Clinical trial NCT03006432: PHASE III RANDOMISED TRIAL to EVALUATE FOLFOX with or WITHOUT DOCETAXEL (TFOX) AS 1st LINE CHEMOTHERAPY for LOCALLY ADVANCED or METASTATIC OESOPHAGO-GASTRIC CARCINOMA
Official title: ESSAI DE PHASE III RANDOMISE EVALUANT LE FOLFOX AVEC OU SANS DOCETAXEL (TFOX) EN 1ère LIGNE DE CHIMIOTHERAPIE DES ADENOCARCINOMES OESO-GASTRIQUES LOCALEMENT AVANCES OU METASTATIQUES
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: OESOPHAGO-GASTRIC CARCINOMA
Keywords: OESOPHAGO-GASTRIC CARCINOMA
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
Collaborators: name: UNICANCER
name: GERCOR - Multidisciplinary Oncology Cooperative Group
First posted: 2016-12-30
Enrollment: 507
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: Gastric cancer is the fourth commonest cancer and the second largest cause of mortality from cancer. Surgical resection of localised forms of gastric cancer offers the only chance of a cure. The vast majority of patients, however, present with advanced disease from the outset (locally advanced or metastatic) or recurrent after resection of a localised form.

For metastatic or locally advanced stages of gastric or gastro-oesophageal junction adenocarcinoma, the combination of 2 chemotherapy drugs (dual therapy) as compared with monotherapy or no chemotherapy, makes it possible to improve the tumour response and patient survival. Dual therapy comprising cisplatin + fluoropyrimidine (CF protocol) is considered as one of the first-line chemotherapy treatment standards.

The addition of docetaxel to the CF regime (referred to as the DCF protocol) has made it possible to improve the tumour response rate, the time to tumour progression and overall survival in a randomised phase III trial. This improvement in treatment efficacy was achieved, however, at the expense of a significant increase in grade 3-4 toxicity, including diarrhoea , neutropenia, and neutropenia with complications. Although DCF is considered as a therapeutic standard for advanced forms of gastric cancer, its use is limited in clinical practice due to its high toxicity.

Oxaliplatin has shown its usefulness in treatment of oesophagogastric cancer, with an efficacy at least equal to that of cisplatin. Peripheral sensory neuropathy was less common in the 5FU-cisplatin arm. In terms of treatment efficacy, 5FU-oxaliplatin versus 5FU-cisplatin was associated with a non-significant improvement in median progression free survival rates, and overall survival.

All these data thus suggest that 5FU-oxaliplatin is at least as efficacious and is better tolerated than 5FU-cisplatin, and also that docetaxel-5FU-cisplatin is more efficacious than 5FU-cisplatin, with limited use due to its high toxicity. In the logical continuation of development of chemotherapy protocols for metastatic gastric cancer, the question therefore arises of the usefulness of adding docetaxel to 5FU-oxaliplatin, in terms of efficacy and also tolerance.

In France, chemotherapy with FOLFOX is used extensively as a first line of treatment in advanced gastric cancer, but with progression-free survival and median survival rates that are still too low, and a poor response rate. The use of docetaxel at a dose of 50 mg/m2 every 2 weeks in combination with FOLFOX (TFOX protocol) has shown very interesting results in phase II studies in terms of efficacy and tolerability, and these are worth confirming through a phase III randomised trial. In fact, if these results are confirmed in phase III, TFOX could become the new first-line therapeutic standard for advanced gastric cancer, while limiting toxicity and preserving patients' quality of life, and could become the reference treatment to accompany the targeted therapies currently being developed for this disease.

The primary objective of this randomised phase III trial is to compare the progression-free survival on dual therapy with 5FU-oxaliplatin (FOLFOX protocol) with triple therapy with 5FU-oxaliplatin-docetaxel (TFOX protocol) in treatment of advanced forms of gastric or oesophagogastric junction adenocarcinoma. The secondary objectives are overall survival, the tumour response rate, toxicity, quality of life and the therapeutic index, defined as the ratio between the median progression-free survival and the febrile neutropenia rate.


Eligibility criteria: Inclusion Criteria:

* Gastric or gastro-oesophageal junction adenocarcinoma (all Siewert), histologically proven (on primary tumour or metastatic lesion),
* HER2 negative (positive HER2 status is defined by a positive IHC test of 3+ or IHC of 2+ with positive FISH)
* Metastatic or non-resectable (locally advanced) disease
* Disease measurable according to RECIST v1.1 criteria (at least one measurable lesion)
* No major surgical procedure during the 4 weeks prior to randomisation:
* Patient eligible for a 1st line of chemotherapy based on 5FU, folinic acid and oxaliplatin (FOLFOX) with or without docetaxel (TFOX)
* WHO: 0-1
* Age ≥ 18
* BMI \> 18
* Life expectancy \> 3 months
* PNN \> 1500/mm3, platelets \> 100,000/mm3, Hb \> 10 g/dL
* AST, ALT ≤ 3.5 times the UNL, alkaline phosphatase \< 6 times the UNL
* Bilirubin ≤ 1.5 times the UNL,
* Creatinine clearance according to Cockcroft and Gault formula \> 50 mL/min
* Women of childbearing age must have a negative pregnancy test (β HCG) before starting treatment
* Women of childbearing age and men (who are in a sexual relationship with women of childbearing age) must agree to use effective contraception without interruption for the duration of the treatment and for 6 months after administration of the last dose of treatment
* Patient affiliated to a social security scheme
* Patient information and signature of informed consent form

Exclusion Criteria:

* Presence of cerebral or meningeal metastases
* Presence of \> grade 2 neuropathy according to NCIC-CTC 4.0
* Known DPD deficiency
* QT/QTc interval \> 450 msec for men and \> 470 msec for women
* K+ \< LNL, Mg2+ \< LNL, Ca2+ \< LNL
* Any known specific contraindication or allergy to the treatments used in the study (cf RCP Appendix 7)
* Chemotherapy or radio-chemotherapy in an adjuvant situation finished less than 12 months ago
* Prior chemotherapy including oxaliplatin (except for adjuvant chemotherapy)
* Prior chemotherapy including docetaxel
* Any progressive pathology not stabilised over the past 6 months: liver impairment, renal impairment, respiratory or cardiac failure
* HIV+ patients
* Radiotherapy during the 4 weeks prior to randomisation
* Other concomitant cancer or a history of cancer during the previous 5 years, with the exception of carcinoma in situ of the cervix or basal cell carcinoma or epidermoid cell carcinoma of the skin which is considered to be cured
* Patient already included in another clinical trial involving an experimental drug
* Pregnant or breastfeeding woman
* Persons in custody or under wardship
* Impossibility of undergoing medical monitoring during the trial for geographical, social or psychological reasons

Primary outcomes:
measure: progression-free survival
timeFrame: 12 months after laste randomisation
Secondary outcomes:
measure: Overall survival Toxicity events (adverse events) according to NCI-CTC v4.0
timeFrame: 12 months after laste randomisation
measure: Objective response rate
timeFrame: 12 months after laste randomisation
measure: Toxicity events according to NCI-CTC v4.0
timeFrame: 12 months after laste randomisation
Other outcomes:
Locations:
city: Paris
country: France
facility: HEGP
state: Ile de France
city: Abbeville CEDEX
country: France
facility: CH d'Abbeville
city: Amiens
country: France
facility: CHU Amiens-Picardie
city: Angers CEDEX 9
country: France
facility: CHU d'Angers
city: Antony
country: France
facility: Hôpital Privé D'Antony
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy
city: Auxerre
country: France
facility: CH d'Auxerre
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Beauvais
country: France
facility: CH
city: Bethune CEDEX
country: France
facility: CH Germont et Gauthier
city: Bethune
country: France
facility: Centre Hospitalier Germon Et Gauthier
city: Beuvry
country: France
facility: Centre de Radiothérapie Pierre Curie
city: Blois
country: France
facility: CH de Blois
city: Bordeaux CEDEX
country: France
facility: Institut Bergonie
city: Bordeaux CEDEX
country: France
facility: Polyclinique de Bordeaux Nord
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Boujan-sur-Libron
country: France
facility: Polyclinique Saint Privat
city: Boulogne Sur Mer
country: France
facility: Hôpital Duchenne
city: Boulogne-sur-Mer
country: France
facility: CMCO Côte d'Opale
city: Bourg En Bresse
country: France
facility: Centre Hospitalier Fleyriat
city: Bourgoin Jallieu
country: France
facility: Centre Hospitalier Pierre Oudot
city: Bourgoin-Jallieu
country: France
facility: Hôpital Pierre Oudot
city: Caen
country: France
facility: CHU Côte de Nacre
city: Caluire-et-Cuire
country: France
facility: Infirmerie Protestante de Lyon
city: Challes-les-Eaux
country: France
facility: Médipôle de Savoie
city: Chalon Sur Saone
country: France
facility: Centre Hospitalier William Morey
city: Chalon-sur-Saône
country: France
facility: CH William Morey
city: Chambery
country: France
facility: CH Metropole Savoie
city: Champigny Sur Marne
country: France
facility: Hopital Prive Paul D Engine
city: Chartres
country: France
facility: Hopitaux de Chartres, Centre Hospitalier Louis Pasteur
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Châlons-en-Champagne
country: France
facility: Centre Hospitalier Général
city: Clamart
country: France
facility: Hopital D Instruction Des Armées Percy
city: Colmar
country: France
facility: Hopitaux civils de Colmar
city: Compiègne CEDEX
country: France
facility: Clinique Saint Côme
city: Corbeil Essonnes
country: France
facility: Centre Hospitalier Sud Francilien
city: Cornebarrieu
country: France
facility: Clinique des Cèdres
city: Creil
country: France
facility: Groupe Hospitalier Du Sud de L'Oise
city: Creteil
country: France
facility: CHI
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
city: Dinan
country: France
facility: Centre Hospitalier de Dinan
city: Elbeuf
country: France
facility: CHI Elbeuf-Louvier-Val de Reuil
city: Elbeuf
country: France
facility: Centre Hospitalier Intercommunal Elbeuf-Louviers/Val de Reuil
city: Flers CEDEX
country: France
facility: Hôpital Jacques Monod
city: Fréjus
country: France
facility: CHI de Fréjus Saint-Raphaël
city: Grenoble CEDEX 1
country: France
facility: GHM Institut Daniel Hollard
city: Grenoble
country: France
facility: Chu Albert Michallon
city: Hyeres
country: France
facility: Hôpital privé Toulon/Hyères
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: La Tronche
country: France
facility: CHU Grenoble - Hôpital Albert Michallon
city: Le Puy En Velay
country: France
facility: Centre Hospitalier Emile Roux
city: Levallois Perret
country: France
facility: Institut Hospitalier Franco-Britannique
city: Lille
country: France
facility: Chu Claude Huriez
city: Limoges
country: France
facility: Clinique François Chénieux
city: Limoges
country: France
facility: CHU Dupuytren
city: Longjumeau
country: France
facility: CH Longjumeau
city: Lyon CEDEX 09
country: France
facility: Clinique de la Sauvegarde
city: Lyon
country: France
facility: CHU de Lyon - Croix Rousse
city: Lyon
country: France
facility: CH Saint Joseph - Saint Luc
city: Lyon
country: France
facility: Centre Léon Berard
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Lyon
country: France
facility: Hopital Saint Joseph -Saint Luc
city: Lyon
country: France
facility: Hôpital Privé Jean Mermoz
city: Mantes La Jolie
country: France
facility: Centre Hospitalier Francois Quesnay
city: Marseille CEDEX 20
country: France
facility: Hôpital Nord
city: Marseille CEDEX 5
country: France
facility: CHU La Timone
city: Marseille
country: France
facility: Association Hopital Saint Joseph de Marseille
city: Marseille
country: France
facility: Hôpital Européen
city: Meaux
country: France
facility: CH
city: Melun
country: France
facility: Hopital Marc Jacquet
city: Montfermeil
country: France
facility: Ghi Le Raincy-Montfermeil
city: Montivilliers
country: France
facility: Hôpital Monod
city: Montpellier
country: France
facility: Institut Régional du Cancer Montpellier
city: Montélimar
country: France
facility: Centre Hospitalier
city: Nancy
country: France
facility: Chu de Nancy
city: Nantes
country: France
facility: Hôpital privé du Confluent SAS
city: Nantes
country: France
facility: Chu de Nantes
city: Nevers
country: France
facility: CH Pierre Bérégovoy
city: Niort
country: France
facility: CH de Niort
city: Orléans CEDEX 2
country: France
facility: Hôpital de la source
city: Orléans
country: France
facility: CH Régional de la Source
city: Paris CEDEX 20
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: CHU Cochin
city: Paris
country: France
facility: Croix Saint Simon
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Centre Hospitalier Paris Saint Joseph
city: Paris
country: France
facility: Groupe Hospitalier Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Pau CEDEX
country: France
facility: Centre Hospitalier
city: Perigueux
country: France
facility: Polyclinique Francheville
city: Perpignan
country: France
facility: Centre Hospitalier Saint Jean
city: Pessac CEDEX
country: France
facility: Hôpital Haut Leveque
city: Pierre-Bénite CEDEX
country: France
facility: CHU Lyon Sud
city: Poitiers
country: France
facility: Hôpital de la Milétrie
city: Pringy
country: France
facility: CH Annecy Genevois
city: Reims CEDEX
country: France
facility: CHU Robert Debré
city: Reims
country: France
facility: Institut Jean Godinot
city: Romans Sur Isere
country: France
facility: Centre Hospitalier de Romans Sur Isere
city: Rouen CEDEX 01
country: France
facility: CHU Charles Nicolle
city: Saint Germain En Laye
country: France
facility: Chi Poissy Saint Germain
city: Saint Gregoire
country: France
facility: Centre Hospitalier Prive Saint Gregoire
city: Saint Jean de Luz
country: France
facility: Polyclinique Côte Basque
city: Saint Jean
country: France
facility: Clinique de L Union
city: Saint Malo
country: France
facility: Clinique de La Cote D Emeraude
city: Saint Nazaire
country: France
facility: Clinique Mutualiste de L Estuaire
city: Saint Priest En Jarez
country: France
facility: Institut Lucien Neuwirth
city: Saint Quentin
country: France
facility: Plyclinique Saint Claude
city: Saint-Malo
country: France
facility: Centre Hospitalier de Saint Malo
city: Saint-Martin-Boulogne
country: France
facility: Centre Joliot Curie
city: Saint-Priest-en-Jarez
country: France
facility: CHU de Saint Etienne - Hôpital Nord
city: Sainte Colombe
country: France
facility: Clinique Trenel
city: Sainte-foy-les-lyon
country: France
facility: Clinique Charcot
city: Sarcelles
country: France
facility: Centre de cancérologie
city: Senlis CEDEX
country: France
facility: CH
city: Soissons
country: France
facility: Centre Hospitalier de Soissons
city: Strasbourg
country: France
facility: Clinique Sainte Anne
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Strasbourg
country: France
facility: Les Hopitaux Universitaires de Strasbourg
city: Thonon-les-Bains
country: France
facility: Hôpitaux du Leman
city: Toulouse
country: France
facility: Clinique Pasteur
city: Tours CEDEX 9
country: France
facility: Hôpital Trousseau
city: Troyes CEDEX
country: France
facility: Centre Hospitalier de Troyes
city: Troyes
country: France
facility: Centre Hospitalier de Troyes
city: Valenciennes
country: France
facility: entre Hospitalier
city: Vandœuvre-lès-Nancy
country: France
facility: CHU Nancy-Brabois
city: Villeneuve Saint Georges
country: France
facility: Centre Hospitalier Intercommunal
city: Villeneuve-d'Ascq
country: France
facility: Hôpital Privé de Villeneuve d'Asq
city: Villeurbanne
country: France
facility: Medipole Hopital Mutualiste Lyon Villeurbanne
city: Fort de France
country: Martinique
facility: Chu Martinique
city: Fort-de-France
country: Martinique
facility: CHU de Fort de France
Study officials:
affiliation: HEGP, Paris
name: Aziz ZAANAN
role: STUDY_CHAIR
References:
citation: Zaanan A, Samalin E, Aparicio T, Bouche O, Laurent-Puig P, Manfredi S, Michel P, Monterymard C, Moreau M, Rougier P, Tougeron D, Taieb J, Louvet C. Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study). Dig Liver Dis. 2018 Apr;50(4):408-410. doi: 10.1016/j.dld.2018.01.119. Epub 2018 Mar 1.