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

Downstaging of Unresectable Intrahepatic or Hilar Cholangiocellular Carcinoma by Selective Intra-arterial Floxuridine and Systemic Cisplatin and Gemcitabine. A Dose Finding Single Center Phase IIa Study

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

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