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

Sun Yat-sen University

Status and phase

Enrolling

Phase 2

Conditions

BRAF V600 Colorectal Cancer

Treatments

Drug: Iparomlimab and Tuvonralimab

Drug: Bevacizumab

Drug: Irinotecan (drug)

Drug: 5-Fluorouracil

Study type

Interventional

Funder types

Other

Identifiers

NCT07150247

IB-FOLFIRI

Details and patient eligibility

About

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

Full description

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.

Enrollment

20 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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.