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

Bile Duct Cancer Clinical Trial

— AMEBICA  

Official title:

Randomised Phase II/III Study, Assessing the Safety and Efficacy of Modified Folfirinox Versus Gemcis in Locally Advanced, Unresectable and/or Metastatic Bile Duct Tumours

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02591030
• Other study ID #: 1408212
• Secondary ID: 2015-002282-35
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: December 15, 2015
• Est. completion date: January 16, 2020

Study information

• Verified date: February 2022
• Source: Centre Hospitalier Universitaire de Saint Etienne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 191
• Est. completion date: January 16, 2020
• Est. primary completion date: June 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bile Duct Cancer
• Bile Duct Neoplasms
• Cholangiocarcinoma

Intervention

Drug:
• 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.
• 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

Locations

Country	Name	City	State
France	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	Centre Léon Bérard	Lyon
France	Clinique de la Sauvegarde	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

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Saint Etienne	Federation Francophone de Cancerologie Digestive

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	percentage of patients who are alive without radiological progession	In phase II, the primary endpoint is the percentage of patients alive without radiological progression (assessed according to the RECIST v1.1 criteria) at 6 months (after randomisation).; Patients who are in radiological progression or who have died before the 6 months have elapsed will be considered a failure for the primary endpoint at 6 months (after randomisation).; A medical review will be conducted to decide on patients without radiological progression at 6 months; in the light of their entire medical file, they may be considered a failure (i.e. in progression) or they may be considered to be truly non-assessable (a 5% surplus of patients has been planned for this situation).	up to 6 months
Primary	overall survival	In phase III, the primary endpoint is overall survival. This is defined as the period between the date of randomisation and the date of death (regardless of the cause). Patients who are lost to follow-up will be censored at the end-point for the analysis, or at the date when they were last heard of.	up to 6 years
Secondary	overall survival	In phase II, this is defined as the period between the date of randomisation and the date of death (regardless of the cause). Patients who are lost to follow-up will be censored at the end-point for the analysis, or at the date when they were last heard of.	up to 6 months
Secondary	Tumour response	In phase II, the best tumour response will be assessed across all the treatments and will be described using the figures for the different categories: complete response, partial response, stable, progression or non-assessable.	up to 6 months
Secondary	Tumour response	In phase III, the best tumour response will be assessed across all the treatments and will be described using the figures for the different categories: complete response, partial response, stable, progression or non-assessable.	up to 6 years
Secondary	Toxicity of the treatment assessed according to NCI-CTC v 4.0	In phase II, different types of toxicity assessed according to NCI-CTC v 4.0. Type of toxicity : Haematological (platelets and Neutrophils), Non-haematological (except for nausea, vomiting and alopecia) and neurological (paraesthesia)	up to 6 months
Secondary	Toxicity of the treatment assessed according to NCI-CTC v 4.0	In phase III, different types of toxicity assessed according to NCI-CTC v 4.0. Type of toxicity : Haematological (platelets and Neutrophils), Non-haematological (except for nausea, vomiting and alopecia) and neurological (paraesthesia)	up to 6 years
Secondary	Biliary complications	In phase III : angiocholitis, obstruction of the main bile ducts or biliary stent obstruction	up to 6 years
Secondary	Biliary complications	In phase II : angiocholitis, obstruction of the main bile ducts or biliary stent obstruction	up to 6 months
Secondary	quality of life (EORTC QLQ-C30 )	EORTC QLQ-C30 quality of life. Quality-of-life assessments will be performed until progression of the disease	up to 6 years