A Study of Systemic Chemotherapy With/Without HAI in Patients With Initially Unresectable Colorectal Liver Metastasis

Systemic Chemotherapy With or Without Hepatic Arterial Infusion With Floxuridine in Patients With Initially Unresectable Colorectal Liver Metastasis: A Prospective, Randomised, Controlled Study

The primary objective of this study is to determine whether systemic chemotherapy combined with hepatic arterial infusion with floxuridine and dexamethasone can increase the complete resection rate (R0) and improve the overall survival in patients with initially unresectable colorectal liver metastasis.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: mFOLFOX6; Drug: HAI

Detailed Description

Recent studies and our experience have proved the efficacy and safety of systemic chemotherapy combined with hepatic arterial infusion (HAI) with floxuridine and dexamethasone in patients with initially unresectable colorectal liver metastasis. However, most of them are retrospective studies, phase I or II clinical researches, which could not provide high-level evidence. Therefore, we designed this study to determine whether systemic chemotherapy combined with HAI can increase the complete resection rate (R0) and improve the overall survival in patients with initially unresectable colorectal liver metastasis.

• Study Type: Interventional
• Enrollment (Estimated): 142
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yu-hong Li, MD, Ph D; Email: liyh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-Sen University Cancer Center
      • Contact: Yu-hong Li, MD, Ph D; Email: liyh@sysucc.org.cn
      • Principal Investigator: Yu-hong Li, MD, Ph D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: 18-70 years old
• Histologically confirmed colorectal adenocarcinoma
• Radiologically or pathologically confirmed diagnosis of colorectal liver metastasis
• Initially unresectable colorectal liver metastasis confirmed by the multidisciplinary team (MDT)
• With no prior treatment for liver metastasis, including chemotherapy, operation, radiotherapy, transcatheter hepatic arterial chemoembolization (TACE) and targeted therapy
• Without extra-hepatic metastasis confirmed by CT, MRI or PET/CT (if necessary) scanning
• With adequate bone marrow function: platelets ≥ 90 x 109/L; white blood cells ≥ 3×109/L; absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Serum bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 5 x ULN
• Patient has no ascites and with adequate blood coagulation function, albumin ≥ 35 g/L
• Grade A level of Child-Push Liver Function
• Creatinine ≤ 1× ULN, or Calculated Creatinine Clearance >50ml/min （Cockcroft-Gault Equation）
• ECOG performance status of 0-2
• Life expectancy ≥ 3 months
• Not appropriate for anti-EGFR or any other targeted therapy (with KRAS mutation or could not afford it)
• Patients have provided a signed Informed Consent Form
• With good compliance

Exclusion Criteria:

• With any extra-hepatic metastasis and/or primary tumor recurrence
• Severe arterial embolism or ascites
• With hemorrhagic tendency or coagulation disorders
• Hypertensive crisis or hypertensive encephalopathy
• Severe and uncontrolled systemic complications such as infections or diabetes
• Serious cardiovascular diseases such as cerebrovascular accident (within 6 months before enrollment), myocardial infarction (within 6 months before enrollment), uncontrolled hypertension even with appropriate drug intervention, unstable angina pectoris, congestive heart failure (NYHA 2-4 degree), arrhythmia that needs medication intervention
• Patient who has suffered from central nervous system diseases such as primary brain tumor, uncontrolled epilepsy even with standard treatment, any brain metastasis or stroke
• Patient who has a concurrent malignancy or has a malignancy within 5 years before study enrollment, (with the exception of radically resected skin basal cell carcinoma or cervical carcinoma in situ)
• Patient who has received any investigational antineoplastic agent within 28 days before the enrollment
• Any residual toxicity from prior chemotherapy (with the exception of alopecia), such as grade 2 or more sensory peripheral neuropathy (NCI CTC v3.0), oxaliplatin-based regimen will not be considered
• Patient who is allergic to oxaliplatin, leucovorin, 5-Fluorouracil, floxuridine or dexamethasone
• Pregnant or lactating women
• Patient who does not use or refuses to take any appropriate contraceptive measures (intrauterine contraceptive ring, barrier contraception combined with spermicidal gel or sterilization operation), including women of childbearing age (within 2 years after the last menstrual period) and men who are with possible fertility
• Unable or unwilling to comply with the research plan
• The existence of any other disease, dysfunction caused by metastatic lesions, or suspicious disease found on the regular examination, which indicating contraindications to the use of study drugs or may bring high risks of treatment related complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Systemic chemotherapy; Patients will receive mFOLFOX6 every 28 days: Oxaliplatin 85 mg/m2 IV over 3 hours on Day 1, 15; Leucovorin (l-LV) 200mg/m2 IV over 2 hours on Day 1, 15; followed by 5-Fluorouracil 2.4 g/m2 for 46 hours continuous infusion on Day 1, 15.	Drug: mFOLFOX6; Patients will receive mFOLFOX6 every 28 days: Oxaliplatin 85 mg/m2 IV over 3 hours on Day 1, 15; Leucovorin (l-LV) 200mg/m2 IV over 2 hours on Day 1, 15; followed by 5-Fluorouracil 2.4 g/m2 for 46 hours continuous infusion on Day 1, 15.; Other Names: 5-fluorouracil; Leucovorin; Oxaliplatin
Experimental: Systemic chemotherapy combined with HAI; Patients will receive mFOLFOX6+HAI every 28 days: Oxaliplatin 85 mg/m2 IV over 3 hours on Day 1, 15; Leucovorin (l-LV) 200mg/m2 IV over 2 hours on Day 1, 15; followed by 5-Fluorouracil 2.4 g/m2 for 46 hours continuous infusion on Day 1, 15. 0.12 mg/kg/day floxuridine (FUDR) and 25 mg dexamethasone in normal saline to a total volume of 300 ml will be administered through the HAI pump. This will be repeated on Day 1 of each 28-day cycle. FUDR will be administered through a 14-day continuous infusion with the HAI pump.	Drug: mFOLFOX6; Patients will receive mFOLFOX6 every 28 days: Oxaliplatin 85 mg/m2 IV over 3 hours on Day 1, 15; Leucovorin (l-LV) 200mg/m2 IV over 2 hours on Day 1, 15; followed by 5-Fluorouracil 2.4 g/m2 for 46 hours continuous infusion on Day 1, 15.; Other Names: 5-fluorouracil; Leucovorin; Oxaliplatin; Drug: HAI; Patients will receive HAI every 28 days: 0.12 mg/kg/day floxuridine (FUDR) and 25 mg dexamethasone in normal saline to a total volume of 300 ml will be administered through the HAI pump. This will be repeated on Day 1 of each 28 day cycle. FUDR administration will be a 14-day continuous infusion using the HAI pump.; Other Names: dexamethasone; floxuridine (FUDR)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete resection rates (R0 resection rates) (defined as no macroscopic or microscopic residual tumor) of both arms	Up to 2-4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rates (ORR) of both arms		Up to 4-8 monthes
R1 resection rates (with microscopic residual tumor) of both arms		Up to 2-4 monthes
Specific R0/R1 resection plus radiofrequency ablation rates of both arms		Up to 2-4 monthes
Recurrence-free survival (RFS) of both arms	Time to recurrence or death	Up to 5 years
5 year cancer specific survival rate of the whole population		Up to 5 years
Progression free survival(PFS) of both arms		From the date of first drug administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 monthes
Overall survival (OS) of both arms		From the date of first drug administration until the date of death, assessed up to 5 years
Number of participants with surgical complications, AES and SAEs as a measure of safety		Each follow up visit, assessed up to 2 years

Collaborators and Investigators

• Sponsor: Yuhong Li
• Investigators: Principal Investigator: Yu-hong Li, MD, Ph D, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 31, 2014
• First Submitted That Met QC Criteria: March 31, 2014
• First Posted (Estimated): April 3, 2014

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Dexamethasone; Fluorouracil; Oxaliplatin; Leucovorin; Floxuridine
• Other Study ID Numbers: Frozen-2