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

NCT01442935 | Completed Phase 2 DMC

• 2 other identifiers: PRODIGE 14 / ACCORD 21/09052009-012813-22
• Study Type: interventional
• Target: 256
• Locations: 1 country
• Sites: 1

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

Keywords

Adenocarcinoma; Non-resectable hepatic metastases; First-line treatment

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• The objective response rate (CR and PR) after 4 cycles of treatment

  after 8 weeks

• Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)

  6 months

• Specific resection rates R0/R1/R2

  24 weeks

• Complete pathological response

  24 weeks

• Toxicity of treatment

  Every 2 weeks

Study Arms (3)

Arm A1 : Folfiri + targeted therapy

ACTIVE COMPARATOR

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; Drug: 5-FU; Drug: Irinotecan; Drug: Bevacizumab; Drug: Cetuximab

Arm A2 : Folfox 4 + targeted therapy

ACTIVE COMPARATOR

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; Drug: Folinic Acid; Drug: 5-FU; Drug: Bevacizumab; Drug: Cetuximab

Arm B : Folfirinox + targeted therapy

EXPERIMENTAL

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; Drug: Folinic Acid; Drug: 5-FU; Drug: Irinotecan; Drug: Bevacizumab; Drug: Cetuximab

Interventions

Oxaliplatin DRUG

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

Arm A2 : Folfox 4 + targeted therapy; Arm B : Folfirinox + targeted therapy

Folinic Acid DRUG

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

Arm A1 : Folfiri + targeted therapy; Arm A2 : Folfox 4 + targeted therapy; Arm B : Folfirinox + targeted therapy

5-FU DRUG

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

Also known as: 5-Fluoro uracil

Arm A1 : Folfiri + targeted therapy; Arm A2 : Folfox 4 + targeted therapy; Arm B : Folfirinox + targeted therapy

Irinotecan DRUG

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

Arm A1 : Folfiri + targeted therapy

Bevacizumab DRUG

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

Arm A1 : Folfiri + targeted therapy; Arm A2 : Folfox 4 + targeted therapy; Arm B : Folfirinox + targeted therapy

Cetuximab DRUG

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

Arm A1 : Folfiri + targeted therapy; Arm A2 : Folfox 4 + targeted therapy; Arm B : Folfirinox + targeted therapy

Eligibility Criteria

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

You may qualify if:

• 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,

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• UNICANCER: lead

Study Sites (1)

Centre Val d'Aurelle

Montpellier, 34298, France

Location

Related Publications (1)

• 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.

  PMID: 31142037 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Adenocarcinoma

Interventions

Oxaliplatin; Leucovorin; Fluorouracil; 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

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; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Marc YCHOU, Pr

  Centre Val d'Aurelle

  PRINCIPAL INVESTIGATOR

• Eric FRANCOIS, Dr

  Centre Antoine Lacassagne, Nice

  PRINCIPAL INVESTIGATOR

• Laurent MINEUR, Dr

  Institut Ste Catherine-AVIGNON

  PRINCIPAL INVESTIGATOR

• Olivier BOUCHE, Pr

  CHU de Reims

  PRINCIPAL INVESTIGATOR

• Driffa MOUSSATA, Dr

  Centre hospitalier Lyon Sud-PIERRE BENITE

  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

• Yves BECOUARN, Dr

  Institut Bergonié Bordeaux

  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

• Julien FORESTIER, Dr

  Hôpital Edouard Herriot-LYON

  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

  PRINCIPAL INVESTIGATOR

• Marie-Pierre GALAIS, Dr

  Centre François Baclesse-CAEN

  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: August 10, 2011
• First Posted: September 29, 2011
• Study Start: February 1, 2011
• Primary Completion: December 1, 2015
• Study Completion: January 1, 2021
• Last Updated: June 18, 2021

Record last verified: 2021-06

Locations

FR (1)