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

The study will consist of 4 phases: a screening, an induction, randomization and follow-up
phase.

Screening phase: Screening assessments will be conducted within 28 days prior to initiation
of Induction Phase treatment to determine each patient's overall eligibility. These
assessments will include medical history; physical examination; Eastern Cooperative Oncology
Group (ECOG) performance status (PS); 12 lead electrocardiogram (ECG); echocardiogram (ECHO);
vital signs; laboratory assessments; radiologic assessments of disease status; and an
evaluation of the vasculature compatibility for Percutaneous Hepatic Perfusion (PHP).

Induction phase: The initial 12 weeks of the study, all patients will receive 4 cycles of
cisplatin/gemcitabine. Each cycle will be comprised of cisplatin dosed at 25 mg per square
meter of body-surface area (BSA), followed by gemcitabine dosed at 1000 mg per square meter
of BSA; dosing will occur on Days 1 and 8 of each cycle. At the completion of 3 cycles (week
8 (+1 week)) of cisplatin/gemcitabine, an imaging scan is performed as per standard of care
to determine if the patient has progressed on treatment or should continue receiving the
cisplatin/gemcitabine induction therapy for one more cycle (4th cycle - prior to
randomization). At the completion of 4 cycles (week 12 (+1 week)) of cisplatin/gemcitabine,
patients will undergo whole-body imaging to determine the status of their disease. Patients
with progressive disease (PD) will be discontinued from study treatment, and will receive
further treatment to be determined by the principal investigator (PI). They will continue to
be followed until death or the end of the study. Patients who have at least stable disease
(SD) at imaging after induction phase of 4 cycles of cisplatin/gemcitabine (week 12 (+ 1
week)) will go on to the next phase of the study (Randomized Treatment Phase).

Randomization phase: Patients who have at least stable disease via imaging at the end of the
Induction Phase will be randomized in a 1:1 ratio to Melphalan/HDS treatment or to continue
cisplatin/gemcitabine in cycles previously described in the Induction Phase, until
progressive disease (PD) or unacceptable toxicity is observed. Patients who were randomized
to treatment with Melphalan/HDS (dosed at 3.0 mg/kg Ideal Body Weight [IBW]) must undergo
their first treatment within 14 days following the whole body imaging performed at end of the
Induction Phase. For Melphalan/HDS treatment, patients will receive up to 6 treatments. Each
treatment cycle will consist of 6 weeks with an acceptable delay for up to another 2 weeks
before the next planned treatment to allow for additional recovery, if needed. After the
Melphalan/HDS treatment, in the absence of disease progression, the patient should undergo a
re-induction of CisGem. Tumor response will be assessed in both treatment arms every 8 weeks
(+ 1 week) until PD.

The assessment scans will be reviewed by Independent Review Committee (IRC). At any time when
PD is observed, the patient will be removed from further study treatment; any further
treatment will be at the discretion of the investigator. Melphalan/HDS treatment will also be
discontinued in the event that recovery requires more than 8 weeks from last treatment. An
end-of-treatment visit will be conducted approximately 6 to 8 weeks following the final dose
of study treatment. Ongoing adverse events (AEs) at the end-of-treatment visit will be
followed until the severity returns to common terminology criteria for adverse events (CTCAE)
Grade < 1.

Follow-up phase: In the event that disease has not progressed at the end-of-treatment visit,
disease assessment scans will continue every 8 weeks (+ 1 week) until PD is documented.
Patients will be contacted by phone every 6 months for survival status for the first two
years following the completion of study treatment, then yearly thereafter until death,
withdrawal of informed consent or they become lost to follow-up, whichever occurs first.
Patients will be monitored for two years following the completion of study treatment for the
development of myelodysplasia and secondary leukemia.

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