E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatic-Dominant Ocular Melanoma |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the eye that has spread to the liver |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068117 |
E.1.2 | Term | Metastatic ocular melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Objective Response Rate (ORR) (complete response + partial response) as determined by Independent Central Review Committee (IRC). |
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E.2.2 | Secondary objectives of the trial |
• Duration of Response (DOR) as determined by Independent Central Review Committee.
• Disease Control Rate (DCR) as determined by Independent Central Review Committee.
• Overall Survival (OS).
• Progression Free Survival (PFS) as determined by Independent Central Review Committee.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria for study entry:
1. Male or female patients ≥ 18 years of age.
2. 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).
3. 50% or less histologically or cytologically-proven ocular melanoma metastases in the parenchyma of the liver.
4. Disease in the liver must be measurable by computed tomography (CT) and/or magnetic resonance imaging (MRI).
5. Evidence of limited extrahepatic disease on preoperative radiological studies is acceptable if the life threatening component of disease is in the liver. Limited extrahepatic disease is defined in this protocol as follows: metastasis in bone, subcutaneous, lung or lymph nodes that is amenable to resection or radiation and has a defined treatment plan. Patients with extra-hepatic tumor burden which does not have a defined treatment plan (i.e. monitor or is unable to be resected or radiated) must not be included in the trial.
6. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to eligibility. An MRI of the liver is required at screening to validate that CT accurately reflects the extent of disease in the liver. For patients with MRI intolerance, a 3-phase liver CT is to be done in place of liver MRI.
7. Patients must not have had chemotherapy, radiotherapy, chemoembolization, radioembolization, or immunoembolization for their malignancy within 30 days prior to treatment and must have recovered from all side effects of therapeutic and diagnostic interventions except those listed in Appendix B of the study protocol. 8. Patients receiving anti programmed cell death protein 1 (PD-1) immunotherapy such as pembrolizumab or nivolumab, or human cytotoxic T-lymphocyte antigen 4 blocking antibody such as ipilimumab must have completed treatment 8 weeks prior to study eligibility.
9. Patients must have an ECOG PS of 0-1 at screening .
10. Patients must have adequate hepatic function as evidenced by total serum bilirubin ≤1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of the upper normal limit. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) must be ≤ 2.5 x ULN.
11. Patients must have a platelet count > 100,000/μL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count ≥ 1.5 x 109/L, and a serum creatinine ≤ 1.5 mg/dL unless the measured creatinine clearance is > 40 mL/min/1.73 m2.
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (β-human chorionic gonadotropin) within 7 days prior to eligibility.
13. Provided signed informed consent. |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from study entry:
1. Patients with Child-Pugh Class B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies.
2. 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.
3. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
4. Women of childbearing potential (WOCBP, i.e., fertile meaning not permanently sterilized and having had a menstrual period within the past 12 months): unwilling or unable to undergo hormonal suppression to avoid menstruation during treatment.
5. WOCBP and fertile males (not permanently sterile by bilateral orchidectomy) unwilling or unable to use highly effective contraception method from consent 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).
6. Females that are pregnant or breastfeeding patients.
7. Patients taking immunosuppressive drugs; however, oral corticosteroids ≤ 10 mg/ day are allowed.
8. Patients who are unable to be temporarily removed from chronic anti-coagulation therapy.
9. Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate therapy.
10. Patients with severe allergic reaction to iodine contrast, which cannot be controlled by premedication with antihistamines and steroids.
11. Patients with a history of or known hypersensitivity to melphalan or the components of the Melphalan/HDS system.
12. Patients with latex allergy.
13. Patients with a history of hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
14. Patients with a history of bleeding disorders or evidence of intracranial abnormalities which would put them at risk for bleeding with anti-coagulation (e.g., strokes, active metastases).
15. Patients with a history of gastrinoma; NOTE: For patients with a history of liver surgery or major vasculature surgery, a CT angiogram or MR angiogram is required during screening to assure the patient does not have hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting.
16. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer.
17. Patients with prior Whipple’s procedure.
18. Patients with brain metastases or presence of other intracranial lesions at risk for bleeding by history or baseline radiologic imaging.
19. Patients with an active infection, including Hepatitis B and Hepatitis C infection. Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are exception(s).
20. Uncontrolled endocrine disorders including diabetes mellitus, hypothyroidism, or hyperthyroidism.
21. Received any investigational agent for any indication within 30 days prior to first treatment.
22. Not recovered from side effects of prior therapy to ≤ Grade 1 (according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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.
23. Patients who have been institutionalized by governmental or legal decree or who are
employees of the sponsor, Investigator, or study site.
24. Cancers other than ocular melanoma for which the patient is currently under treatment or still deemed to be not cancer free. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy outcome measure:
• Objective Response Rate (ORR) (complete response + partial response) as determined by Independent Central Review Committee |
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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) |
Secondary efficacy outcome measures:
• Duration of Response (DOR) as determined by Independent Central Review Committee
• Disease Control Rate (DCR) determined by Independent Central Review Committee
• Overall Survival (OS)
• Progression Free Survival (PFS) as determined by Independent Central Review Committee
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In the event that disease has not progressed at the end-of-treatment visit, disease assessment scans will continue every 12 weeks (+ 2 weeks) beginning after the date of the first treatment until disease progression is documented. All treated patients are to be contacted by phone every 3 months for survival status until death. |
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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 | Yes |
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) | No |
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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 18 |
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 |
Austria |
France |
Germany |
Italy |
Spain |
Switzerland |
United Kingdom |
United States |
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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
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End of study is determined based on the maximum observation for survival after detection of metastases; 80% of patients die within 1 year and 92% within 2 years. Therefore, patients will be followed until death. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |