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    Summary
    EudraCT Number:2015-002549-72
    Sponsor's Protocol Code Number:PH-L19IL2TNF-02/15
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-07-03
    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 ConcernedGermany - PEI
    A.2EudraCT number2015-002549-72
    A.3Full title of the trial
    A Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment followed by surgery versus surgery alone in clinical stage IIIB and IIIC melanoma patients.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the efficacy of intratumoral injections of L19IL2/L19TNF followed by surgery to prevent or retard appearance of new metastases
    A.3.2Name or abbreviated title of the trial where available
    Neoadjuvant L19IL2/L19TNF- Pivotal study
    A.4.1Sponsor's protocol code numberPH-L19IL2TNF-02/15
    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 SponsorPhilogen S.p.A.
    B.1.3.4CountryItaly
    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 supportPhilogen S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPhilogen S.p.A.
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street AddressLocalità Bellaria 35
    B.5.3.2Town/ citySovicille (Siena)
    B.5.3.3Post code53018
    B.5.3.4CountryItaly
    B.5.4Telephone number0039057717816
    B.5.5Fax number003905771781690
    B.5.6E-mailregulatory@philogen.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDarleukin
    D.3.2Product code L19IL2
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratumoral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDarleukin
    D.3.9.3Other descriptive nameL19IL2
    D.3.9.4EV Substance CodeSUB27376
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number13000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 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 nameFibromun
    D.3.2Product code L19TNF
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratumoral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFibromun
    D.3.9.3Other descriptive nameL19TNFALFA
    D.3.9.4EV Substance CodeSUB29010
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Malignant melanoma of the skin in subjects with completely resectable stage IIIB and IIIC disease and presence of injectable cutaneous and/or subcutaneous or nodal lesions.
    E.1.1.1Medical condition in easily understood language
    Specific malignant melanoma of the skin in subjects with completely resectable disease and presence of injectable cutaneous and/or subcutaneous or nodal lesions.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Efficacy of L19IL2/L19TNF measured as recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization

    E.2.2Secondary objectives of the trial
    Efficacy of L19IL2/L19TNF as:
    - Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 y after randomization.
    - LRFS rate and DMFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 y after surgery (for both arms).
    - RFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus Arm 2, assessed at 2-y and 3-y after randomization.
    - Overall survival (OS) in Arm 1 vs Arm 2, assessed at 1y after randomization and at 2y and 3y after randomization.
    - Safety of intratumoral administration of L19IL2/L19TNF
    - Biomarker studies: immunophenotyping of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations over time. Study of blood biomarkers
    - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:
    1. Diagnosis of malignant melanoma of the skin in clinical stage III B and III C, eligible for complete surgical resection.
    2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
    3. Males or females, age ≥ 18 years
    4. ECOG Performance Status/WHO Performance Status ≤ 1
    5. Life expectancy of at least 24 months (see paragraph 6.3.1)
    6. Absolute neutrophil count > 1.5 x 109/L
    7. Hemoglobin > 9.0 g/dL
    8. Platelets > 100 x 109/L
    9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)
    10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
    11. Serum creatinine < 1.5 x ULN
    12. LDH serum level ≤ 1.0 x ULN
    13. Documented negative test for HIV, HBV and HCV.
    For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required.
    14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
    15. All female subjects must have negative pregnancy test results at the screening. Women of childbearing potential (WOCBP) must be using, from the screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the end of treatment visit.
    16. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
    17. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
    18. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
    E.4Principal exclusion criteria
    Patients exclusion criteria:
    1. Uveal melanoma and mucosal melanoma
    2. Evidence of distant metastases at screening
    3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (TA, Tis & Ti), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
    4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
    5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
    6. Inadequately controlled cardiac arrhythmias including atrial fibrillation
    7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
    8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
    9. Uncontrolled hypertension
    10. Ischemic peripheral vascular disease (Grade IIb-IV)
    11. Severe diabetic retinopathy
    12. Active autoimmune disease
    13. History of organ allograft or stem cell transplantation
    14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
    15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
    16. Breast feeding female
    17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment
    18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment
    19. Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment
    20. Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
    21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy of L19IL2/L19TNF measured as recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization.


    E.5.1.1Timepoint(s) of evaluation of this end point
    RFS rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization.
    E.5.2Secondary end point(s)
    - Efficacy of L19IL2/L19TNF:
    --> Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization.
    --> Local recurrence-free survival (LRFS) rate and distant metastasis-free survival (DMFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after surgery (for both arms).
    ---> Recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 2-y and 3-y after randomization.
    - Overall survival (OS) in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization and at 2-y and 3-y after randomization.
    - Safety of intratumoral administration of L19IL2/L19TNF
    - Biomarker studies (both Arms): immunophenotypic characterization of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations (e.g., Tregs, MDSCs etc.) over time (only for patients recruited in German centers) . Study of blood biomarkers (e.g., S100b, LDH ratio etc.)
    - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - LRFS rate and DMFS rate in Arm 1 vs Arm 2, assessed at 1 y after randomization.
    - LRFS rate and DMFS rate in Arm 1vs Arm 2, assessed at 1 y after surgery (both arms).
    - Recurrence-free survival (RFS) rate in Arm 1 vs Arm 2, assessed at 2y and 3y after randomization.
    - Overall survival (OS) in Arm 1 versus Arm 2, assessed at 1y after randomization and at 2y and 3y after randomization.
    - Safety of intratumoral administration of L19IL2/L19TNF
    - Biomarker studies: immunophenotyping of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations over time. Study of blood biomarkers
    - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.
    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 Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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
    Elective surgical resection of the tumor
    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 concerned8
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 treatment: corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2.
    End of trial: LPLV
    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 days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 94
    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 state114
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 214
    F.4.2.2In the whole clinical trial 214
    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)
    n.a.
    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 Decision2015-12-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-02
    P. End of Trial
    P.End of Trial StatusOngoing
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