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    Summary
    EudraCT Number:2014-000185-22
    Sponsor's Protocol Code Number:20110265
    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:2015-08-27
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-000185-22
    A.3Full title of the trial
    A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable, Stage IIIB to IVM1c Melanoma (MASTERKEY-265)
    Studio di fase 1b/3, multicentrico, su talimogene laherparepvec in combinazione con Pembrolizumab (MK-3475) per il trattamento del melanoma non resecabile di stadio da IIIB a IVM1c (MASTERKEY-265)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab (MK 3475) With Talimogene Laherparepvec or placebo in Unresectable Melanoma
    Pembrolizumab (MK 3475) con Talimogene Laherparepvec o placebo nel trattamento del melanoma non resecato
    A.4.1Sponsor's protocol code number20110265
    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 SponsorAmgen 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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportMerck Sharp and Dohme International GmbH
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ medical Info-Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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.2.1.1.1Trade name IMLYGIC
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTalimogene Laherparepvec
    D.3.2Product code AMG 678
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntralesional use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalimogene laherparepvec
    D.3.9.2Current sponsor codeAMG 678
    D.3.9.3Other descriptive nameTALIMOGENE LAHERPAREPVEC
    D.3.9.4EV Substance CodeSUB130338
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberClassified as a Gene Therapy Medicinal Product EMA/CAT/451866/2012
    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 Yes
    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 IMLYGIC
    D.2.1.1.2Name of the Marketing Authorisation holderEU/1/15/1064
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTalimogene Laherparepvec
    D.3.2Product code AMG 678
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntralesional use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalimogene laherparepvec
    D.3.9.2Current sponsor codeAMG 678
    D.3.9.3Other descriptive nameTALIMOGENE LAHERPAREPVEC
    D.3.9.4EV Substance CodeSUB130338
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberClassified as a Gene Therapy Medicinal Product EMA/CAT/451866/2012
    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 Yes
    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: 3
    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 Keytruda
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameKeytruda
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form 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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameMK-3475
    D.3.9.4EV Substance CodeSUB91641
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntralesional use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Unresectable Stage IIIB to IVM1c Melanoma
    Melanoma non-resecato di stadio da IIIB a IVM1c
    E.1.1.1Medical condition in easily understood language
    Melanoma
    Melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10053571
    E.1.2Term Melanoma
    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
    Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in subjects with previously untreated, unresectable, stage IIIB to IVM1c melanoma.

    Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded central review using modified Response Evaluation Criteria in Solid Tumors 1.1 [RECIST]) and overall survival (OS).
    Fase 1b: Valutare la sicurezza, determinata in base all’incidenza della tossicità dose limitante (DLT), di talimogene laherparepvec in combinazione con pembrolizumab in soggetti con melanoma di stadio da IIIB a IVM1c, precedentemente non trattato, non resecato.
    Fase 3: Valutare l’efficacia del trattamento con talimogene laherparepvec in combinazione con pembrolizumab verso placebo con pembrolizumab, determinata in base alla sopravvivenza libera da progressione (PFS) (valutazione centralizzata in cieco della risposta utilizzando i criteri RECIST modificati 1.1 [Response Evaluation Criteria in Solid Tumors]) e alla sopravvivenza globale (OS).
    E.2.2Secondary objectives of the trial
    Phase 1b:
    • To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab, as assessed by:
    − ORR,BOR,DRR,DOR,DCR,&PFS
    − OS
    • To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab,assessed by incidence of treatment-emergent and -related AEs
    Phase 3:
    • Evaluate efficacy of talimogene laherparepvec with pembrolizumab, versus placebo with pembrolizumab, as assessed by:
    − ORR,BOR,DRR,DOR,DCR
    − PFS
    − Landmark survival by year
    • Evaluate safety of talimogene laherparepvec with pembrolizumab, versus placebo with pembrolizumab, as assessed by incidence of treatment-emergent and -related AEs.
    • Evaluate efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, pembrolizumab in subjects whose tumors are either PD-L1-negative or PD-L1-positive prior to initiating therapy (as assessed by the ORR, BOR, PFS, DRR, DOR, DCR,OS, and landmark survival by year.
    • Evaluate patient reported outcomes (PRO)
    Fase 1b: Valutare l’efficacia di TVEC in combinazione con pembrolizumab, determinata in base a: - Tasso di risposta obiettiva confermato, miglior risposta globale, DRR, durata della risposta, tasso di controllo della malattia e PFS
    - OS. Valutare la sicurezza di TVEC in combinazione con pembrolizumab determinata in base all’incidenza di EA .
    Fase 3:Valutare l’efficacia di TVEC in combinazione con pembrolizumab, placebo con pembrolizumab, in base a:
    - ORR, BOR, DRR, DOR, DCR, PFS - Analisi della sopravvivenza a un determinato punto temporale per anno, Valutare la sicurezza di TVEC in combinazione con pembrolizumab, rispetto a placebo con pembrolizumab, determinata in base all’incidenza di EA . Valutare l’efficacia di TVEC in combinazione con pembrolizumab, rispetto a placebo con pembrolizumab, in soggetti i cui tumori, prima di iniziare la terapia, sono sia PD-L1 negativi che PD-L1 positivi. Valutare l’outcome riferito dai pazienti
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Male or female age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to IVM1c for whom surgery in not recommended. . Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, renal, and coagulation function.

    Subjects enrolled in phase 1b must be treatment naïve (i.e., must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy) given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.
    Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that prior adjuvant therapy with inhibitors of PD-1 or PD-L1 is not allowed. However, if the subject received adjuvant therapy, the subject must have completed therapy at least 3 months prior to enrolment.

    Subjects enrolled in phase 3 with BRAFV600 wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.

    Subjects enrolled in phase 3 with serine/threonine protein kinase B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as their only prior systemic therapy are eligible for the
    phase 3 of this study. At the discretion of the investigator, subjects with BRAFV600 mutant melanoma or unknown BRAFV600 mutation status who have not received a BRAF inhibitor are also eligible for the phase 3 of this study as first-line treatment if they meet the following criteria: lactate dehydrogenase (LDH) < upper limit of normal (ULN), no clinically significant tumor related symptoms, and absence of rapidly progressing metastatic melanoma. Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or use of investigational agents in the adjuvant setting). However, if the subject received adjuvant therapy, the subject must have completed therapy at least 28 days prior to enrollment.
    Subjects must have a tumor sample (archival sample or newly obtained biopsy) that is adequate for PD-L1 assessment prior to randomization.
    Soggetti di sesso maschile o femminile, di età ≥18 anni, con diagnosi istologicamente confermata di melanoma di stadio da IIIB a IVM1c, per i quali non è raccomandato l’intervento chirurgico. I soggetti devono presentare malattia misurabile ed essere candidati alla somministrazione intralesionale del farmaco all’interno di lesioni cutanee, sottocutanee o nodulari. I soggetti devono presentare un performance status ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1 e un’adeguata funzionalità ematologica, epatica, renale e coagulativa.
    Solo nella Fase 1b:
    I soggetti arruolati nella fase 1b devono essere naïve al trattamento (ovvero, non devono essere stati in precedenza trattati con terapie antitumorali sistemiche, quali chemioterapia, immunoterapia o terapia mirata per il melanoma non resecato di stadio da IIIB a IVM1c) somministrato in un regime non-adiuvante per melanoma non resecabile di stadio da IIIB a IVM1c. I soggetti sottoposti a una pregressa terapia adiuvante per il melanoma non saranno esclusi (comprese, ma non limitato a, radioterapia, terapia con interferone, l’infusione/perfusione d’arto o l’uso di agenti sperimentali nel setting adiuvante) con l'eccezione che una precedente terapia adiuvante con inibitori di PD-1 o PD-L1 non è permessa. Tuttavia, se sottoposti a terapia adiuvante, i soggetti dovranno aver completato la terapia almeno 3 mesi prima dell’arruolamento. soggetti arruolati nella fase 3 con tumori BRAFV600 wild-type non devono essere stati in precedenza trattati con terapie antitumorali sistemiche, quali chemioterapia, immunoterapia o terapia mirata somministrata in un regime non adiuvante per il melanoma non resecato di stadio da IIIB a IVM1c. I soggetti arruolati nella fase 3 con tumori serina/treonina protein-chinasi BRAFV600 mutati, precedentemente trattati con BRAF-inibitori in monoterapia o in combinazione con un MEK-inibitore come unica terapia sistemica pregressa sono eleggibili per la fase 3 di questo studio. A discrezione dello sperimentatore, saranno eleggibili per la fase 3 di questo studio, come terapia di prima linea, anche i soggetti affetti da melanoma con mutazione BRAFV600 o con stato mutazionale BRAFV600 ignoto non sottoposti a terapia con un BRAF-inibitore se rispondono ai seguenti criteri: LDH < ULN (cioè al di sotto del limite superiore di normalità), nessun sintomo clinicamente significativo correlato al tumore e assenza di melanoma metastatico in rapida progressione. I soggetti sottoposti a una pregressa terapia adiuvante per il melanoma non saranno esclusi (comprese, ma non limitato a, terapia con interferone, ipilimumab, l’infusione/perfusione d’arto o l’uso di agenti sperimentali nel setting adiuvante) con l'eccezione che una precedente terapia adiuvante con inibitori di PD-1 o PD-L1 non è permessa. Tuttavia, se sottoposti a terapia adiuvante, i soggetti dovranno aver completato la terapia almeno 28 giorni prima dell’arruolamento. I soggetti devono disporre di un campione tumorale (presente in archivio o da nuova biopsia) adeguato per la valutazione del PD-L1 prima della randomizzazione.
    E.4Principal exclusion criteria
    Subjects must not have clinically active cerebral metastases. Subjects with up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or Gamma Knife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment. Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states (e.g., hereditary immune deficiency, organ transplant, or leukemia), or history of other malignancy within the past 3 years with the exceptions of the prior malignancies noted in Section 4.1.2. Subjects may not have been previously treated with talimogene laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2. Prior treatment with other immunotherapies ( e.g., anti-CD137, or cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibitor, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways), is allowed only in the adjuvant setting. Subjects must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression. Subjects must not have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
    I soggetti non devono presentare metastasi cerebrali clinicamente attive. Potranno essere arruolati i soggetti con un massimo di 3 metastasi cerebrali, a condizione che tutte le lesioni siano state adeguatamente trattate con radioterapia stereotassica, craniotomia o trattamento con Gamma Knife, senza evidenze di progressione, e che non abbiano necessitato di steroidi per almeno 2 mesi prima dell’arruolamento. I soggetti non devono presentare melanoma primitivo uveale o delle mucose, anamnesi o evidenze di melanoma associato a stati di immunodeficienza (ad es. immunodeficienza ereditaria, trapianto d’organi o leucemia), o anamnesi positiva per altre neoplasie maligne negli ultimi 3 anni sono escluse le neoplasie maligne pregresse indicate nel paragrafo 4.1.2. I soggetti possono non essere stati in precedenza sottoposti a trattamento con talimogene laherparepvec, qualsiasi altro virus oncolitico, pembrolizumab, qualsiasi altro inibitore di PD-1, anti-PD-L1, anti-PD-L2. Precedenti trattamenti con altre immunoterapie (es. anti-CD137, un altro inibitore del CTLA-4 (Cytotoxic T-Lymphocyte Associated Antigen 4), o qualsiasi altro anticorpo o farmaco diretto in modo specifico contro le vie di costimolazione dei linfociti T o le vie di checkpoint) sono permessi solo nel setting adiuvante. I soggetti non devono presentare un’anamnesi o evidenze di polmonite, glomerulonefrite o vasculite autoimmuni sintomatiche, oppure di altre patologie autoimmuni sintomatiche, anamnesi documentata positiva per patologie o sindromi autoimmuni che hanno richiesto un trattamento sistemico negli ultimi 2 anni (ovvero con uso di agenti modificanti la malattia, steroidi o agenti immunosoppressivi) a eccezione della vitiligine o dell’asma/atopia infantile risolta, o evidenze di immunosoppressione clinicamente significativa. I soggetti non devono presentare lesioni cutanee erpetiche attive o complicanze pregresse di infezione erpetica (ad es. cheratite erpetica o encefalite) e non devono necessitare di un trattamento cronico o intermittente con un antierpetico (ad es. aciclovir), se non per uso topico intermittente.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b:
    • Incidence of DLT
    Phase 3:
    • Progression-free Survival (PFS): Time from randomization to the date of disease progression (response evaluation by blinded central review using modified RECIST 1.1) or death, whichever occurs earlier.
    • Overall Survival (OS): Time from randomization date to the date of death from any cause.
    Fase 1b:
     Incidenza di DLT
    Fase 3:
     Progression libera da malattia (PFS): tempo trascorso dalla randomizzazione fino alla progression della malattia (valutazione centralizzata in cieco della risposta utilizzando i criteri RECIST 1.1) o morte, a seconda di quale avviene prima
     Overall survival (OS): tempo trascorso dalla randomizzazione alla morte, per qualsiasi causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary Completion: The time when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary analysis of phase 3. The timing of the primary analyses for PFS and OS of phase 3 will be triggered when 407 PFS events and 348 OS events have occurred, respectively.

    End of Trial: The time when the last subject is assessed or receives an intervention for evaluation in the study. The end of study will occur when the last subject discontinues the study treatment and has had the opportunity to complete the safety follow-up visit or
    the long-term survival follow-up, whichever is later.
    Completamento primario: quando l’ultimo soggetto è valutato o riceve un intervento per la raccolta finale di dati per l’analisi primaria di fase 3. Il completamento primario avviene quando all’incirca 348 decessi si saranno verificati nella fase 3.
    Fine dello studio: quando l’ultimo soggetto è valutato o riceve un intervento di valutazione per lo studio. La fine dello studio si verificherà quando l’ultimo soggetto discontinuerà il trattamento e avrà completato le visite di follow up di safety o il long-term follow up di sopravvivenza, a seconda di quello che si verifica più tardi.
    E.5.2Secondary end point(s)
    Phase 1b:
    • Confirmed ORR (CR+PR) (response evaluation by investigator using modified irRC).
    • BOR, DRR (CR or PR for duration of 6 months or longer), DOR (the time from date of the initial confirmed response to the date of the first documented PD or death; a single, unconfirmed PD at the last assessment will also be considered for the end of DOR), PFS and DCR (response evaluation by investigator using modified irRC).
    • OS.
    • Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest).
    Phase 3:
    • ORR (CR+PR), BOR, DRR, DOR (the time from date of the initial confirmed response to the date of the first documented PD or death; a single, unconfirmed PD at the last assessment will also be considered for the end of DOR), DCR (response evaluation by blinded central review assessed modified RECIST 1.1 and investigator-assessed irRC-RECIST).
    • PFS (response evaluation by investigator-assessed irRC-RECIST).
    • Landmark survival by year.
    • BOR, DRR, DOR, (response evaluation by blinded central review assessed modified RECIST 1.1 and investigator-assessed irRC-RECIST), OS, and landmark survival by year for subjects with PD-L1 negative or positive tumors based on pre-treatment biopsy specimen.
    • Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest.
    • Summary scores at each assessment and changes from baseline of PROs in phase 3 as assessed by EQ-5D and the QLQ-C30
    Fase 1b:
     ORR (CR+PR) confermato (valutazione della risposta da parte dello sperimentatore utilizzando i criteri irRC modificati)
     BOR, DRR, DOR, PFS e DCR (valutazione della risposta da parte dello sperimentatore utilizzando i criteri irRC modificati)
     OS
     Incidenza degli eventi avversi emersi durante il trattamento e correlati al trattamento (con l’inclusione di tutti gli eventi avversi, degli eventi avversi di grado ≥3, degli eventi avversi seri, degli eventi avversi fatali, degli eventi avversi definiti come eventi di interesse)
    Fase 3:
     ORR (CR+PR), BOR, DRR, DOR e DCR (valutazione centralizzata in cieco della risposta mediante criteri RECIST modificati e da parte dello sperimentatore mediante criteri irRC-RECIST)
     PFS (valutazione della risposta da parte dello sperimentatore mediante criteri irRC-RECIST)
     Analisi della sopravvivenza a un determinato punto temporale per anno
     BOR, DRR, DOR, DCR, (valutazione centralizzata in cieco della risposta mediante criteri RECIST modificati e da parte dello sperimentatore mediante criteri irRC-RECIST), OS e analisi della sopravvivenza a un determinato punto temporale per anno per i soggetti con tumori PD-L1-negativi o PD-L1-positivi in base al campione bioptico pretrattamento
     Incidenza degli eventi avversi emersi durante il trattamento e correlati al trattamento (con l’inclusione di tutti gli eventi avversi, degli eventi avversi di grado ≥3, degli eventi avversi seri, degli eventi avversi fatali, degli eventi avversi definiti come eventi di interesse)
     Riassunto dei punteggi ad ogni valutazione e variazioni rispetto al basale dei PROs, in base ai questionari EuroQoL-5D (EQ-5D) e EORTC QLQ-C30
    E.5.2.1Timepoint(s) of evaluation of this end point
    The clinical study report (CSR) will be written based on the results for primary analysis of phase 3 (PFS), which will also include phase 1b data. Results from the primary analysis of OS in phase 3 will be included in a supplemental CSR.
    Il clinical study report (CSR) verrà redatto sulla base dei risultati dell’analisi primaria di fase 3 (PFS), che includerà anche i dati di fase 1. I risultati dell’analisi primaria di OS nella fase 3 saranno inclusi in un CSR supplementare.
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1b to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT)
    Fase 1b per valutare la sicurezza, come valutato dall’incidenza della dose limitante la tossicità
    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 No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) Yes
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Australia
    Canada
    South Africa
    Switzerland
    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
    The time when the last subject is assessed or receives an intervention for
    evaluation in the study. The end of study will occur when the last subject discontinues the study treatment and has had the opportunity to complete the safety follow-up visit or the long-term survival follow-up, whichever is later.
    Il momento in cui l'ultimo soggetto viene valutato o riceve un intervento per la valutazione nello studio. La fine dello studio si verifica quando l'ultimo soggetto interrompe il trattamento in studio e ha avuto l'opportunità di completare la visita del follow-up di sicurezza o il follow della sopravvivenza a lungo termine, se posteriore
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    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: 330
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 350
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 330
    F.4.2.2In the whole clinical trial 680
    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)
    None
    Nessuno
    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 Decision2016-07-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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