IB-FOLFIRI for BRAF V600E 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

This trial tests whether adding the immune drugs Iparomlimab and Tuvonralimab to bevacizumab and FOLFIRI helps adults with BRAF V600E metastatic colorectal cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Sun Yat-sen University (other)
• Drugs / interventions: bevacizumab, cetuximab, Iparomlimab, Tuvonralimab
• Locations: 1 site (Guangzhou, Guangdong)
• Trial ID: NCT07150247 on ClinicalTrials.gov

What this trial studies

This single-arm Phase II trial gives adults with BRAF V600E-mutant metastatic colorectal cancer a combination regimen of Iparomlimab, Tuvonralimab, bevacizumab, and FOLFIRI every two weeks. The primary clinical outcome is objective response rate versus historical controls, with close monitoring of safety and tolerability. Blood and tumor tissue will be collected for biomarker studies including circulating tumor DNA sequencing. Regular imaging and clinical assessments will be used to document tumor response and adverse events, and exploratory analyses aim to identify mechanisms of resistance.

Who should consider this trial

Good fit: Adults 18–75 with histologically confirmed metastatic colorectal adenocarcinoma harboring a BRAF V600E mutation who progressed after at least one prior line of therapy and have adequate organ function are eligible.

Not a fit: Patients without the BRAF V600E mutation, those who progressed on prior irinotecan-containing regimens or who have inadequate organ function are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the regimen could improve tumor response and extend survival for patients with the poor-prognosis BRAF V600E subtype.

How similar studies have performed: Targeted BRAF-inhibitor plus EGFR-inhibitor combinations have shown benefit in this population, but the specific combination of dual immunotherapy with bevacizumab and FOLFIRI is novel with limited prior clinical data.

Eligibility criteria

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.

Where this trial is running

Guangzhou, Guangdong

• Sun Yat-sen University Cancer Center — Guangzhou, Guangdong, China (RECRUITING)

Study contacts

• Study coordinator: Deshen Wang, PhD

Conditions: BRAF V600 Colorectal Cancer, Objective response rate, Circulating tumor DNA, Phase II clinical trial, BRAF V600E colorectal cancer