Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   44237   clinical trials with a EudraCT protocol, of which   7338   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2021-003669-36
    Sponsor's Protocol Code Number:MS100070_0119
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-09-13
    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 number2021-003669-36
    A.3Full title of the trial
    A Phase II, Multicenter, Randomized, Open Label, Parallel-Arm, Umbrella Study of Avelumab (MSB0010718C) in Combination with Other Anti-Tumor Agents as a Maintenance Treatment in Participants with Locally Advanced or Metastatic Urothelial Carcinoma Whose Disease Did Not Progress with First Line Platinum-Containing Chemotherapy
    Studio di fase II,multicentrico,randomizzato, n aperto,a bracci paralleli (Umbrella study) di avelumab (MSB0010718C) in combinazione con altri agenti antitumorali come trattamento di mantenimento in partecipanti con carcinoma uroteliale localmente avanzato o metastatico la cui malattia non è progredita con chemioterapia di prima linea a base di platino
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma
    Uno studio sulla sicurezza e l'efficacia di varie combinazioni di Avelumab come terapia nel carcinoma uroteliale localmente avanzato o metastatico
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN Bladder Medley
    Studio su sic., efficacia di combinb. di avelumab terapia carc. uroteliale loc. avanzato o metast.
    A.4.1Sponsor's protocol code numberMS100070_0119
    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 SponsorMERCK KGAA
    B.1.3.4CountryGermany
    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 supportMerck Healthcare KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Healthcare KGaA
    B.5.2Functional name of contact pointCommunication Center
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Str. 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+496151725200
    B.5.5Fax number+496151722000
    B.5.6E-mailservice@merckgroup.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 nameBAVENCIO
    D.3.2Product code [MSB0010718C]
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNAVELUMAB
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.4EV Substance CodeSUB180078
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 namesacituzumab govitecan
    D.3.2Product code [IMMU-132]
    D.3.4Pharmaceutical form Powder for 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.3.9.2Current sponsor codeIMMU-132
    D.3.9.4EV Substance CodeSUB191213
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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) 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 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.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 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 nameM6223
    D.3.2Product code [M6223]
    D.3.4Pharmaceutical form Concentrate for solution for injection/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.3.9.2Current sponsor codeM6223
    D.3.9.4EV Substance CodeSUB260695
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeM6223
    D.3.9.4EV Substance CodeSUB260695
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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: 4
    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 nameNKTR-255
    D.3.2Product code [NKTR-255]
    D.3.4Pharmaceutical form Powder for 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 INNAvipendekin pegol
    D.3.9.2Current sponsor codeNKTR-255
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 Yes
    D.3.11.13.1Other medicinal product typeNKTR-255 is a novel immunotherapeutic anticancer drug candidate that consists of rhIL-15 covalently bound to a 40 kDa polyethylene glycol (PEG) moiety.
    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
    Advanced or metastatic urothelial carcinoma whose disease did not progress with 1L platinum-containing chemotherapy.
    Carcinoma uroteliale avanzato o metastatico la cui malattia non è progredita con la chemioterapia 1L contenente platino.
    E.1.1.1Medical condition in easily understood language
    Bladder cancer
    Cancro alla vescica
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To evaluate PFS of maintenance treatment with avelumab treatment combination regimens compared to maintenance avelumab monotherapy.
    -To evaluate the safety and tolerability of avelumab combination regimens.
    -Valutare la PFS del trattamento di mantenimento con regimi di combinazione di trattamento con avelumab rispetto alla monoterapia di mantenimento con avelumab.
    -Valutare la sicurezza e la tollerabilità dei regimi di combinazione di avelumab.
    E.2.2Secondary objectives of the trial
    -To evaluate OS of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy followed by subsequent anticancer treatment.
    -To evaluate OR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
    -To evaluate DoR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
    -To collect PK concentration data of avelumab, M6223, SG (derived from total SN-38 and unconjugated SN-38), and NKTR-255 to contribute to respective PopPK analyses and exposure-response analyses.
    -To characterize the immunogenicity of avelumab administered alone or in combination with SG, NKTR-255 or M6223.
    To characterize the immunogenicity of M6223, SG or NKTR-255 in combination with avelumab.
    -To evaluate the effect of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy on disease related physical symptoms.
    -Valutare l'OS del tratt. di mantenimento con regimi di combinazione di avelumab rispetto alla monoterapia di mantenimento di avelumab seguita da un successivo tratt. antitumorale e con regimi di combinazione di avelumab rispetto alla monoterapia di mantenimento con avelumab.
    -Valutare il DoR del tratt. di mant. con regimi di combinazione di avelumab rispetto alla monoterapia di mantenimento di avelumab.
    -Raccogliere dati di concentrazione PK di avelumab, M6223, SG (derivato da SN-38 totale e SN-38 non coniugato), e NKTR-255 per contribuire alle rispettive analisi PopPK e alle analisi esposizione-risposta.
    -Caratterizzare l'immunogenicità di avelumab somministrato da solo o in combinazione con SG, NKTR-255 o M6223.
    Caratterizzare l'immunogenicità di M6223, SG o NKTR-255 in combinazione con avelumab.
    -Valutare effetto tratt. di manten. con regimi di combinazione di avelumab rispetto alla monoterapia di mantenimento con avelumab sui sintomi fisici legati alla malattia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Are = 18 years of age at the time of signing the informed consent.
    2.Has
    a.Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
    b.Documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
    3. Prior 1L chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other chemotherapy regimens are allowed in this study. (Note: Switch between platinum agents due for toxicity to complete a total of - 4 to 6 cycles first line platinum-based chemotherapy is acceptable).
    4.The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study.
    5.Participants without progressive disease as per RECIST v1.1 guidelines (i.e., with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles of 1L chemotherapy.
    Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
    6.All participants must provide archival formalin-fixed paraffin embedded (FFPE) tumor tissues (ideally < 6 months old prior to participant enrollment) from most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within 24 months prior to randomization, with no intervening systemic anticancer therapy between the time the tissue was obtained and initiation of first line chemotherapy. Please see protocol for more deatails.
    7.Participants who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
    8.Estimated life expectancy of at least 3 months.
    9.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
    10.Adequate bone marrow function, including:
    a.Absolute neutrophil count (ANC) = 1,500/mm3 or = 1.5 × 109/L;
    b.Platelets = 100,000/mm3 or = 100 × 109/L;
    c.Hemoglobin = 9 g/dL (may have been transfused).
    11.Adequate renal function, defined as estimated creatinine clearance = 30 mL/min as calculated using the Cockcroft-Gault equation or by 24-hour urine collection for creatinine clearance or according to the local institutional standard method.
    12.Adequate liver function, including:
    a.Total serum bilirubin = 1.5 × upper limit of normal (ULN);
    b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 × ULN, or, for participants with documented metastatic disease to the liver, AST and ALT levels = 5 × ULN.
    13.All sexes allowed. The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below.

    Please see Protocol for more details about this inclusion criteria.

    14.Capable of giving signed informed consent, as indicated in Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
    15.Participants with known human immunodeficiency virus (HIV) infections are eligible if the following criteria are met:
    16.Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are eligible if the following criteria are met:

    Please see Protocol for more details about inclusion criteria 15 and 16.
    1.Ha = 18 anni di età al momento della firma del consenso informato.
    2. 2. Ha:
    a. Un carcinoma uroteliale non resecabile, localmente avanzato o metastatico, confermato istologicamente. Sono ammesse sia le istologie a cellule transizionali che quelle miste a cellule transizionali/non transizionali, ma il carcinoma a cellule transizionali deve essere l'istologia predominante.
    b. Malattia documentata in stadio IIIA/IIIB con N1-N3 o in stadio IV (secondo il sistema dell’American Joint Committee on Cancer/International Union for Cancer Control, Tumor, Node, Metastasis [Comitato congiunto americano sul cancro/Unione internazionale per il controllo del cancro, Tumori, noduli, metastasi], 8ª edizione) all'inizio della chemioterapia di prima linea.
    3. La chemioterapia di prima linea (1L) precedente deve aver incluso almeno 4 cicli e non più di 6 cicli di gemcitabina + cisplatino e/o gemcitabina + carboplatino. In questo studio non sono consentiti altri regimi chemioterapici. (Nota: il passaggio tra agenti di platino per tossicità al fine di completare un numero totale di cicli compreso tra 4 e 6 di chemioterapia di prima linea a base di platino è accettabile).
    4. L'ultima dose di chemioterapia di prima linea deve essere stata somministrata non meno di 4 settimane e non più di 10 settimane prima della randomizzazione nel presente studio.
    5. Partecipanti che non presentano malattia progressiva secondo le linee guida RECIST v1.1 (ovvero, con una risposta completa [RC], risposta parziale [RP] o malattia stabile [SD] in corso) dopo il completamento di 4-6 cicli di chemioterapia 1L.
    L’idoneità basata su questo criterio sarà determinata dalla revisione da parte dello Sperimentatore delle valutazioni radiologiche precedenti e successive alla chemioterapia (scansioni TAC/RMI).
    6. Tutti i partecipanti devono fornire tessuti tumorali d'archivio fissati in formalina e inclusi in paraffina (FFPE) (idealmente risalenti a <6 mesi prima dell’arruolamento), ma entro 24 mesi prima della randomizzazione, senza terapia oncologica sistemica tra il momento in cui il tessuto è stato ottenuto e l’inizio della chemioterapia di prima linea. Se non è possibile fornire un blocco di tessuto FFPE d'archivio. Si veda protocollo per maggiori dettagli.
    7. Partecipanti che desiderino e possano rispettare le visite programmate, i piani di trattamento, gli esami di laboratorio e le altre procedure dello studio.
    8. Aspettativa di vita stimata di almeno 3 mesi.
    9. Stato di validità (PS) secondo l’Eastern Cooperative Oncology Group (ECOG) [Gruppo cooperativo orientale di oncologia] pari a 0 o 1.
    10. Funzionalità del midollo osseo adeguata, tra cui:
    a. Conta assoluta dei neutrofili (ANC) = 1.500/mm3 o = 1,5 × 109/l;
    b. Piastrine = 100.000/mm3 o = 100 × 109/l;
    c. Emoglobina = 9 g/dl (può essere stata trasfusa).
    11. Funzione renale adeguata, definita da una clearance della creatinina stimata = 30 ml/min secondo la formula di Cockcroft-Gault o mediante l’analisi delle urine delle 24 ore per la clearance della creatinina o secondo il metodo standard istituzionale utilizzato a livello locale.
    12. Funzionalità epatica adeguata, in particolare:
    a. bilirubina sierica totale = 1,5 volte il limite superiore della norma (ULN);
    b. aspartato aminotransferasi (AST) e alanina aminotransferasi (ALT) = 2,5 × ULN oppure, per i partecipanti con malattia metastatica epatica documentata, livelli di AST e ALT = 5 × ULN.
    13. È consentita la partecipazione di soggetti di tutti i sessi. Lo Sperimentatore confermerà che ciascun partecipante accetti di utilizzare un metodo di contraccezione e di barriera adeguati, se pertinente. La contraccezione, i metodi di barriera e i requisiti per i test di gravidanza sono indicati di seguito.
    14.Il soggetto è in grado di fornire un consenso informato firmato, come indicato nell’Appendice 2 prot.
    Vedere prot. per criteri di inclusione per maggiori dettagli.
    E.4Principal exclusion criteria
    1.Participants with symptomatic central nervous system (CNS) metastases requiring steroids. Participants with diagnosed CNS metastases are eligible if they have completed treatment, recovered from the acute effects of radiation therapy or surgery prior to randomization and off steroid treatment 7 days before randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
    2.Persisting toxicity related to prior therapy NCI-CTCAE v5.0 Grade > 1; however, alopecia, sensory neuropathy Grade = 2 is acceptable, or other Grade = 2 adverse events not constituting a safety risk based on the Investigator’s judgment are acceptable.
    3.Diagnosis of any other malignancy unless a complete remission without further recurrence was achieved and the participant was deemed to have been cured with no additional therapy required or anticipated to be required. The exceptions to this criterion may include carcinoma in situ of cervical, colorectal, breast, or all localized prostate cancer that is not being treated. Possible exceptions to this criterion will be discussed on a by participant basis according to medical need.
    4.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    5.Current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 ms on triplicate 12-lead ECG or impaired cardiovascular function.
    6.Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication (except for atrial fibrillation that is well controlled with antiarrhythmic medication).
    7.Active infection 48 hours before randomization requiring systemic therapy.
    8.Known severe hypersensitivity reactions to monoclonal antibodies (Grade = 3), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
    9.Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
    10.Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy.
    11.Pregnant female participants; breastfeeding female participants; and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in the protocol for the duration of the study and for at least 6 months after the last dose of investigational product.
    12.Other severe acute or chronic medical conditions including but not limited to inflammatory bowel disease (colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of enrollment, Please see protocol for more datails.
    13.Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization.
    14.Prior immunotherapy with IL-2, IL-15, IFN-a, or an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or CTLA-4 antibody (including ipilimumab), anti TROP2, any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or any of the investigational drugs used in combination with avelumab.
    15.Major surgery = 4 weeks or major radiation therapy = 2 weeks prior to randomization. Prior palliative (pain management or hemostatic) radiotherapy is permitted, provided it has been completed at least 48 hours prior to randomization.
    16.Current or prior use of immunosuppressive medication within 7 days prior to randomization, Please see protocol for more datails.
    Please refer to Protocol for the full list.
    1.Partecipanti con metastasi sintomatiche del sistema nervoso centrale (SNC) che richiedono l’uso di steroidi. I partecipanti con diagnosi di metastasi al SNC sono idonei se hanno completato il trattamento, si sono ripresi dagli effetti acuti della radioterapia o dell’intervento chirurgico prima della randomizzazione, non ricevono il trattamento con steroidi durante i 7 giorni prima della randomizzazione, hanno interrotto il trattamento con corticosteroidi per queste metastasi per almeno 4 settimane e sono neurologicamente stabili.
    2. Tossicità persistente correlata alla precedente terapia di grado > 1 secondo i criteri NCI-CTCAE v5.0; tuttavia, sono ammissibili l’alopecia, la neuropatia sensoriale di grado = 2 o altri eventi avversi di grado = 2 che non costituiscono una base di rischio per la sicurezza a giudizio dello Sperimentatore.
    3.Diagnosi di qualsiasi altra neoplasia maligna a meno che non sia stata raggiunta una remissione completa senza ulteriori recidive e premesso che il partecipante sia stato considerato guarito senza necessità o previsione di alcuna terapia aggiuntiva. Si prega di far riferimento al protocollo per maggiori dettagli.
    4.Malattia autoimmune in fase attiva che potrebbe peggiorare durante il trattamento con un agente immunostimolante.Si prega di far riferimento al protocollo per maggiori dettagli.
    5. Anomalie significative in corso relative alla conduzione cardiaca, ivi compreso il prolungamento dell’intervallo QT corretto (QTcF, corretto con la formula di Fridericia) di > 450 ms all’ECG a 12 derivazioni in triplicato o funzione cardiovascolare compromessa.
    6. Malattia cardiovascolare clinicamente significativa (ovvero, in fase attiva): Si prega di far riferimento al protocollo per maggiori dettagli.
    7. Infezione attiva 48 ore prima della randomizzazione che richieda una terapia sistemica.
    8. Gravi reazioni note di ipersensibilità ad anticorpi monoclonali (di grado = 3), anamnesi di anafilassi o asma incontrollata (ovvero 3 o più caratteristiche di controllo dei sintomi dell’asma secondo il progetto Global Initiative for Asthma 2015 [Iniziativa globale per l’asma]).
    9. Ipersensibilità nota pregressa o sospetta ai farmaci dello studio o a qualsiasi componente presente nelle loro formulazioni.
    10. Diagnosi di pregressa immunodeficienza o trapianto d’organo che richieda una terapia immunosoppressiva.
    11. Partecipanti di sesso femminile in gravidanza, partecipanti in fase di allattamento al seno e partecipanti di sesso femminile con potenziale di fertilità che non desiderino o non possano utilizzare un metodo contraccettivo altamente efficace come indicato nel protocollo per tutta la durata dello studio e per almeno 6 mesi dopo l’ultima dose del prodotto sperimentale.
    12. Altre gravi condizioni mediche acute o croniche. Si prega di far riferimento al prot. per maggiori dettagli
    13. Precedente terapia sistemica adiuvante o neoadiuvante entro 12 mesi dalla randomizzazione.
    14. Precedente immunoterapia con IL-2, IL-15, IFN-a o un anticorpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o CTLA-4 (incluso ipilimumab), anti-TROP2, o qualsiasi altro anticorpo o farmaco mirato specificamente alla costimolazione dei linfociti T o a vie del checkpoint immunitario o qualsiasi farmaco sperimentale utilizzato in combinazione con avelumab.
    15. Intervento chirurgico maggiore eseguito = 4 settimane o radioterapia maggiore eseguita = 2 settimane prima della randomizzazione. Una precedente radioterapia palliativa (con gestione del dolore o emostatica), a condizione che sia stata completata almeno 48 ore prima della randomizzazione.
    16. Uso concomitante o precedente di farmaci immunosoppressori nei 7 giorni precedenti la randomizzazione. Si prega di far riferimento al protocollo per maggiori dettagli.
    Si prega di fare riferimento al protocollo per la lista completa.
    E.5 End points
    E.5.1Primary end point(s)
    -Progression-free survival (PFS) as defined from date of randomization to PD according to RECIST v1.1 as assessed by Investigator or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization.
    -Occurrence of TEAEs, treatment- related AEs, and AESIs as per Qualitative Toxicity Scale (NCI-CTCAE 5.0).
    -Sopravvivenza libera da progressione (PFS) definita dalla data di randomizzazione a PD secondo RECIST v1.1 come valutato dallo sperimentatore o morte, che si verifica entro due valutazioni programmate del tumore dopo l'ultima valutazione valutabile o la randomizzazione.
    -Insorgenza di TEAE, AE correlati al trattamento e AESI secondo la scala di tossicità qualitativa (NCI-CTCAE 5.0).
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS will be evaluated when 56 PFS events per treatment-control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis).

    Occurrence of TEAEs, treatment- related AEs, and AESIs will be monitored during safety DMCs as well as for interim and primary analysis as defined for the PFS endpoint.
    La PFS sarà valutata quando saranno stati osservati 56 eventi PFS per confronto trattamento-controllo (analisi ad interim). Poi sarà valutato di nuovo quando 65 eventi PFS per confronto trattamento-controllo sono stati osservati (analisi primaria).

    Il verificarsi di TEAEs, AEs correlati al trattamento e AESIs sarà monitorato durante i DMCs di sicurezza così come per l'analisi ad interim e primaria come definito per l'endpoint PFS.
    E.5.2Secondary end point(s)
    -Overall survival (OS) as measured by time from randomization to death.
    -Objective response (OR) according to RECIST v1.1 assessed by Investigator.
    -DoR according to RECIST v1.1 assessed by Investigator defined as time from first documentation of objective response to PD or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization.
    -Concentration will be listed and descriptively summarized as appropriate. Population PK and exposure-response results will be reported separately in a standalone report, as it may also include data from other studies.
    -Immunogenicity of avelumab, SG, NKTR-255 and M6223, as measured by ADA assay.
    -Change from baseline score of NCCN FACT FBlSI-18 DRS-P.
    -Sopravvivenza complessiva (OS) misurata in base al tempo dalla randomizzazione alla morte.
    -Risposta obiettiva (OR) secondo RECIST v1.1 valutata dallo sperimentatore.
    -Risposta obiettiva (OR) secondo RECIST v1.1 valutata dallo sperimentatore, definita come tempo dalla prima documentazione di una risposta obiettiva a PD o morte, che si verifica entro due valutazioni programmate del tumore dopo l'ultima valutazione valutabile o la randomizzazione.
    -La concentrazione sarà elencata e descrittivamente riassunta come appropriato. I risultati della PK della popolazione e dell'esposizione-risposta saranno riportati separatamente in un rapporto a sé stante, in quanto possono includere anche dati di altri studi.
    -Immunogenicità di avelumab, SG, NKTR-255 e M6223, come misurata dal test ADA.
    -Cambiamento dal punteggio basale di NCCN FACT FBlSI-18 DRS-P.
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS, OR and DoR will be evaluated when 56 PFS events per treatment-control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis).

    PK will be evaluated for safety DMCs as well as for interim and primary analysis as defined above.

    Immunogenicity and change from baseline score of NCCN FACT FBlSI-18 DRS-P will be evaluated for primary analysis.
    OS, OR e DoR saranno valutati quando saranno stati osservati 56 eventi PFS per confronto trattamento-controllo (analisi ad interim). Poi sarà valutato di nuovo quando saranno stati osservati 65 eventi PFS per confronto trattamento-controllo (analisi primaria).

    La PK sarà valutata per le DMC di sicurezza così come per l'analisi ad interim e primaria come definito sopra.

    L'immunogenicità e il cambiamento dal punteggio basale di NCCN FACT FBlSI-18 DRS-P saranno valutati per l'analisi primaria.
    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 Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA57
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Korea, Republic of
    Taiwan
    United States
    France
    Spain
    Germany
    Greece
    Italy
    Belgium
    Denmark
    United Kingdom
    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
    The end of the study is defined as the date of two years after treatment start of the last participant or until all the participants discontinued the study, whichever occurs first.
    La fine dello studio è definita come la data di due anni dopo l'inizio del trattamento dell'ultimo partecipante o fino a quando tutti i partecipanti hanno interrotto lo studio, se si verifica prima.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 252
    F.1.3Elderly (>=65 years) No
    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 state51
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 152
    F.4.2.2In the whole clinical trial 252
    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)
    Participants will be offered continued access to the study intervention that they received during the study after study completion, when appropriate, within defined limitations and as described below.
    Ai partecipanti sarà offerto l'accesso continuato all'intervento di studio che hanno ricevuto durante lo studio dopo il completamento dello studio, quando appropriato, entro limiti definiti e come descritto di seguito.
    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 Decision2022-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-10
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA