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

Summary

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

Eligibility

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.

Conditions2

Browse More Trials