Safety and Efficacy of IB-FOLFIRI in BRAF V600E-Mutant Metastatic Colorectal Cancer

A Phase II Single-Arm Study of Iparomlimab and Tuvonralimab Combined With Bevacizumab and FOLFIRI in BRAF V600E-Mutant Metastatic Colorectal Cancer

The goal of this clinical trial is to learn if Iparomlimab and Tuvonralimab combined with bevacizumab and FOLFIRI (IB-FOLFIRI) is safe and effective in treating adults with BRAF V600E-mutant metastatic colorectal cancer (mCRC). The main questions it aims to answer are:

Does IB-FOLFIRI improve clinical outcomes compared with historical outcomes in this population?

What is the safety profile of IB-FOLFIRI in patients with BRAF V600E-mutant mCRC?

Participants will:

Receive Iparomlimab and Tuvonralimab, bevacizumab, and FOLFIRI every two weeks

Have blood samples and/or tumor tissue collected for biomarker analysis (e.g., ctDNA sequencing)

Undergo regular imaging and clinical evaluations to assess treatment response and safety

This is a single-arm, phase II clinical trial designed to evaluate the safety and efficacy of Iparomlimab and Tuvonralimab plus bevacizumab combined with FOLFIRI (IB-FOLFIRI) in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). Patients with this genetic subtype have limited treatment options and a poor prognosis, underscoring the urgent need for more effective therapeutic strategies.

This study will generate prospective clinical data on the efficacy and safety of the IB-FOLFIRI regimen in a genetically defined subgroup of colorectal cancer. Furthermore, exploratory biomarker analyses may provide new insights into resistance mechanisms, potentially guiding future precision-medicine strategies for BRAF V600E-mutant mCRC.

Inclusion Criteria:

• Age ≥18 years and ≤75 years
• Histologically confirmed metastatic colorectal adenocarcinoma
• BRAF V600E mutation confirmed by tissue pathology or ctDNA testing (PCR or NGS)
• Disease progression after at least one line of treatment: FOLFOX/XELOX (oxaliplatin-based doublet) ± bevacizumab or FOLFOXIRI (irinotecan-based triplet) ± bevacizumab. Note: Irinotecan must not have failed during prior treatment, and disease must not have progressed within three months of stopping treatment
• Patients who have received first-line treatment with cetuximab combined with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) are allowed
• At least one measurable lesion according to RECIST v1.1 criteria
• Adequate hematologic unction: Platelets > 90 × 10⁹/L; Hemoglobin > 100 g/L; White blood cells > 3 × 10⁹/L; Neutrophils > 1.5 × 10⁹/L; Adequate liver function; Total bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present); Alkaline phosphatase ≤ 2.5 × ULN; No ascites; Coagulation: PT ≤ 1.5 × ULN, INR ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN, Albumin ≥ 30 g/L
• Adequate renal function: CrCl ≥ 50 mL/min or serum creatinine ≤ 1.5 × ULN
• Liver function Child-Pugh class A
• ECOG performance status 0-1
• Expected survival > 3 months
• Signed written informed consent
• Willing and able to comply with follow-up until death, study completion, or study termination
• For women of childbearing potential: Negative serum pregnancy test within 14 days prior to treatment; Willing to use medically accepted contraception during the study and for 3 months after the last dose
• For male participants with partners of childbearing potential: Must have undergone surgical sterilization, or use effective contraception during the study and for 3 months after the last dose

Exclusion Criteria:

• KRAS or NRAS mutation
• MSI-H/dMMR patients
• Prior treatment with PD-1, PD-L1, or CTLA-4 inhibitors
• Known contraindications to irinotecan at the planned dose
• Use of systemic immunosuppressive drugs within 1 week prior to treatment
• Active autoimmune disease requiring treatment, or history of such disease within the past 2 years
• Known primary immunodeficiency
• History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
• Retinal vein occlusion or risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or high intraocular pressure)
• History of acute or chronic pancreatitis
• Chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory, immunosuppressive therapy, or surgery) within 12 months prior to enrollment
• Gastrointestinal disorders that may significantly affect oral drug absorption (e.g., severe GI ulcers, uncontrolled vomiting, malabsorption syndrome, short bowel syndrome)
• Neuromuscular diseases associated with elevated CK (e.g., inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Residual ≥Grade 2 toxicity from prior anti-tumor therapy (excluding ≥Grade 2 alopecia or neuropathy)
• History of HIV infection
• History of Gilbert's syndrome
• Interstitial pneumonia or extensive symptomatic interstitial pulmonary fibrosis
• Severe uncontrolled systemic comorbidities
• Severe cardiovascular disease, including:
• Stroke within 6 months prior to enrollment
• Myocardial infarction within 6 months prior to enrollment
• Hypertension not controlled with appropriate medications
• Unstable angina
• Congestive heart failure (NYHA class 2-4)
• Cardiac arrhythmias requiring treatment
• Current or prior central nervous system disease, including: Primary brain tumor; Epilepsy not controlled by standard treatment; Any brain metastases or history of stroke
• Other uncontrolled comorbidities, including active bleeding, uncontrolled infection or non-malignant medical conditions that could be worsened by study therapy, or uncontrolled psychiatric/social conditions
• History of other malignancies within the past 5 years (except for curatively treated basal cell carcinoma, cervical carcinoma in situ, or thyroid cancer)
• Allergy to any study drug
• Pregnant or breastfeeding women
• Women of childbearing potential (last menstrual period <2 years) or men who refuse to use effective non-hormonal contraception (IUD, barrier method plus spermicide, or sterilization)
• Inability or unwillingness to comply with study protocol
• Any other disease, metastatic lesion-related functional impairment, or suspicious findings on physical examination that may indicate contraindication to study drug use or place the patient at high risk of treatment-related complications.