Activity of Regorafenib in Combination With Chemotherapy in Patients With Advanced Biliary Tract Cancer

Inclusion Criteria:

* Adenocarcinoma of the biliary tract
* Metastatic disease with no curative surgery option or metastatic recurrence after resection.
* Only for phase II: At least one measurable lesion in a non-irradiated area according to Response Evaluation Criteria in Solid Tumors
* No biliary obstruction.
* Age between 18 and 75 years.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life expectancy higher than 3 months.
* No prior chemotherapy for advanced disease. Previous adjuvant chemotherapy including Gemcitabine and/or platinum based is allowed if completed at least 6 months previously and relapsing after completion of the last dose.
* Total bilirubin ≤ 2.5 times the upper limit of the normal range. Patients with jaundice or evidence of bile duct obstruction, in whom the biliary tree can be decompressed by endoscopic or percutaneous endoprothesis (at least 15 days before inclusion) with subsequent reduction in total bilirubin ≤ 3 ULN, will be eligible for the study.
* Aminotransferases (AST, ALT) ≤ 2.5 ULN (≤ 5 ULN in case of diffuse hepatic involvement), INR \< 1.5 (following vitamin K1 injection in patients with current or recent history of jaundice or bile duct obstruction), serum creatinine clearance calculated \> 50 mL/min/1.73m² according to the Modification of Diet in Renal Disease (MDRD) formula, neutrophils ≥ 1.5.109/L, platelets ≥ 100.109/L, hemoglobin ≥ 9 g/dL (red blood cell transfusion is allowed if needed).
* Signed informed consent obtained before any study specific procedures.
* Patients must be affiliated to a Social Security System.

Exclusion Criteria:

* Known central nervous system metastases.
* Known history of human immunodeficiency virus (HIV) infection
* Contraindication or history of allergic reaction to one of the treatment components.
* Previous irradiation (external radiotherapy or brachytherapy) within 30 days prior to study treatment.
* Major surgery within 30 days prior to study treatment.
* Participation in another clinical trial within 30 days prior to study treatment.
* Concomitant systemic immunotherapy, chemotherapy, antitumor hormone therapy, targeted therapy or any experimental therapy.
* Active uncontrolled infection, peripheral neuropathy grade ≥ 2, acute or subacute bowel obstruction, history of inflammatory bowel disease, interstitial pneumonitis, respiratory failure, renal failure, dysphagia or any malabsorption condition.
* Symptomatic coronary heart disease or myocardial infarction in the past 6 months, congestive heart failure (NYHA class II), prior cerebrovascular accident.
* Uncontrolled hypertension (systolic blood pressure (BP) \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management).
* Proteinuria of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) ≥ grade 2 (i.e. urinary protein ≥ 1.0 g/24 hrs).
* Patients with current or anticipated need for strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.
* Pregnancy (or positive β-HCG dosage at inclusion), breast-feeding, or lack of effective contraception in male or female patients of reproductive potential.
* Other malignancies either currently active or in the last 5 years, except adequately treated in situ carcinoma of the cervix and basal or squamous cell skin carcinoma.
* Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study