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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Folinic Acid; Drug: 5-fluoro-uracil; Drug: Irinotecan; Drug: Bevacizumab; Drug: Cetuximab

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Saint-herblain, France, 44805
    • Centre Rene Gauducheau

Participation Criteria

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:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (OR)	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.	12 months
Progression-free survival (PFS)	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
Overall survival (OS)	Overall survival is defined as the time from randomization to death any cause or last follow-up (censored data).	until death or progression (24 months)
Overall survival from the date of the first-line chemotherapy used on the metastatic disease	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).	until death or progression (24 months)
Treatment tolerance	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)).	Every 2 weeks, during the treatment.
Quality of life	Quality of life will be evaluated with the EORTC QLQ - C30.	every 6 weeks

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: 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: Alice GAGNAIRE, Dr, Hôpital Bocage-DIJON; Principal Investigator: Antoine ADENIS, Pr, Centre Oscar Lambret-LILLE; 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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2010
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: September 5, 2011
• First Submitted That Met QC Criteria: September 27, 2011
• First Posted (Estimate): September 28, 2011

Study Record Updates

• Last Update Posted (Actual): January 11, 2022
• Last Update Submitted That Met QC Criteria: January 7, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Adenocarcinoma; Metastatic; Second-line treatment; Progressive disease after first-line treatment with bevacizumab; Non-mutated (wild-type) KRAS.
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Disease Progression; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid; Cetuximab
• Other Study ID Numbers: PRODIGE 18 / ACCORD 22/0906

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No