Ivosidenib Plus mFOLFOXIRI and Celecoxib for BRAF-targeted Therapy-refractory BRAF V600E-mutant Colorectal Cancer Patients

This study is a prospective, investigator-initiated, single-arm, phase II trial to evaluate the efficacy and safety of ivonescimab (AK112) combined with FOLFOXIRI and celecoxib in patients with BRAF-mutated advanced/metastatic colorectal cancer who have developed resistance to prior chemotherapy and BRAF inhibitors . The inclusion criteria: histologically confirmed BRAF V600E-mutated advanced or metastatic colorectal cancer; documented resistance/progression after at least one line of standard chemotherapy ( FOLFOX/FOLFIRI-based) and BRAF inhibitor-based targeted therapy; measurable disease per RECIST 1.1; ECOG performance status 0-1; adequate organ function; no active brain metastases or other uncontrolled comorbidities (specific criteria can be supplemented as needed). Patients received ivonescimab combined with mFOLFOXIRI (modified FOLFOXIRI regimen) and celecoxib for up to 6-8 cycles or until progression/toxicity, followed by maintenance therapy of continued ivonescimab with 5-FU/leucovorin and celecoxib. All patients will be evaluated every four cycles of treatment using imaging CT/MRI. The primary objective is to assess the objective response rate (ORR) per RECIST 1.1, with secondary endpoints including progression-free survival (PFS), disease control rate (DCR), safety profile, and exploratory biomarkers .

Inclusion criteria

• Signed the informed consent form voluntarily.
• Aged 18-70.
• Colorectal adenocarcinoma with definite histological evidence, with evidence of distant metastasis;
• Diagnosed with colon or rectal adenocarcinoma, with evidence of distant metastasis;
• Genetic testing indicates a BRAF V600E mutation;
• Previously received first-line treatment including FOLFOX/CAPOX or FOLFIRI/CAPIRI and experienced disease progression or intolerance. Among them, patients who used oxaliplatin in adjuvant therapy should have experienced disease progression within 12 months after completing adjuvant therapy; Previously received anti-BRAF V600E targeted therapy and failed, including but not limited to vemurafenib, dabrafenib, and encorafenib;
• Patients must have measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• Adequate organ function based on the following laboratory test values obtained within 7 days prior to treatment: neutrophil count ≥1.5×109/L, platelet count ≥75×109/L, serum total bilirubin ≤1.5× upper limit of normal value (UNL), aspartate transferase ≤2.5×UNL, alanine transferase ≤2.5×UNL, serum creatinine ≤2.5×UNL;
• Female subjects must be either postmenopausal for at least 1 year, have undergone surgical sterilization at least 6 weeks prior, or must agree to use appropriate contraceptive measures;
• Male subjects must agree to use appropriate contraceptive measures to prevent their partners from becoming pregnant;
• Willing and able to comply with research protocols and visit plans.

Exclusion criteria

• Prior to enrollment, ctDNA testing shows known KRAS mutation, NRAS mutation, or ERBB2 gene amplification; tumor tissue testing shows mismatch repair gene deficiency or high microsatellite instability, KRAS mutation, NRAS mutation, or ERBB2 gene amplification;
• Presence of intestinal obstruction, active bleeding, or intestinal perforation requiring emergency intervention;
• Underwent major surgery or severe trauma in the previous 4 weeks;
• Active coronary artery disease, severe/unstable angina, or newly diagnosed angina or myocardial infarction within 12 months prior to study participation;
• Occurrence of thrombotic or embolic events within the past 6 months;
• New York Heart Association (NYHA) class II or higher congestive heart failure;
• Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis;
• Any active, known, or suspected autoimmune disease.
• Presence of interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic disease;
• Any unresolved treatment-related adverse events of grade 2 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (excluding peripheral neuropathy, anemia, hair loss, and skin pigmentation);
• Previous treatment with programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies;
• Known or suspected history of allergy to any of the related drugs used in the study;
• Pregnant or breastfeeding women.