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    Summary
    EudraCT Number:2014-000934-53
    Sponsor's Protocol Code Number:104-13-302
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-09-17
    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 number2014-000934-53
    A.3Full title of the trial
    A Phase III, Randomized, Double Blind, Dummy-Controlled Study of ThermoDox® (Lyso-Thermosensitive Liposomal Doxorubicin-LTLD) in Hepatocellular Carcinoma (HCC) using standardized Radiofrequency Ablation (RFA) treatment time ≥ 45 minutes for solitary lesions ≥ 3 cm to ≤ 7 cm.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate efficacy for patients with primary liver cancer scheduled to be treated with Radiofrequency Ablation (RFA). This study will compare RFA plus an investigational drug of liposomal doxorubicin versus RFA without investigational drug.
    A.3.2Name or abbreviated title of the trial where available
    Optima Trial
    A.4.1Sponsor's protocol code number104-13-302
    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 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 supportCelsion Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelsion Corporation
    B.5.2Functional name of contact pointDirector, Clinical Operations
    B.5.3 Address:
    B.5.3.1Street Address997 Lenox Drive, Suite 100
    B.5.3.2Town/ cityLawrenceville, New Jersey
    B.5.3.3Post code08648
    B.5.3.4CountryUnited States
    B.5.4Telephone number1+609896-9100
    B.5.5Fax number1+609896-2200
    B.5.6E-mailOptima@celsion.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/833
    D.3 Description of the IMP
    D.3.1Product nameThermoDox®
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNDoxorubicin hydrochloride (in heat-sensitive liposomes)
    D.3.9.1CAS number 25316-40-9
    D.3.9.3Other descriptive nameDOXORUBICIN HYDROCHLORIDE, Lyso-Thermosensitive Liposomal Doxorubicin (LTLD)
    D.3.9.4EV Substance CodeSUB01827MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatocellular Carcinoma (HCC)
    E.1.1.1Medical condition in easily understood language
    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 17.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare overall survival (OS) between patients receiving RFA plus ThermoDox versus RFA alone, using a standardized Radiofrequency Ablation (sRFA) treatment dwell time ≥ 45 minutes.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to compare progression-free survival (PFS) and safety between patients receiving sRFA plus ThermoDox versus sRFA alone, using a standardized RFA treatment dwell time ≥ 45 minutes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must fulfill all of the following inclusion criteria to be eligible to participate in the study.
    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 (see Appendix 20.8). Subjects not meeting AASLD criteria for HCC will need a biopsy for confirming HCC prior to randomization.
    1. Male or female ≥ 18 years of age
    2. Diagnosed with a single HCC lesion ≥ 3.0 cm but ≤ 7.0 cm in maximum diameter based on diagnosis at screening.
    • Subjects meeting the AASLD criteria may be randomized without a biopsy, but will undergo a biopsy during the RFA procedure unless contraindicated or unattainable.
    •Subjects not meeting the AASLD criteria for HCC will need a biopsy to confirm HCC prior to randomization.
    3. Be an appropriate candidate for receiving RFA as a medically indicated treatment as evaluated by the following factors:
    • The position and accessibility of the target lesion allows for the safe administration of multiple ablation cycles or deployments to achieve a probe dwell time of ≥ 45 minutes.
    • Not a candidate for surgical resection according to the local guidelines for resection and in the Investigator’s judgment.
    4. Child-Pugh Class A without either current encephalopathy or ascites
    5. Left ventricular ejection fraction (LVEF) ≥ 50%
    6. ECOG performance status 0
    7. Willing to sign an informed consent form, indicating awareness of the investigational nature of this study that is in keeping with the policies of the institution.
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria will be excluded from the study:
    1. Is scheduled for liver transplantation.
    2. Expected ablation volume > 30% of total liver volume or removal of 3 hepatic segments
    3. More than 1 lesion identified during baseline.
    4. Have previously received therapeutic treatment for HCC outside the study protocol or is expected to receive concomitant HCC treatment prior to PFS event.
    5. 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.
    6. Have previously received any anthracycline outside the protocol.
    7. Have extrahepatic metastasis.
    8. Have portal or hepatic vein tumor invasion/thrombosis.
    9. Have body temperature > 101ºF (38.3ºC) immediately prior to study treatment.
    10. Baseline laboratories (repeat lab tests are permitted to evaluate eligibility during the Screening Period. Lab results must be within protocol range prior to study treatment.)
    • Absolute neutrophil count < 1500/mm3
    • Platelet count < 75,000/mm3
    • 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)
    Note: If clinically indicated, subjects may receive platelets or packed RBC transfusions and be re-evaluated after condition is treated.
    11. Baseline Chemistry
    • Serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤ 25.0 mL/min.
    • Serum bilirubin > 3.0 mg/dL.
    • Serum albumin < 2.8 g/dL.
    12. Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents that prohibit the ability to complete the imaging requirements.
    13. Are pregnant or breast-feeding. In women of childbearing potential, a negative serum pregnancy test is required prior to study treatment.
    14. Women of childbearing potential and men 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 or men who have undergone a vasectomy must use a second form of birth control).
    15. 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 may be re-screened after condition is treated or anticoagulant is withheld.
    16. Have contraindications to receiving doxorubicin HCl.
    17. Are being treated with other investigational agents.
    18. Use of an investigational drug outside this study within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.
    19. Have other concurrent malignancy (subjects with treated squamous cell carcinoma of the skin 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. HIV positive.
    21. NYHA class III or IV functional classification for heart failure.
    22. Evidence of hemachromatosis.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint: Survival
    All patients will be monitored for survival by recording their visits during routine follow up for response to treatment. The visits are scheduled to occur every four months from the first imaging study confirming complete ablation until month 25 or radiological progression, whichever comes first. If patients have not demonstrated radiological progression at month 25 then the imaging visit schedule is reduced to every six months until progression.
    Survival is confirmed at every imaging visit.
    Once radiological progression is confirmed then follow up for overall survival is required. Sites are required to confirm contact with the subject during either a clinic visit or a telephone contact every three months. It is expected that subject follow up will be about five years.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Overall Survival Evaluation at every imaging visit.
    E.5.2Secondary end point(s)
    Secondary Endpoint: Progression Free Survival
    The protocol incorporates modified RECIST (mRECIST) developed for HCC clinical research as a basis to evaluate tumor response. The mRECIST enables assessment of overall response by taking into account target lesion response, and presence or absence of new lesions. A separate imaging manual and imaging training program has
    been developed for this study in order to ensure uniformity in imaging technique and imaging review in
    accordance with mRECIST.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression Free Survival
    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 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA20
    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
    Canada
    China
    Germany
    Hong Kong
    Italy
    Korea, Republic of
    Malaysia
    Philippines
    Spain
    Taiwan
    Thailand
    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
    End of the trial is scheduled when Overall Survival Reports reach 197 events (deaths) observed. Overall Survival records the date of death from time of randomization.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    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: 360
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 600
    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)
    Following study treatment, subjects will undergo CT or MRI imaging scans (chest, abdomen, and pelvis) at months 1, 5, 9, 13, 17, 21, and 25 (+/- 2 weeks), then at 6-month intervals (+/- 2 weeks) until radiological progression is seen.
    Post-progression treatments will be reported and the subject will continue to be followed for OS.
    Please refer to protocol for further post treatment details
    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 Decision2014-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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