Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
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).
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).
-  Histologically or cytologically confirmed carcinoma of the colon and/or rectum with
 evidence of liver metastases (new confirmation of metastatic disease is required in
 case the time interval from last histological diagnosis to enrolment exceeds 3 years).

 -  Patient with wild type (WT) KRAS tumor status

 -  Patient whose liver metastases are considered to be non resectable with curative
 intent in medico-surgical staff meeting. In particular patients with at least one of
 the following criteria, which prevent complete local treatment of liver metastasis
 with surgery alone or surgery plus radiofrequency ablation because:

 -  less than 30% estimated residual liver after resection

 -  disease in contact with liver main vessels

 -  documented progressive disease on imaging documents or doubling of serum levels
 of carcino-embryonic antigen (CEA) or CA19.9 over the past 90 days or less

 -  Patient with up to three resectable extrahepatic nodules of <= 10 mm

 -  One, two or three prior chemotherapy lines for colorectal cancer.

 -  Written informed consent.

 -  Age >=18 years.

 -  Patient must be able to comply with the protocol.

 -  Life expectancy of at least 3 months.

 -  At least one measurable metastatic liver lesion (as per RECIST criteria).

 -  World Health Organization performance status of 0 or 1.

 -  Adequate hematological function: absolute neutrophil count (ANC) >=1.0 x 10^9/L;
 platelets >=75 x 10^9/L, hemoglobin (Hb) >=8.5 g/dL.

 -  International normalized ratio (INR) <=1.5 and activated partial thromboplastin time
 (aPTT) <=1.5 x upper limit of normal (ULN) within 7 days prior to starting study
 treatment, in the absence of anticoagulant therapy.

 -  Liver function: serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <5
 x ULN (liver metastases).

 -  Serum creatinine <= 1.5 x ULN.

 -  Fertile women and men of childbearing potential (<2 years after last menstruation in
 women) must use effective means of contraception (oral contraceptives, intrauterine
 contraceptive device, barrier method of contraception in conjunction with spermicidal
 jelly or surgically sterile).

 Exclusion Criteria:

 -  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.