Systemic Oxaliplatin or Intra-arterial Chemotherapy Combined With LV5FU2 +/- Irinotecan and an Target Therapy in First Line Treatment of Metastatic Colorectal Cancer Restricted to the Liver
- Conditions
- Colorectal Neoplasms
- Interventions
- Drug: 5 FU bolusDrug: 5 FU continuous
- Registration Number
- NCT02885753
- Lead Sponsor
- Federation Francophone de Cancerologie Digestive
- Brief Summary
Colorectal cancer is the 3rd most common cancer in France and the 2nd cause of death from cancer. Between 30 to 60% of patients develop limited or predominant liver metastases. Surgical resection of these metastases, only curative treatment is not immediately possible in 10-15% of cases. In unresectable patients, current palliative treatments are based on systemic chemotherapy associated or not with the targeted therapies (anti-EGFR (panitumumab), anti-VEGF (bevacizumab)). In this patient population, special attention was paid to intensified treatment regimens in order to improve their efficiency and improving the tumoral response rate, the intensity of the response and its earliness correlate with improved overall and progression-free survival.
The intra-arterial use of oxaliplatin coupled with IV chemotherapy has yielded OR levels of 64% in patients having survived one or more lines of chemotherapy IV and 62% in patients who have progressed on oxaliplatin IV. In addition, the HIA administration of oxaliplatin limits systemic and especially neurological toxicities, thanks to a greater hepatic clearance.
In conclusion, the combination of systemic chemotherapy, targeted therapy and HIAC with oxaliplatin has showed promising efficacy results associated with good tolerance from the first line onwards. Indeed, we can expect from the Phase II recent data, a control rate close to 100%, with high response rates associated with early maturity and depth responses as well as prolonged survival. However, to date, in the absence of randomized trial testing this combination, this strategy does not have sufficient evidence to be integrated in our routine practices, and HIAC remains limited to a few expert centers in treatment catch-up.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 348
- Histologically proven colorectal adenocarcinoma with hepatic metastasis(es)
- At least one measurable hepatic metastasis according to the criteria RECIST v1.1
- No other metastatic sites except lung nodules if number ≤ 3 and < 10 mm
- RAS mutation status known (determination of KRAS mutation (exons 2,3 and 4) and determination of the NRAS mutation (exons 2,3 and 4))
- Age ≥ 18
- WHO ≤ 2 (Appendix 4)
- No prior treatment by chemotherapy except perioperative or adjuvant chemotherapy discontinued for more than 12 months
- Life expectancy > 3 months
- PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dLq
- Bilirubin < 25 mmol/L, AST < 5x ULN, ALT < 5 x ULN, ALP < 5 x ULN, TP > 60%, proteinuria from 24H < 1 g
- Creatinine clearance > 50 mL/min according to MDRD formula (Appendix 4)
- Patient affiliated to a social security scheme
- Patient information and signature of the informed consent
- Contraindications specific to the installation of a KTHIA: thrombosis of the hepatic artery, arterial vascular anatomy may compromise a secondary hepatic resection.
- Patient immediately eligible for a curative therapy (surgical and/or percutaneous) after discussion in CPR
- Following alterations in the 6 months prior to inclusion: myocardial infarction, angina, severe/unstable angina, coronary artery bypass surgery, congestive heart failure NYHA class II, III or IV, stroke or transient ischemic attack
- Hypertension not controlled by medical treatment (SBP > 140 mmHg and/or DBP> 90 mmHg with blood pressure taken according to the diagram of the HAS)
- A history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding in the 6 months preceding the start of treatment
- Progressive gastroduodenal ulcer, wound or fractured bone
- Abdominal or major extra-abdominal surgery (except diagnostic biopsy) or irradiation in the 4 weeks before starting the treatment
- Transplant patients, HIV positive or other immune deficiency syndromes
- Any progressive pathology not balanced over the past 6 months: hepatic failure, renal failure, respiratory failure
- Peripheral neuropathy > 1
- Patient with interstitial pneumonitis or pulmonary fibrosis
- History of chronic diarrhea or inflammatory disease of the colon or rectum, or unresolved occlusion or sub-occlusion in symptomatic treatment
- History of malignant pathologies during the past 5 years except basocellular skin carcinoma considered in complete remission or in situ cervical carcinoma, properly treated
- Patient already included in another clinical trial with an experimental molecule
- Any known specific contraindication or allergy or hypersensitivity to the drugs used in the study (cf RCP Appendix 7)
- Known deficit in DPD
- QT/QTc range > 450 msec for men and > 470 msec for women
- K+ < LNL, Mg2+ < LNL, Ca2+ < LNL
- Lack of effective contraception in patients (men and/or women) of childbearing age, pregnant or breastfeeding women, women of childbearing age not having had a pregnancy test
- Persons deprived of liberty or under supervision
- Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status Oxaliplatin intravenous Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status 5 FU continuous Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status Oxaliplatin intra-arteriel Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status 5 FU bolus Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab Oxaliplatin intra-arteriel Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status 5 FU continuous Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status 5 FU bolus Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab 5 FU continuous Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab Oxaliplatin intravenous Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab 5 FU continuous Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status Folinic acid Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status Panitumumab Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status Bevacizumab Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status Folinic acid Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status Panitumumab Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status Bevacizumab Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab Folinic acid Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab Bevacizumab Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab Irinotecan Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab Folinic acid Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab Bevacizumab Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab Irinotecan Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours
- Primary Outcome Measures
Name Time Method progression-free survival 24 months after randomization comparison of radiological/clinical progression free survival
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (85)
Hôpital André Mignot
🇫🇷Le Chesnay, France
Hôpital Belle Isle
🇫🇷Metz, France
CHR
🇫🇷Orleans, France
CH d'Auxerre
🇫🇷Auxerre, France
CHIC
🇫🇷Quimper, France
CHU de Pont Chaillou
🇫🇷Rennes CEDEX 9, France
CHU Charles Nicolle
🇫🇷Rouen CEDEX 01, France
Centre Paul Strauss
🇫🇷Strasbourg, France
Hôpital Sainte Musse
🇫🇷Toulon, France
Institut de cancérologie de Lorraine
🇫🇷Vandœuvre-lès-Nancy, France
Centre Hospitalier de Saint Malo
🇫🇷Saint-Malo, France
Hôpital Paul BROUSSE
🇫🇷Villejuif, France
CAC - Gustave Roussy
🇫🇷Villejuif, France
CH D'Abbeville
🇫🇷Abbeville CEDEX, France
CHU - Hôtel Dieu
🇫🇷Nantes, France
Centre François Baclesse
🇫🇷Caen, France
Hôpital Privé d'Antony
🇫🇷Antony, France
CH de Beauvais
🇫🇷Beauvais, France
Centre de Radiothérapie Pierre Curie
🇫🇷Beuvry, France
PRIVE - Infirmerie Protestante de Lyon
🇫🇷Caluire-et-Cuire, France
Centre Hospitalier Métropole Savoie
🇫🇷Chambéry CEDEX, France
CH William Morey
🇫🇷Chalon-sur-Saône, France
Centre Georges-François Leclerc
🇫🇷Dijon, France
Hôpital Henri Mondor
🇫🇷Créteil CEDEX, France
GHM Institut Daniel Hollard
🇫🇷Grenoble CEDEX 1, France
CHU Grenoble - Hôpital Albert Michallon
🇫🇷La Tronche, France
Ch - Chd Vendee
🇫🇷La Roche Sur Yon, France
CMC Les Ormeaux
🇫🇷Le Havre, France
CH Annecy Genevois
🇫🇷Pringy, France
Polyclinique Francheville
🇫🇷Périgueux, France
Hôpial Privé du Confluent Le Confluent Centre Catherine de Sienne
🇫🇷Nantes, France
CHU - Hôpital Européen George Pompidou
🇫🇷Paris, France
CH - Pau
🇫🇷Pau, France
Institut Curie
🇫🇷Paris, France
CH René Dubois
🇫🇷Pontoise, France
CHU Robert Debré
🇫🇷Reims CEDEX, France
Hôpital Drome Nord
🇫🇷Romans-sur-Isère, France
CAC - Eugène Marquis
🇫🇷Rennes, France
Clinique Mutualiste de l'Estuaire - Cité Sanitaire
🇫🇷Saint Nazaire, France
PRIVE - Saint Grégoire
🇫🇷Saint-Grégoire, France
Chu - Hopital Nord Chu Saint Etienne
🇫🇷Saint-Priest-en-Jarez, France
Clinique Trenel
🇫🇷Sainte Colombe, France
CHU de Saint Etienne - Hôpital Nord
🇫🇷Saint-Priest-en-Jarez, France
CHU Nancy-Brabois
🇫🇷Vandœuvre-lès-Nancy, France
Hôpitaux du Leman
🇫🇷Thonon-les-Bains, France
Hôpital Sud
🇫🇷Amiens, France
Centre Hospitalier du pays d'Aix
🇫🇷Aix-en-Provence, France
PRIVE - Polyclinique Bordeaux Nord
🇫🇷Bordeaux, France
CH - Côte Basque
🇫🇷Bayonne CEDEX, France
PRIVE - Sainte Catherine
🇫🇷Avignon, France
CH Jean Minjoz
🇫🇷Besançon, France
CMCO Côte d'Opale
🇫🇷Boulogne-sur-Mer, France
Hôpital Duchenne
🇫🇷Boulogne-sur-Mer, France
Institut Bergonié
🇫🇷Bordeaux CEDEX, France
Hôpital Louis Pasteur
🇫🇷Chartres, France
Clinique Saint Côme
🇫🇷Compiègne CEDEX, France
Hôpital Privé Sainte Marie
🇫🇷Chalon-sur-Saône, France
CH - Sud Francilien
🇫🇷Corbeil-Essonnes, France
Hopitaux Civils de Colmar
🇫🇷Colmar, France
CHU - Hôpital François Mitterand
🇫🇷Dijon, France
Institut de Cancérologie de Bourgogne - GRRECC
🇫🇷Dijon, France
CH Marne La Vallée-Jossigny - Hôpital André Mignot
🇫🇷Jossigny, France
CH du Mans
🇫🇷Le Mans CEDEX 9, France
CAC - Léon Bernard
🇫🇷Lyon, France
Hôpital de Bicêtre
🇫🇷Le Kremlin-Bicêtre, France
CH - Saint Joseph
🇫🇷Marseille, France
Hôpital Edouard Herriot
🇫🇷Lyon, France
CHU La Timone
🇫🇷Marseille CEDEX 5, France
Hôpital Francobritannique
🇫🇷Levallois-Perret, France
CH de Meaux
🇫🇷Meaux, France
PRIVE - Hôpital Européen
🇫🇷Marseille, France
Centre Hospitalier
🇫🇷Montélimar, France
Centre d'Imagerie médicale du Confluent- IRIS GRIM
🇫🇷Nantes, France
Hôpital Saint Antoine
🇫🇷Paris, France
Hôpital Cochin
🇫🇷Paris, France
CHU - Saint Louis
🇫🇷Paris, France
PRIVE - Saint Joseph
🇫🇷Paris, France
CH - Centre Hospitalier de Pau
🇫🇷Pau, France
CHU - Haut Lévêque
🇫🇷Pessac, France
CH
🇫🇷Soissons CEDEX, France
CH Lyon Sud
🇫🇷Pierre-Bénite CEDEX, France
CHU
🇫🇷Poitiers, France
CAC - ICO Site René Gauducheau
🇫🇷Saint-Herblain, France
CHU - Rangueil
🇫🇷Toulouse, France
CH - Kantonsspital Baden
🇨🇭Baden, Switzerland