Clinical trial NCT07026422: Iparomlimab/Tuvonralimab Integrating With Total Neoadjuvant Therapy for pMMR/MSS Locally Advanced Rectal Cancer (IT-TNT)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Rectal Malignant Neoplasms
Lead sponsor: Shandong Cancer Hospital and Institute
Sponsor class: OTHER
First posted: 2025-06-18
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall complete response (CR) rate
timeFrame: 1 year
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 3 year
measure: Rate of surgical complications
timeFrame: 1 year
measure: Organ preservation rate
timeFrame: 1 year
measure: 3 year disease free survival (DFS) rate
timeFrame: 3 year
measure: 3 year local recurrence free survival (LRFS) rate
timeFrame: 3 year
measure: The incidence and grade of adverse events
timeFrame: 1 year
Other outcomes:
Locations:
city: Jinan
country: China
facility: Shandong Cancer Hospital and Institute
state: Shandong
Study officials:
affiliation: Shandong Cancer Hospital and Institute, Department of Radiation Oncology
name: Jinbo Yue, Docter
role: PRINCIPAL_INVESTIGATOR
References: