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Optimal Control of Liver Metastases With Intravenous Cetuximab and Hepatic Artery Infusion of Three-drug Chemotherapy in Patients With Liver-only Metastases From Colorectal Cancer. A European Multicenter Phase II Trial

Phase 2
18 Years
Open (Enrolling)
Metastatic Colorectal Cancer, Liver Metastases, Hepatic Lesions

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Trial Information

Optimal Control of Liver Metastases With Intravenous Cetuximab and Hepatic Artery Infusion of Three-drug Chemotherapy in Patients With Liver-only Metastases From Colorectal Cancer. A European Multicenter Phase II Trial

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.


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
- 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.


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).

Inclusion Criteria

- 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

- 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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of complete macroscopic resections (R0+R1) of unresectable liver metastases following chemotherapy.

Outcome Time Frame:

evaluation every 6th week up to 18 weeks

Safety Issue:


Principal Investigator

Francis A. Lévi, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Paul Brousse Hospital, Villejuif, France


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

July 2008

Completion Date:

December 2015

Related Keywords:

  • Metastatic Colorectal Cancer
  • Liver Metastases
  • Hepatic Lesions
  • colorectal cancer
  • unresectable metastases
  • neo-adjuvant chemotherapy
  • liver metastases
  • chronotherapy
  • cetuximab
  • irinotecan
  • oxaliplatin
  • 5-fluorouracil
  • hepatic artery infusion
  • Unresectable hepatic lesions
  • 1 to 3 prior chemotherapy regimens
  • Colorectal Neoplasms
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Liver Neoplasms