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Chemotherapies Associated With Targeted Therapies on the Resection Rate of Hepatic Metastases

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ClinicalTrials.gov Identifier: NCT01442935
Recruitment Status : Active, not recruiting
First Posted : September 29, 2011
Last Update Posted : May 8, 2018
Sponsor:
Information provided by (Responsible Party):
UNICANCER

Brief Summary:

The main objective is to compare resection rates (R0 or R1) for hepatic metastases in the experimental arm (tri chemotherapy plus targeted therapy) versus the control arm (bi chemotherapy plus targeted therapy); in both arms the targeted therapy is selected according to K-Ras status of the patient's tumor.

The secondary objectives are to evaluate the objective response rate (CR and PR) after 4 cycles of treatment, according the RECIST V1.1 evaluation scale.

  • the rate of complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle).
  • the specific rates of resection R0, R1, R2.
  • the complete pathological response Rate,
  • the relapse-free survival rate in (R0 or R1) resected patients,
  • the response duration in non-resected patients,
  • the toxicity according to CTC AE V4 scale except for the neurotoxicity that will be evaluated with the Levi scale,
  • the post operative complications using the DINDO classification,
  • the progression-free survival (PFS) and overall survival (OS).

The objectives of the biological study are:

  • to evaluate tumor-related predictive factors such as somatic mutations (KRAS, BRAF, TP53) and genetic amplification related factors (EGFR),
  • to evaluate patient-related predictive factors in connection with genetic polymorphisms (Fc gamma and VEGF receptors),
  • to evaluate ADCC activity via immunohistochemistry in order to analyze the lympho free and progression-free survival,
  • to study circulating of tumor cells as prognostic factor for metastatic colorectal cancer, non- resectable at presentation.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Oxaliplatin Drug: Folinic Acid Drug: 5-FU Drug: Irinotecan Drug: Bevacizumab Drug: Cetuximab Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 256 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Multicentric Randomized Trial, Evaluating the Best Protocol of Chemotherapy, Associated With Targeted Therapy According to the Tumor KRAS Status, in Metastatic Colorectal Cancer (CCRM) Patients With Initially Non-resectable Hepatic Metastases
Actual Study Start Date : February 2011
Actual Primary Completion Date : December 2015
Estimated Study Completion Date : February 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A1 : Folfiri + targeted therapy

Every 2 weeks :

  • irinotecan 180 mg/m² D1
  • Folinic acid 400 mg/m² D1
  • 5FU 400 mg/m² bolus
  • 5FU 2400 mg/m² infusion over 46 h, D1

And targeted therapy in function of Kras:

  • For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days
  • For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.
Drug: Folinic Acid
400mg/m² over 120 mn every 2 weeks up to progression or toxicity

Drug: 5-FU
400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
Other Name: 5-Fluoro uracil

Drug: Irinotecan
180mg/m² over 90 mn every 2 weeks up to progression or toxicity

Drug: Bevacizumab
5mg/kg over 90 mn every 2 weeks up to progression or toxicity

Drug: Cetuximab
500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Active Comparator: Arm A2 : Folfox 4 + targeted therapy

Every 2 weeks :

  • oxaliplatin 85 mg/m² D1
  • Folinic acid 400 mg/m² D1
  • 5FU 400 mg/m² bolus
  • 5FU 2400 mg/m² infusion over 46 h, D1

And targeted therapy in function of Kras:

  • For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days
  • For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.
Drug: Oxaliplatin
85mg/m² over 120 mn every 2 weeks up to progression or toxicity

Drug: Folinic Acid
400mg/m² over 120 mn every 2 weeks up to progression or toxicity

Drug: 5-FU
400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
Other Name: 5-Fluoro uracil

Drug: Bevacizumab
5mg/kg over 90 mn every 2 weeks up to progression or toxicity

Drug: Cetuximab
500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Experimental: Arm B : Folfirinox + targeted therapy

Every 2 weeks :

  • oxaliplatin 85 mg/m² D1
  • irinotecan 150 mg/m² D1
  • Folinic acid 400 mg/m² D1
  • 5FU 400 mg/m² bolus
  • 5FU 2400 mg/m² infusion over 46 h, D1. From D7 to D12, prophylactic G-CSF such as Granocyte® will be administered.

And targeted therapy in function of Kras:

  • For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days
  • For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.
Drug: Oxaliplatin
85mg/m² over 120 mn every 2 weeks up to progression or toxicity

Drug: Folinic Acid
400mg/m² over 120 mn every 2 weeks up to progression or toxicity

Drug: 5-FU
400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
Other Name: 5-Fluoro uracil

Drug: Irinotecan
150mg/m² over 30-90 mn every 2 weeks up to progression or toxicity

Drug: Bevacizumab
5mg/kg over 90 mn every 2 weeks up to progression or toxicity

Drug: Cetuximab
500mg/m² over 90 mn every 2 weeks up to progression or toxicity




Primary Outcome Measures :
  1. The main objective is to compare resection rates (R0 or R1) for hepatic metastases [ Time Frame: at least 4-6 weeks after the end of chemotherapy ]
    Number of patients (%) with hepatic metastases R0 or R1 resection.


Secondary Outcome Measures :
  1. The objective response rate (CR and PR) after 4 cycles of treatment [ Time Frame: after 8 weeks ]
    The objective response rate (CR and PR) will be evaluated by the investigator with RECIST v1.1 criteria after 4 cycles. Patients with symptoms suggestive of disease progression will have a tumoral evaluation when symptoms will occur

  2. Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle) [ Time Frame: 6 months ]
    Number of patients (%) with complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)

  3. Specific resection rates R0/R1/R2 [ Time Frame: 24 weeks ]
    Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection.

  4. Complete pathological response [ Time Frame: 24 weeks ]
    Number of patients with Complete pathological response, defined as the absence of tumoral residues after the last chemotherapy cycle. It will be evaluated on liver resection piece, based on total or complete tumor necrosis in all tumor nodules

  5. Toxicity of treatment [ Time Frame: Every 2 weeks ]
    Tolerance of the treatment will be based on toxicities of evaluated products by clinical and biological measurements (NCIC/CTC (CTCAE V4) criteria, except for peripheral neuropathy toxicity (Lévi scale)

  6. Post operatory complications [ Time Frame: after 4 weeks ]
    Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004)

  7. Progression-free survival (PFS) [ Time Frame: 8 months ]
    Progression-free survival is defined as the time from randomization to progression (RECIST v1.1 criteria) or death. Patients alive without progression will be censored at the last follow-up.

  8. Overall survival (OS) [ Time Frame: 14 months ]
    Overall survival is defined as the time from randomization to death any cause or last follow-up news for patients alive (censored data).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven colorectal adenocarcinoma,
  • Primary tumor of the colon or rectum, resectable or resected at least 3 weeks before randomization or 4 weeks before the beginning of the study treatment,
  • Metastatic disease with synchronous or metachronous (> 3 months after diagnosis of the primary tumor) hepatic metastasis,
  • Non-resectable (with respect to curative intent) hepatic metastasis at presentation. This criterion must be validated by both a surgeon and a radiologist during the RCP (Multidisciplinary cancer case presentation committee) patient's evaluation meeting (either technically non-resectable metastases (absolute contraindication): i.e. impossibility to resect all metastases in a single operation while preserving at least 30% of healthy liver tissues and/or impossibility to preserve the portal vein and hepatic artery homolateral to the liver or a portal pedicle, or due to oncological non-resectability (relative contraindication): presence of > 5 nodules and bilateral invasion),
  • Hepatic metastases, without spread to other sites except in case of ≤ 3 resectable pulmonary metastases of diameter < 2 cm, detected by thoracic scanner,
  • K-Ras status determined before randomization,
  • Measurable disease according to the RECIST V1.1 criteria,
  • No prior treatment of the hepatic metastases,
  • Previous 5FU +/- oxaliplatin-based adjuvant chemotherapy administered after colorectal tumor resection is authorized if complete more than 1 year before,
  • Age ≥ 18 & ≤ 75 years
  • Performance status : ECOG 0 or 1,
  • Life expectancy ≥ 3 months,
  • Hemoglobin ≥ 9 g/dl,
  • Polynuclear neutrophiles ≥ 1500/mm3,
  • Platelets ≥ 100 000 mm3,
  • Creatinemia ≤ 135 µmol/l (1,35 mg/dl)
  • Total bilirubin ≤ 1.25 times the Upper Limit of Normal (ULN).
  • Hepatic enzymes ASAT and ALAT < 5 x ULN,
  • Negative pregnancy test for women of child-bearing age,
  • Information given to the patient and signed informed consent,
  • Public Health insurance coverage.

Exclusion Criteria:

  • Non metastatic and/or non measurable disease according to the RECIST v1.1 criteria.
  • Non-resectable primary tumor (e.g.: T4 tumors) or incomplete resection R2.
  • History of intestinal inflammatory disease.
  • Specific contraindication to any of the study treatments.
  • Patient who have previously received anti-EGFr (e.g., cetuximab) or anti-VEGF monoclonal antibody treatment (e.g., bevacizumab) or treatment with irinotecan.
  • History of cancer considered as not cured.
  • Stroke/CVA or pulmonary embolism within 6 months before inclusion.
  • Significant concomitant disease such as: coagulopathy, respiratory or cardiac congestive insufficiency, non-medically controlled/unstable angina pectoris, myocardial infarction within 6 months prior to study entry, arterial hypertension and uncontrolled arrhythmia, severe infections.
  • Clinical neuropathy, grade ≥1.
  • Patient already included in another therapeutic trial using an experimental molecule.
  • Pregnant women or women who might become pregnant during the study or lactating women.
  • Men or women who can procreate and who do not abide with the use of a contraceptive means.
  • Persons kept in detention or incapable of giving consent
  • Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic social or psychological reasons.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01442935


Locations
France
Centre Val d'Aurelle
Montpellier, France, 34298
Sponsors and Collaborators
UNICANCER
Investigators
Principal Investigator: Marc YCHOU, Pr Centre Val d'Aurelle
Principal Investigator: Eric FRANCOIS, Dr Centre Antoine Lacassagne-NICE
Principal Investigator: Laurent MINEUR, Dr Institut Ste Catherine-AVIGNON
Principal Investigator: Olivier BOUCHE, Pr CHU de Reims
Principal Investigator: Driffa MOUSSATA, Dr Centre hospitalier Lyon Sud-PIERRE BENITE
Principal Investigator: Rosine GUIMBAUD, Pr Centre hospitalier Rangueil-TOULOUSE
Principal Investigator: Roger FAROUX, Dr CHD Vendée -LA ROCHE SUR YON
Principal Investigator: Karine BOUHIER-LEPORRIER, Dr CHU Côte de Nacre-CAEN
Principal Investigator: Alice GAGNAIRE, Dr CHU Dijon - Hôp. Du Bocage
Principal Investigator: Yves BECOUARN, Dr Institut Bergonié-BORDEAUX
Principal Investigator: François GHIRINGHELLI, Dr Centre G. F. Leclerc-DIJON
Principal Investigator: Rosine GUIMBAUD, Pr Centre hospitalier Purpan-TOULOUSE
Principal Investigator: Gaël DEPLANQUE, Dr Centre Hospitalier Saint-Joseph-PARIS
Principal Investigator: Julien FORESTIER, Dr Hôpital Edouard Herriot-LYON
Principal Investigator: Pascale MARIANI, Dr Institut Curie Paris
Principal Investigator: Jean-Louis LEGOUX, Dr CHR d'Orléans - La Source
Principal Investigator: Cédric LECAILLE, Dr Polyclinique de Bordeaux Nord
Principal Investigator: Marie-Pierre GALAIS, Dr Centre François Baclesse-CAEN
Principal Investigator: Philippe HOUYAU, Dr Clinique Claude Bernard -ALBI

Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT01442935     History of Changes
Other Study ID Numbers: PRODIGE 14 / ACCORD 21/0905
First Posted: September 29, 2011    Key Record Dates
Last Update Posted: May 8, 2018
Last Verified: May 2018

Keywords provided by UNICANCER:
Adenocarcinoma
Non-resectable hepatic metastases
First-line treatment

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Bevacizumab
Oxaliplatin
Irinotecan
Camptothecin
Cetuximab
Fluorouracil
Leucovorin
Folic Acid
Levoleucovorin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors