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    Summary
    EudraCT Number:2014-001585-98
    Sponsor's Protocol Code Number:PHP-HCC-202
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-04-25
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-001585-98
    A.3Full title of the trial
    An International Multi-center Phase 2 Study to Evaluate the Efficacy and Safety of Melphalan/HDS Treatment in Patients with Unresectable Hepatocellular Carcinoma or Intra hepatic Cholangiocarcinoma.
    Internationale multizentrische Phase-2-Studie zur Bewertung der Wirksamkeit und Sicherheit einer Melphalan/HDS-Behandlung bei Patienten mit inoperablem hepatozellularem Karzinom oder intrahepatischem Cholangiokarzinom.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An International Multi-center Phase 2 Study to Evaluate the Efficacy and Safety of Melphalan/HDS Treatment in Patients with Unresectable Hepatocellular Carcinoma or Intra hepatic Cholangiocarcinoma.
    A.4.1Sponsor's protocol code numberPHP-HCC-202
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDelcath Systems, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDelcath Systems, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDelcath Systems, Inc
    B.5.2Functional name of contact pointClinical Trials Desk
    B.5.3 Address:
    B.5.3.1Street Address1301 Avenue of the Americas, 43rd Floor
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10019
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 212489 2100 234
    B.5.5Fax number+1 212489 2102
    B.5.6E-mailjjohn@delcath.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMelphalan
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarterial use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELPHALAN
    D.3.9.1CAS number 3223-07-2
    D.3.9.3Other descriptive nameMELPHALAN HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB126965
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MELPHALAN HYDROCHLORIDE
    D.2.1.1.2Name of the Marketing Authorisation holderMylan Institutional LLC
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMelphalan
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarterial use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELPHALAN
    D.3.9.1CAS number 3223-07-2
    D.3.9.3Other descriptive nameMELPHALAN HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB126965
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    unresectable hepatocellular carcinoma (HCC) confined to the liver and Intra hepatic Cholangiocarcinoma confined to the liver.
    E.1.1.1Medical condition in easily understood language
    inoperable liver cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10073077
    E.1.2Term Intrahepatic cholangiocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the objective response rate (ORR) of Melphalan/Hepatic Delivery System (HDS) treatment in patients with unresectable hepatocellular carcinoma (HCC) or intra-hepatic cholangiocarcinoma (ICC) confined to the liver.
    E.2.2Secondary objectives of the trial
    Secondary
    • To evaluate the safety of melphalan administered by Melphalan/Hepatic Delivery System (HDS)
    • To assess the progression free survival (PFS) of patients receiving Melphalan/Hepatic Delivery System (HDS)

    Exploratory
    • To characterize the systemic exposure of melphalan administered by Melphalan/Hepatic Delivery System (HDS) at selected study sites
    E.2.3Trial contains a sub-study No
    E.3Principal 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 extra-hepatic disease (minor lesions [≤ 1 cm and not consistent with metastatic disease] acceptable) based on computed tomography (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. Child-Pugh Class A.
    5. ECOG PS 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 or imaging study.
    2. Unresectable ICC without clinically significant extra-hepatic disease (minor lesions [≤ 1 cm and not consistent with metastatic disease] acceptable) 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. Child-Pugh Class A.
    5. ECOG PS 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 ICC, if any, must have been completed at least 4 weeks prior to baseline imaging.
    7. Age ≥ 18 years.
    8. Signed informed consent.
    E.4Principal 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, for both the HCC and ICC cohorts, 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, 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. 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 [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.
    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 and 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).
    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 (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 [β-HCG]) 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.
    E.5 End points
    E.5.1Primary end point(s)
    objective response rate of Melphalan/HDS treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    The study endpoint will be measured at the conclusion of Melphalan/HDS treatment.
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will have the end-of-treatment visit in 6 to 8 weeks following the last Melphalan/HDS treatment. Ongoing AEs at the end-of-treatment visit will be followed until the severity returns to baseline or CTCAE Grade ≤ 1. All patients will be followed for disease status and chronic toxicity up to 2 years after the last dose of study treatment until death, consent withdrawal or the patient is lost to follow-up, whichever occurs the earliest.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Italy
    Netherlands
    United Kingdom
    United States
    E.8.7Trial 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 will have the end-of-treatment visit within 30 days following the last Melphalan/HDS treatment. On-going adverse events (AEs) at the end-of-treatment visit will be followed until the severity returns to baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1. All patients will be followed for these on-going AEs up to 1 year after the last dose of study treatment, until death, consent withdrawal or the patient is lost to follow-up, whichever occurs the earliest.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 21
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 21
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 42
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Once the subject has ended his/her participation in the trial they will be treated by their physician with standard of care treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-07-31
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