncontrolled cardiac clinical symptoms or disease 7. Active autoimmune disease or immunodefciencies, known history of organ transplantation or systematic use of immunosuppressive agents 8. Abnormal coagulation (INR\>1.5 or PT\>16s), bleeding tendency or on thrombolytic or anticoagulant therapy 9. Known history and current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonitis, or severely impaired lung function 10. Known history of prior antitumor therapy, including radiotherapy, chemotherapy, immune checkpoint inhibitors, T-cell related therapy, etc. 11. 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

Locations (1)

Shandong Cancer Hospital and Institute

Jinan, Shandong, China