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

NCT06776757 | Recruiting Phase 1

• 1 other identifier: YW2023-25-2
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer

Keywords

Sintilimab, Cetuximab, Chemotherapy, first-line, mCRC

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The objective response rate is estimated by the proportion (percentage) of participants with the best response of complete response (CR), or partial response (PR) by RECIST 1.1 criteria, with corresponding exact 95% confidence limits being reported.

  Up to 6 months

Secondary Outcomes (2)

• Progression-free Survival (PFS)

  up to 12 months

• Overall Survival (OS)

  Up to 2 years

Study Arms (2)

Phase 1b Dose Exploration

EXPERIMENTAL

Cetuximab and chemotherapy dose fixed, Sintilimab dose escalation to determine maximum tolerated dose in patients with RAS/BRAF wild-type mCRC

Drug: Sintilimab+Cetuximab+Chemotherapy (mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI)

Phase 2 Expansion

EXPERIMENTAL

Phase 2 evaluation of the clinical activity of intilimab in combination with Cetuximab and chemotherapy in patients with RAS/BRAF wild-type mCRC

Drug: Sintilimab+Cetuximab+Chemotherapy (mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI)

Interventions

Sintilimab+Cetuximab+Chemotherapy (mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI) DRUG

Sintilimab (100mg,150mg, 200mg; Q3W) +Cetuximab (500mg/m²,Q2W)+Chemotherapy（mFOLFOX6/FOLFIRI/CAPEOX/CAPIRI）

Phase 1b Dose Exploration

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sign a written informed consent before implementing any trial-related procedures.
• Age between 18 and 75 years old.
• No gender restrictions.
• Histologically or cytologically confirmed inoperable or recurrent metastatic colorectal cancer (AJCC 8th edition, Stage IV).
• No prior systemic antitumor treatment, or at least 6 months since the completion of adjuvant therapy.
• At least one measurable lesion as per the RECIST 1.1 criteria for solid tumors.
• Tumor tissue with both RAS and BRAF mutations being wild-type. 8.Tumor tissue with PD-L1 CPS ≥1, TPS ≥1%, or CD8+ TILs ≥2%. 9.ECOG performance status score of 0 or 1. 10.Expected survival time \>3 months. 11.Sufficient organ function and bone marrow compensation function are required, and the subjects must meet the following laboratory criteria:
• Neutrophil Absolute Count (ANC) ≥ 1.5 x 10\^9/L, provided that granulocyte colony-stimulating factor has not been used in the past 14 days.
• Platelet count ≥ 90 x 10\^9/L, provided that no blood transfusion has been received in the past 14 days.
• Hemoglobin \> 9 g/dL, provided that no blood transfusion or erythropoiesis-stimulating agents have been used in the past 14 days.
• Total bilirubin ≤ 1.5× Upper Limit of Normal (ULN); or total bilirubin \> ULN but direct bilirubin ≤ ULN.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5× ULN (patients with liver metastasis are allowed to have ALT or AST ≤ ULN).
• Serum creatinine ≤ 1.5× ULN, and creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 ml/min.
• Normal coagulation function, defined as International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5× ULN.
• Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with normal total T3 (or FT3) and FT4 levels may also be included.

You may not qualify if:

• Previously received chemotherapy, cetuximab, or other anti-EGFR targeted therapies;
• Previously received any of the following therapies: anti-PD-L1, anti-PD-L2 drugs, or drugs targeting other stimulatory or co-inhibitory T cell receptors (e.g., CTLA-4, OX-40, CD137) (adjustable);
• Symptomatic or high-risk conditions such as obstruction, bleeding, perforation, pneumonia (including non-infectious pneumonia treated with corticosteroids or ongoing pneumonia treatment);
• Diagnosed with other malignant diseases outside of colorectal cancer within 5 years prior to the first dose (excluding surgically cured basal cell carcinoma, squamous cell carcinoma of the skin, and/or surgically resected carcinoma in situ);
• Currently participating in an interventional clinical trial or received other investigational drugs or devices within 4 weeks prior to the first dose;
• Received traditional Chinese medicine with antitumor indications or immune-regulating drugs (including thymosin, interferons, interleukins, excluding local use for pleural effusion) as systemic therapy within 2 weeks prior to the first dose;
• Experienced an active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapies (e.g., thyroid hormone, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments;
• Receiving systemic corticosteroid therapy (excluding nasal, inhaled, or other forms of localized corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study drug. Note: Physiological doses of corticosteroids (≤10 mg/day of prednisone or equivalent) are allowed;
• Received blood transfusion within 7 days prior to the first dose of treatment;
• Clinically uncontrolled pleural or peritoneal effusion (patients who do not require drainage or have stable effusion for 3 days after stopping drainage may be enrolled);
• Known history of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Known allergy to the study drug, sindilizumab, chemotherapy, targeted drug active ingredients, or excipients;
• Presence of multiple factors affecting oral drug absorption (e.g., difficulty swallowing, post-gastrointestinal resection, chronic diarrhea, intestinal obstruction, etc.);
• Not fully recovered from toxicity and/or complications caused by any previous interventions before starting treatment (i.e., ≤ Grade 1 or back to baseline, excluding fatigue or alopecia);
• Known history of HIV infection (i.e., HIV 1/2 antibody positive).

Sponsors & Collaborators

• Cancer Hospital Chinese Academy of Medical Science, Shenzhen Center: lead

Study Sites (1)

National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital

Shenzhen, Guangdong, 518116, China

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2025
• First Posted: January 15, 2025
• Study Start: December 25, 2023
• Primary Completion: June 25, 2025
• Study Completion: December 25, 2025
• Last Updated: January 15, 2025

Record last verified: 2024-12

Locations

CN (1)