Percutaneous Hepatic Perfusion vs. Cisplatin/Gemcitabine in Patients With Intrahepatic Cholangiocarcinoma

Inclusion Criteria:

1. Are willing and able to provide signed informed consent.
2. Intrahepatic cholangiocarcinoma diagnosed by histology.
3. Unresectable ICC, with less than 50% of the liver involved, and without clinically significant extra-hepatic disease (regional lymph node lesions [≤ 2 cm] are acceptable) based on CT
4. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and liver) must be performed within 28 days prior to initiation of Induction Phase treatment.
5. At least one target lesion based on the evaluation criteria in solid tumors (RECIST 1.1).
6. Patients must have an ECOG PS of 0-1 at screening.
7. Male or female patients aged ≥ 18 years.
8. Patients must weigh ≥ 35 kg (due to possible size limitations with respect to percutaneous catheterization of the femoral artery and vein using the Delcath Hepatic Delivery System).

Exclusion Criteria:

1. Greater than 50% tumor burden in the liver by imaging.
2. History of orthotopic liver transplantation, hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting. Prior Whipple procedure is permitted provided the anatomy is still compatible for perfusion with the Melphalan/HDS system.
3. History of, or known, hypersensitivity to any components of melphalan or the components of the Melphalan/HDS system.
4. History of, or known, hypersensitivity to gemcitabine or platinum-containing compounds.
5. Known hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
6. Prior treatment with gemcitabine or platinum-containing compounds, including in the adjuvant setting.
7. Received an investigational agent for any indication within 30 days prior to first treatment.
8. Prior radiation therapy to the liver including 90Y , I131 based loco regional therapy. Prior loco regional therapy, including resection, based on other technology for ICC, if any, must have been completed at least 4 weeks prior to baseline imaging.
9. Not recovered from side effects of prior therapy to ≤ Grade 1 (according to National Cancer Institute [NCI] CTCAE version 4.03). Certain side effects that are unlikely to develop into serious or life-threatening events (e.g. alopecia) are allowed at > Grade 1.
10. Those with New York Heart Association functional classification II, III or IV; active cardiac conditions including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.
11. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
12. Any evidence of severe or uncontrolled systemic diseases which, in the view of the investigator, makes it undesirable for the patient to participate in the trial (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease).
13. Patients with active bacterial infections with systemic manifestations (malaise, fever, leukocytosis) are not eligible until completion of appropriate therapy. Patients taking low-dose antibiotics for biliary obstruction are exempted from this exclusion criterion.
14. History of prior malignancy that will interfere with the response evaluation (exceptions include in-situ carcinoma of the cervix treated by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the skin, any early stage (stage I) malignancy adequately resected for cure greater than 5 years previously).
15. Acute or active hepatitis B or hepatitis C infection. Patients with anti-hepatitis B core antigen (HBc) positive, or hepatitis B surface antigen (HBsAg) but viral deoxyribonucleic acid (DNA) negative are exception(s).
16. History of bleeding disorders which would put a patient at risk for bleeding with anti-coagulation or patients with an increased risk of thromboembolic or hemorrhagic events (e.g., stroke).
17. Brain lesions or intracranial abnormalities at risk for bleeding, by history or radiologic imaging (e.g., active metastases).
18. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer.

19. Inadequate hematologic function as evidenced by any of the following:

    1. Platelets < 100,000/µL
    2. Hemoglobin < 10.0 g/dL, independent of transfusion or growth factor support
    3. White blood cell count (WBC) < 2,000/µL
    4. Neutrophils < 1,500 cells/µL.
20. Serum creatinine > 1.5 mg/dL. If serum creatinine > 1.5 mg/dL, the measured creatinine clearance must be measured and patient is eligible if creatinine clearance > 45 mL/min.

21. Inadequate liver function as evidenced by any of the following:

    1. Total serum bilirubin > 1.5 times ULN
    2. Aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) > 5 times ULN
    3. Serum albumin < 2.9 g/dL.
22. Known alcohol or drug abuse that would preclude compliance with study procedures.
23. For female patients of childbearing potential (defined as having had a menstrual period within the past 12 months): a positive serum pregnancy test (β-human chorionic gonadotropin [β HCG]) within 7 days prior to enrollment; or unwilling or unable to undergo hormonal suppression to avoid menstruation during treatment; or if breastfeeding, unwilling or unable to stop breastfeeding while on study treatment.
24. Sexually active females of childbearing potential and sexually active males with partners of reproductive potential: unwilling or unable to use appropriate contraception from screening until at least 6 months after last administration of study treatment.
25. Patients taking immunosuppressive drugs or who are unable to be temporarily removed from chronic anti-coagulation therapy.
26. Patients with biliary stents.
27. Patients with a history of external percutaneous transhepatic cholangiography catheter placement.
28. Patients previously treated with any intra-arterial regional hepatic therapy such as trans-arterial chemoembolization.
29. Patients with severe allergic reactions to iodine contrast which cannot be controlled by premedication with antihistamines and steroids.
30. Patients with a latex allergy