Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy

NCT00852228

Last updated date
Study Location
Clinique Saint-Joseph
Liège, , 4000, Belgium
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Metastatic Colorectal Cancer, Liver Metastases, Hepatic Lesions
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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.

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Metastatic Colorectal Cancer, Liver Metastases, Hepatic LesionsOptimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
NCT00852228
  1. Liège,
  2. Bordeaux,
  3. Boulogne-Billancourt,
  4. Clermont-Ferrand,
  5. Lille,
  6. Paris,
  7. Paris,
  8. Toulouse,
  9. Villejuif,
  10. Villejuif,
  11. Chieti,
  12. Pordenone,
  13. Roma,
  14. Amadora,
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
Official Title  ICMJE 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
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Colorectal Cancer
  • Liver Metastases
  • Hepatic Lesions
Intervention  ICMJE
  • Drug: IV cetuximab
    Cetuximab is administered every two weeks at the dose of 500 mg/m² over 2h30 (150 minutes).
    Other Name: Erbitux
  • Drug: HAI chronomodulated chemotherapy

    Irinotecan (180 mg/m²) on day 2 as a 6 hour infusion, starting at 2:00, with a peak at 5:00

    Oxaliplatin (85 mg/m²) in split daily doses for 3 days, starting on day 2. Daily sinusoidal infusion duration will last from 10:15 to 21:45, with peak delivery rate at 16:00.

    5-Fluorouracil (2800 mg/m²) in split daily doses for 3 days, alternating with oxaliplatin infusions, starting on day 2. Daily sinusoidal infusions will last from 22:15 to 9:45 , with peak delivery at 4:00.

    Treatments will be repeated every 2 weeks.

    Other Names:
    • Campto
    • Eloxatin
  • Drug: HAI conventional chemotherapy

    Irinotecan (180 mg/m²) on day 1 as a one hour infusion, then

    Oxaliplatin (85 mg/m²) on day 1 as a two hour infusion, then

    5-Fluorouracil (2800 mg/m²) as a 48 h infusion starting on day 2, after completion of oxaliplatin delivery.

    Treatments will be repeated every 2 weeks.

    Other Names:
    • Campto
    • Eloxatin
Study Arms  ICMJE
  • Experimental: chronomodulated HAI chemotherapy
    Interventions:
    • Drug: IV cetuximab
    • Drug: HAI chronomodulated chemotherapy
  • Experimental: conventional HAI chemotherapy
    Interventions:
    • Drug: IV cetuximab
    • Drug: HAI conventional chemotherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: February 25, 2009)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2015
Actual Primary Completion Date March 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Italy,   Portugal
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00852228
Other Study ID Numbers  ICMJE OPTILIV07
EUDRACT number: 2007-004632-24
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Study Sponsor  ICMJE Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Collaborators  ICMJE
  • Gustave Roussy, Cancer Campus, Grand Paris
  • Merck Serono International SA
  • Pfizer
  • CRESGE
Investigators  ICMJE
Principal Investigator:Francis A. Lévi, M.D., Ph.D.Paul Brousse Hospital, Villejuif, France
PRS Account Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Verification Date December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP