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

NCT01442649 | Completed Phase 2 DMC

• 1 other identifier: PRODIGE 18 / ACCORD 22/0906
• Study Type: interventional
• Target: 133
• Locations: 1 country
• Sites: 1

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

Keywords

Adenocarcinoma; Metastatic; Second-line treatment; Progressive disease after first-line treatment with bevacizumab; Non-mutated (wild-type) KRAS.

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) at 4 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.

  4 months

Secondary Outcomes (6)

• Objective response rate (OR)

  12 months

• Progression-free survival (PFS)

  4 months

• Overall survival (OS)

  until death or progression (24 months)

• Overall survival from the date of the first-line chemotherapy used on the metastatic disease

  until death or progression (24 months)

• Treatment tolerance

  Every 2 weeks, during the treatment.

Study Arms (2)

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy

EXPERIMENTAL

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; Drug: Folinic Acid; Drug: 5-fluoro-uracil; Drug: Irinotecan; Drug: Bevacizumab

Arm B : cetuximab + fluoropyrimidine-based chemotherapy

EXPERIMENTAL

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; Drug: Folinic Acid; Drug: 5-fluoro-uracil; Drug: Irinotecan; Drug: Cetuximab

Interventions

Oxaliplatin DRUG

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

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy; Arm B : cetuximab + fluoropyrimidine-based chemotherapy

Folinic Acid 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

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy; Arm B : cetuximab + fluoropyrimidine-based chemotherapy

5-fluoro-uracil DRUG

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

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy; Arm B : cetuximab + fluoropyrimidine-based chemotherapy

Irinotecan DRUG

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

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy; Arm B : cetuximab + fluoropyrimidine-based chemotherapy

Bevacizumab DRUG

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

Arm A : bevacizumab + fluoropyrimidine-based chemotherapy

Cetuximab DRUG

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

Arm B : cetuximab + fluoropyrimidine-based chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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.
• 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.
• Persons deprived of liberty or under guardianship.
• Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Sponsors & Collaborators

• UNICANCER: lead

Study Sites (1)

Centre rené Gauducheau

Saint-Herblain, 44805, France

Location

Related Publications (1)

• 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.

  PMID: 30422156 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Adenocarcinoma; Neoplasm Metastasis

Interventions

Oxaliplatin; Leucovorin; Irinotecan; Bevacizumab; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• 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 de 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 5, 2011
• First Posted: September 28, 2011
• Study Start: December 1, 2010
• Primary Completion: October 1, 2015
• Study Completion: December 31, 2017
• Last Updated: January 11, 2022

Record last verified: 2022-01

Locations

FR (1)