Safety and Efficacy of Modified Folfirinox Versus Gemcis in Bile Duct Tumours

NCT ID: NCT02591030

Last Updated: 2022-02-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 191 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-15
• Study Completion Date: 2020-01-16

Brief Summary

Bile duct tumours are rare. They are the 6th most common type of digestive cancer. Their therapeutic management is complex and must be multidisciplinary in nature. Most of the time, an endoscopic or radiological biliary drainage is necessary before any tumour treatment.

Their prognosis is poor due to the fact that they are normally diagnosed late, which makes curative surgery impossible. A population study in the Côte d'Or region of France reported a survival rate at 5 years of approximately 10%.

For the locally advanced or metastatic forms, treatment has not been properly codified. With respect to chemotherapy, prospective studies, most often phase II, are difficult to interpret due to a limited number of patients and due to the heterogeneity of this type of tumour (bile duct and pancreas tumours). Treatment with 5FU alone provides an objective response in approximately 10% of cases. In combination with mitomycin or carboplatin, the objective response rate is 20%, with a median survival period of 5 months. Interferon combined with 5FU has a better response rate (30%), but occurrences of different types of toxicity are more frequent.

More recently, gemcitabine and the 5FU-cisplatin combinations demonstrated objective tumour control in 50% of patients with a median survival period of 10 months. Gemcitabine combined with oxiplatin or with cisplatin has shown the same response rate but a median survival period of approximately 12 months.

The benefit of this combination has been confirmed in a phase III trial that compared the gemcitabine-cisplatin combination to gemcitabine alone, in 410 patients with locally advanced unresectable and/or metastatic bile duct cancer. The results were in favour of the combined treatment with a median survival period of 11.7 months (versus 8.1 months - HR 0.64 [0.52 - 0.80]). This combination is currently the reference first-line treatment.

Detailed Description

At the same time as these results, triple therapies involving 5FU + oxiplatin + irinotecan have objectively shown a significant increase in overall survival of patients with metastatic pancreatic adenocarcinoma compared to gemcitabine alone (median of 11.1 months versus 6.8 months, HR = 0.57 [0.45 - 0.73] p < 0.0001). The response rate and progression-free survival (PFS) have also been improved with these triple therapies; the response rates were 31.6% versus 9.4% p < 0.001 and the median PFS 6.4 months versus 3.3 months p < 0.001, respectively.

The adverse events observed with the triple therapy occurred more frequently, for febrile neutropaenia (5.4%), with the need to treat with growth factors (G-CSF for 42.5% of patients). Haematological and digestive toxicity was also higher: grade 3-4 neutropaenia was observed for 45.7% of patients in the FOLFIRINOX arm and 18.7% of patients in the gemcitabine arm (p = 0.0001); vomiting was noted for 14.5% of patients in the FOLFIRINOX arm and 4.7% in the gemcitabine arm (p = 0.002). Quality of life was improved in the FOLFIRINOX arm.

Due to the histological, therapeutic and prognostic similarities between pancreatic and bile duct cancer, it is interesting to assess this triple therapy compared to the current reference treatment in bile duct cancers: gemcitabine combined with cisplatin (GEMCIS). Due to the known higher levels of toxicity for this triple therapy (digestive and haematological), the investigators modified the conventional FOLFIRINOX regimen (mFOLFIRINOX) by removing the 5-FU bolus at D1 of each cycle. This modification to the regimen would appear not to decrease the efficacy of the treatment.

Conditions

Bile Duct Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GEMCIS

Group Type: PLACEBO_COMPARATOR

GEMCIS

Intervention Type: DRUG

At D1 and D8 of each cycle, i.e. every 21 days for 6 months:

• Cisplatin 25 mg/m² over 1 hour at D1 and D8
• Gemcitabine 1000 mg/m² over 30 minutes at D1 and D8.

mFOLFIRINOX

Group Type: EXPERIMENTAL

mFolfirinox

Intervention Type: DRUG

At D1 of each cycle, i.e. every 15 days for 6 months:

• Oxiplatin: 85 mg/m² (IP/120 minutes)
• Irinotecan: 180 mg/m² (IV/90 minutes)
• Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine [calcium levofolinate]) (IV/2 hours), via a Y connector at the same time as irinotecan
• 5-FU: 2400 mg/m² (IV over 46 hours) without 5FU bolus at D1

Interventions

GEMCIS

At D1 and D8 of each cycle, i.e. every 21 days for 6 months:

• Cisplatin 25 mg/m² over 1 hour at D1 and D8
• Gemcitabine 1000 mg/m² over 30 minutes at D1 and D8.

Intervention Type: DRUG

mFolfirinox

At D1 of each cycle, i.e. every 15 days for 6 months:

• Oxiplatin: 85 mg/m² (IP/120 minutes)
• Irinotecan: 180 mg/m² (IV/90 minutes)
• Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine [calcium levofolinate]) (IV/2 hours), via a Y connector at the same time as irinotecan
• 5-FU: 2400 mg/m² (IV over 46 hours) without 5FU bolus at D1

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• - WHO 0 or 1
• Age ≥ 18 years
• Tumour of the intrahepatic or extrahepatic (and/or hilar) bile ducts, or of the gallbladder
• Measurable abdominal metastases (at least a lesion >10 mm) and/or measurable, unresectable primary tumour
• Disease proven by histopathology or cytology (on metastasis or primary tumour)
• If there are no abdominal metastases, the unresectability must be confirmed by a hepatobiliary surgeon in a multidisciplinary team (MDT) meeting
• Bilirubin <1.5 N (after endoscopic or trance hepatic optimum biliary drainage, if necessary), AST and ALT <10N
• Serum creatinine <130 µmol/L, creatinine clearance >60 mL/min
• Neutrophils ≥ 1500/mm3 and platelets ≥ 75,000/mm3
• Prothrombin index > 70%
• Serum albumin > 25 g/L
• Patient registered with a social security scheme (including CMU)
• Signed informed consent form

Exclusion Criteria

• - Non-measurable metastases and primary tumour
• Ampullary carcinoma or cancer of the pancreas with infiltration of the bile ducts or mixed tumours (hepatocholangiocarcinoma)
• Chemotherapy and/or radiotherapy within the last 4 months
• Other malignant tumour except in situ basal cell carcinoma or curatively treated carcinoma of the uterine cervix or other malignant tumour that has been treated and has been considered cured for at least 5 years
• Major comorbidity factors (unstable angina, myocardial infarction that has occurred within the last 6 months, heart failure ≥2 according to the NYHA classification, uncontrolled high blood pressure)
• Woman who is pregnant or breastfeeding, or patient of either sex who is of childbearing age and not using an adequate contraceptive method
• Not able to undergo the trial medical follow-up for geographical, social or psychological reasons.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Federation Francophone de Cancerologie Digestive

OTHER

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jean-Marc Phelip, PhD

Role: PRINCIPAL_INVESTIGATOR

CHU SAINT-ETIENNE

Locations

Chu Picardie

Amiens, , France

Ico Paul Papin

Angers, , France

CH Victor Dupouy

Argenteuil, , France

CH de la Côte Basque

Bayonne, , France

CHRU Besançon

Besançon, , France

Hôpital Avicenne

Bobigny, , France

Hôpital Saint-André

Bordeaux, , France

Polyclinique Nord

Bordeaux, , France

Hôpital Duchenne

Boulogne-sur-Mer, , France

Centre François Baclesse

Caen, , France

Chu D'Estaing

Clermont-Ferrand, , France

Hôpitaux Civils

Colmar, , France

Ch Sud Francilien

Corbeil-Essonnes, , France

Centre de radiothérapie et oncologie du Parc

Dijon, , France

Centre Georges François Leclerc

Dijon, , France

Hôpital Michallon

Grenoble, , France

CHD Vendée

La Roche-sur-Yon, , France

Clinique du cap d'Or

La Seyne-sur-Mer, , France

CH Le Kremlin Bicetre

Le Kremlin-Bicêtre, , France

CHRU Lille

Lille, , France

Centre Hospitalier de Longjumeau

Longjumeau, , France

Clinique de la Sauvegarde

Lyon, , France

Centre Léon Bérard

Lyon, , France

Hôpital de la Croix Rousse

Lyon, , France

Hôpital Lyon Sud

Lyon, , France

Hôpital Saint-Joseph

Marseille, , France

Centre Catherine de Sienne

Nantes, , France

CHR Orléans

Orléans, , France

HEGP

Paris, , France

Hôpital Cochin

Paris, , France

Hôpital Saint-Jean

Perpignan, , France

CHU La Miletrie

Poitiers, , France

CHU Reims

Reims, , France

Centre Eugène Marquis

Rennes, , France

Hôpital Drôme Nord

Romans-sur-Isère, , France

Chu Rouen

Rouen, , France

CHU Saint-Etienne

Saint-Etienne, , France

CH Saint-Jean de Luz

Saint-Jean-de-Luz, , France

CH Saint-Quentin

Saint-Quentin, , France

Ch Robert Morlevat

Semur-en-Auxois, , France

CAC Paul Strauss

Strasbourg, , France

CHU Tours

Tours, , France

Countries

France

References

Phelip JM, Desrame J, Edeline J, Barbier E, Terrebonne E, Michel P, Perrier H, Dahan L, Bourgeois V, Akouz FK, Soularue E, Ly VL, Molin Y, Lecomte T, Ghiringhelli F, Coriat R, Louafi S, Neuzillet C, Manfredi S, Malka D; PRODIGE 38 AMEBICA Investigators/Collaborators. Modified FOLFIRINOX Versus CISGEM Chemotherapy for Patients With Advanced Biliary Tract Cancer (PRODIGE 38 AMEBICA): A Randomized Phase II Study. J Clin Oncol. 2022 Jan 20;40(3):262-271. doi: 10.1200/JCO.21.00679. Epub 2021 Oct 18.

Reference Type: DERIVED

PMID: 34662180 (View on PubMed)

Other Identifiers

2015-002282-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1408212

Identifier Type: -

Identifier Source: org_study_id