This trial will be conducted to evaluate the efficacy, safety and tolerability of a combination of gemcitabine plus sorafenib in comparison of gemcitabine plus placebo as a first-line palliative therapy in chemo-naive advanced or metastatic CCC. There is strong scientific rationale for exploring the role of sorafenib in combination with gemcitabine in advanced CCC.

Sorafenib is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGF-R2, R3 and PDGFR-β.

Mutations in these signaling pathways display by far the most common genetic alterations in CCC and overexpression correlates to poor prognosis. Furthermore, there is no evidence of a consistent or meaningful pharmacokinetic interaction between sorafenib and gemcitabine, suggesting that sorafenib can safely be combined with gemcitabine.

Clinical results of a combination of sorafenib and gemcitabine in a phase I study in pancreatic cancer suggested a therapeutic effect, and the safety and efficacy results together with the knowledge of the molecular pathology of CCC provide a rationale for a randomized, placebo-controlled phase II trial consisting of gemcitabine plus sorafenib in advanced CCC.

Inclusion Criteria:

• Male and female patients aged 18 years and older

• Signed and dated informed consent before the start of specific protocol procedures

• Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer

  • Not amenable to curative surgical resection
  • With at least one unidimensionally measurable target lesion in non-irradiated (or treated by photodynamic therapy, PDT) area (largest diameter ≥ 1 cm (spiral CT scan or MRI) or ≥ 2 cm (conventional CT scan)
  • With pain and biliary obstruction controlled
  • Cytologically or histologically confirmed

• Note : in case of uncertain biliary tract origin (e.g., intrahepatic CCCs), inclusion is possible if

  • extensive search for primary tumor (thoracic and abdomino pelvic CT scan, colonoscopy, upper digestive endoscopy, serum PSA level for men or mammography for women, and FDG-PET if possible) is negative
  • histological examination is consistent with bile duct adenocarcinoma, with IHC positive for cytokeratin 7 and 19 and negative for cytokeratin 20 [Shimonishi, 2000].
  • No histological evidence of hepatocellular carcinoma (HCC)
  • No prior palliative (radio)-chemotherapy (gemcitabine or fluoropyrimidine-based chemotherapy)

• Note:

  • previous adjuvant chemotherapy is allowed (completed since ≥ 6 months if containing gemcitabine or platinum salts);
  • previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed, provided that there is at least one unidimensionally measurable target lesion in untreated area

• Resolution of all side effects of prior surgical procedures to grade ≤ 1 (except for the laboratory values specified below)

• At least 4 weeks from any major surgery (at first dose of study drug)

• ECOG Performance Status of 0-2

Exclusion Criteria:

• Surgery (except diagnostic biopsy), external radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment.
• Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion
• History of cardiac disease: congestive heart failure > NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
• Any of the following within the 12 months prior to starting the study treatment,: coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
• Ongoing cardiac dysrhythmias of grade ≥ 2, atrial fibrillation of any grade, or QTc interval > 450 msec for males or > 470 msec for females
• Hypertension that cannot be controlled by medications ( > 150/100 mmHg despite optimal medical therapy)
• History of HIV infection
• Active clinically serious infections ( > grade 2 NCI-CTC version 3.0)
• Known Central Nervous System tumors including metastatic brain disease
• Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
• History of organ allograft
• Patients with evidence or history of bleeding diathesis
• Active disseminated intravascular coagulation, or patients prone to thromboembolism
• Patients undergoing renal dialysis
• Pregnant or breast-feeding patients