PHASE III RANDOMISED TRIAL TO EVALUATE FOLFOX WITH OR WITHOUT DOCETAXEL (TFOX) AS 1st LINE CHEMOTHERAPY FOR LOCALLY ADVANCED OR METASTATIC OESOPHAGO-GASTRIC CARCINOMA

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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OESOPHAGO-GASTRIC CARCINOMA

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: 5Fluorouracil bolus
* Drug: 5Fluorouracil continu
* Drug: Docetaxel
* Drug: Folinic Acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FOLFOX<br>Cycles every 15 days until progression desease | Drug: Oxaliplatin<br> <br> Drug: 5Fluorouracil bolus<br> <br> Drug: 5Fluorouracil continu<br> <br> Drug: Folinic Acid<br> <br> |
| Experimental: TFOX<br>Cycles every 15 days until progression desease | Drug: Oxaliplatin<br> <br> Drug: 5Fluorouracil continu<br> <br> Drug: Docetaxel<br> <br> Drug: Folinic Acid<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival |  | 12 months after laste randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival Toxicity events (adverse events) according to NCI-CTC v4.0 |  | 12 months after laste randomisation | 
| Objective response rate |  | 12 months after laste randomisation | 
| Toxicity events according to NCI-CTC v4.0 |  | 12 months after laste randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OESOPHAGO-GASTRIC CARCINOMA