Efficacy of Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by UNICANCER
Sponsor:
Information provided by (Responsible Party):
UNICANCER
ClinicalTrials.gov Identifier:
NCT01442649
First received: September 5, 2011
Last updated: March 1, 2013
Last verified: March 2013
  Purpose

The main objective is to evaluate progression-free survival (PFS) at 4 months.

The secondary objectives are to evaluate the objective response rate (OR) (= complete responses (CR) and partial responses (PR)) according to the RECIST v1.1 criteria, the progression-free survival (PFS), the overall survival (OS), the overall survival from the date of the first-line chemotherapy used on the metastatic disease, the treatment tolerance (NCI CTC AE V4 criteria, except for peripheral neurological toxicity (Lévi Scale)), the quality of life according to the EORTC QLQ-C30 criteria.

The objectives of the biological study are to evaluate potentially predictive anti-EGFR and anti-VEGF response factors and CEC rates as predictive biomarkers for the efficacy of bevacizumab associated with chemotherapy in mCRC treatment.


Condition Intervention Phase
Colorectal Cancer
Drug: Oxaliplatin
Drug: Folinic Acid
Drug: 5-fluoro-uracil
Drug: Irinotecan
Drug: Bevacizumab
Drug: Cetuximab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II, Multicentric Randomized Trial, Evaluating the Efficacy of Fluoropyrimidine-based Standard Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab

Resource links provided by NLM:


Further study details as provided by UNICANCER:

Primary Outcome Measures:
  • Progression-free survival (PFS) at 4 months [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Objective response rate (OR) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    The objective response rate is defined as the occurence of a complete response [CR] or a partial responses [PR] according to RECIST V1.1 between date of randomization and date of end of treatment. It will be evaluated by the investigator with RECIST v1.1 criteria every 6 weeks up to disease progression.

  • Progression-free survival (PFS) [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
    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.

  • Overall survival (OS) [ Time Frame: until death or progression (24 months) ] [ Designated as safety issue: Yes ]
    Overall survival is defined as the time from randomization to death any cause or last follow-up (censored data).

  • Overall survival from the date of the first-line chemotherapy used on the metastatic disease [ Time Frame: until death or progression (24 months) ] [ Designated as safety issue: Yes ]
    Overall survival from the date of the first-line chemotherapy used on the metastatic disease is defined as the time from the first day of the first-line chemotherapy used on the metastatic disease to death any cause or last follow-up news (censored data).

  • Treatment tolerance [ Time Frame: Every 2 weeks, during the treatment. ] [ Designated as safety issue: Yes ]
    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)).

  • Quality of life [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
    Quality of life will be evaluated with the EORTC QLQ - C30.


Estimated Enrollment: 132
Study Start Date: December 2010
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A : bevacizumab + fluoropyrimidine-based chemotherapy

Every 2 weeks :

- mFOLFOX6 : Oxaliplatin 85 mg/m2 over 120 mn IV on D1, Folinic Acide 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h.

OR

- FOLFIRI : Irinotecan 180 mg/m2 en 90 mn IV on day D1, Folinic acid 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h.

AND

Bevacizumab 5 mg/kg IV every 2 weeks.

Drug: Oxaliplatin
85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity
Drug: Folinic Acid
400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1 (in the same time that oxaliplatin or irinotecan) every 2 weeks up to progression or toxicity
Drug: 5-fluoro-uracil
400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
Drug: Irinotecan
180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity
Drug: Bevacizumab
5 mg/kg IV over 90 mn on D1 every 2 weeks up to progression or toxicity
Experimental: Arm B : cetuximab + fluoropyrimidine-based chemotherapy

Every 2 weeks :

- mFOLFOX6 : Oxaliplatin 85 mg/m2 over 120 mn IV on D1, Folinic Acide 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h.

OR

- FOLFIRI : Irinotecan 180 mg/m2 en 90 mn IV on day D1, Folinic acid 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h.

AND

Cetuximab : 500 mg/m² IV every 2 weeks

Drug: Oxaliplatin
85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity
Drug: Folinic Acid
400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1 (in the same time that oxaliplatin or irinotecan) every 2 weeks up to progression or toxicity
Drug: 5-fluoro-uracil
400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
Drug: Irinotecan
180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity
Drug: Cetuximab
500mg/m² on D1 every 2 weeks up to progression or toxicity

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically proven adenocarcinoma of the colon expressing non-mutated (wild-type) KRAS.
  • Progressive metastatic disease after first-line treatment with chemotherapy alone: based on 5-FU (iv or per os) with irinotecan or oxaliplatin associated to bevacizumab.
  • Prior adjuvant chemotherapy (of the primary tumor) with fluoropyrimidine and oxaliplatin is allowed if the time interval between the end of this chemotherapy and the beginning of the first-line metastatic treatment is ≥ 6 months.
  • Measurable disease (at least one measurable metastatic lesion) according to the RECIST V1.1 criteria (the lesion should not be located in a previous field of radiation).
  • Previous radiotherapy is authorized if discontinued ≥ 15 days prior to randomization and if the measurable metastatic lesions are outside the radiation area.
  • Sites of disease evaluated within 28 days prior to randomization with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest Xray)
  • Age ≥18 years
  • Patient with ECOG 0 or 1
  • Life Expectancy ≥ 3 months
  • Hematologic function (polynuclear neutrophiles ≥ 1.5.109/L ; platelets ≥ 100.109/L ; hemoglobin ≥ 9 g/dL
  • Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of hepatic metastases), alkaline phosphatases ≤ 2.5 ULN (≤ 5 ULN in case of hepatic metastases), total bilirubinemia ≤ 1.5 ULN
  • Renal function (creatinemia ≤1.5 ULN; creatine clearance ≥ 50 mL/mn (Cockcroft and Gault) ; urine test strip < 2+. If proteinuria is ≥ +2 at inclusion, the serum urea test must be redone and show proteinuria ≤ 1 g/L within 24 h)
  • Completion of the EORTC QLQ-C30 quality of life form
  • Negative pregnancy test for women of child-bearing age
  • Information given to the patient and signed informed consent
  • Public Health insurance coverage

Exclusion Criteria:

  • Known meningeal or brain metastases
  • Pre-treatment with anti-EGFR
  • Specific contraindication or known hypersensitivity to one treatment product
  • Patient with known allergy or hypersensitivity to monoclonal antibodies (bevacizumab, cetuximab
  • Clinically significant affection of the coronaries or myocardial infarction within 6 months prior to inclusion.
  • Peripheral neuropathy of grade > 1 (CTCAE scale version 4.0).
  • Known depletion of the dihydropyrimidine dehydrogenase (DPD).
  • Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
  • Uncontrolled Arterial hypertension (systolic pressure > 150 mmHg and/or diastolic pressure > 100 mmHg with and without antihypertensive medication. Patients with high hypertension are eligible if antihypertensive medication lowers their arterial pressure to the level of acceptability specified by the inclusion criteria.
  • History of hypertensive crisis or hypertensive encephalopathy
  • Other concomitant malignancy or history cancer (except carcinoma in situ of the cervix, or non melanoma skin cancer, with curative intent treatment, when considered in complete remission for at least 5 years before randomization.
  • Any treatment including an experimental drug, or participation in another clinical trial within 28 days preceding inclusion.
  • Persons deprived of liberty or under guardianship.
  • Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01442649

Contacts
Contact: Beata JUZYNA +33(1)44235567 b-juzyna@fnclcc.fr

Locations
France
Centre rené Gauducheau Recruiting
Saint-herblain, France, 44805
Contact: Jaafar BENNOUNA, Dr    +33 (0)2 40 67 99 78    j-bennouna@nantes.fnclcc.fr   
Principal Investigator: Jaafar BENNOUNA, Dr         
Sub-Investigator: Hélène SENELLART, Dr         
Sub-Investigator: Jean-Yves DOUILLARD, Dr         
Sub-Investigator: Sandrine HIRET, Dr         
Sponsors and Collaborators
UNICANCER
Investigators
Principal Investigator: Jaafar BENNOUNA, Dr Centre René Gauducheau
Principal Investigator: Christophe BORG, Pr CHU Jean Minjoz-BESANCON
Principal Investigator: Christian BOREL, Dr Centre Paul Strauss-STRASBOURG
Principal Investigator: Jean-Pierre DELORD, Pr Institut Claudius Regaud-TOULOUSE
Principal Investigator: Christophe BORG, Pr. Centre Hospitalier du Mittan-MONTBELIARD
Principal Investigator: Jean-François SEITZ, Pr CHU Timone-MARSEILLE
Principal Investigator: Thierry CONROY, Pr Centre Alexis Vautrin-VANDOEUVRE LES NANCY
Principal Investigator: Roger FAROUX, Dr CHD Vendée-LA ROCHE SUR YON
Principal Investigator: Eric FRANCOIS, Dr Centre Antoine Lacassagne-NICE
Principal Investigator: Alice GAGNAIRE, Dr Hôpital Bocage-DIJON
Principal Investigator: Antoine ADENIS, Pr Centre Oscar Lambret-LILLE
Principal Investigator: Cédric LECAILLE, Dr Polyclinique Bordeaux Nord Aquitaine-BORDEAUX
Principal Investigator: Gaël DEPLANQUE, Dr Groupe hospitalier St Joseph-PARIS
Principal Investigator: Pascal ARTRU, Dr Hôpital Privé Jean Mermoz-LYON
Principal Investigator: Oana COJOCARASU, Dr Centre hospitalier du Mans-LE MANS
Principal Investigator: Laurent MIGLIANICO, Dr CHP Saint Grégoire-SAINT GREGOIRE
Principal Investigator: Olivier BOUCHE, Pr Hôpital Robert Debré - CHU Reims
Principal Investigator: You-Heng LAM, Dr Centre Hospitalier Cholet
Principal Investigator: David TOUGERON, Dr CHU de Poitiers-POITIERS
Principal Investigator: Barbara DAUVOIS, Dr CHR d'Orléans - Hôpital la Source
Principal Investigator: Philippe HOUYAU, Dr Clinique Claude Bernard-ALBI
  More Information

No publications provided

Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT01442649     History of Changes
Other Study ID Numbers: PRODIGE 18 / ACCORD 22/0906
Study First Received: September 5, 2011
Last Updated: March 1, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by UNICANCER:
Adenocarcinoma
Metastatic
Second-line treatment
Progressive disease after first-line treatment with bevacizumab
Non-mutated (wild-type) KRAS.

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Bevacizumab
Cetuximab
Fluorouracil
Folic Acid
Irinotecan
Levoleucovorin
Oxaliplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Hematinics
Hematologic Agents

ClinicalTrials.gov processed this record on October 20, 2014