Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

April 13, 2016 updated by: Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Randomised Phase 2 Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

To analyze the pathological tumor response on resected colorectal cancer metastases after preoperative treatment with cetuximab combined with FOLFOX or FOLFIRI regimen in a prospective cohort (RAS and B-RAF WT tumors) and to correlate this response with patient's outcome.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This is a phase II , openlabel, randomized study in patients with confirmed diagnosis of potentially or borderline resectable metastatic colorectal adenocarcinoma (RAS and B-RAF WT tumors ), who have not received prior chemotherapy for their metastatic disease.

The study is designed to compare pathological responses observed after pre-operative chemotherapy cetuximab with FOLFOX or FOLFIRI.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Bouge, Belgium, 5004
        • Clinique Saint Luc
      • Brussels, Belgium, 1200
        • Cliniques universitaires Saint-Luc - UCL
      • La Louvière, Belgium, 7100
        • Centre Hospitalier Jolimont Lobbes
      • Liège, Belgium, 4000
        • CHU liège (Sart Timan)
      • Ottignies, Belgium, 1340
        • Clinique Saint Pierre Ottignies
      • Yvoir, Belgium, 5530
        • CHU-UCL Dinant-Godinne
    • Hainaut
      • Charleroi, Hainaut, Belgium, 6000
        • Grand Hôpital de Charleroi

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Female or male patients with at least 18 years at the time the informed consent is signed
  2. ECOG performance status 0 or 1
  3. Histological or cytological confirmed diagnostic of adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Wild-type RAS and B-RAF tumor status.
  4. Patients with potentially resectable metastatic disease at diagnosis and for whom a chemotherapy first in a curative intent is recommended . Resectability could be planed in one or multiple stage if indicated. As commonly admitted, resectability means the surgical clearance (+/- radiofrequency ablation) of all detectable (liver) lesions with tumor-free margins and compatible with an adequate hepatic reserve. Practically, bilateral tumor location, number and location of lesions, and inadequate hepatic reserve remain the main decisional factors.
  5. Partial and minor resection of metastatic disease is allowed within 3 months before inclusion if patient has never received chemotherapy for mCRC.
  6. Extra hepatic metastatic location is limited to 1 site.
  7. Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to inclusion (12 months for oxaliplatin). Previous radiotherapy to the pelvis is not an exclusion criterion.

  8. Adequate haematological, renal and hepatic function as follows:

    Haematological:

    haemoglobin >9g/dl Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L

    Renal:

    Creatinine< 1.5 x ULN (Upper Limit of Normal)

    Hepatic:

    Bilirubin < or equal 1.5 X ULN AST (Aspartate Aminotransferase),and ALT (Alanine Aminotransferase)< or equal 5 x ULN, Phos Alc< or equal 5 x ULN

  9. Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception.
  10. Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception.
  11. Life expectancy of at least 3 months without any active treatment.

Exclusion Criteria:

  • 1.Definitively non resectable mCRC at diagnosis
  • 2.Prior chemotherapy or systemic therapy for mCRC. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to inclusion. Oxaliplatin-based chemotherapy must be completed more than 1 year prior to inclusion.
  • 3.Prior utilization of cetuximab, panitumumab (or other anti-EGFR (epidermal growth factor receptor)therapy).
  • 4.Previous radiotherapy delivered to the upper abdomen.
  • 5 Non mesurable disease( RECIST 1.1 criteria)
  • 6.Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiologic assessment.
  • 7.Prior major liver resection: remnant liver < 50% of the initial liver volume.
  • 8.Non-malignant disease that would render the patient unsuitable for treatment according to this protocol.
  • 9.Concurrent central nervous systems metastases
  • 10.Peripheric neuropathy ≥ grade 2.
  • 11.Interstitial lung disease
  • 12.Pregnant or breast feeding.
  • 13.The patient has previous or concomitant malignancies, except: Invasive malignancies in remission for more than 5 years and non melanoma skin cancer or carcinoma in situ of the cervix.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: oxaliplatin +leucovorin L+5FU+ cetuximab
oxaliplatin +leucovorinL+5-Fluorouracile +cetuximab+'Metastases Resection ( multiple steep surgery possible)
Procedure: Metastases Resection ( multiple steep surgery possible)
Metastases resection will be process by surgery, after a randomized chemotherapy (FOLFOX or FOLFIRI) + Target therapy (Cetuximab). The surgery will allow to compare the pathological response on the resected metastases by the chemotherapy + target therapy type.
Drug: 5-Fluorouracile
5-FU bolus 400 mg/m2, IV bolus every 2 weeks 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion every 2 weeks
Other Names:
  • 5FU
Drug: leucovorin L
Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, 2-hour IV infusion
Other Names:
  • elvorine
  • isovorin
Drug: Oxaliplatin
Oxaliplatin 85 mg/m² in 150 ml NaCl 0.9%, 2-hour IV infusion every 2 weeks
Other Names:
  • Eloxatin
Drug: Cetuximab
Cetuximab 400 mg/m² in 100 ml NaCl 0.9% 2-hour IV infusion for 1rst cycle and after the 1rst cycle 250 mg/m² in 100 ml NaCl 0.9% 1-hour IV infusion
Other Names:
  • erbitux
Active Comparator: Irinotecan+ + leucovorinL +5-Fluorouracil +cetuximab
Irinotecan+ + leucovorinL +5-Fluorouracile + cetuximab +'Metastases Resection ( multiple steep surgery possible)
Procedure: Metastases Resection ( multiple steep surgery possible)
Metastases resection will be process by surgery, after a randomized chemotherapy (FOLFOX or FOLFIRI) + Target therapy (Cetuximab). The surgery will allow to compare the pathological response on the resected metastases by the chemotherapy + target therapy type.
Drug: 5-Fluorouracile
5-FU bolus 400 mg/m2, IV bolus every 2 weeks 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion every 2 weeks
Other Names:
  • 5FU
Drug: leucovorin L
Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, 2-hour IV infusion
Other Names:
  • elvorine
  • isovorin
Drug: Cetuximab
Cetuximab 400 mg/m² in 100 ml NaCl 0.9% 2-hour IV infusion for 1rst cycle and after the 1rst cycle 250 mg/m² in 100 ml NaCl 0.9% 1-hour IV infusion
Other Names:
  • erbitux
Drug: Irinotecan
Irinotecan 180 mg/m² in 150 ml NaCl 0.9%, 1.30-hour IV infusion every 2 weeks
Other Names:
  • Campto
  • Irinosin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major Pathological Response Rate
Time Frame: Average 3 months (after resection of metastases)
Major pathological response rate (MPRR) is defined as the proportion of patients presenting a major pathological response. Pathologic response will be evaluated according the Rubbia-Brandt Tumor Regression Grade classification .For patients with multiple colorectal metastases the global pathological response will be categorized based on the mean TRG of all metastases.: a major response is defined as a mean TRG < 3, a partial response is defined for patient presenting a mean TRG ≥3 and <4, and a no response for patient with a mean TRG ≥4.
Average 3 months (after resection of metastases)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
progression free survival
Time Frame: at 6 months and at 12 months after randomization
-Progression Free Survival (PFS) is defined as the time from randomization to the time of first event (relapse of the original mCRC, development of a new colorectal cancer or death due to any cause). Patients without any such event at the time of data analysis will be censored at the last date they were known to be event-free. PFS analysis will be based on tumour assessments and survival follow-up assessments.
at 6 months and at 12 months after randomization
Overall survival
Time Frame: At the end of the study
The overall survival will be analyzed at the end of study (3 year of recruitment and one year of follow-up).
At the end of the study
Clinical response rate
Time Frame: at time of surgery -
Clinical response rate at time of surgery: Clinical tumour response will be measured according to the RECIST 1.1 criteria
at time of surgery -
Metabolic response rate
Time Frame: At time of surgery - average 3 months
Metabolic response rate at time of surgery (in selected centres only, optional): Metabolic tumour response will be measured according to the EORTC criteria . PET-Scan evaluation remains optional to selected centres only.
At time of surgery - average 3 months
post operative complications
Time Frame: one month after surgery

. Severe pre- or postoperative complications within 30 days of surgery:

  • surgery-associated bleeding requiring replacement with > 4 units of erythrocyte concentrates,
  • wound infection,
  • intra-abdominal infection,
  • severe sepsis (American College of Chest physicians/Society of Critical Care Medicine, 1992),
  • impaired wound healing,
  • subphrenic or perihepatic abscess requiring drainage during hospital stay or within 30 days after the operation,
  • re-laparotomy connected with the resection,
  • a biliary fistula for more than 10 days with a discharge of > 100 mL/day,
  • transient liver failure (bilirubin > 10 mg/dL lasting > 3 days),
  • renal failure requiring dialysis,
  • respiratory failure with renewed necessary mechanical ventilation, venous thromboembolism,
  • cardiac failure,
  • death of the patient as a result of the operation.
one month after surgery
Curative resection rate
Time Frame: At time of surgery
Curative resection rate (R0 resection) is defined by the surgical clearance (+/- radiofrequency ablation) of all detectable hepatic lesions with tumor-free margins at histo-pathological evaluation.
At time of surgery
Chemotherapy-associated hepatotoxicity:
Time Frame: at time of surgery
Systemic neo-adjuvant chemotherapy in mCRC frequently causes morphological lesions involving hepatic microvasculature . Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non tumoral liver, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin.
at time of surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Collaborators

Grand Hôpital de Charleroi

Investigators

  • Principal Investigator: Marc Van den Eynde, MD, Cliniques universitaires Saint-Luc - UCL
  • Principal Investigator: Javier Carrasco, MD PhD, Grand Hôpital de Charleroi

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2014

Primary Completion (Actual)

November 1, 2015

Study Completion (Actual)

November 1, 2015

Study Registration Dates

First Submitted

May 7, 2013

First Submitted That Met QC Criteria

May 20, 2013

First Posted (Estimate)

May 21, 2013

Study Record Updates

Last Update Posted (Estimate)

April 15, 2016

Last Update Submitted That Met QC Criteria

April 13, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CET-ONCO2012
  • 2012-005249-19 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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