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

NCT ID: NCT01442935

Last Updated: 2021-06-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 256 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-28
• Study Completion Date: 2021-01-31

Brief Summary

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.

Conditions

Colorectal Cancer

Study Design

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

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Folinic Acid

Intervention Type: DRUG

400mg/m² over 120 mn every 2 weeks up to progression or toxicity

5-FU

Intervention Type: DRUG

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

Irinotecan

Intervention Type: DRUG

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

Bevacizumab

Intervention Type: DRUG

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

Cetuximab

Intervention Type: DRUG

500mg/m² over 90 mn every 2 weeks up to progression or toxicity

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.

Group Type: ACTIVE_COMPARATOR

Oxaliplatin

Intervention Type: DRUG

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

Folinic Acid

Intervention Type: DRUG

400mg/m² over 120 mn every 2 weeks up to progression or toxicity

5-FU

Intervention Type: DRUG

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

Bevacizumab

Intervention Type: DRUG

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

Cetuximab

Intervention Type: DRUG

500mg/m² over 90 mn every 2 weeks up to progression or toxicity

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.

Group Type: EXPERIMENTAL

Oxaliplatin

Intervention Type: DRUG

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

Folinic Acid

Intervention Type: DRUG

400mg/m² over 120 mn every 2 weeks up to progression or toxicity

5-FU

Intervention Type: DRUG

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

Irinotecan

Intervention Type: DRUG

150mg/m² over 30-90 mn every 2 weeks up to progression or toxicity

Bevacizumab

Intervention Type: DRUG

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

Cetuximab

Intervention Type: DRUG

500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Interventions

Oxaliplatin

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

Intervention Type: DRUG

Folinic Acid

400mg/m² over 120 mn every 2 weeks up to progression or toxicity

Intervention Type: DRUG

5-FU

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

Intervention Type: DRUG

Irinotecan

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

Intervention Type: DRUG

Irinotecan

150mg/m² over 30-90 mn every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Bevacizumab

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

Intervention Type: DRUG

Cetuximab

500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Intervention Type: DRUG

Other Intervention Names

5-Fluoro uracil

Eligibility Criteria

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.

• 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

Marc YCHOU, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre Val d'Aurelle

Eric FRANCOIS, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre Antoine Lacassagne, Nice

Laurent MINEUR, Dr

Role: PRINCIPAL_INVESTIGATOR

Institut Ste Catherine-AVIGNON

Olivier BOUCHE, Pr

Role: PRINCIPAL_INVESTIGATOR

CHU de Reims

Driffa MOUSSATA, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre hospitalier Lyon Sud-PIERRE BENITE

Rosine GUIMBAUD, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre hospitalier Rangueil-TOULOUSE

Roger FAROUX, Dr

Role: PRINCIPAL_INVESTIGATOR

CHD Vendée -LA ROCHE SUR YON

Karine BOUHIER-LEPORRIER, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU Côte de Nacre-CAEN

Alice GAGNAIRE, Dr

Role: PRINCIPAL_INVESTIGATOR

CHU Dijon - Hôp. Du Bocage

Yves BECOUARN, Dr

Role: PRINCIPAL_INVESTIGATOR

Institut Bergonié Bordeaux

François GHIRINGHELLI, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre G. F. Leclerc-DIJON

Rosine GUIMBAUD, Pr

Role: PRINCIPAL_INVESTIGATOR

Centre hospitalier Purpan-TOULOUSE

Gaël DEPLANQUE, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Saint-Joseph-PARIS

Julien FORESTIER, Dr

Role: PRINCIPAL_INVESTIGATOR

Hôpital Edouard Herriot-LYON

Pascale MARIANI, Dr

Role: PRINCIPAL_INVESTIGATOR

Institut Curie Paris

Jean-Louis LEGOUX, Dr

Role: PRINCIPAL_INVESTIGATOR

CHR d'Orléans - La Source

Cédric LECAILLE, Dr

Role: PRINCIPAL_INVESTIGATOR

Polyclinique de Bordeaux Nord

Marie-Pierre GALAIS, Dr

Role: PRINCIPAL_INVESTIGATOR

Centre François Baclesse-CAEN

Philippe HOUYAU, Dr

Role: PRINCIPAL_INVESTIGATOR

Clinique Claude Bernard, Albi

Locations

Centre Val d'Aurelle

Montpellier, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 31142037 (View on PubMed)

Other Identifiers

2009-012813-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PRODIGE 14 / ACCORD 21/0905

Identifier Type: -

Identifier Source: org_study_id