Alternating Systemic and Hepatic Artery Infusion Therapy As Adjuvant Treatment After Resection of Liver Metastases From Colorectal Cancer

Study Overview
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Brief Summary
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This adaptive seamless Phase II/III trial is to compare the efficacy and safety of adjuvant systemic chemotherapy (SCT) with or without hepatic arterial infusion (HAI) after complete hepatic resection for Chinese patients with metastatic colorectal cancer.

Official Title
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Efficacy and Safety of Alternating Systemic and Hepatic Artery Infusion Therapy Versus Systemic Chemotherapy Alone As Adjuvant Treatment After Resection of Liver Metastases From Colorectal Cancer: A Randomized, Parallel-Group, Open-Labelled, Active-Controlled Phase II/III Trial in China

Conditions
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Resected Liver Metastases From Colorectal Cancer

Intervention / Treatment
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* Drug: Floxuridine (FUDR),Dexamethasone (DXM), Heparin in combination with Oxaliplatin and Capecitabine (CapeOX) or in combination with Oxaliplatin and Leucovorin and 5-FU (mFOLFOX6)
* Drug: Oxaliplatin and Capecitabine (CapeOX) or Oxaliplatin and Leucovorin and 5-FU (mFOLFOX6)


Participation Criteria
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Eligibility Criteria
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Diagnosis Criteria: All patients should have histologically confirmed colorectal adenocarcinoma with hepatic metastases and primary tumours completely resected during the operation and with colorectal metastatic to the liver confirmed pathologically after the operation as well as with negative surgical margin. Main criteria for inclusion: Aged 18-75 years Diagnosed as colorectal adenocarcinoma which only spread to the liver and with no extra-hepatic metastases Prior curative resection of primary tumours (R0 resection) or concurrent feasible curative resection of primary tumours and hepatic metastases (R0 resection is met) Performance status ECOG 0-1 No serious complication occurred during or after metastases resection and affected subsequent treatment. Hematology: White blood count ≧ 4.0X10^9/L, Absolute neutrophil count ≧1.5X10^9/L, Platelet count ≧ 100 X10^9/L, Hemoglobin ≧ 100g/L Blood biochemistry: Total bilirubin ≦2mg/dL , Direct bilirubin equal or less than 1.5 times upper limit of normal (ULN), Alanine aminotransferase (ALT) no greater than 2.5 times ULN, Aspartate aminotransferase (AST) no greater than 2.5 times ULN, Serum creatinine no greater than ULN, or glomerular filtration rate equal or greater than 60 mL/min/1.73m^2 Not pregnant or nursing at present Fertile patients must use effective contraception Able to withstand major operative procedure No prior or concurrent malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of any organ No prior hepatic artery infusion therapy with 5-FU or floxuridine No prior systemic chemotherapy for metastatic disease No other concurrent chemotherapy Able to understand and sign off informed consent form

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Systemic Chemotherapy plus Hepatic Artery Infusion (HAI)<br> | Drug: Floxuridine (FUDR),Dexamethasone (DXM), Heparin in combination with Oxaliplatin and Capecitabine (CapeOX) or in combination with Oxaliplatin and Leucovorin and 5-FU (mFOLFOX6)<br>* Hepatic Artery Infusion for four cycles: Floxuridine (FUDR) 500mg/d, Day 1-2; DXM 1mg/day added to FUDR 2-day infusion; Heparin 1000U/day added to FUDR 2-day infusion In combination with Systemic Chemotherapy CapeOX for 8 cycles: Oxaliplatin 130 mg/m^2 iv over 2 hours, Day 1. Capecitabine 850mg/m^2/d PO Bid, given in the morning and evening, Day 1-14 Or in combination with Systemic Chemotherapy mFOLFOX6 for 12 cycles: Oxaliplatin 85mg/m^2 IV over 2 hours, Day 1. Leucovorin 400mg/m^2 IV over 2 hours, Day 1 5-fluorouracil (FU) 400mg/m^2 IV and then 2400mg/m^2 over 48 hours IV continuous infusion. Day 1<br>|
| Active Comparator: Systemic Chemotherapy<br> | Drug: Oxaliplatin and Capecitabine (CapeOX) or Oxaliplatin and Leucovorin and 5-FU (mFOLFOX6)<br>* Systemic Chemotherapy CapeOX alone for 8 cycles: Oxaliplatin 130 mg/m^2 iv over 2 hours, Day 1. Capecitabine 850mg/m^2/d PO Bid, given in the morning and evening, Day 1-14 Or Systemic Chemotherapy mFOLFOX6 alone for 12 cycles: Oxaliplatin 85mg/m^2 IV over 2 hours, Day 1. Leucovorin 400mg/m^2 IV over 2 hours, Day 1 5-fluorouracil (FU) 400mg/m^2 IV and then 2400mg/m^2 over 48 hours IV continuous infusion. Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival will be measured from the date of randomization up to the date of death of any cause | 5-year | 
| Liver Relapse-Free Survival Rate | Liver Relapse-Free Survival (LRFS) is defined as the interval from the date of randomization to the date of liver localized metastatic relapse (with the exception of curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix) or death from any cause whichever occurs first. | 3-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival | DFS is defined as the time interval from the date of randomization to the time of the first relapse at any site, death from any cause, or last recorded follow-up visit. | 3-year |