Iparomlimab and tuvonralimab added to total neoadjuvant therapy for pMMR/MSS locally advanced rectal cancer

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

This study tests if adding the immunotherapies iparomlimab and tuvonralimab to total neoadjuvant chemoradiotherapy improves tumor response in people with pMMR/MSS locally advanced rectal cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 54 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Shandong Cancer Hospital and Institute (Academic / other)
• Drugs / interventions: chemotherapy, radiation, ipilimumab, nivolumab, iparomlimab, tuvonralimab, bevacizumab, immunotherapy
• Locations: 1 site (Jinan, Shandong)
• Trial ID: NCT07026422 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional trial enrolls patients with pMMR/MSS locally advanced rectal adenocarcinoma and integrates dual immune checkpoint blockade (iparomlimab/tuvonralimab) into a total neoadjuvant therapy (TNT) backbone that includes chemoradiotherapy (CRT), surgery (total mesorectal excision), and adjuvant chemotherapy. The regimen uses a "sandwich" or TNT approach to deliver systemic chemotherapy and CRT in a sequence intended to increase pathological complete response (pCR) rates and reduce distant recurrence. Immune checkpoint inhibitors are given alongside CRT to try to convert an immune-cold tumor microenvironment into a more responsive one for pMMR/MSS tumors. The trial will monitor tumor response, safety, and surgical outcomes at a single center in Jinan, Shandong.

Who should consider this trial

Good fit: Ideal candidates are adults 18–75 years with histologically confirmed pMMR/MSS rectal adenocarcinoma staged as clinical II/III, tumors within 12 cm of the anal verge with specified high-risk features, ECOG 0–1, and no distant metastases.

Not a fit: Patients with dMMR/MSI-H tumors, significant uncontrolled myelosuppression, or distant metastases are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could raise pCR rates and lower the risk of recurrence for patients with pMMR/MSS locally advanced rectal cancer.

How similar studies have performed: Prior data show mixed but encouraging signals: the Dutch NICHE trial reported some pathological responses with neoadjuvant dual immunotherapy in MSS CRC and a separate study combining iparomlimab/tuvonralimab with chemotherapy and bevacizumab showed high response rates in advanced disease, but pMMR/MSS rectal cancer remains challenging.

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

Where this trial is running

Jinan, Shandong

• Shandong Cancer Hospital and Institute — Jinan, Shandong, China (Recruiting)

Study contacts

• Principal investigator: Jinbo Yue, Docter — Shandong Cancer Hospital and Institute, Department of Radiation Oncology
• Study coordinator: Jinbo Yue, Docter

Conditions Rectal Malignant Neoplasms