Clinical trial NCT02885753: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Colorectal Neoplasms
Keywords: colorectal
cancer
metastasis
hepatic
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2016-08-31
Enrollment: 348
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: progression-free survival
timeFrame: 24 months after randomization
Secondary outcomes:
Other outcomes:
Locations:
city: Abbeville CEDEX
country: France
facility: CH D'Abbeville
city: Aix-en-Provence
country: France
facility: Centre Hospitalier du pays d'Aix
city: Amiens
country: France
facility: Hôpital Sud
city: Angers
country: France
facility: CHU - Hôtel Dieu
city: Antony
country: France
facility: Hôpital Privé d'Antony
city: Auxerre
country: France
facility: CH d'Auxerre
city: Avignon
country: France
facility: PRIVE - Sainte Catherine
city: Bayonne CEDEX
country: France
facility: CH - Côte Basque
city: Beauvais
country: France
facility: CH de Beauvais
city: Besançon
country: France
facility: CH Jean Minjoz
city: Beuvry
country: France
facility: Centre de Radiothérapie Pierre Curie
city: Bordeaux CEDEX
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: PRIVE - Polyclinique Bordeaux Nord
city: Boulogne-sur-Mer
country: France
facility: CMCO Côte d'Opale
city: Boulogne-sur-Mer
country: France
facility: Hôpital Duchenne
city: Caen
country: France
facility: Centre François Baclesse
city: Caluire-et-Cuire
country: France
facility: PRIVE - Infirmerie Protestante de Lyon
city: Chalon-sur-Saône
country: France
facility: CH William Morey
city: Chalon-sur-Saône
country: France
facility: Hôpital Privé Sainte Marie
city: Chambéry CEDEX
country: France
facility: Centre Hospitalier Métropole Savoie
city: Chartres
country: France
facility: Hôpital Louis Pasteur
city: Colmar
country: France
facility: Hopitaux Civils de Colmar
city: Compiègne CEDEX
country: France
facility: Clinique Saint Côme
city: Corbeil-Essonnes
country: France
facility: CH - Sud Francilien
city: Créteil CEDEX
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Institut de Cancérologie de Bourgogne - GRRECC
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Dijon
country: France
facility: CHU - Hôpital François Mitterand
city: Grenoble CEDEX 1
country: France
facility: GHM Institut Daniel Hollard
city: Jossigny
country: France
facility: CH Marne La Vallée-Jossigny - Hôpital André Mignot
city: La Roche Sur Yon
country: France
facility: Ch - Chd Vendee
city: La Tronche
country: France
facility: CHU Grenoble - Hôpital Albert Michallon
city: Le Chesnay
country: France
facility: Hôpital André Mignot
city: Le Havre
country: France
facility: CMC Les Ormeaux
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital de Bicêtre
city: Le Mans CEDEX 9
country: France
facility: CH du Mans
city: Levallois-Perret
country: France
facility: Hôpital Francobritannique
city: Longjumeau
country: France
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Lyon
country: France
facility: CAC - Léon Bernard
city: Marseille CEDEX 5
country: France
facility: CHU La Timone
city: Marseille
country: France
facility: CH - Saint Joseph
city: Marseille
country: France
facility: PRIVE - Hôpital Européen
city: Meaux
country: France
facility: CH de Meaux
city: Metz
country: France
facility: Hôpital Belle Isle
city: Montceau-les-Mines
country: France
facility: Centre Hospitalier
city: Montélimar
country: France
facility: Centre Hospitalier
city: Nantes
country: France
facility: Centre d'Imagerie médicale du Confluent- IRIS GRIM
city: Nantes
country: France
facility: CHU - Hôtel Dieu
city: Nantes
country: France
facility: Hôpial Privé du Confluent Le Confluent Centre Catherine de Sienne
city: Orleans
country: France
facility: CHR
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: CHU - Hôpital Européen George Pompidou
city: Paris
country: France
facility: CHU - Saint Louis
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: PRIVE - Saint Joseph
city: Pau
country: France
facility: CH - Centre Hospitalier de Pau
city: Pau
country: France
facility: CH - Pau
city: Perpignan
country: France
facility: CH
city: Pessac
country: France
facility: CHU - Haut Lévêque
city: Pierre-Bénite CEDEX
country: France
facility: CH Lyon Sud
city: Poitiers
country: France
facility: CHU
city: Pontoise
country: France
facility: CH René Dubois
city: Pringy
country: France
facility: CH Annecy Genevois
city: Périgueux
country: France
facility: Polyclinique Francheville
city: Quimper
country: France
facility: CHIC
city: Reims CEDEX
country: France
facility: CHU Robert Debré
city: Rennes CEDEX 9
country: France
facility: CHU de Pont Chaillou
city: Rennes
country: France
facility: CAC - Eugène Marquis
city: Romans-sur-Isère
country: France
facility: Hôpital Drome Nord
city: Rouen CEDEX 01
country: France
facility: CHU Charles Nicolle
city: Saint Nazaire
country: France
facility: Clinique Mutualiste de l'Estuaire - Cité Sanitaire
city: Saint-Grégoire
country: France
facility: PRIVE - Saint Grégoire
city: Saint-Herblain
country: France
facility: CAC - ICO Site René Gauducheau
city: Saint-Malo
country: France
facility: Centre Hospitalier de Saint Malo
city: Saint-Priest-en-Jarez
country: France
facility: CHU de Saint Etienne - Hôpital Nord
city: Saint-Priest-en-Jarez
country: France
facility: Chu - Hopital Nord Chu Saint Etienne
city: Sainte Colombe
country: France
facility: Clinique Trenel
city: Senlis CEDEX
country: France
facility: CH
city: Soissons CEDEX
country: France
facility: CH
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Thonon-les-Bains
country: France
facility: Hôpitaux du Leman
city: Toulon
country: France
facility: Hôpital Sainte Musse
city: Toulouse
country: France
facility: CHU - Rangueil
city: Vandœuvre-lès-Nancy
country: France
facility: CHU Nancy-Brabois
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de cancérologie de Lorraine
city: Villejuif
country: France
facility: CAC - Gustave Roussy
city: Villejuif
country: France
facility: Hôpital Paul BROUSSE
city: Baden
country: Switzerland
facility: CH - Kantonsspital Baden
Study officials:
affiliation: HEGP, Paris
name: Julien TAIEB, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pernot S, Pellerin O, Mineur L, Monterymard C, Smith D, Lapuyade B, Gallois C, Khemissa Akouz F, De Baere T, Tougeron D, Thirot-Bidault A, Audemar F, Simon M, Lecaille C, Louafi S, Lepage C, Ducreux M, Taieb J. Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49. Dig Liver Dis. 2022 Mar;54(3):324-330. doi: 10.1016/j.dld.2021.12.012. Epub 2022 Jan 11.