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

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ClinicalTrials.gov Identifier: NCT02591030
Recruitment Status : Recruiting
First Posted : October 29, 2015
Last Update Posted : October 29, 2018
Sponsor:
Collaborator:
Federation Francophone de Cancerologie Digestive
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Saint Etienne

Tracking Information
First Submitted Date  ICMJE October 26, 2015
First Posted Date  ICMJE October 29, 2015
Last Update Posted Date October 29, 2018
Actual Study Start Date  ICMJE December 15, 2015
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2015)
  • percentage of patients who are alive without radiological progession [ Time Frame: up to 6 months ]
    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).
  • overall survival [ Time Frame: up to 6 years ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02591030 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2015)
  • overall survival [ Time Frame: up to 6 months ]
    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.
  • Tumour response [ Time Frame: up to 6 months ]
    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.
  • Tumour response [ Time Frame: up to 6 years ]
    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.
  • Toxicity of the treatment assessed according to NCI-CTC v 4.0 [ Time Frame: up to 6 months ]
    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)
  • Toxicity of the treatment assessed according to NCI-CTC v 4.0 [ Time Frame: up to 6 years ]
    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)
  • Biliary complications [ Time Frame: up to 6 years ]
    In phase III : angiocholitis, obstruction of the main bile ducts or biliary stent obstruction
  • Biliary complications [ Time Frame: up to 6 months ]
    In phase II : angiocholitis, obstruction of the main bile ducts or biliary stent obstruction
  • quality of life (EORTC QLQ-C30 ) [ Time Frame: up to 6 years ]
    EORTC QLQ-C30 quality of life. Quality-of-life assessments will be performed until progression of the disease
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Modified Folfirinox Versus Gemcis in Bile Duct Tumours
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bile Duct Cancer
Intervention  ICMJE
  • 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.
  • 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
Study Arms  ICMJE
  • Placebo Comparator: GEMCIS
    Intervention: Drug: GEMCIS
  • Experimental: mFOLFIRINOX
    Intervention: Drug: mFolfirinox
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 28, 2015)
316
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2023
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jean-Marc Phelip, PhD (0)477828320 ext +33 j.marc.phelip@chu-st-etienne.fr
Contact: Lila GABA-BERKOUK (0)3 80 39 34 83 ext +33 lila.gaba@u-bourgogne.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02591030
Other Study ID Numbers  ICMJE 1408212
2015-002282-35 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Centre Hospitalier Universitaire de Saint Etienne
Study Sponsor  ICMJE Centre Hospitalier Universitaire de Saint Etienne
Collaborators  ICMJE Federation Francophone de Cancerologie Digestive
Investigators  ICMJE
Principal Investigator: Jean-Marc Phelip, PhD CHU Saint-Etienne
PRS Account Centre Hospitalier Universitaire de Saint Etienne
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP