search
Back to results

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

Primary Purpose

Metastatic Colorectal Cancer, Liver Metastases, Hepatic Lesions

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
IV cetuximab
HAI chronomodulated chemotherapy
HAI conventional chemotherapy
Sponsored by
Association pour la Recherche sur le Temps Biologique et la Chronothérapie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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.

Sites / Locations

  • Clinique Saint-Joseph
  • CHU de Bordeaux, Hôpital Saint-André
  • Hôpital Ambroise Paré
  • Centre Jean Perrin
  • CHRU de Lille, Hôpital Claude Huriez
  • Hôpital Cochin
  • Hôpital Européen Georges Pompidou
  • CHU Toulouse
  • Chronotherapy Unit, Medical Oncology Department, Paul Brousse Hospital
  • Institut Gustave Roussy
  • Università G. d'Annunzio
  • Azienda Ospedaliera S.Maria Degli Angeli
  • Istituto Regina Elena
  • Hospital Fernando Fonesca

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

chronomodulated HAI chemotherapy

conventional HAI chemotherapy

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

The rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy
The relapse-free survival 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 per-operative and post-operative complications associated to liver surgery

Full Information

First Posted
February 25, 2009
Last Updated
December 10, 2013
Sponsor
Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Collaborators
Gustave Roussy, Cancer Campus, Grand Paris, Merck Serono International SA, Pfizer, CRESGE
search

1. Study Identification

Unique Protocol Identification Number
NCT00852228
Brief Title
Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy
Acronym
OPTILIV
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Unknown status
Study Start Date
July 2008 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
December 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Collaborators
Gustave Roussy, Cancer Campus, Grand Paris, Merck Serono International SA, Pfizer, CRESGE

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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. 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. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer, Liver Metastases, Hepatic Lesions
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
chronomodulated HAI chemotherapy
Arm Type
Experimental
Arm Title
conventional HAI chemotherapy
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
IV cetuximab
Other Intervention Name(s)
Erbitux
Intervention Description
Cetuximab is administered every two weeks at the dose of 500 mg/m² over 2h30 (150 minutes).
Intervention Type
Drug
Intervention Name(s)
HAI chronomodulated chemotherapy
Other Intervention Name(s)
Campto, Eloxatin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
HAI conventional chemotherapy
Other Intervention Name(s)
Campto, Eloxatin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of complete macroscopic resections (R0+R1) of unresectable liver metastases following chemotherapy.
Time Frame
evaluation every 6th week up to 18 weeks
Secondary Outcome Measure Information:
Title
The rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy
Time Frame
every 2 month up to 3 years
Title
The relapse-free survival in the resected patients
Time Frame
every 2nd month up to 3 years
Title
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)
Time Frame
every 2nd month up to 3 years
Title
The objective response rate
Time Frame
every 6 weeks up to 18 weeks
Title
The rate of adverse events
Time Frame
continuous up to 30 days following end of treatment
Title
The per-operative and post-operative complications associated to liver surgery
Time Frame
continuous up to 3 months following surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francis A. Lévi, M.D., Ph.D.
Organizational Affiliation
Paul Brousse Hospital, Villejuif, France
Official's Role
Principal Investigator
Facility Information:
Facility Name
Clinique Saint-Joseph
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
CHU de Bordeaux, Hôpital Saint-André
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Facility Name
Hôpital Ambroise Paré
City
Boulogne-Billancourt
ZIP/Postal Code
92100
Country
France
Facility Name
Centre Jean Perrin
City
Clermont-Ferrand
ZIP/Postal Code
63011
Country
France
Facility Name
CHRU de Lille, Hôpital Claude Huriez
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital Cochin
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
Hôpital Européen Georges Pompidou
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
CHU Toulouse
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Chronotherapy Unit, Medical Oncology Department, Paul Brousse Hospital
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Università G. d'Annunzio
City
Chieti
ZIP/Postal Code
66100
Country
Italy
Facility Name
Azienda Ospedaliera S.Maria Degli Angeli
City
Pordenone
ZIP/Postal Code
33170
Country
Italy
Facility Name
Istituto Regina Elena
City
Roma
ZIP/Postal Code
00144
Country
Italy
Facility Name
Hospital Fernando Fonesca
City
Amadora
ZIP/Postal Code
27000
Country
Portugal

12. IPD Sharing Statement

Citations:
PubMed Identifier
27768923
Citation
Bouchahda M, Boige V, Smith D, Karaboue A, Ducreux M, Hebbar M, Lepere C, Focan C, Guimbaud R, Innominato P, Awad S, Carvalho C, Tumolo S, Truant S, De Baere T, Castaing D, Rougier P, Morere JF, Taieb J, Adam R, Levi F; ARTBC International. Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer. Eur J Cancer. 2016 Nov;68:163-172. doi: 10.1016/j.ejca.2016.09.011. Epub 2016 Oct 18.
Results Reference
derived
PubMed Identifier
26578731
Citation
Levi FA, Boige V, Hebbar M, Smith D, Lepere C, Focan C, Karaboue A, Guimbaud R, Carvalho C, Tumolo S, Innominato P, Ajavon Y, Truant S, Castaing D, De Baere T, Kunstlinger F, Bouchahda M, Afshar M, Rougier P, Adam R, Ducreux M; Association Internationale pour Recherche sur Temps Biologique et Chronotherapie (ARTBC International). Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV. Ann Oncol. 2016 Feb;27(2):267-74. doi: 10.1093/annonc/mdv548. Epub 2015 Nov 16.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs