Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
PRODIGE 51
- NCT ID:
NCT03006432
Conditions
- OESOPHAGO-GASTRIC CARCINOMA
Interventions
| Drug | Synonyms | Arms |
|---|
| Oxaliplatin | | FOLFOX |
| 5Fluorouracil bolus | | FOLFOX |
| 5Fluorouracil continu | | FOLFOX |
| Docetaxel | | TFOX |
| Folinic Acid | | FOLFOX |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| FOLFOX | Active Comparator | Cycles every 15 days until progression desease | - Oxaliplatin
- 5Fluorouracil bolus
- 5Fluorouracil continu
- Folinic Acid
|
| TFOX | Experimental | Cycles every 15 days until progression desease | - Oxaliplatin
- 5Fluorouracil continu
- Docetaxel
- Folinic Acid
|
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | progression-free survival |
| Time Frame: | 12 months after laste randomisation |
| Safety Issue: | |
| Description: | |
Secondary Outcome Measures
| Measure: | Overall survival Toxicity events (adverse events) according to NCI-CTC v4.0 |
| Time Frame: | 12 months after laste randomisation |
| Safety Issue: | |
| Description: | |
| Measure: | Objective response rate |
| Time Frame: | 12 months after laste randomisation |
| Safety Issue: | |
| Description: | |
| Measure: | Toxicity events according to NCI-CTC v4.0 |
| Time Frame: | 12 months after laste randomisation |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Federation Francophone de Cancerologie Digestive |
Trial Keywords
- OESOPHAGO-GASTRIC CARCINOMA
Last Updated
October 14, 2020
