A Phase II Single-Arm Study of Iparomlimab and Tuvonralimab Combined With Bevacizumab and FOLFIRI in BRAF V600E-Mutant Metastatic Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Objective Response Rate
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Iparomlimab and Tuvonralimab+ Bevacizumab + FOLFIRI
Given every two weeks
干预措施: Iparomlimab and Tuvonralimab (Drug)
Iparomlimab and Tuvonralimab+ Bevacizumab + FOLFIRI
Given every two weeks
干预措施: Bevacizumab (Drug)
Iparomlimab and Tuvonralimab+ Bevacizumab + FOLFIRI
Given every two weeks
干预措施: 5-Fluorouracil (Drug)
Iparomlimab and Tuvonralimab+ Bevacizumab + FOLFIRI
Given every two weeks
干预措施: Irinotecan (drug) (Drug)
结局指标
主要结局
Objective Response Rate
时间窗: Assessed after every 4 cycles (each cycle is 2 weeks) from treatment initiation until radiographic disease progression, treatment discontinuation, or completion of the 3-year follow-up, whichever occurs first
The percentage of patients in a study group who have a partial or complete response to treatment according to RECIST v1.1 criteria
次要结局
- Progression Free Survival(Assessed throughout the study duration (3 years))
- Overall survival(Assessed throughout the study duration (5 years))
- Adverse events(Assessed throughout the study duration (3 years))
研究者
Deshen Wang
Professor
Sun Yat-sen University