Sintilimab in Combination with Cetuximab and Chemotherapy As First-line Treatment for RAS/BRAF Wild-type Advanced Colorectal Cancer

Sponsor
Cancer Hospital Chinese Academy of Medical Science, Shenzhen Center
Study ID
NCT06776757
Phase
PHASE1/PHASE2
Status
Recruiting
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Conditions

  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
18 Years - 75 Years
Healthy Volunteers
Not accepted

Interventions

  • Sintilimab+Cetuximab+Chemotherapy (mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI) — DRUG
    Sintilimab (100mg,150mg, 200mg; Q3W) +Cetuximab (500mg/m²,Q2W)+Chemotherapy（mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI）
  • Sintilimab+Cetuximab+Chemotherapy (mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI) — DRUG
    Sintilimab (Based on Phase 1b recommended dose; Q3W) +Cetuximab (500mg/m²,Q2W)+Chemotherapy（mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI）

Study Details

In 2018, global cancer incidence reached 18.1 million new cases, with 9.6 million cancer-related deaths. Colorectal cancer ranked as the third most common malignancy by incidence. Data from the U.S. NIH SEER database indicate a five-year survival rate for colorectal cancer of approximately 65%. Specifically, the survival rate is 90% for localized (non-metastatic) cases, 71% for regional (lymph node metastasis) cases, and only 14% for advanced metastatic cases. According to the China Society of Clinical Oncology (CSCO) guidelines, first-line therapy for advanced colorectal cancer typically involves chemotherapy combined with targeted agents, such as bevacizumab or cetuximab, yielding a median survival of 20-30 months. Prognosis is generally better for RAS wild-type patients compared to those with RAS mutations. In subsequent lines of therapy, chemotherapy combined with targeted therapy results in remission for approximately 22% of patients, although overall survival rarely exceeds 12 months. Basic research has demonstrated that cetuximab, when combined with chemotherapy, enhances the infiltration of NK cells, cytotoxic T cells, and other immune cells into the tumor microenvironment. In head and neck cancer, an increase in PD-1+ and TIM-3+ tumor-infiltrating lymphocytes (TILs) during cetuximab treatment was negatively correlated with treatment response. Blocking these immune checkpoints may improve cetuximab-based immunotherapy by reversing CD8+ TIL dysfunction, potentially enhancing clinical outcomes. The cetuximab-chemotherapy regimen increases tumor immunogenicity by inducing tumor cell death and antigen release. When combined with immune checkpoint inhibitors, cetuximab may convert "cold tumors" into "hot tumors," thus synergistically improving tumor cell elimination. Additionally, cetuximab has been shown to activate tumor-promoting M2 macrophages, particularly CD163-positive macrophages in colorectal cancer, which produce high levels of Fc-γ receptors and PD-L1, supporting the theoretical basis for combining cetuximab with immune checkpoint inhibitors in colorectal cancer treatment. In patients with locally advanced colorectal cancer, immune checkpoint inhibitors like PD-1 and CTLA-4 inhibitors have shown preliminary efficacy. The NICHE study reported a 100% pathological response in MSI-H patients and a 27% response in MSS-type patients, indicating potential benefits and safety of immunotherapy in both MSI-H sensitive and MSS/pMMR populations. For first-line treatment of advanced colorectal cancer, the BBCAPX Phase II study showed that sintilimab combined with CapeOX and bevacizumab resulted in an objective response rate (ORR) of 84% and a 100% disease control rate in RAS-mutant, MSS-type metastatic colorectal cancer (mCRC) patients. Similarly, the AIO-KRK-0216 study found that a combination of Avelumab (PD-L1), cetuximab, and chemotherapy produced an ORR of 79.5% in first-line MSS-type metastatic colorectal cancer. In later-line therapy, the REGONIVO Phase II study reported a 36% ORR for PD-1 monoclonal antibody combined with anti-angiogenesis agents (chemotherapy, targeted therapy) in metastatic colorectal cancer, with a 33% ORR for MSS-type patients. The median progression-free survival (PFS) was 7.9 months, though median overall survival (OS) had not been reached.

Key Dates

First listed
Jan 15, 2025
Start date
Dec 25, 2023
Status verified
Dec 2024
Primary completion
Jun 25, 2025
Completion
Dec 25, 2025

Study Design

Enrollment
30 participants (estimated)
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Phase 1b Dose Exploration
    Cetuximab and chemotherapy dose fixed, Sintilimab dose escalation to determine maximum tolerated dose in patients with RAS/BRAF wild-type mCRC
  • Experimental: Phase 2 Expansion
    Phase 2 evaluation of the clinical activity of intilimab in combination with Cetuximab and chemotherapy in patients with RAS/BRAF wild-type mCRC

Primary Outcome Measure

Objective Response Rate (ORR) [ Time Frame: Up to 6 months ]

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