Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
- Conditions
- Hepatic LesionsMetastatic Colorectal CancerLiver Metastases
- Interventions
- Drug: IV cetuximabDrug: HAI chronomodulated chemotherapyDrug: HAI conventional chemotherapy
- Registration Number
- NCT00852228
- Lead Sponsor
- Association pour la Recherche sur le Temps Biologique et la Chronothérapie
- Brief Summary
The primary objective of the study is to increase by 15% the complete macroscopic resection rate of predominantly liver metastases from metastatic colorectal cancer through combining systemic cetuximab and hepatic artery infusion of three-drug chemotherapy (irinotecan, oxaliplatin and 5-fluorouracil).
- Detailed Description
Primary end-point: incidence of complete macroscopic resections of liver metastases (R0+R1).
Secondary end-points:
* the rate of histologic complete responses,
* the individual rates of R0 and R1 resections,
* the rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy,,
* the relapse-free survival curve and median in the resected patients,
* the progression-free and the overall survival in the patients receiving at least 4 full courses of HAI therapy and in all the patients (intent to treat),
* the objective response rate,
* the rate of adverse events,
* the dose intensities over 3, 6 and 9 courses,
* the per-operative and post-operative complications associated to liver surgery.
The study also includes a pharmacokinetic analysis, a translational research and a rest/activity monitoring investigation.
Open, label, European, non randomized, multicenter, phase II study of intravenous cetuximab (ERBITUX®) and hepatic artery infusion of three-drug chemotherapy (irinotecan, 5-fluorouracil and oxaliplatin) using conventional or chronomodulated delivery (according to institution experience) in patients with liver metastases from colorectal cancer.
Patients undergo partial hepatectomy after 6 ± 3 courses of therapy whenever possible. The minimum of 3 and the maximum of 9 courses before liver surgery depend upon results from iterative onco-surgical evaluations. A minimum of 6 and up to 9 additional courses of therapy will be administered after surgery, depending upon results of liver surgery, pathology report and patient's status. Overall, the patients will receive 9 to 18 courses of protocol therapy.
The interval between the last course of cetuximab-HAI chemotherapy and surgery will be 2 to 4 weeks. Post operative treatment will be initiated 2 to 4 weeks after liver surgery.
TRANSLATIONAL RESEARCH:
1. Pharmacokinetics:
For a subset of 16 patients (8 on conventional administration and 8 on chronotherapeutic delivery), plasma pharmacokinetics of irinotecan, 5-FU and oxaliplatin and main metabolites will be evaluated after the first course.
2. Rest-Activity monitoring:
Rest-activity will be monitored with a wrist-worn actigraph (Ambulatory Monitoring, USA) for 1 week prior to treatment onset and during the 2 weeks following treatment onset (3 weeks). This evaluation will be repeated before, during and after the 4th treatment course and before during and after 7th treatment course. Participation of the centers to this investigation will be left optional.
Time series will be analyzed before, during and after chemotherapy course, with the time courses of the following parameters:
* Autocorrelation coefficient at 24 h (r24)
* Dichotomy index I\<O
* Wavelet-based model function at baseline, and deviation from this model function during and after treatment course delivery.
3. Predictive molecular factors:
In primary tumor and/or in metastases obtained any time prior to inclusion and in resected metastases and non tumoral liver:
* EGFR immunohistochemistry and gene expression or amplification and polymorphism.
* K-ras mutations.
* Clock genes polymorphism or mRNA or protein expression.
* Gene polymorphisms or expression for main pharmacology determinants of irinotecan, 5- FU and oxaliplatin efficacy.
* Inflammatory and immune cell subsets infiltration. Whenever possible, a biopsy of a liver metastasis will also be obtained before treatment onset for documenting these translational endpoints.
In serum, upon inclusion and after 3 courses:
· Determination of serum levels of TGFa, EGF, VEGF, IL-6, IL-8, amphiregulin and epiregulin.
In blood cells upon inclusion:
· Constitutive polymorphisms for ADCC (FCII and FCIII), circadian clock and EGFR.
STATISTICAL METHODS AND SAMPLE SIZE:
The main endpoint will be the incidence of macroscopically complete resections of liver metastases (R0+R1). The confidence intervals (CI) for the response rate will be based on the exact binomial distribution.
For the secondary endpoints, rate of histologic complete responses, rate of R0 resections, rate of R1 resections, rate of relapses, rate of objective responses, the results will be estimated with CI based on the exact binomial distribution. Overall survival time (OS) and progression free survival (PFS) will be analyzed by Kaplan Meier curve. Multivariate analysis will be performed using the Cox proportional hazard model. This analysis will include the following factors: center, performance status, gender, liver disease characteristics, leucocyte count and alkaline phosphatases upon inclusion and treatment delivery schedule, Relapse incidence (RI) is defined as the probability of having had a relapse before time t. Death without experiencing a relapse is a competing event. The method of analysis will be therefore the estimation of Cumulative Incidence curve in a competing risk setting. Multivariate analysis will be performed by the Fine \& Gray model. All patients achieving complete remission will be analyzed.
The goal is to increase the rate of complete resections (R0+R1) by 15%, i.e. from 15% (p0=0.15) to 30% (p1=0.30). According to the exact single-stage phase II design method, the trial for accepting that p1 is to be preferred to p0 (with a=5% and b=20%) requires 48 patients assessable for response. To obtain 48 patients assessable for response, 60 patients will be included in the trial.
A major additional effect expected further from this combined treatment modality is the increase of complete histologic responses, a secondary endpoint in this trial, from 5% (with systemic chemotherapy) to 20% with combined cetuximab and 3-drug HAI. This improvement should further reduce the risk of relapse in the liver or outside the liver by 15 %, i.e. from 80% to 65%.
Therefore, the total number of patients will be 60 patients, including 48 assessable and 12 estimated as unassessable for technical reasons (i.e. HAI catheter dysfunction within the first 2 months).
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 60
Not provided
- Patient whose primary tumor or metastasis displays mutation of K-Ras (codon 12 and/or 13).
- Unresectable extrahepatic diseases.
- More than three resectable extrahepatic nodules.
- Size of extra hepatic nodules > 1 cm
- Prior HAI of the 3 drugs.
- More than 2 prior surgical attempts for metastatic disease
- Prior radiotherapy for metastatic disease
- Known documented intolerance or hypersensitivity to any of the drugs used.
- Sensory neuropathy grade 3 (National Cancer Institute-Common Terminology Criteria for Adverse Events -NCI-CTCAE, Version 3.0).
- Past or current history (within the last 2 years prior to treatment start) of malignancy other than colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
- Serious, non healing wound, ulcer, or bone fracture.
- Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that puts the patient at high risk for treatment-related complications.
- Pregnancy or lactation
- Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
Prior systemic administration of cetuximab or other anti-EGFR agent is not an exclusion criterion.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description chronomodulated HAI chemotherapy HAI chronomodulated chemotherapy - conventional HAI chemotherapy IV cetuximab - chronomodulated HAI chemotherapy IV cetuximab - conventional HAI chemotherapy HAI conventional chemotherapy -
- Primary Outcome Measures
Name Time Method Incidence of complete macroscopic resections (R0+R1) of unresectable liver metastases following chemotherapy. evaluation every 6th week up to 18 weeks
- Secondary Outcome Measures
Name Time Method The relapse-free survival in the resected patients every 2nd month up to 3 years The rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy every 2 month up to 3 years The progression-free and the overall survival in the patients receiving at least 4 full courses of HAI therapy and in all the patients (intent to treat) every 2nd month up to 3 years The objective response rate every 6 weeks up to 18 weeks The rate of adverse events continuous up to 30 days following end of treatment The per-operative and post-operative complications associated to liver surgery continuous up to 3 months following surgery
Trial Locations
- Locations (14)
Centre Jean Perrin
🇫🇷Clermont-Ferrand, France
CHU de Bordeaux, Hôpital Saint-André
🇫🇷Bordeaux, France
Hôpital Cochin
🇫🇷Paris, France
CHRU de Lille, Hôpital Claude Huriez
🇫🇷Lille, France
Clinique Saint-Joseph
🇧🇪Liège, Belgium
Hôpital Ambroise Paré
🇫🇷Boulogne-Billancourt, France
Hospital Fernando Fonesca
🇵🇹Amadora, Portugal
Azienda Ospedaliera S.Maria Degli Angeli
🇮🇹Pordenone, Italy
Istituto Regina Elena
🇮🇹Roma, Italy
Hôpital Européen Georges Pompidou
🇫🇷Paris, France
Università G. d'Annunzio
🇮🇹Chieti, Italy
Institut Gustave Roussy
🇫🇷Villejuif, France
CHU Toulouse
🇫🇷Toulouse, France
Chronotherapy Unit, Medical Oncology Department, Paul Brousse Hospital
🇫🇷Villejuif, France