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

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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 256
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34298
    • Centre Val d'Aurelle

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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 5-Fluoro uracil; Drug: Irinotecan; 180mg/m² over 90 mn every 2 weeks up to progression or toxicity; 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
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 Names: 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 Names: 5-Fluoro uracil; Drug: Irinotecan; 180mg/m² over 90 mn every 2 weeks up to progression or toxicity; 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The objective response rate (CR and PR) after 4 cycles of treatment	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	after 8 weeks
Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)	Number of patients (%) with complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)	6 months
Specific resection rates R0/R1/R2	Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection.	24 weeks
Complete pathological response	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	24 weeks
Toxicity of treatment	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
Post operatory complications	Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004)	after 4 weeks
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.	8 months
Overall survival (OS)	Overall survival is defined as the time from randomization to death any cause or last follow-up news for patients alive (censored data).	14 months

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Driffa MOUSSATA, Dr, Centre hospitalier Lyon Sud-PIERRE BENITE; Principal Investigator: Marie-Pierre GALAIS, Dr, Centre François Baclesse-CAEN; Principal Investigator: Yves BECOUARN, Dr, Institut Bergonié Bordeaux; Principal Investigator: Julien FORESTIER, Dr, Hôpital Edouard Herriot-LYON; Principal Investigator: Marc YCHOU, Pr, Centre Val d'Aurelle; Principal Investigator: Laurent MINEUR, Dr, Institut Ste Catherine-AVIGNON; Principal Investigator: Olivier BOUCHE, Pr, CHU de Reims; 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: 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: 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

Publications and helpful links

General Publications

• Bidard FC, Kiavue N, Ychou M, Cabel L, Stern MH, Madic J, Saliou A, Rampanou A, Decraene C, Bouche O, Rivoire M, Ghiringhelli F, Francois E, Guimbaud R, Mineur L, Khemissa-Akouz F, Mazard T, Moussata D, Proudhon C, Pierga JY, Stanbury T, Thezenas S, Mariani P. Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial. Cells. 2019 May 28;8(6):516. doi: 10.3390/cells8060516.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2011
• Primary Completion (ACTUAL): December 1, 2015
• Study Completion (ACTUAL): January 1, 2021

Study Registration Dates

• First Submitted: August 10, 2011
• First Submitted That Met QC Criteria: September 28, 2011
• First Posted (ESTIMATE): September 29, 2011

Study Record Updates

• Last Update Posted (ACTUAL): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 14, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Adenocarcinoma; First-line treatment; Non-resectable hepatic metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; 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 14 / ACCORD 21/0905; 2009-012813-22 (EUDRACT_NUMBER)

Drug and device information, study documents

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