Chemoembolization (Lifepearls-Irinotecan) in Patients With Colorectal Cancer and Metastatic Disease

Study Overview
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Brief Summary
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Non-commercial, prospective, randomized, multicenter, national, phase II, open-label comparative clinical trial. The patients will be randomized in a 1: 1 ratio in two arms: Control arm. Systemic chemotherapy with FOLFOX6m + monoclonal Ab Experimental arm. Systemic chemotherapy with FOLFOX6m + monoclonal Ab + Intra-arterial liver chemotherapy with LIFEPEARLS-IRINOTECAN (catheterization and infusion of 100 +/- 50 micron microspheres loaded with 100 mg of irinotecan in both liver lobes) cycles 2 and 4. The main objective is to evaluate the radiological objective response rate according to the RECIST version 1.1 criteria at 6 months. Secondary objectives include: Evaluate overall survival, progression-free survival (PFS), safety profile, hepatic PFS, R0 liver surgery rate.

Detailed Description
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Hepatic intra-arterial therapy (TACE) with irinotecan has been used in several prospective studies demonstrating an acceptable toxicity profile. Two randomized phase II studies have evaluated the efficacy of TACE with irinotecan compared to conventional chemotherapy in metastatic colon cancer. A second-line treatment study demonstrated an increase in PFS in the TACE versus FOLFIRI treatment arm. A prospective open, randomized, multicenter phase II study is proposed that will include patients with liver metastases of colorectal origin with poor prognostic criteria. LIFEPEARLS® is a CE marked medical device consisting of microspheres for use in chemoembolization. The device uses 100 +/- 50 micron microspheres of hydrogel into which chemotherapeutic agents are loaded and delivered into the hepatic artery to treat liver tumors. This device allows the continuous release of irinotecan in liver tumors causing a specific necrosis. The penetration of irinotecan into the tumor tissue is deeper thanks to the microspheres, avoiding proximal occlusion of the vessels supplying the tumor. Systemic treatment will be administered according to the usual guidelines: -FOLFOX6m for 6 months + monoclonal Ab (cycles are repeated every 15 days) Premedication: Dexamethasone 20 mg IV + ondansetron 8mg IV The dose of FOLFOX will be: Leucovorin: 400 mg / m2 IV over 15 minutes on day 1 of each cycle. Fluorouracil (5-FU): 400mg / m2 IV bolus (15 min) followed by continuous IV infusion for 46 h of 2,400 mg / m2 on day 1 of each cycle. Oxaliplatin 85 mg / m2 IV over 120 minutes on cycle day 1. In case of RAS wt colorectal cancer administer anti-EGFR together with FOLFOX6m, and in case of mutated RAS colorectal cancer administer Bevacizumab together with FOLFOX6m. In the combination arm of systemic chemotherapy with IRINOPEARL, in the 2nd and 4th cycles, chemotherapy will be replaced by treatment with hepatic chemoembolization with IRINOPEARL. The disease will be evaluated by CT or MRI at baseline and every 12 weeks until progression according to RECIST 1.1 criteria.

Official Title
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Randomized, Multicenter Phase II Study of Monoclonal FOLFOX6m + mAb Alone or in Combination With Liver Chemoembolization (Lifepearls-Irinotecan) in Patients With Colorectal Cancer and Metastatic Disease Limited to the Liver With Poor Prognosis

Conditions
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Colorectal Cancer Metastatic, Liver Metastasis Colon Cancer

Intervention / Treatment
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* Drug: FOLFOX regimen
* Biological: Anti-EGFR or Bevacizumab
* Drug: LIVERPEARLS-Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 18 years. Patients with colorectal cancer and exclusive liver metastases with poor prognostic criteria,> 3 lesions and / or size> 5 cm. Patients with a diagnosis of liver metastases with synchronous presentation or with a disease-free interval may be included. If the primary tumor has not been resected, it must be clinically stable. Measurable disease following RECIST version 1.1 criteria Adequate bone marrow function, according to: Hemoglobin ≥ 9.0 g / dl (patients with hemoglobin <9 g / dl can be transfused before inclusion in the study Platelet count ≥ 100 x 109 / L Absolute Neutrophil Count (ANC) ≥ 1.5x 109 / L Adequate liver function, according to: Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN. Alkaline phosphatase ≤ 5 x ULN or ≤10 x ULN in the presence of bone metastases Adequate renal function, with creatinine levels <1.5 mg / dL. Blood Ureic Nitrogen (BUN)> 50 ml / min. Albumin> 3.0 g / dL Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Patients capable of understanding the information and giving their written informed consent to participate in the study Women of childbearing potential must commit to sexual abstinence or use of barrier contraceptive methods during the study and must have a negative pregnancy test. Exclusion Criteria: Extension of the disease> 50% of the liver parenchyma (evaluated by CT performed within the month prior to inclusion) Previous chemotherapy treatment for metastatic colorectal cancer Clinically significant cardiovascular diseases: cerebrovascular accident / stroke (≤ 6 months before inclusion in the trial), myocardial infarction (≤ 6 months before inclusion in the trial), unstable angina, uncontrolled hypertension, congestive heart failure of New York Heart Association (NYHA) grade II or higher or severe cardiac arrhythmia. History of malignancy in the last three years, except for basal cell carcinoma of the skin or carcinoma in situ of the cervix treated appropriately. Altered coagulation (Quick> 50%) Patients with active infectious processes Patients with any of the contraindications specified in the technical data sheet of the study drug or with allergies to some of the drugs used Pregnant or lactating patients Portal thrombosis Severe portal hypertension Extrahepatic metastases

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
Interventional Model Description: Patients will be randomized in a 1: 1 ratio in the 2 arms: Control Arm. Systemic chemotherapy with FOLFOX6m + monoclonal Ab Experimental Arm. Systemic chemotherapy with FOLFOX6m + monoclonal Ab + Intra-arterial liver chemotherapy with LIFEPEARLS-IRINOTECAN (catheterization and infusion of 100 +/- 50 micron microspheres loaded with 100 mg of irinotecan in both liver lobes) cycles 2 and 4.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Systemic chemotherapy with FOLFOX6m + monoclonal Ab (anti-EGFR or bevacizumab). | Drug: FOLFOX regimen<br>* Leucovorin: 400 mg / m2 IV over 15 minutes on day 1 of each cycle. Fluorouracil (5-FU): 400mg / m2 IV bolus (15 min) followed by continuous IV infusion for 46 h of 2,400 mg / m2 on day 1 of each cycle. Oxaliplatin 85 mg / m2 IV over 120 minutes on cycle day 1<br>* Other names: Leucovorin/Fluorouracil/Oxaliplatin;Biological: Anti-EGFR or Bevacizumab<br>* In case of RAS wt colorectal cancer administer anti-EGFR together with FOLFOX6m, and in case of mutated RAS colorectal cancer administer Bevacizumab together with FOLFOX6m. Treatment administered following Summary of medicinal Product Characteristics (SmPC) approved indications.<br>* Other names: monoclonal antibody anti EGFR (RASwt) or Bevacizumab (RASmut);|
| Experimental: Experimental<br>Systemic chemotherapy with FOLFOX6m + monoclonal Ab (anti-EGFR or bevacizumab) + Intra-arterial liver chemotherapy with LIFEPEARLS-IRINOTECAN (catheterization and infusion of 100 +/- 50 micron microspheres loaded with 100 mg of irinotecan in both liver lobes) cycles 2 and 4. | Drug: FOLFOX regimen<br>* Leucovorin: 400 mg / m2 IV over 15 minutes on day 1 of each cycle. Fluorouracil (5-FU): 400mg / m2 IV bolus (15 min) followed by continuous IV infusion for 46 h of 2,400 mg / m2 on day 1 of each cycle. Oxaliplatin 85 mg / m2 IV over 120 minutes on cycle day 1<br>* Other names: Leucovorin/Fluorouracil/Oxaliplatin;Biological: Anti-EGFR or Bevacizumab<br>* In case of RAS wt colorectal cancer administer anti-EGFR together with FOLFOX6m, and in case of mutated RAS colorectal cancer administer Bevacizumab together with FOLFOX6m. Treatment administered following Summary of medicinal Product Characteristics (SmPC) approved indications.<br>* Other names: monoclonal antibody anti EGFR (RASwt) or Bevacizumab (RASmut);Drug: LIVERPEARLS-Irinotecan<br>* Chemoembolization of Irinotecan in 100 +/- 50 micron hydrogel microspheres. Irinotecan will be loaded at a dose of 100 mg. LIFEPEARLS® is a CE marked medical device consisting of microspheres for use in chemoembolization. This device allows the continuous release of irinotecan in liver tumors causing a specific necrosis. The penetration of irinotecan into the tumor tissue is deeper thanks to the microspheres, avoiding proximal occlusion of the vessels supplying the tumor.<br>* Other names: Chemoembolization of Irinotecan in hydrogel microspheres;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The proportion of patients with tumor size reduction according to RECIST 1.1 criteria at 6 months | Evaluated at 6 months after first investigation drug administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from randomization until death from any cause. Patients still alive at the last contact or lost to follow-up will be censored. | Through study completion, average 2 years | 
| Progression free survival | Time from from the date of randomization to the date of first documented disease progression according to RECIST 1.1 criteria or the date of death due to any cause. Patients without radiological documentation of progression will be censored on the date of the last control without evidence of progression. | Through study completion, average 2 years. Evaluated during a total of 2 years (estimated) by CT scan or MR every 12 weeks | 
| Frequency of adverse events | Percentage of adverse events, laboratory alterations and treatment discontinuations observed in both treatment arms classified by type and severity (Safety) | Through study completion, average 2 years | 
| Hepatic Progression free survival | Time from from the date of randomization to the date of first documented disease progression within the liver according to RECIST 1.1 criteria or the date of death due to any cause. Patients without radiological documentation of progression will be censored on the date of the last control without evidence of progression. | Through study completion, average 2 years. Evaluated during a total of 2 years (estimated) by CT scan or MR every 12 weeks | 
| Proportion of patients with liver surgery | Proportion of patients undergoing R0 surgery for liver metastases | Through study completion, average 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Chemoembolization, LIVERPEARLS-Irinotecan, Liver metastasis