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

Sun Yat-sen University

Status and phase: Enrolling; Phase 2

Conditions: Colorectal Cancer Metastatic

Treatments: Drug: Dexamethasone; Drug: Bevacizumab; Drug: Irinotecan; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Fluorouracil; Drug: Anisodamine

Study type: Interventional

Funder types: Other

Identifiers

NCT05727163

New Triumph

Details and patient eligibility

About

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.

Full 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.

Enrollment: 194 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

1. Histologically confirmed colorectal adenocarcinoma
2. Imaging or pathological confirmation of liver metastases
3. 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.
4. Patients with mutated RAS and BrafV600E
5. No previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapy
6. 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)
7. Normal hematological function (platelets >90×109/L; white blood cells >3×109/L; neutrophils >1.5×109/L)
8. Serum bilirubin ≤ 1.5 times the upper limit of normal value (ULN), transaminases ≤ 5 times ULN
9. No ascites, normal coagulation function, albumin ≥35g/L
10. Liver function Child-Push grade A
11. Serum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min (using Cockcroft-Gault formula)
12. ECOG score 0-1
13. Life expectancy > 3 months
14. Signed written informed consent

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

1. Presence of any extrahepatic metastases and/or primary tumor not amenable to radical surgical resection
2. Development of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOX
3. Severe arterial embolism or ascites
4. Bleeding tendency or coagulation disorder
5. Hypertensive crisis or hypertensive encephalopathy
6. Severe uncontrolled systemic complications such as infections or diabetes mellitus
7. 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
8. 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)
9. 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)
10. Treatment using any investigational drug within the last 28 days prior to the study
11. 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
12. History of allergy to any of the drugs in the study
13. 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
14. Unable or unwilling to comply with the study protocol
15. 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

194 participants in 2 patient groups

HAI group

Experimental group

Description:

FOLFOX given via Hepatic Artery Infusion (HAI) in Combination With intravenous Irinotecan With or Without Bevacizumab. Dexamethasone 25 mg via HAI (Pre-chemotherapy) Anisodamine (654-2) 10 mg HAI (Pre-chemotherapy) Oxaliplatin 85 mg/m2 via HAI over 3 hours Leucovorin 200 mg/m2 via HAI FU 400 mg/m2 via HAI FU 2.4g/m2 via HAI over 48 hours Irinotecan 150 mg/m2 intravenously Bevacizumab 5 mg/kg intravenously The above regimen was given on Day 1 and repeated after 14 days. Patients will typically receive a maximum of 12 courses (preoperative and/or postoperative) unless disease progression is detected, intolerable adverse effects, or the patient refuses further treatment.

Treatment:

Drug: Oxaliplatin

Drug: Leucovorin

Drug: Anisodamine

Drug: Fluorouracil

Drug: Leucovorin

Drug: Oxaliplatin

Drug: Irinotecan

Drug: Bevacizumab

Drug: Fluorouracil

Drug: Dexamethasone

Systemic Chemotherapy group

Active Comparator group

Description:

Systemic FOLFOXIRI With or Without Bevacizumab Irinotecan 150mg/m2 intravenously Oxaliplatin 85 mg/m2 intravenously over 3 hours Leucovorin 200 mg/m2 intravenously FU 400 mg/m2 intravenously 5-FU 2400 mg/m2 continuous intravenous infusion over 46 hours Bevacizumab 5 mg/kg intravenously Note: (UGT\*28 7/7, UGT\*6 A/A, UGT\*28 6/7 and UGT\*6 A/G patients, Irinotecan dosage was reduced to 130 mg/m2) The above regimen was given on Day 1 and repeated after 14 days. Patients will typically receive a maximum of 12 courses (preoperative and/or postoperative) unless disease progression is detected, intolerable adverse effects, or the patient refuses further treatment.

Treatment:

Drug: Oxaliplatin

Drug: Leucovorin

Drug: Fluorouracil

Drug: Leucovorin

Drug: Oxaliplatin

Drug: Irinotecan

Drug: Bevacizumab

Drug: Fluorouracil