A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer

Обзор

Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition. Preclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy. This is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.

Вмешательства

• Препарат Ipilimumab N01
  1mg/kg ivd，q6w or 3mg/kg ivd，q12w followed by maintenance therapy with Ipilimumab N01 1 mg/kg ivd, q6w. The specific dosage and administration schedule should be referred to the relevant study design.
• Препарат Sintilimab
  2mg/kg ivd, q3w
• Препарат Cetuximab
  500mg/m2 ivd，q2w
• Препарат Dabrafenib
  150mg po bid

Первичные конечные точки

• Progression-Free Survival (PFS) [Срок оценки: up to 2 years]

Вторичные конечные точки (4)

• Disease Control Rate (DCR) [Срок оценки: up to 1 year]
• Objective Response Rate (ORR) [Срок оценки: up to 1 year]
• Overall Survival (OS) [Срок оценки: up to 3 years]
• Treatment-Related Adverse Events (TRAE) [Срок оценки: up to 3 years]

Критерии участия

Критерии включения

• Provided written informed consent.
• Age ≥ 18 years.
• Histologically or pathologically confirmed colorectal adenocarcinoma.
• Documented microsatellite stable (MSS) and BRAF V600E mutation by prior genomic testing.
• Locally advanced unresectable disease or distant metastasis.
• No prior treatment with BRAF/MEK/ERK inhibitors, EGFR inhibitors, or immune checkpoint inhibitors (ICI).
• Presence of measurable target lesions per RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.
• Adequate organ function, based on the following laboratory values obtained within 7 days prior to Cycle 1 Day 1:

• Hemoglobin ≥ 9.0 g/dL.
• Absolute neutrophil count ≥ 1,500/mm³ (≥ 1.5 × 109/L).
• Platelet count ≥ 80,000/mm³ (≥ 80 × 109/L).
• Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min.
• Willing and able to comply with study procedures and visit schedule.

Критерии исключения

• Received any approved or investigational systemic anti-tumor therapy within 4 weeks prior to enrollment.
• Underwent any surgery or invasive procedure within 4 weeks prior to study initiation (exceptions include venous catheter placement and paracentesis/drainage).
• Multiple primary malignancies (exceptions include completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, superficial bladder cancer, or any other cancer that has been in complete remission for at least 3 years).
• Presence of severe comorbidities or serious medical conditions.
• Pregnant or breastfeeding females.
• The investigator deems the patient unsuitable for participation in this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 4 центра

• Peking union medical college hospital — Пекин
• Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and — Ухань
• West China Hospital Sichuan University — Чэнду
• Tianjin Medical University Cancer Institute and Hospital — Тяньцзинь

Идентификаторы

NCT: NCT07506109 · SICD-BRAF

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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