E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
unresectable hepatocellular carcinoma (HCC) confined to the liver
and Intra hepatic Cholangiocarcinoma confined to the liver |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10073077 |
E.1.2 | Term | Intrahepatic cholangiocarcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 estimate the objective response rate of Melphalan/HDS treatment in patients with unresectable HCC or intra hepatic cholangiocarcinoma (ICC) confined in the liver. |
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E.2.2 | Secondary objectives of the trial |
Secondary
• To evaluate the safety of melphalan administered by Melphalan/HDS
• To assess the progression free survival of patients receiving Melphalan/HDS
Exploratory
• To characterize the systemic exposure of melphalan administered by Melphalan/HDS at selected study sites
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with HCC must meet all of the following criteria for study entry:
1. HCC diagnosed by tissue or imaging study
2. Unresectable HCC without clinically significant extrahepatic disease based on CT
3. At least one target lesion based on mRECIST for HCC. In patients with prior loco-regional therapy, the target lesion(s) must be located in area(s) outside previous treatment or having progressed after prior treatment if located within previous treatment field.
4. Child-Pugh Class A
5. Eastern Cooperative Oncology Group Performance Status 0-1
6. No prior radiation therapy to the liver including Y90-, I131-based loco-regional therapy. Prior loco-regional therapy, including resection, based on other technology for HCC, if any, must have been completed at least 4 weeks prior to baseline imaging
7. Age ≥ 18 years
8. Signed informed consent
Patients with ICC must meet all of the following criteria for study entry:
1. ICC diagnosed by tissue biopsy and imaging study
2. Unresectable ICC without clinically significant extra hepatic disease based on CT
3. At least one target lesion based on mRECIST. In patients with prior loco regional therapy, the target lesion(s) must be located in area(s) outside previous treatment or must have progressed after prior treatment if located within previous treatment field.
4. ECOG PS 0-1
5. No prior radiation therapy to the liver including Y90 , 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
6. Age ≥ 18 years
7. Signed informed consent
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E.4 | Principal exclusion criteria |
For the HCC cohort, patients for whom transplantation, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or systemic treatment with sorafenib are better therapeutic options are to be excluded from study entry.
Additionally, patients who meet any of the following criteria will be excluded from study entry:
1. Greater than 50% tumor burden in the liver by imaging
2. History of orthotopic liver transplantation, Whipple’s procedure, hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting
3. Evidence of ascites on imaging study, or the use of diuretics for ascites
4. Clinically significant encephalopathy
5. History of, or known, hypersensitivity to any components of melphalan or the components of the Melphalan/HDS system
6. Known hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia
7. Received an investigational agent for any indication within 30 days prior to first treatment
8. Not recovered from side effects of prior therapy to ≤ grade 1 (according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [NCI CTCAE v. 4.03]). Certain side effects that are unlikely to develop into serious or life–threatening events (e.g. alopecia) are allowed at > grade 1
9. 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
10. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia
11. Uncontrolled diabetes mellitus, hypothyroidism, or hyperthyroidism
12. Active infection, including Hepatitis B, Hepatitis C infection. Patients with anti-HBc positive, or HBsAg but DNA negative are exception(s)
13. History of bleeding disorders
14. Brain lesions with a propensity to bleed
15. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer
16. Previous malignancy within 3 years prior to enrollment, except for curatively-treated basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, bladder carcinoma in situ or breast cancer in situ
17. Inadequate hematologic function as evidenced by any of the following:
a. Platelets < 90,000/µL
b. Hemoglobin < 8 g/dL, independent of transfusion or growth factor support
c. Neutrophils < 1,500 cells/µL
18. Serum creatinine > 1.5 mg/dL
19. Inadequate liver function as evidenced by any of the following:
a. Total serum bilirubin ≥ 2.0 mg/dL
b. Prothrombin time International Normalized Ratio (INR) > 1.5
c. Aspartate aminotransferase (AST) > 10 times ULN or alanine transaminase (ALT) > 5 times ULN
d. Serum albumin < 3.0 g/dL
Patients with ICC must meet the following:
a. Total serum bilirubin ≥ 3.0 mg/dL
b. Prothrombin time (PT)/international normalized ratio (INR) > 1.5
c. Aspartate aminotransferase (AST) > 10 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) > 5 times ULN
d. Serum albumin < 3.0 g/dL
20. Known alcohol abuse
21. For female subjects of childbearing potential (i.e., have had a menstrual period within the past 12 months): a positive serum pregnancy test (β-human chorionic gonadotropin) within 7 days prior to enrollment; or unwilling or unable to undergo hormonal suppression to avoid menstruation during treatment
22. 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 30 days after last administration of study treatment
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E.5 End points |
E.5.1 | Primary end point(s) |
objective response rate of Melphalan/HDS treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study endpoint will be measured at the conclusion of Melphalan/HDS treatment. |
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E.5.2 | Secondary end point(s) |
• To evaluate the safety of melphalan administered by Melphalan/HDS
• To assess the progression free survival of patients receiving Melphalan/HDS
•To characterize the systemic exposure of melphalan administered by Melphalan/HDS at selected study sites |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety will be assessed on an ongoing basis. Patients will be followed for safety from study entry until at least 30 days from their last study treatment. Chronic toxicity, if any, will be followed for one year after last dose, until death, withdrawal of informed consent or lost to follow-up, whichever occurs earliest.
Time points for the endpoint outcome measurements are detailed in section 5.6 and schedule of events in the protocol. |
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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 | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Germany |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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Patients will have end-of-treatment visit within 30 days following the last Melphalan/HDS treatment. Ongoing adverse events at end-of-treatment visit will be followed until severity recovers to base-line or CTCAE Grade ≤ 1. All patients will be followed for disease status, chronic toxicity up to one year after the last dose of study treatment, death, withdrawal of informed consent or lost to follow-up, whichever occurs earliest. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |