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    Summary
    EudraCT Number:2020-002818-41
    Sponsor's Protocol Code Number:MO42319
    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:2021-05-20
    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 number2020-002818-41
    A.3Full title of the trial
    A RANDOMIZED, MULTICENTER, DOUBLEBLIND, PLACEBO-CONTROLLED PHASE III STUDY OF THE EFFICACY AND SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION WITH ATEZOLIZUMAB OR PLACEBO IN PATIENTS WITH HER2-POSITIVE AND PD-L1-POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR TRASTUZUMAB- (+/- PERTUZUMAB) AND TAXANE-BASED THERAPY (KATE3).
    STUDIO DI FASE III, RANDOMIZZATO, MULTICENTRICO, IN DOPPIO CIECO, CONTROLLATO CON PLACEBO PER VALUTARE L’EFFICACIA E LA SICUREZZA DI TRASTUZUMAB EMTANSINE IN ASSOCIAZIONE CON ATEZOLIZUMAB O PLACEBO IN PAZIENTI AFFETTI DA TUMORE MAMMARIO LOCALMENTE AVANZATO O METASTATICO HER2-POSITIVO E PD-L1-POSITIVO CHE HANNO RICEVUTO IN PRECEDENZA TERAPIA A BASE DI TRASTUZUMAB (+/- PERTUZUMAB) E TAXANI (KATE3)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination with Atezolizumab or Placebo in Patients with HER2-Positive and PD-L1-Positive Locally Advanced or Metastatic Breast Cancer who Have Received Prior Trastuzumab- (+/- Pertuzumab) and Taxane-Based Therapy (KATE3).
    Studio sull'efficacia e la sicurezza di Trastuzumab Emtansine in Associazione con Atezolizumab o Placebo in pazienti con HER2-positivo e PD-L1-positivo cancro al seno localmente avanzato o metastatico che hanno ricevuto una precedente terapia con trastuzumab (+/- Pertuzumab) e taxane (KATE3).
    A.3.2Name or abbreviated title of the trial where available
    KATE3
    KATE3
    A.4.1Sponsor's protocol code numberMO42319
    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 SponsorF. HOFFMANN - LA ROCHE LTD.
    B.1.3.4CountrySwitzerland
    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 supportF.Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenentech Inc. c/o F. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 KADCYLA®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH - EU/1/13/885/002
    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 nameKADCYLA®
    D.3.2Product code [Trastuzumab Emtansine]
    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 INNTRASTUZUMAB EMTANSINE
    D.3.9.1CAS number 1018448-65-1
    D.3.9.2Current sponsor codeRO5304020
    D.3.9.3Other descriptive nameT-DM1, Trastuzumab-MCC-DM1
    D.3.9.4EV Substance CodeSUB35467
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    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 typeAntibody-drug conjugate comprised of a humanized monoclonal antibody (trastuzumab) and emtansine (DM1).
    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 Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH-EU/1/17/1220/001
    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 nameTecentriq
    D.3.2Product code [ATEZOLIZUMAB]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A, Anti-PDL1, Anti-PD-L1, aPDL1, PRO#303280
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 typeAntineoplastic agent, humanized immunoglobulin G1 (IgG1) monoclonal antibody.
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally advanced / metastatic breast cancer
    Tumore mammario localmente avanzato o metastatico
    E.1.1.1Medical condition in easily understood language
    Breast cancer where the tumor has spread to nearby tissues or lymph nodes (locally advanced breast cancer, LABC) or has spread to other parts of the body (metastatic breast cancer, MBC)
    Cancro al seno in cui il tumore si è diffuso ai tessuti o ai linfonodi vicini (carcinoma mammario localmente avanzato) o si è diffuso ad altre parti del corpo (carcinoma mammario metastatico)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER2 positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10072740
    E.1.2Term Locally advanced breast cancer
    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
    To demonstrate superiority of the experimental over the control treatment with respect to progression-free survival (PFS) and overall survival (OS).
    L’obiettivo primario dello studio consiste nel dimostrare la superiorità del trattamento sperimentale rispetto al trattamento di controllo nell’ambito della sopravvivenza libera da progressione e della sopravvivenza globale
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo beyond PFS and OS;
    • To evaluate the safety of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo;
    • To characterize the pharmacokinetics (PK) of trastuzumab emtansine and atezolizumab when given in combination;
    • To evaluate the immune response to atezolizumab and trastuzumab emtansine when given in combination.
    • valutare l’efficacia dell’associazione trastuzumab emtansine più atezolizumab rispetto a trastuzumab emtansine più placebo sulla base della sopravvivenza libera da progressione e della sopravvivenza globale
    • valutare la sicurezza dell’associazione trastuzumab emtansine più atezolizumab rispetto a trastuzumab emtansine più placebo
    • Caratterizzare la farmacocinetica di trastuzumab emtansine e atezolizumab somministrato in associazione
    • valutare la risposta immunitaria ad atezolizumab e trastuzumab emtansine somministrati in associazione
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age >= 18 years
    • Histologically determined HER2+/PD-L1+ LABC or MBC that is unresectable and who have received prior trastuzumab- (+/- pertuzumab) and taxane-based therapy
    • Measurable disease per RESIST version 1.1
    • Histologically centrally determined HER2+ and PD-L1+ of representative tumor tissue specimen(s) prior to randomization
    • For patients with bilateral breast cancer, HER2 positivity must be centrally determined preferably in a metastatic biopsy or if not available in primary tumor from both left and right breast; at least one biopsy must be centrally determined as PD-L1 positive
    • A formalin-fixed paraffin-embedded tumor specimen in a paraffin block or at least 17 slides containing unstained, freshly cut, serial sections must be submitted prior to study enrollment
    • Willing to provide blood samples before treatment start, while on-study, and at progression, for standard of care follow-up and exploratory research on biomarkers
    • Eastern Cooperative Oncology Group Performance Status of 0 or 1
    • Life expectancy >= 6 months
    • Adequate hematologic and end-organ function
    • Negative HIV test at screening
    • For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs during the treatment period and for 7 months after the final dose of study treatment
    • For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 7 months after the final dose of study treatment.
    • Età >= 18 anni
    • LABC o MBC inoperabile HER2+/PD-L1 precedente trattato con trastuzumab (+/- pertuzumab) e taxani
    • Malattia misurabile in base ai criteri RECIST v1.1.
    • Conferma mediante analisi prima della randomizzazione, di uno o più campioni di tessuto tumorale rappresentativi di HER2+ e PD-L1+
    • Per i pazienti con tumore mammario bilaterale la positività per HER2 dovrà essere confermata dall’analisi di un laboratorio centrale preferibilmente su un campione metastatico o, se non disponibile, su un campione del tumore primario di entrambe le mammelle; la positività per PD-L1 dovrà essere confermata dall’analisi in almeno un campione bioptico.
    • Fornitura di un campione di tessuto tumorale fissato in formalina e incluso in paraffina in un blocchetto di paraffina o di almeno 17 vetrini contenenti sezioni seriali appena tagliate prima dell’arruolamento nello studio.
    • Disponibilità a fornire campioni ematici prima dell’inizio del trattamento, nel corso dello studio e alla progressione della malattia per lo svolgimento del follow-up di cura standard e per la conduzione di analisi esplorative sui biomarcatori.
    • Eastern Cooperative Oncology Group (ECOG) pari a 0 o 1.
    • Aspettativa di vita >= 6 mesi.
    • Adeguata funzionalità ematologica, epatica e renale
    • Risultato negativo al test di screening per HIV
    • Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti o a fare uso di metodi contraccettivi, nonché consenso ad astenersi dalla donazione degli ovociti durante il periodo di trattamento e per 7 mesi dopo l’ultima dose del trattamento,
    • Per gli uomini: consenso a praticare l’astinenza dai rapporti o a far uso di metodi contraccettivi, nonché consenso ad astenersi dalla donazione del seme durante il periodo di trattamento e per 7 mesi dopo l’ultima dose del trattamento
    E.4Principal exclusion criteria
    • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to Cycle 1, Day 1
    • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
    • Receipt of any anti-cancer drug/biologic or investigational treatment 21 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility criteria
    • Prior treatment with trastuzumab emtansine in metastatic setting
    • History of exposure to protocol defined cumulative doses of anthracyclines
    • Symptomatic or actively progressing central nervous system metastases; asymptomatic CNS lesions = 2cm without clinical requirement for local intervention or asymptomatic patients with treated CNS lesions are eligible after fulfillment more detailed requirements of the protocol
    • History of leptomeningeal disease
    • Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
    • Uncontrolled tumor-related pain
    • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
    • Uncontrolled or symptomatic hypercalcemia
    • Current Grade >= 3 peripheral neuropathy (according to the NCI CTCAE v5.0)
    • Active hepatitis B and hepatitis C
    • Current treatment with anti-viral therapy for HBV
    • Active or history of autoimmune disease or immune deficiency
    • Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
    • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
    • Active tuberculosis
    • Cardiopulmonary dysfunction
    • Major surgical procedure, other than for diagnosis, or significant traumatic injury within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
    • History of other malignancy within the previous 5 years
    • Current severe, uncontrolled systemic disease
    • Prior allogeneic stem cell or solid organ transplantation
    • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
    • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of study treatment
    • Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
    • Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
    • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion proteins
    • Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
    • Known allergy or hypersensitivity to any component of the trastuzumab emtansine formulation
    • Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of study treatment.
    Infezione batterica, virale, fungina, micobatterica, parassitaria o di altro tipo o episodio rilevante di infezione necessitante terapia antibiotica e.v. o ricovero ospedaliero nelle 4w precedenti il G 1 del C 1.
    • Trattamento con antibiotici terapeutici per via orale o e.v. nelle 2w precedenti inizio trattamento.
    • Trattamento con qualsiasi farmaco sperimentale o antineoplastico/biologico nei 21 giorni precedenti il G 1 del C 1, ad eccezione della terapia ormonale, che potrà essere somministrata fino a 7 giorni prima del G 1 del C 1
    • Precedente trattamento con trastuzumab emtansine nel contesto metastatico.
    • Positività anamnestica per esposizione alle dosi cumulative di antracicline:
    • Metastasi a carico dell’SNC sintomatiche o in progressione attiva; lesioni a carico dell’SNC asintomatiche, <= 2 cm senza necessità clinica di intervento locale o pazienti asintomatici con lesioni a carico dell’SNC trattate saranno ritenuti idonei purché vengano soddisfatti i requisiti del protocollo
    • Positività anamnestica per malattia leptomeningea.
    • Compressione del midollo spinale non trattata con chirurgia e/o radioterapia oppure precedentemente diagnosticata e trattata senza evidenza di malattia clinicamente stabile per > 2w prima della randomizzazione.
    • Dolore correlato al tumore, non controllato.
    • Casi non controllati di versamento pleurico, versamento pericardico o ascite che richiedono procedure di drenaggio ricorrenti
    • Ipercalcemia non controllata o sintomatica
    • Neuropatia periferica in atto di grado >= 3
    • Epatite B o epatite C in fase attiva.
    • Terapia antivirale in corso per il trattamento dell’HBV.
    • Presenza attiva di o positività anamnestica per malattia autoimmune o immunodeficienza
    • Casi non controllati di anemia emolitica autoimmune o trombocitopenia immunitaria.
    • Positività anamnestica per fibrosi polmonare idiopatica, polmonite in organizzazione, polmonite indotta da farmaci o polmonite idiopatica, oppure evidenza di polmonite attiva alla tomografia computerizzata (TC) del torace in sede di screening.
    • Tubercolosi attiva.
    • Disfunzione cardiopolmonare
    • Procedura chirurgica maggiore, a scopo non diagnostico, o lesione traumatica significativa nelle 4w precedenti inizio del trattamento o necessità prevista di una procedura chirurgica maggiore durante lo studio.
    • Positività anamnestica per altra neoplasia maligna nei 5 anni precedenti
    • Malattia sistemica grave in atto, non controllata
    • Precedente trapianto allogenico di cellule staminali o di organi solidi.
    • Qualsiasi altra malattia, disfunzione metabolica, obiettività o referto di laboratorio che rappresenti una controindicazione all’uso di un farmaco sperimentale, che possa interferire con l’interpretazione dei risultati o che esponga il paziente ad alto rischio di complicanze correlate al trattamento.
    • Trattamento con un vaccino vivo attenuato nelle 4w precedenti inizio del trattamento o necessità prevista di somministrare un tale vaccino durante il trattamento con atezolizumab o nei 5 mesi successivi all’ultima dose del trattamento
    • Trattamento con immunostimolanti sistemici nelle 4w o 5 emivite di eliminazione del farmaco precedenti l’inizio del trattamento
    • Trattamento con immunosoppressori sistemici nelle 2w precedenti inizio del trattamento o necessità prevista di immunosoppressori sistemici durante il trattamento
    • Positività anamnestica per reazioni allergiche o anafilattiche gravi o altre reazioni da ipersensibilità agli anticorpi chimerici o umanizzati, agli eccipienti di qualsiasi farmaco contenente polisorbato 80 o 20 nella formulazione o alle proteine di fusione.
    • Ipersensibilità nota ai prodotti derivati da cellule ovariche di criceto cinese o a qualsiasi componente della formulazione di atezolizumab.
    • Allergia o ipersensibilità nota a qualsiasi componente della formulazione di trastuzumab emtansine.
    • Gravidanza o allattamento o intenzione di iniziare una gravidanza durante lo studio o nei 7 mesi successivi ultima dose trattamento
    E.5 End points
    E.5.1Primary end point(s)
    1. Progression-free survival (investigator assessed)
    2. Overall survival
    1. sopravvivenza libera da progressione (valutata dallo sperimentatore)
    2. sopravvivenza globale
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-2. Up to 78.1 months.
    1-2. Fino a 78.1 mesi
    E.5.2Secondary end point(s)
    1. Objective response rate
    2. Duration of response
    3. Progression-free survival by a blinded independent central review committee
    4. Progression-free survival in patients with baseline brain metastases
    5. Overall survival in patients with baseline brain metastases
    6. Central nervous system progression-free survival
    7. Mean absolute and mean change-from-baseline scores in function (Physical, Role) and global health status/quality of life (QoL) as measured by the scales of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30
    8. The proportion of patients with clinically meaningful deterioration in GHS/QoL physical, and role function as measured by scales of the EORTC QLQ-C30
    9. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
    10. Change from baseline in targeted clinical laboratory test results
    11. Presence, frequency of occurrence, severity, and/or degree of interference with daily function of selected symptomatic treatment toxicities, as measured by the National Cancer Institute Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument
    12. Change from baseline in symptomatic treatment toxicities, as measured by the PRO-CTCAE at pre-specified time points and an additional item regarding the overall burden experienced due to side effects of treatment from the EORTC item library
    13. Serum concentration of atezolizumab, trastuzumab emtansine, total trastuzumab, and plasma DM1, versus time
    14. To characterize the prevalence and incidence of anti-drug antibody (ADA) to atezolizumab in the presence of trastuzumab emtansine at pre-specified timepoints
    15. To characterize the prevalence and incidence of ADA to trastuzumab emtansine in the presence and absence of atezolizumab at pre-specified timepoints
    1. Tasso di risposta obiettiva
    2. Durata della risposta obiettiva
    3. Sopravvivenza libera da progressione valutata in cieco da un comitato di revisione centrale indipendente
    4. Sopravvivenza libera da progressione nei pazienti con metastasi cerebrali al basale
    5. Sopravvivenza globale nei pazienti con metastasi cerebrali al basale
    6. Sopravvivenza libera da progressione a livello del sistema nervoso centrale
    7. Media assoluta e variazioni medie rispetto ai punteggi basali delle scale funzionali e delle condizioni generali di salute/della qualità di vita misurate mediante il questionario sulla qualità della vita (EORTC QLQ-C30);
    8. Percentuale di pazienti con peggioramento clinicamente significativo in GHS/QoL e nelle dimensioni “funzionamento fisico” e “funzionamento di ruolo”, misurata mediante lo strumento EORTC QLQ-C30
    9. Incidenza e severità degli eventi avversi, con grado di severità determinato utilizzando i criteri comuni di terminologia per gli eventi avversi del National Cancer Institute versione 5.0 (NCI CTCAE v5.0)
    10. Variazione, rispetto al basale, dei risultati delle analisi cliniche target di laboratorio
    11. Presenza, frequenza di manifestazione, severità e/o grado di interferenza con la funzionalità quotidiana di una selezione di tossicità sintomatiche correlate al trattamento valutati secondo lo strumento NCI CTCAE integrato mediante l’acquisizione degli esiti riferiti dai pazienti PRO; PRO-CTCAE
    12. Variazione, rispetto al basale, delle tossicità sintomatiche correlate al trattamento, misurata mediante lo strumento PRO-CTCAE a punti temporali predeterminati e di un item supplementare riguardante il fastidio complessivo arrecato dagli effetti indesiderati del trattamento, derivato dall’apposita libreria EORTC.
    13. Concentrazione sierica di atezolizumab, trastuzumab emtansine, trastuzumab totale e DM1 plasmatico, rispetto al tempo
    14. Caratterizzare la prevalenza e l’incidenza degli anticorpi antifarmaco (Anti-Drug Antibody, ADA) diretti contro atezolizumab in presenza di trastuzumab emtansine a punti temporali predefiniti;
    15. Caratterizzare la prevalenza e l’incidenza degli ADA diretti contro trastuzumab emtansine in presenza e in assenza di atezolizumab a punti temporali predefiniti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-6. Up to 78.1 months
    7-8. Day 1 of Cycle 1-3, 5, 7, 9, 11, 13, every second cycle thereafter, at study discontinuation (SD)/early discontinuation (ED) visit, 3 months after SD/ED visit
    9. Up to 78.1 months
    10. Up to 78.1 months
    11. Up to 78.1 months
    12. Up to 78.1 months
    13. For atezolizumab: Day 1 of Cycle 1-4, 8, every 8 cycles thereafter, at SD/ED; for trastuzumab emtansine, total trastuzumab: Day 1 of Cycle 1, 2 and 4, SD/ED; for DM1: Day 1 of Cycle 1, 2 and 4
    14. Day 1 of Cycle 1-4, 8, every 8 cycles thereafter, SD/ED
    15. Day 1 of Cycle 1, 2 and 4, SD/ED
    1-6. Fino a 78.1 mesi
    7-8. Giorno 1 del ciclo 1-3, 5, 7, 9, 11, 13, successivamente ogni secondo ciclo, alla visita di interruzione dello studio (SD) / interruzione anticipata (ED), 3 mesi dopo la visita di SD / ED
    9. Fino a 78.1 mesi
    10. Fino a 78.1 mesi
    11. Fino a 78.1 mesi
    12. Fino a 78.1 mesi
    13. Per atezolizumab: giorno 1 del ciclo 1-4, 8, successivamente ogni 8 cicli, a SD / ED; per trastuzumab emtansine, trastuzumab totale: giorno 1 del ciclo 1, 2 e 4, SD / ED; per DM1: giorno 1 del ciclo 1, 2 e 4
    14. Giorno 1 del ciclo 1-4, 8, successivamente ogni 8 cicli, SD / ED
    15. Giorno 1 del ciclo 1, 2 e 4, SD / ED
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, biomarker, health status (patient-reported outcomes)
    Immunogenicità, biomarcatore, stato di salute (risultati riportati dai pazienti)
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    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
    Brazil
    Canada
    China
    Colombia
    Croatia
    Egypt
    Finland
    France
    Germany
    Greece
    Hungary
    Italy
    Korea, Republic of
    Mexico
    Norway
    Philippines
    Poland
    Portugal
    Russian Federation
    Slovenia
    Spain
    Turkey
    United Kingdom
    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 end of study is planned to occur after approximately 184 OS events are obtained (approximately 40 months after the primary efficacy analysis of PFS [and concurrent first interim analysis of OS]). The end of this study is defined as the date when the last patient, last visit occurs, or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later.
    La fine dello studio, che è prevista verificarsi dopo la registrazione di circa 184 eventi di OS (circa 40 mesi dopo l’analisi primaria di efficacia relativa alla PFS [e la prima e concomitante analisi ad interim dell’OS]), coinciderà con la data di esecuzione dell’ultima visita dell’ultimo paziente o con la data di ricezione degli ultimi dati necessari per l’analisi statistica o il follow-up per la sicurezza dell’ultimo paziente, a seconda della circostanza che si verificherà per ultima.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 210
    F.4.2.2In the whole clinical trial 350
    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)
    The Sponsor will offer continued access to Roche IMPs (trastuzumab emtansine and atezolizumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following website: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    Patients may be eligible to receive trastuzumab emtansine or trastuzumab emtansine in combination with atezolizumab as part of an extension study.
    Lo Sponsor offrirà l'accesso continuo agli IMP Roche (trastuzumab emtansine e atezolizumab) gratuitamente ai pazienti idonei in conformità con la Roche Global Policy, disponibile sul seguente sito web: http: //www.roche. it / policy_continued_access_to_investigational_medicines.pdf
    I pazienti possono essere idonei a ricevere trastuzumab emtansine o trastuzumab emtansine in combinazione con atezolizumab come parte di uno studio di estensione.
    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 Decision2021-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-04
    P. End of Trial
    P.End of Trial StatusOngoing
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