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

NCT ID: NCT01442649

Last Updated: 2022-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 133 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-12-31
• Study Completion Date: 2017-12-31

Brief Summary

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Oxaliplatin

Intervention Type: DRUG

85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity

Folinic Acid

Intervention Type: DRUG

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

5-fluoro-uracil

Intervention Type: DRUG

400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity

Irinotecan

Intervention Type: DRUG

180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity

Bevacizumab

Intervention Type: DRUG

5 mg/kg IV over 90 mn on D1 every 2 weeks up to progression or toxicity

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

Group Type: EXPERIMENTAL

Oxaliplatin

Intervention Type: DRUG

85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity

Folinic Acid

Intervention Type: DRUG

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

5-fluoro-uracil

Intervention Type: DRUG

400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity

Irinotecan

Intervention Type: DRUG

180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity

Cetuximab

Intervention Type: DRUG

500mg/m² on D1 every 2 weeks up to progression or toxicity

Interventions

Oxaliplatin

85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity

Intervention Type: 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

Intervention Type: DRUG

5-fluoro-uracil

400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Irinotecan

180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Bevacizumab

5 mg/kg IV over 90 mn on D1 every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Cetuximab

500mg/m² on D1 every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Eligibility 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

• 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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jaafar BENNOUNA, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre René Gauducheau

Christophe BORG, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Jean Minjoz-BESANCON

Christian BOREL, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre Paul Strauss-STRASBOURG

Jean-Pierre DELORD, Pr

Role: PRINCIPAL_INVESTIGATOR

Institut Claudius Regaud-TOULOUSE

Christophe BORG, Pr.

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier du Mittan-MONTBELIARD

Jean-François SEITZ, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU Timone-MARSEILLE

Thierry CONROY, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre Alexis Vautrin-VANDOEUVRE LES NANCY

Roger FAROUX, Dr

Role: PRINCIPAL_INVESTIGATOR

CHD Vendée-LA ROCHE SUR YON

Eric FRANCOIS, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre Antoine Lacassagne, Nice

Alice GAGNAIRE, Dr

Role: PRINCIPAL_INVESTIGATOR

Hôpital Bocage-DIJON

Antoine ADENIS, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre Oscar Lambret-LILLE

Cédric LECAILLE, Dr

Role: PRINCIPAL_INVESTIGATOR

Polyclinique Bordeaux Nord Aquitaine-BORDEAUX

Gaël DEPLANQUE, Dr

Role: PRINCIPAL_INVESTIGATOR

Groupe hospitalier St Joseph-PARIS

Pascal ARTRU, Dr

Role: PRINCIPAL_INVESTIGATOR

Hôpital Privé Jean Mermoz-LYON

Oana COJOCARASU, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre hospitalier du Mans-LE MANS

Laurent MIGLIANICO, Dr

Role: PRINCIPAL_INVESTIGATOR

CHP Saint Grégoire-SAINT GREGOIRE

Olivier BOUCHE, Pr

Role: PRINCIPAL_INVESTIGATOR

Hôpital Robert Debré - CHU Reims

You-Heng LAM, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier de Cholet

David TOUGERON, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU de Poitiers-POITIERS

Barbara DAUVOIS, Dr

Role: PRINCIPAL_INVESTIGATOR

CHR d'Orléans - Hôpital la Source

Philippe HOUYAU, Dr

Role: PRINCIPAL_INVESTIGATOR

Clinique Claude Bernard, Albi

Locations

Centre rené Gauducheau

Saint-Herblain, , France

Countries

France

References

Bennouna J, Hiret S, Bertaut A, Bouche O, Deplanque G, Borel C, Francois E, Conroy T, Ghiringhelli F, des Guetz G, Seitz JF, Artru P, Hebbar M, Stanbury T, Denis MG, Adenis A, Borg C. Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer: The UNICANCER PRODIGE18 Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):83-90. doi: 10.1001/jamaoncol.2018.4465.

Reference Type: DERIVED

PMID: 30422156 (View on PubMed)

Other Identifiers

PRODIGE 18 / ACCORD 22/0906

Identifier Type: -

Identifier Source: org_study_id