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

Sponsor

Yuhong Li (Other)

Overall Status

Recruiting

CT.gov ID

NCT02102789

Collaborator

(none)

142

Enrollment

Location

Arms

129.1

Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: mFOLFOX6 Drug: HAI	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

142 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2014

Anticipated Primary Completion Date :

Aug 1, 2020

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

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: Oxaliplatin Leucovorin 5-fluorouracil
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: Oxaliplatin Leucovorin 5-fluorouracil 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: floxuridine (FUDR) dexamethasone

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

Other Names:

Oxaliplatin

Leucovorin

5-fluorouracil

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

Other Names:

Oxaliplatin

Leucovorin

5-fluorouracil

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:

floxuridine (FUDR)

dexamethasone

Outcome Measures

Primary Outcome Measures

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

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 [Up to 5 years]
Time to recurrence or death
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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