BRAF V600E, Cetuximab, Colorectal Cancer, Dabrafenib, Ipilimumab N01, MSS (Microsatellite Stable), Sintilimab
Conditions
Brief summary
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.
Interventions
DRUGIpilimumab 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.
DRUGSintilimab
2mg/kg ivd, q3w
DRUGCetuximab
500mg/m2 ivd，q2w
DRUGDabrafenib
150mg po bid
Sponsors
Tianjin Medical University Cancer Institute and Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provided written informed consent. 2. Age ≥ 18 years. 3. Histologically or pathologically confirmed colorectal adenocarcinoma. 4. Documented microsatellite stable (MSS) and BRAF V600E mutation by prior genomic testing. 5. Locally advanced unresectable disease or distant metastasis. 6. No prior treatment with BRAF/MEK/ERK inhibitors, EGFR inhibitors, or immune checkpoint inhibitors (ICI). 7. Presence of measurable target lesions per RECIST 1.1. 8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1. 9. Adequate organ function, based on the following laboratory values obtained within 7 days prior to Cycle 1 Day 1: 1. Hemoglobin ≥ 9.0 g/dL. 2. Absolute neutrophil count ≥ 1,500/mm³ (≥ 1.5 × 109/L). 3. Platelet count ≥ 80,000/mm³ (≥ 80 × 109/L). 4. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN. 6. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min. 10. Willing and able to comply with study procedures and visit schedule.
Exclusion criteria
1. Received any approved or investigational systemic anti-tumor therapy within 4 weeks prior to enrollment. 2. Underwent any surgery or invasive procedure within 4 weeks prior to study initiation (exceptions include venous catheter placement and paracentesis/drainage). 3. 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). 4. Presence of severe comorbidities or serious medical conditions. 5. Pregnant or breastfeeding females. 6. The investigator deems the patient unsuitable for participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | up to 2 years | PFS is defined as the time from study entry until the first occurrence of disease progression or death from any cause, whichever comes first. If a subject does not experience disease progression during the trial, PFS is defined as the date of the last confirmed progression-free survival assessment for that subject. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | up to 1 year | DCR: The percentage of patients with a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) that is maintained for at least 4 weeks, among all patients evaluable for efficacy. |
| Objective Response Rate (ORR) | up to 1 year | ORR: The proportion of patients who achieve a reduction in tumor size of a predefined magnitude that is maintained for a specified duration, including cases of CR and PR. Tumor objective response will be assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. All subjects must have measurable tumor lesions at baseline. Efficacy assessments will be categorized as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) based on RECIST v1.1 criteria. |
| Overall Survival (OS) | up to 3 years | OS is defined as the time from study entry to death from any cause. For subjects who are still alive at the final follow-up, OS will be censored at the time of the final follow-up. For lost-to-follow-up subjects, OS will be censored at the time of the last confirmed alive assessment prior to loss to follow-up. OS for censored subjects is defined as the time from study entry to the censoring date. |
| Treatment-Related Adverse Events (TRAE) | up to 3 years | Treatment-Related Adverse Events (TRAE) as assessed by CTCAE v5.0, including serious adverse events (SAEs) |
Countries
China
Outcome results
None listed