FOLFOX Via HAI Plus Intravenous Irinotecan With or Without Bevacizumab Versus Systemic FOLFOXIRI With or Without Bevacizumab in Initially Unresectable RAS-mutated CRLM Patients

Official title

FOLFOX Via Hepatic Artery Infusion Chemotherapy (HAI) Plus Systemic Irinotecan With or Without Bevacizumab Versus Systemic FOLFOXIRI With or Without Bevacizumab in Patients With Initially Unresectable RAS-mutated Colorectal Cancer With Liver Metastases: A Prospective, Randomized, Controlled Clinical Study

Overview

This prospective, randomized, controlled clinical study aims to evaluate the objective remission rate of FOLFOX hepatic artery infusion chemotherapy (HAI) in combination with systemic irinotecan with or without bevacizumab versus systemic intravenous FOLFOXIRI with or without bevacizumab in initially unresectable RAS-mutated colorectal cancer patients with liver metastases.

Detailed description

PRIMARY OBJECTIVES:

The goal of this prospective, randomized, controlled clinical trial is to evaluate the objective remission rate (ORR) of FOLFOX hepatic artery infusion chemotherapy (HAI) in combination with irinotecan with or without bevacizumab systemic intravenous chemotherapy versus systemic intravenous FOLFOXIRI with or without bevacizumab in initially unresectable RAS-mutated colorectal cancer patients with liver metastases.

SECONDARY OBJECTIVES:

To assess and compare the depth of response (DpR), R0 surgical resection rate, No evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), recurrence-free survival (RFS) in resectable patients and safety (chemotherapy-related adverse events, catheterization-related adverse events, surgical complications, etc.) between the two intervention groups.

OUTLINE:

Patients in the HAI group receive FOLFOX via hepatic artery infusion chemotherapy plus intravenous irinotecan with or without bevacizumab every 14 days, while patients in the systemic group receive intravenous FOLFOXIRI regimen with or without bevacizumab every 14 days. Patients will receive a maximum of 12 cycles in total (before and after surgery) unless there is disease progression, unacceptable toxicity, or if the patient withdraws from the study.

Interventions

• Drug Dexamethasone
  25mg via HAI (Pre-chemotherapy)
• Drug Anisodamine
  10 mg via HAI (Pre-chemotherapy)
• Drug Oxaliplatin
  85 mg/m2 via HAI over 3 hours
• Drug Leucovorin
  200 mg/m2 via HAI
• Drug Fluorouracil
  400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours
• Drug Irinotecan
  150 mg/m2 intravenously
• Drug Bevacizumab
  5 mg/kg intravenously
• Drug Oxaliplatin
  85 mg/m2 intravenously over 3 hours
• Drug Leucovorin
  200 mg/m2 intravenously
• Drug Fluorouracil
  400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours

Primary outcome measures

• Objective Remission Rate (ORR) [Time frame: Assessed up to 48 months]

Secondary outcome measures (7)

• Depth of Response (DpR) [Time frame: Assessed up to 48 months]
• R0 surgical resection rate [Time frame: Assessed up to 48 months]
• No evidence of disease rate (NED) [Time frame: Assessed up to 48 months]
• Progression Free Survival (PFS) [Time frame: Assessed up to 48 months]
• Overall Survival (OS) [Time frame: Assessed up to 48 months]
• Recurrence Free Survival in resectable patients [Time frame: Assessed up to 48 months]
• Safety (including chemotherapy-related adverse events, catheterization-related adverse events, surgical complications, etc.) [Time frame: Assessed up to 48 months]

Eligibility criteria

Inclusion criteria

• Histologically confirmed colorectal adenocarcinoma
• Imaging or pathological confirmation of liver metastases
• The multidisciplinary team determined that the liver metastases were unresectable, defined as (i) ≥5 metastases; (ii) inability to perform R0 resection; (iii) insufficient volume of liver expected to remain after resection; (iv) failure to preserve all 3 hepatic veins after resection, failure to ensure that blood flow to and from the liver and bile ducts can be preserved, and failure to preserve 2 adjacent liver segments. If any of the above criteria are met, it can be considered as initially unresectable liver metastases.
• Patients with mutated RAS and BrafV600E
• No previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapy
• No extrahepatic metastases confirmed by CT, MRI, or PET/CT (if necessary) (consider enrollment if there is a lung or lymph node lesion less than 10 mm and metastases are difficult to identify)
• Normal hematological function (platelets >90×109/L; white blood cells >3×109/L; neutrophils >1.5×109/L)
• Serum bilirubin ≤ 1.5 times the upper limit of normal value (ULN), transaminases ≤ 5 times ULN
• No ascites, normal coagulation function, albumin ≥35g/L
• Liver function Child-Push grade A
• Serum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min (using Cockcroft-Gault formula)
• ECOG score 0-1
• Life expectancy > 3 months
• Signed written informed consent

Exclusion Criteria (Patients meeting any of the following criteria will be excluded from the study):

• Presence of any extrahepatic metastases and/or primary tumor not amenable to radical surgical resection
• Development of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOX
• Severe arterial embolism or ascites
• Bleeding tendency or coagulation disorder
• Hypertensive crisis or hypertensive encephalopathy
• Severe uncontrolled systemic complications such as infections or diabetes mellitus
• Clinically significant cardiovascular disease such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medication, unstable angina pectoris, congestive heart failure (NYHA class 2-4), arrhythmias requiring medication
• History or physical examination revealing a central nervous system disease (e.g., primary brain tumor, epilepsy not manageable by standard therapy, presence of brain metastases, or history of stroke)
• Previous malignancy within the last 5 years (except post-radical surgery basal cell carcinoma of the skin and/or carcinoma in situ of the cervix)
• Treatment using any investigational drug within the last 28 days prior to the study
• Any residual toxicity from prior chemotherapy (except alopecia), such as peripheral neuropathy ≥ NCI CTC v3.0 grade 2, will not be considered for treatment with oxaliplatin-containing regimens
• History of allergy to any of the drugs in the study
• Women of childbearing potential (<2 years after last menstruation) or men of childbearing potential who are not using or have refused to use an effective non-hormonal contraceptive (IUD, barrier method combined with spermicidal gel or sterilization) during pregnancy and lactation
• Unable or unwilling to comply with the study protocol
• Presence of any other disease, dysfunction due to metastatic lesions, or suspicious medical findings that suggest a possible contraindication to the use of the study drug or that would place the patient at risk of treatment-related complications

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen University Cancer Center — Guangzhou

Identifiers

NCT: NCT05727163 · New Triumph

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗