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    Summary
    EudraCT Number:2008-000963-41
    Sponsor's Protocol Code Number:104-06-301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2008-09-26
    Trial 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2008-000963-41
    A.3Full title of the trial
    A Phase III, Randomized, Double-Blinded, Dummy-Controlled Study of the Efficacy and Safety of ThermoDox (Thermally Sensitive Liposomal Doxorubicin) in Combination with Radiofrequency Ablation (RFA) Compared to RFA-Alone in the Treatment of Non-Resectable Hepatocellular Carcinoma
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code number104-06-301
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCELSION CORPORATION
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 No
    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 nameThermodox
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLYSO-THERMOSENSITIVE LIPOSOMAL DOXORUBICIN
    D.3.9.2Current sponsor codeThermodox
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    patients with Non-Resectable Hepatocellular Carcinoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10049010
    E.1.2Term Carcinoma hepatocellular
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of systemically delivered, heat-activated liposome encapsulated doxorubicin (ThermoDox) in combination with radiofrequency ablation (RFA) by comparison to RFA-alone in the treatment of hepatocellular carcinoma (HCC) as measured by progression free survival (PFS).
    E.2.2Secondary objectives of the trial
    The secondary objectives are to assess the effect of RFA plus ThermoDox versus the control arm in the treatment of hepatocellular carcinoma as measured by: Overall Survival (OS). Patient-Reported Outcomes (PRO) (FHSI-8 questionnaire). Time to Local Recurrence (TTLR). Evaluation of safety.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects may be randomized without a biopsy if they meet American Association for the Study of Liver Disease (AASLD) criteria for the diagnosis of HCC. These patients will be required to have a biopsy during the RFA procedure unless the biopsy is not possible or is contraindicated. Subjects not meeting AASLD criteria for HCC will need a biopsy for confirming HCC prior to randomization. 1. Diagnosed hepatocellular carcinoma (HCC). 2. No more than 4 HCC lesions with at least one &#8805; 3.0 cm and none > 7.0 cm in maximum diameter, based on diagnosis at screening. If a subject has a large lesion (5.0 - 7.0 cm), any other lesions must be less than 5.0 cm. Anticipated ablation volume will be no larger than either removal of 3 hepatic segments or removal of more than 30% of total liver volume (as per maximum surgical limit). If additional lesions are discovered during the laparoscopic or open treatment procedure, that were undetectable by CT at screening, the size and location of the lesion(s) will be recorded in the CRF and the lesion(s) will be treated at the discretion of the physician and guided by the local standard of care. The subject will remain on study if all lesions are treated. If any lesions cannot be completely ablated within two treatment attempts the subject will be considered a treatment failure. Study subjects being considered for re-treatment after disease progression may have more than 4 lesions. 3. Male or female 18 years of age or older. 4. Are willing to sign an informed consent form, indicating that they are aware of the investigational nature of this study that is in keeping with the policies of the institution. 5. Be an appropriate candidate for receiving RFA as a medically indicated treatment as evaluated by the following factors: Number of lesions Size of lesions Overall health of liver Not a candidate for surgical resection 6. Have an echocardiogram revealing a Left Ventricular Ejection Fraction (LVEF) &#8805; 50%. Measurements with a MUGA scan are allowed if an echocardiogram cannot be performed. The same method of measurement should be used to evaluate ejection fraction (EF) of the subject for the duration of the study. 7. Willing to return to the study site for their study visits. 8. Have life expectancy of &#8805; 4 months. 9. Have Child-Pugh Class A or B liver disease without encephalopathy or/and ascites.
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria will be excluded from the study: 1. Have serious medical illnesses including, but not limited to, congestive heart failure,myocardial infarction or cerebral vascular accident within the last six months, or life threatening cardiac arrhythmias. 2. Is scheduled for liver transplantation. 3. Have previously received any treatment for HCC (except for study subjects being considered for completion of treatment or re-treatment). 4. Have previously received any doxorubicin (study subjects being considered for completion of treatment or re-treatment may have received ThermoDox previously). 5. Have extrahepatic metastasis. 6. Are pregnant or breastfeeding. In women of childbearing potential, a negative pregnancy test (serum) is required prior to study treatment. 7. Women of childbearing potential who are not practicing an acceptable form of birth control (i.e. diaphragm, cervical cap, condom, surgical sterility or birth control pills. Women whose partner has undergone a vasectomy must use a second form of birth control). 8. Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents to be used in this study 9. Have portal or hepatic vein tumor invasion/thrombosis. 10. Have INR > 1.5 times the Institution’s upper normal limit (UNL), except in subjects who are therapeutically anticoagulated for medical conditions unrelated to HCC such as atrial fibrillation. Subjects can be re-screened after condition is treated or anticoagulant is withheld. 11. Have platelet count < 75,000/mm3, absolute neutrophil count < 1500/mm3, or Hgb < 10.0 g/dL (unless the hemoglobin value has been stable, the subject is cardiovascularly stable, asymptomatic and judged able to withstand the RFA procedure). 12. Have serum creatinine &#8805; 2.5 mg/dL or calculated creatinine clearance (CrCl) &#8804; 25.0 mL/min. 13. Have serum bilirubin > 3.0 mg/dL. 14. Have serum albumin < 2.8 g/dL. 15. Have body temperature >1010F (38.30C) immediately prior to study treatment. 16. Have contraindications to receiving doxorubicin HCl. 17. Are being treated with other investigational agents. 18. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication (study subjects being considered for completion of treatment or re-treatment may have received ThermoDox previously). 19. Have other concurrent malignancy (subjects with treated squamous cell carcinoma or basal cell carcinoma of the skin may be included), evidence of extrahepatic cancer from their primary malignancy, or ongoing, medically significant active infection. 20. Documented HIV positive. 21. NYHA class III or IV functional classification for heart failure. 22. Evidence of hemachromatosis. 23. Have history of contrast-induced nephropathy.
    E.5 End points
    E.5.1Primary end point(s)
    Safety: Safety assessments will include vital signs, ECGs, echocardiograms/MUGA, physical and laboratory examinations, and evaluations of adverse events and concomitant medications. Safety data will be collected from time of informed consent until discontinuation for all subjects (including re-treatment). Efficacy: Primary Endpoint: PFS will be measured from the date of randomization to the first date on which one of the following occurs. o Local recurrence of HCC tumor (as determined by CT scan) after complete initial ablation. o Repeat RFA procedure required for later local recurrence. o Any new distant intrahepatic HCC tumor. o Any new extrahepatic HCC tumor. o Death from any cause. Secondary Endpoints: Overall Survival as measured by time from randomization to death or the end of the study. Time to definite worsening as per Patient-Reported Outcomes (FHSI-8). Time to Local Recurrence. Safety data will be collected from time of informed consent until discontinuation or the end of the study. An Independent Radiology Review Committee (IRRC) will adjudicate the CT image data for the primary outcome (PFS) for each subject under blinded conditions.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    RFA da sola
    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 concerned7
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Unexpected,significant,or unacceptable risk to the subjects enrolled;Failure to enter subjects at an acceptable rate;protocol non-compliance;Lack of evaluable and/or complete data;Changes in drug developmental plan;Regulatory authority decision
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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.1.3Elderly (>=65 years) Yes
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state128
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 128
    F.4.2.2In the whole clinical trial 600
    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 Decision2008-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-07-03
    P. End of Trial
    P.End of Trial StatusOngoing
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