Downsizing of Unresectable Cholangiocarcinoma by Combined Intravenous and Intra-arterial Chemotherapy

An open label, prospective, non-randomized single arm study. Combination of two treatment modalities - HAI with FUDR and systemic chemotherapy with cisplatin and gemcitabine.

Definition of the maximum tolerated dose (MTD) of intravenous gemcitabine in combination with intravenous cisplatin and intra-arterial FUDR. Definition of safety and toxicity of this combined regional and systemic treatment approach. Definition of the response rate after 3 months of hepatic intra-arterial chemotherapy with continuous infusion FUDR with or without ligation of the right or left portal vein, in combination with 3 months of systemic cisplatin and gemcitabine in patients with unresectable intrahepatic or hilar CCC.

A total of 9-18 patients are required. 3-6 patients per dose level. A maximum of three dose levels (1 - 3) has been defined.

Statistical Methodology: Traditional 3+3 dosing algorithm to find MTD.

* Trial with medicinal product


Eligibility Criteria:
Inclusion criteria:

* Histologically or cytologically proven cholangiocellular carcinoma including gallbladder cancer.
* Non-resectable cholangiocellular carcinoma as judged within an interdisciplinary tumor-board including senior hepatobiliary surgeons. Non- resectability is based on insufficient remnant liver volume.
* Patient is not a candidate for liver transplantation
* WHO Performance Score 0 or 1
* No extrahepatic tumor, as evaluated by PET/CT scan of the chest and the abdomen/pelvis with the exception of potentially resectable small lung nodules or hilar lymph node involvement.
* The assessment is done within 21 days before registration.
* Adequate liver function or kidney function tests, including any of the following:

  * Bilirubin \< 2 x ULN
  * Aspartate-Aminotransferase (AST) \< 5 x ULN
  * Alanine-Aminotransferase (ALT) \< 5 x ULN
  * Alkaline phosphatase \< 5 x ULN
  * Estimated creatinine clearance \> 60 ml/min (using the Cockcroft formula)
* Adequate hematological values:

  * Hemoglobin \> 80 G/L
  * Leucocytes \> 3.00 G/L,
  * Neutrophils \> 1.00 G/Ll
  * Platelets \> 100 G/L
* Signed written informed consent
* Patient age \>/= 18 years
* Presentation of the case at the interdisciplinary tumor-board attended by hepatobiliary surgeons, oncologists, hepatologists and radiologists
* Women who are not breastfeeding and are using effective contraception if sexually active, who are not pregnant and agree not to become pregnant during the 12 months thereafter. A negative pregnancy test before inclusion into the trial is required for women \< 50 years.
* Men who agree not to father a child during participation in the trial or during the 12 months thereafter.
* Patient compliance and geographic proximity allow proper staging and follow- up.

Exclusion criteria:

* Anatomic variant in arteriogram which prevents selective delivery of the chemotherapy to the liver
* Life expectancy \< 3 months
* Severe medical or psychiatric co-morbidity prohibiting the planned treatment or the giving of informed consent
* Any man or woman of childbearing age in case of inadequate contraception
* Pregnancy or breastfeeding woman
* Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
* Treatment in clinical trial within 30 days prior to trial entry.
* Active heart disease defined as congestive heart failure \> NYHA class 2
* Past or current history (within the last 2 years prior to treatment start) of other malignancies except basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
* Inability or unwillingness to comply with the study protocol