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    Summary
    EudraCT Number:2015-002549-72
    Sponsor's Protocol Code Number:PH-L19IL2TNF-02/15
    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:2021-06-15
    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 number2015-002549-72
    A.3Full title of the trial
    A pivotal 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 III B/C melanoma patients.
    Studio di Fase III multicentrico, randomizzato ed in aperto, di efficacia del trattamento intratumorale neoadiuvante con L19IL2/L19TNF seguito da chirurgia, verso la sola chirurgia in pazienti affetti da melanoma allo stadio clinico IIIB/C.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy study of L19IL2/L19TNF neoadjuvant intratumoral treatment followed by surgery versus surgery alone in patients with a specific type of melanoma.
    Studio di efficacia del trattamento intratumorale neoadiuvante con L19IL2/L19TNF seguito da chirurgia, comparato alla sola chirurgia, in pazienti affetti da una specifica tipologia di melanoma.
    A.3.2Name or abbreviated title of the trial where available
    Neoadjuvant L19IL2/L19TNF - Pivotal study
    L19IL2/L19TNF Neoadiuvante - Studio Pivotal
    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 number057717816
    B.5.5Fax number05771781690
    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 INNbifikafusp alfa
    D.3.9.1CAS number 1957239-90-5
    D.3.9.2Current sponsor codeL19IL2
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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 INNonfekafusp alfa
    D.3.9.1CAS number 1957239-88-1
    D.3.9.2Current sponsor codeL19TNF
    D.3.9.4EV Substance CodeSUB29010
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeup to
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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 patients with locally advanced and fully resectable melanoma with/without prior therapy and presence of injectable cutaneous and/or subcutaneous or nodal lesions.
    Melanoma metastatico cutaneo in pazienti affetti da melanoma in stadio localmente avanzato e completamente resecabile precedentemente trattato o non trattato con altre terapie e con presenza di lesioni cutanee e/o sottocutanee e/o linfonodi iniettabili.
    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
    Specifico melanoma maligno della pelle in suggetti con patologia che può andare incontro ad intervento chirurgico e presenza di lesioni cutanee e/o subcutanee iniettabili.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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 neoadjuvant treatment followed by surgery to improve in a statistically significant manner the recurrence-free survival (RFS) of patients with locally advanced and fully resectable melanoma with respect to surgery alone: post-surgery adjuvant treatment is allowed in both arms.
    Efficacia di L19IL2/L19TNF come trattamento neadiuvante seguito da chirurgia nel migliorare in maniera statisticamente significativa la sopravvivenza libera da recidiva (Recurrence-free survival rate, RFS) nei pazienti con melanoma in stadio localmente avanzato e completamente resecabile rispetto alla sola chirurgia; eventuali trattamenti adiuvanti successivi alla chirurgia sono permessi in entrambi i bracci.
    E.2.2Secondary objectives of the trial
    Secondary objective of the study is to demonstrate that a neoadjuvant L19IL2/L19TNF treatment followed by surgery improves in a statistically significant manner the overall survival (OS) of patients with fully resectable locally advanced melanoma with respect to surgery.
    Other secondary objectives include a demonstration of improvement of Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) and, for patients included in Arm 1 only, pathological responses (i.e., pathological Complete Response, pathological near- Complete Response, pathological Partial Response, pathological Non Response) assessed on the surgical specimen after tumor removal, demonstration of safety and tolerability of the L19IL2/L19TNF treatment.
    Obiettivo secondario dello studio è dimostrare che il trattamento neoadiuvante L19IL2/L19TNF seguito da chirurgia migliora in maniera statisticamente significativa la sopravvivenza globale (Overall survival, OS) nei apzienti con melanoma in stadio localmente avanzato completamente resecabile nei confronti della sola chirurgia.
    Altri obiettivi secondari includono la dimostrazione del miglioramento della sopravvivenza libera da recidiva locale (Local recurrence-free survival rate, LRFS) e della sopravvivenza libera da recidiva distante (Distant metastasis-free survival rate, DMFS) e, per i pazienti inclusi nel solo braccio 1, la risposta patologica (i.e., pathological Complete Response, pathological near-Complete Response, pathological Partial Response, pathological Non Response) valutati sui campioni chirurgici dopo rimozione della massa tumorale, così come la dimostrazione della sicurezza e della tollerabilità del trattamento con L19IL2/L19TNF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:
    1. Diagnosis of malignant melanoma of the skin with locally advanced disease as defined by clinical stage III B and III C according to AJCC 7th Ed, 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. Prior anti-tumor treatment for the primary melanoma lesion, including surgery and approved adjuvant treatments (e.g., radiotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitors, etc.) is allowed.
    4. Males or females, age = 18 years
    5. ECOG Performance Status/WHO Performance Status = 1
    6. Life expectancy of at least 24 months (see paragraph 6.3.1)
    7. Absolute neutrophil count > 1.5 x 109/L
    8. Hemoglobin > 9.0 g/dL
    9. Platelets > 100 x 109/L
    10. Total bilirubin = 30 µmol/L (or = 2.0 mg/dl)
    11. ALT and AST = 2.5 x the upper limit of normal (ULN)
    12. Serum creatinine < 1.5 x ULN
    13. LDH serum level = 1.5 x ULN
    14. Documented negative test for HIV, HBV and HCV.
    For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBsAg and/or anti-HBc Ab) negative serum HBV-DNA is also required.
    15. 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
    16. Negative pregnancy test at screening for Women Of Childbearing Potential (WOCBP*). Pregnant women are not allowed to participate to this study. 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 Safety Visit (only WOCBP and only for patients in Arm 1).
    17. 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.
    18. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
    19. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
    *Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)
    1. Diagnosi di melanoma cutaneo metastatico con malattia localmente avanzata definita come stadio clinico IIIB e IIIC in accordo al AJCC 7° edizione, in pazienti eleggibili per resezione chirurgica completa di tutte le metastasi.
    2. I soggetti eleggibili debbono avere malattia misurabile ed essere candidati per terapia intralesionale con almeno una lesione iniettabile cutanea, sottocutanea o linfonodale (= 10 mm nell'asse più lungo) o con lesioni multiple iniettabili che in aggregato abbiano un diametro più lungo = 10 mm.
    3. Sono consentiti precedenti trattamenti antitumorale per la lesione primaria del melanoma, compresa la chirurgia e i trattamenti adiuvanti approvati (ad esempio, radioterapia, inibitori del checkpoint immunitario, inibitori BRAF/MEK, ecc.)
    4. Maschi o femmine, età = 18 anni
    5. ECOG Performance Status/WHO Performance Status = 1
    6. Speranza di vita di almeno 24 mesi.
    7. Conta assoluta dei neutrofili > 1.5 x 109/L
    8. Emoglobina > 9.0 g/dL
    9. Piastrine > 100 x 109/L
    10. Bilirubina totale = 30 µmol/L (o = 2.0 mg/dl)
    11. ALT ed AST = 2.5 x il limite superiore della norma (ULN)
    12. Creatinina serica < 1.5 x ULN
    13. Livelli serici di LDH = 1.5 x ULN
    14. Test negativo documentato per HIV, HBV ed HCV.
    Per la sierologia dell'HBV, è richiesta la determinazione di HBsAg ed anti-HBcAg Ab. In pazienti in cui la sierologia documenti un'esposizione precedente ad HBV (ad es. antiHBsAg e/o anti-HBc Ab) é anche richiesto un risultato negativo del test per la presenza di HBV-DNA serico.
    15. Tutti gli effetti tossici acuti (salvo alopecia) di ogni trattamento precedente debbono essersi risolti al grado = 1 del National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03), se non differentemente specificato sopra.
    16. Le donne in età fertile* debbono risultare negative al test di gravidanza effettuato allo screening. Le donne in gravidanza non possono essere arruolate nello studio. Le donne in età fertile debbono usare, a partire dallo screening e fino a tre mesi dopo l'ultima somministrazione del prodotto in studio metodi contraccettivi altamente efficaci, come quelli definiti dalle: "Recommendations for contraception and pregnancy testing in clinical trials" rilasciati dal Direttore del Gruppo "Medicine Agencies' Clinical Trial Facilitation Group" e che includono, ad esempio, contraccezione ormonale basata su progesterone da solo o in combinazione con estrogeni, associata con inibizione dell'ovulazione, dispositivi intrauterini, sistemi di rilascio ormonale intrauterini, occlusione delle tube bilaterale, partner vasectomizzato o astinenza sessuale. Il test di gravidanza sarà ripetuto alla valutazione di sicurezza (solo per le donne in età fertile e solo per le pazienti nel braccio 1).
    17. I soggetti di sesso maschile con partner in età fertile debbono impegnarsi ad usare contemporaneamente due metodi contraccettivi accettabili (ad es. gel spermicida più preservativo) a partire dallo screening e fino a tre mesi dopo l'ultima somministrazione del prodotto in studio.
    18. Evidenza di un documento di Consenso Informato, firmato e datato personalmente dal paziente o dal suo legale rappresentante e con indicazione del fatto che il paziente è stato informato di tutti gli aspetti pertinenti dello studio.
    19. Accettazione e capacità di uniformarsi all'agenda delle visite, al piano di trattamento, ai test di laboratorio ed alle altre procedure previste dallo studio.
    *=Le donne in età fertile sono definite come donne che hanno sperimentato il menarca, non sono in postmenopausa (12 mesi senza mestruazioni senza una causa medica alternativa) e non sono sterilizzate in modo permanente (ad esempio, occlusione delle tube, isterectomia, ooforectomia bilaterale o salpingectomia bilaterale).
    E.4Principal exclusion criteria
    Patients exclusion criteria:
    1. Uveal melanoma, mucosal melanoma or melanoma with unknown primary.
    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 & T1), 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 allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment
    18. Previous in vivo exposure to monoclonal antibodies for biological therapy (except allowed treatments listed at point 3 of Inclusion criteria) in the 6 weeks before enrollment
    19. Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) within 7 days before enrollment
    20. Patient requiring or 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.
    22. Previous enrolment and randomization in this same study
    1. Melanoma uveale, melanoma della mucosa e melanoma primario di eziologia sconosciuta.
    2. Evidenza di metastasi distanti alla visita di screening
    3. Malattia cancerosa precedente o concomitante, distinta nel sito primario o in istologia dal cancro in studio, con l'eccezione di carcinoma cervicale in situ, carcinoma basocellulare trattato, tumori superficiali della vescica (Ta, Tis & T1), un secondo melanoma primario in situ o ogni altro tumore curato < cinque anni prima dell'inizio del presente studio
    4. Presenza di infezioni attive (ovvero che richiedono terapia antimicrobica) o altre malattie gravi concomitanti che, secondo il parere dell'investigatore, esporrebbero il paziente ad un rischio ingiustificato o potrebbero interferire con lo studio
    5. Antecedenti entro un anno di sindromi coronariche acute o subacute con inclusione d'infarto miocardico ed angina pectoris instabile o stabile severa
    6. Aritmia cardiaca non adeguatamente controllata, includente la fibrillazione atriale
    7. Insufficienza cardiaca [> Grado II secondo i criteri della New York Heart Association (NYHA)]
    8. LVEF = 50% e/o anormalità osservate durante l'ECG al basale che sono considerate significative dall'investigatore
    9. Ipertensione non controllata
    10. Malattia ischemica vascolare periferica (Grado IIb-IV)
    11. Retinopatia diabetica severa
    12. Malattia autoimmune attiva
    13. Antecedenti di allotrapianto d'organo o trapianto di cellule staminali
    14. Convalescenza post-traumatica che include chirurgia entro le quattro settimane precedenti l'arruolamento
    15. Antecedenti noti di allergia ad IL2, TNF, o altre proteine/peptidi/anticorpi umani o orni altro componente del prodotto
    16. Paziente di sesso femminile durante un periodo di allattamento al seno
    17. Terapia antitumorale (con l’eccezione dei trattamenti elencati al punto 3 dei criteri di inclusione ) entro quattro settimane dall'arruolamento
    18. Esposizione precedente ad anticorpi monoclonali per terapia biologica (con l’eccezione dei trattamenti elencati al punto 3 dei criteri di inclusione) nelle 6 settimane precedenti l'arruolamento
    19. Somministrazione di fattori di crescita o agenti immunomodulatori (con l’eccezione dei trattamenti elencati al punto 3 dei criteri di inclusione) entro 7 giorni prima dell'arruolamento
    20. Il paziente necessita o assume già corticosteroidi o altri agenti immunosoppressivi su base cronica. Un uso limitato di corticosteroidi per trattare o prevenire reazioni acute di ipersensibilità non è considerato causa di esclusione
    21. Ogni altra condizione che, secondo il parere dell'investigatore, possa risultare di ostacolo all'osservanza del protocollo di studio.
    22. Arruolamento e randomizzazione precedenti in questo stesso studio.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is:
    - Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery followed by adjuvants; Arm 1) versus control arm (surgery followed by adjuvants; Arm 2).
    Obiettivo primario: sopravvivenza libera da recidiva (Recurrence-free survival rate, RFS) nel braccio di trattamento (L19IL2/L19TNF seguito da chirurgia; braccio 1) verso il braccio di controllo (braccio 2).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Recurrence is evaluated every 3 months after surgery up to 36 months
    La sopravvivenza libera da recidiva è valutato ogni 3 mesi dopo la chirurgia, fino a 36 mesi
    E.5.2Secondary end point(s)
    Secondary endpoints are:
    - Overall survival (OS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (surgery; Arm 2).
    - Local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the treatment arm (L19IL2/L19TNF plus surgery - Arm 1) versus control arm (Arm 2).
    - Proportion of patients with pathological responses (defined as the proportion of patients with a pathological CR, pathological near-CR, or pathological PR).
    - 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; the data will be collected for at least 50 patients). Study of blood biomarkers.
    - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.
    Gli endpointi secondari sono:
    • Sopravvivenza globale (Overall survival, OS) nel braccio di trattamento (L19IL2/L19TNF seguito da chirurgia; braccio 1) nei confronti del gruppo di controllo (chirurgia; braccio 2).
    • Sopravvivenza libera da recidiva locale (Local recurrence-free survival rate, LRFS) e sopravvivenza libera da recidiva distante (Distant metastasis-free survival rate, DMFS) nel braccio di trattamento (L19IL2/L19TNF seguito da chirurgia; braccio 1) verso il braccio di controllo (Braccio 2), .
    • Proporzione di pazienti con risposte patologiche (definita come la proporzione di pazienti con una CR patologica, quasi-CR patologica, o PR patologica).
    • Sicurezza della somministrazione intratumorale di L19IL2/L19TNF.
    • Studio di biomarcatori (entrambi i bracci): caratterizzazione immunofenotipica di linfociti del sangue periferico (PBMCs) per modificazioni nel numero assoluto e/o percentuali relative di sottopopolazioni linfocitarie (ad es., Tregs, MDSCs etc.) nel tempo (studio da condursi solo su campioni da pazienti arruolati in Germania;i dati saranno raccolti su almeno 50 pazienti). Studio di biomarcatori nel sangue.
    • Determinazione della formazione di anticorpi umani contro proteine di fusione (human anti-fusion protein antibodies, HAFA) contro L19IL2 e L19TNF
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Overall survival (OS): evaluation every 3 months after surgery up to 36 months; at least every 6 months up to 60 months.
    - LRFS and DMFS: evaluation every 3 months after surgery up to 36 months.
    - Proportion of patients with pathological responses: evaluated after surgery.
    - Safety of intratumoral administration of L19IL2/L19TNF: evaluation throughout the entire study for each patient
    - Biomarker studies, immunophenotypic characterization of PBMCs: assessment at screening; at surgery visit; at first follow-up fisit
    - HAFA assessment will be performed on patients included in Arm 1: on day 1 before drug administration; on day 8 before drug administration; on day 29 at safety visit; at first follow-up visit
    - Overall survival (OS): dopo la chirurgia sarà valutata ogni 3 mesi fino a 36 mesi; dopodichè almeno ogni 6 mesi fino a 60 mesi.
    - LRFS and DMFS: dopo la chirurgia sarà valutata ogni 3 mesi fino a 36 mesi.
    - Percentuale di pazienti con risposta alla patologia: sarà valutata dopo la chirurgia.
    - Sicurezza della somministrazione intratumorale di L19IL2/L19TNF: sarà valutata durante il corso dell’intero studio per ciascun paziente.
    - Studio di biomarcatori, caratterizzazione immunofenotipica di PBMCs Biomarker studies: valutazione alla visita di screening; alla chirurgia; alla prima visita di follow-up.
    - Determinazione della formazione di human anti-fusion protein antibodies (HAFA): nei pazienti del Braccio 1 al Giorno 1, al Giorno 8, al Giorno 29 e alla prima visita di follow-up
    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
    Studio di Fase III multicentrico, randomizzato, in aperto. 214 pazienti saranno arruolati e assegnat
    Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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.
    La fine del trattamento corrisponde al giorno dell'intervento chirurgico per i pazienti randomizzati, sia nel braccio 1 che nel braccio 2.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years7
    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 state50
    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.
    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 Decision2015-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-09
    P. End of Trial
    P.End of Trial StatusOngoing
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