| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intrahepatic cholangiocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bile ducts in the liver |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To compare the overall survival (OS) in patients with intrahepatic cholangiocarcinoma treated with Melphalan/HDS given sequentially following cisplatin/gemcitabine Induction versus cisplatin/gemcitabine. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the overall progression-free survival in patients with intrahepatic cholangiocarcinoma as determined by Blinded Independent Review Committee (BIRC). The PFS will be evaluated at 110 PFS events to determine a “go/no go” decision.
• To compare the objective response rate (ORR = complete response [CR] + partial response [PR]), as determined by the Investigator.
• To evaluate the safety of Melphalan/HDS treatment given sequentially following cisplatin/gemcitabine in patients with intrahepatic cholangiocarcinoma.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. 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. For patients with MRI
intolerance, a 3-phase liver CT is to be done in place of liver MRI.
4. At least one target lesion based on the evaluation criteria in solid tumors (RECIST 1.1).
5. Patients must have an ECOG PS of 0-1 at screening.
6. Male or female patients aged ≥ 18 years.
7. 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).
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (β-human chorionic gonadotropin) within 7 days prior to Induction treatment. |
|
| E.4 | Principal exclusion criteria |
1. >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 permitted provided anatomy is still compatible for perfusion with Melphalan/HDS system.
3. History of/known hypersensitivity to any components of melphalan or components of Melphalan/HDS system.
4. History of/known hypersensitivity to gemcitabine or platinum-containing compounds.
5. Known hypersensitivity to heparin/presence of heparin-induced thrombocytopenia.
6. Prior treatment with gemcitabine/platinum-containing compounds, including in adjuvant setting.
7. Received investigational agent for any indication <30 days prior to first treatment.
8. Prior radiation therapy to liver including 90Y-, I131-based loco-regional therapy. Prior loco-regional therapy, inc. resection, based on other technology for ICC, must have completed >4 weeks prior to baseline imaging.
9. Not recovered from side effects of prior therapy to ≤Grade 1. Certain side effects unlikely to develop into serious/life–threatening events allowed >Grade 1.
10. Those with NYHA functional classification II, III or IV; active cardiac conditions inc. unstable coronary syndromes (unstable/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/evidence of clinically significant pulmonary disease that precludes use of general anesthesia.
12. Any evidence of severe/uncontrolled systemic diseases which, in view of investigator, make it undesirable for patient to participate in the trial.
13. Patients with active bacterial infections with systemic manifestations (malaise, fever, leukocytosis) not eligible until completion of appropriate therapy except patients taking low-dose antibiotics for biliary obstruction.
14. History of prior malignancy that will interfere with response evaluation (exceptions include in-situ carcinoma of 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 >5 years previously).
15. Acute or active hepatitis B or hepatitis C infection. Patients with anti-HBc antigen positive, or HBsAg but viral DNA negative are exception(s).
16. History of bleeding disorders which would put patient at risk for bleeding with anti-coagulation or patients with increased risk of thromboembolic or hemorrhagic events.
17. Brain lesions or intracranial abnormalities at risk for bleeding by history or radiologic imaging.
18. Known varices at risk of bleeding, inc. medium/large esophageal or gastric varices/active peptic ulcer.
19. Inadequate hematologic function as evidenced by any of the following:
a. Platelets <100,000/μL
b. Hemoglobin <10.0g/dL, independent of transfusion or growth factor support
c. White blood cell count <2,000/μL
d. Neutrophils <1,500cells/μL.
20. Serum creatinine >1.5mg/dL. If serum creatinine >1.5mg/dL, measured creatinine clearance must be measured and patient is eligible if creatinine clearance >45mL/min.
21. Inadequate liver function as evidenced by any of the following:
a. Total serum bilirubin >1.5 times ULN
b. Aspartate aminotransferase >5 times the upper limit of normal or alanine aminotransferase >5 times ULN
c. Serum albumin <2.9g/dL.
22. Known alcohol or drug abuse that would preclude compliance with study procedures.
23. Women of childbearing potential (WOCBP i.e. fertile meaning not permanently sterilized and having had a menstrual period within the past 12 months) unable to undergo hormonal suppression to avoid menstruation during treatment.
24. WOCBP and fertile males (not permanently sterile by bilateral orchiectomy) unwilling or unable to use highly effective contraception method from Induction to at least 6 months after the last administration of study treatment. (combined hormonal contraception; progestogen-only hormonal contraception; Intrauterine device, intrauterine hormone-releasing system; bilateral tubal occlusion, vasectomized partner or sexual abstinence)
25. Females that are pregnant or breastfeeding patients.
26. Patients taking immunosuppressive drugs or who are unable to be temporarily removed from chronic anti-coagulation therapy. Note: patients receiving oral corticosteroid treatment (< 10 mg/day) are eligible for enrolment.
27. Patients with biliary stents.
28. Patients with history of external percutaneous transhepatic cholangiography catheter placement.
29. Patients previously treated with any intra-arterial regional hepatic therapy such as trans-arterial chemoembolization.
30. Patients with severe allergic reactions to iodine contrast which cannot be controlled by premedication with antihistamines and steroids.
31. Patients with a latex allergy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is Overall Survival and is defined as the time from date of randomization to date of death. In the absence of confirmation of death, survival time will be censored at the last date of follow-up when the patient was known to be alive (i.e. date reported for study medication, adverse event, vital sign, concomitant medication, phone contact, etc.). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival (OS) at 190 OS events. The study will continue until survival follow-up is complete in all enrolled patients. |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival as determined by Blinded Independent Review Committee (BIRC) is defined as the time from the date of randomization to first objective documentation of tumor progression (irrespective of initiation of a new or different systemic treatment) or to death due to any cause.
2. Objective Response Rate (ORR = CR + PR) as determined by the Investigator is a binary variable identifying whether or not the patient achieved a best overall (hepatic and extra-hepatic) response of PR or CR using RECIST 1.1 criteria. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Progression Free Survival (PFS) interim analysis at 110 PFS events;
• Only if Progression Free Survival is statistically significant at the pre-specified level (p<0.20, two-sided) will the study continue to enrolment of patients for the confirmatory endpoint of overall survival.
2. Progression Free Survival at the time final overall survival analysis takes place
3. Objective Response Rate (ORR) at the time final overall survival analysis takes place
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Patients attend end-of-treatment (EOT) visit 6-8 wks after final administration of study treatment. Ongoing AEs at EOT followed until severity returns to baseline or CTCAE Grade ≤1, is resolved or explained. In event that disease has not progressed at EOT, disease assessment scans continue every 8 wks until PD is documented. Survival status checked every 3-6 monthly for 2 years after EOT for development of myelodysplasia and secondary leukemia. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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