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    Summary
    EudraCT Number:2018-003172-12
    Sponsor's Protocol Code Number:KY1044-CT01
    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:2021-01-22
    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 number2018-003172-12
    A.3Full title of the trial
    A Phase 1/2, open-label, multi-center study of the safety and efficacy of KY1044 as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies
    Studio multicentrico, di fase 1/2, in aperto per valutare la sicurezza e l’efficacia di KY1044 come agente singolo e in combinazione con anti-PD-L1 (atezolizumab) in pazienti adulti con tumori maligni selezionati in stadio avanzato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2, open-label, multi-center study of the safety and efficacy of KY1044 as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies
    Studio multicentrico, di fase 1/2, in aperto per valutare la sicurezza e l’efficacia di KY1044 come agente singolo e in combinazione con anti-PD-L1 (atezolizumab) in pazienti adulti con tumori maligni selezionati in stadio avanzato
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberKY1044-CT01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03829501
    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 SponsorKymab Limited
    B.1.3.4CountryUnited Kingdom
    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 supportKymab Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKymab Ltd
    B.5.2Functional name of contact pointClinical trials information Kymab
    B.5.3 Address:
    B.5.3.1Street AddressThe Bennet Building (B930), Babraham Research Campus
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeCB22 3AT
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailClinicaltrial@kymab.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 nameKY1044
    D.3.2Product code [KY1044]
    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 INNKY1044
    D.3.9.2Current sponsor codeKY1044
    D.3.9.4EV Substance CodeSUB195238
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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: 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
    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 nameAtezolizumab
    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 1380723-44-1
    D.3.9.2Current sponsor codeTECENTRIQ
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1200
    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 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.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/metastatic malignancies, and preferred indications: head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), esophageal cancer, gastric cancer, melanoma, renal cell cancer, pancreatic cancer, cervical cancer, and triple negative breast cancer (BC)
    Tumori maligni in stadio avanzato/metastatici e indicazioni preferenziali: carcinoma della testa e del collo a cellule squamose (HNSCC), carcinoma polmonare non a piccole cellule (NSCLC), carcinoma epatocellulare (HCC), carcinoma esofageo, carcinoma gastrico, melanoma, carcinoma a cellule renali, carcinoma pancreatico, carcinoma della cervice e carcinoma mammario (BC) triplo negativo
    E.1.1.1Medical condition in easily understood language
    selected advanced malignancies
    Tumori maligni in stadio avanzato/metastatici specifici
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10015362
    E.1.2Term Esophageal 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 PT
    E.1.2Classification code 10063916
    E.1.2Term Metastatic gastric 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 10008229
    E.1.2Term Cervical 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 PT
    E.1.2Classification code 10075566
    E.1.2Term Triple negative 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 10077738
    E.1.2Term Hepatocellular carcinoma metastatic
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10033609
    E.1.2Term Pancreatic carcinoma
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10038389
    E.1.2Term Renal 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 PT
    E.1.2Classification code 10025650
    E.1.2Term Malignant melanoma
    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 PT
    E.1.2Classification code 10017758
    E.1.2Term Gastric 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 21.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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 PT
    E.1.2Classification code 10029515
    E.1.2Term Non-small cell lung cancer recurrent
    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 10007416
    E.1.2Term Carcinoma liver
    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
    Phase 1:
    To characterize the safety and tolerability of KY1044 as single agent and in combination with atezolizumab and to identify recommended doses for future studies.

    Phase 2:
    To estimate the anti-tumor efficacy of KY1044 as single agent and in combination with atezolizumab.
    Fase 1:
    caratterizzare la sicurezza e la tollerabilità di KY1044 come agente singolo e in combinazione con atezolizumab e identificare le dosi raccomandate per gli studi futuri

    Fase 2:
    stimare l’efficacia antitumorale di KY1044 come agente singolo e in combinazione con atezolizumab
    E.2.2Secondary objectives of the trial
    - To evaluate the preliminary anti-tumor activity of KY1044 as single agent and in combination with atezolizumab (Phase 1 only)
    - To characterize the safety and tolerability of KY1044 as single agent and in combination with atezolizumab (Phase 2 only)
    - To characterize the PK profile of KY1044 as single agent and in combination with atezolizumab
    - To assess emergence of anti-KY1044 and anti-atezolizumab antibodies following one or more i.v. infusions of KY1044 single agent and/or in combination with atezolizumab
    - To assess changes in biomarkers
    - To describe the survival rate at 12 and 24 months of patients treated with KY1044 as single agent and in combination with atezolizumab for each disease group
    - Valutare l’attività antitumorale preliminare di KY1044 come agente singolo e in combinazione con atezolizumab (solo Fase 1)
    - Caratterizzare la sicurezza e la tollerabilità di KY1044 come agente singolo e in combinazione con atezolizumab (solo Fase 2)
    - Caratterizzare il profilo PK di KY1044 come agente singolo e in combinazione con atezolizumab
    - Valutare la comparsa di anticorpi anti-KY1044 e anti-atezolizumab in seguito a una o più infusioni e.v. di KY1044 come agente singolo e/o in combinazione con atezolizumab, rispettivamente
    - Valutare le variazioni nei biomarcatori rispetto al basale nel tessuto tumorale come potenziali predittori di efficacia di KY1044 come agente singolo e in combinazione con atezolizumab
    - Descrivere il tasso di sopravvivenza a 12 e 24 mesi dei pazienti trattati con KY1044 come agente singolo e in combinazione con atezolizumab per ciascun gruppo di malattia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study must meet all of the following criteria:
    1. Written informed consent must be obtained prior to any procedures
    2. Age =18 years (=20 years in Taiwan)
    3. Histologically documented advanced/metastatic malignancies
    4. Phase 1 and Phase 2 patients with advanced/metastatic malignancies who have measurable disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 will be eligible if, according to the NCCN guidelines, there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options. Additionally, the following specific tumor indications will be enrolled:
    a. Phase 1 (including enrichment part):
    Patients with advanced/metastatic malignancies, and preferred indications as identified in Section 3.1 (NSCLC, HNSCC, HCC, melanoma, cervical, esophageal, gastric, renal, pancreatic, and triple negative BC)
    b. Phase 2 KY1044 single agent:
    Patients with advanced/metastatic malignancies in indications in which signs of anti tumor activity (CR, PR or durable SD with tumor shrinkage that does not qualify for PR) were seen during the dose escalation of KY1044 as single agent.
    c. Phase 2 KY1044 in combination with atezolizumab:
    Patients with advanced/metastatic malignancies in the below selected indications, and/or indications which have shown promising activity in Phase 1:
    • NSCLC (anti PD (L)1 therapy naïve and pre treated)
    • Gastric (anti PD (L)1 therapy naïve and pre treated)
    • HNSCC (anti PD (L)1 therapy naïve and pre treated)
    • Esophageal (anti PD (L)1 therapy naïve and pre treated)
    • Cervical (anti PD (L)1 therapy naïve and pre treated)
    Indications, in which signs of anti tumor activity has been observed in Phase 1 with KY1044 in combination with atezolizumab
    5. Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy
    6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
    7. Life expectancy longer than 12 weeks
    8. Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and during therapy on the study
    9. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for at least 5 months after discontinuing study treatment, or longer if the half-life of KY1044 is observed to exceed that of atezolizumab
    10. For the duration of study participation and for at least 5 months after discontinuing study treatment, or longer if the half-life of KY1044 is observed to exceed that of atezolizumab, sexually active males must use barrier contraception (i.e., condoms).
    Per essere idonei all’inclusione in questo studio, i/le pazienti devono soddisfare tutti i seguenti
    criteri:
    1. Deve essere acquisito il consenso informato scritto prima dell’avvio di qualsiasi procedura
    2. Età =18 anni (=20 anni a Taiwan)
    3. Malignità in stadio avanzato/metastatico con documentazione istologica
    4. I/Le pazienti in fase 1 e fase 2 con malignità in stadio avanzato/metastatico che presentano malattia misurabile (la malattia non-misurabile è consentita solo nella fase 1) come determinato dai criteri di valutazione della risposta nei tumori solidi (RECIST) 1.1 (consultare l’allegato 2) saranno idonei/e se, in base alle linee guida della rete globale nazionale antitumore (NCCN), non sono disponibili terapie conosciute in grado di apportare un beneficio clinico alla loro malattia o se hanno esaurito tali opzioni disponibili. Inoltre, saranno arruolate le seguenti indicazioni tumorali specifiche:
    a. Fase 1 (incluse le parti di arricchimento):
    Pazienti con malignità in stadio avanzato/metastatico e indicazioni preferite come identificate nella sezione 3.1 (carcinoma polmonare non a piccole cellule [NSCLC], carcinoma squamocellulare della testa e del collo [HNSCC], carcinoma epatocellulare [HCC], melanoma, carcinoma della cervice, esofageo, gastrico, renale, pancreatico e tumore al seno triplo negativo)
    b. Fase 2 con KY1044 come agente singolo: Pazienti con malignità in stadio avanzato/metastatico nelle indicazioni in cui siano stati osservati segni di attività antitumorale (risposta completa [CR], risposta parziale [PR] o deviazione standard [SD] duratura con riduzione del tumore che non si è qualificata come PR) durante l’incremento progressivo della dose di KY1044 come agente singolo.
    c. Fase 2 con KY1044 in combinazione con atezolizumab: Pazienti con malignità in stadio avanzato/metastatico nelle indicazioni selezionate di seguito e/o nelle indicazioni che abbiano mostrato attività promettente durante la fase 1:
    • NSCLC (naïve e precedentemente sottoposti/e alla terapia anti-PD-[L]1)
    • Carcinoma gastrico (naïve e precedentemente sottoposti/e alla terapia anti-PD-[L]1)
    • HNSCC (naïve e precedentemente sottoposti/e alla terapia anti-PD-[L]1)
    • Carcinoma esofageo (naïve e precedentemente sottoposti/e alla terapia anti-PD-[L]1)
    • Carcinoma della cervice (naïve e precedentemente sottoposti/e alla terapia anti-PD-[L]1)
    Indicazioni nelle quali siano stati osservati segni di attività antitumorale nella Fase 1 con KY1044 in combinazione con atezolizumab
    5. La precedente terapia con inibitori anti-PD-(L)1 è consentita a condizione che eventuali tossicità attribuite alla precedente terapia mirata anti-PD-(L)1 non abbiano portato all’interruzione della terapia
    6. Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) pari a 0-1
    7. Aspettativa di vita superiore a 12 settimane
    8. Il/La paziente deve presentare un sito di malattia idoneo alla biopsia e deve essere candidato/a alla biopsia tumorale, secondo le linee guida terapeutiche istituzionali. Il/La paziente deve essere disposto/a a sottoporsi a una nuova biopsia tumorale allo screening e durante la terapia nel corso dello studio
    9. Prima di prender parte allo studio, per la durata della partecipazione allo studio e per almeno 5 mesi dopo l'interruzione del trattamento di studio, o per più tempo se si osserva che l'emivita di KY1044 supera quella di atezolizumab, le pazienti in età fertile e gli uomini dovranno usare due metodi contraccettivi altamente efficaci (ormonali, metodi contraccettivi a barriera, astinenza)
    10. Per la durata della partecipazione allo studio e per almeno 5 mesi dopo l'interruzione del trattamento di studio, o per più tempo se si osserva che l'emivita di KY1044 supera quella di atezolizumab, i soggetti maschili sessualmente attivi dovranno usare metodi contraccettivi a barriera (come i profilattici).
    E.4Principal exclusion criteria
    Patients eligible for this study must not meet any of the following criteria:
    1. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks of first dose of study treatment. Patients with treated brain metastasis unless neurologically stable (for 4 weeks posttreatment and prior to study enrolment) and off of steroids for at least 2 weeks before the first dose of study treatment
    2. History of severe hypersensitivity reactions to other mAbs and/or their excipients
    3. Known presence of neutralizing anti-atezolizumab antibodies (for patients previously treated with atezolizumab)
    4. Having out of range laboratory values (creatinine, bilirubin, ALT, AST, Absolute neutrophil count , Platelet count, Hemoglobin)
    5. Impaired cardiac function or clinically significant cardiac disease,
    including any of the following:
    - Clinically significant and/or uncontrolled heart disease such as
    congestive heart failure requiring treatment, uncontrolled hypertension
    or clinically significant arrhythmia
    - QTcF >470 msec on screening ECG or congenital long QT syndrome
    - Acute myocardial infarction or unstable angina pectoris <3 months prior to first dose of study treatment
    6. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
    7. Malignant disease, other than that being treated in this study.
    8. Any medical condition that would, in the Investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
    9. Active autoimmune disease or a documented history of autoimmune disease
    10. Patients previously exposed to anti-PD-(L)1 treatment who are not adequately treated for skin rash or had no replacement therapy for endocrinopathies should be excluded
    11. Patients with a history of drug-induced pneumonitis or current pneumonitis
    12. Systemic steroid therapy or any immunosuppressive therapy. Topical, inhaled, nasal, and ophthalmic steroids are not prohibited
    13. Herbal preparations/medications (including, but not limited to: St.
    John's Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng) are prohibited from the time that patients enter the screening period (at least 7 days prior to first dose of study treatment) until the last dose of study treatment (3 weeks for St John's Wort)
    14. Warfarin and other types of long acting anticoagulants is prohibited within 4 weeks of the first dose of study treatment and patients requiring anticoagulant treatment should switch to low molecular weight heparin
    15. Use of life attenuated vaccines against infectious diseases within 4 weeks of the first dose of study treatment
    16. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, 4 weeks is indicated as washout period
    17. Major surgery within 2 weeks of the first dose of study treatment
    Per essere idonei/e all’inclusione in questo studio, i/le pazienti non devono soddisfare uno qualsiasi dei seguenti criteri:
    1. Presenza di metastasi sintomatiche nel SNC o metastasi del SNC per cui sia necessaria la terapia locale diretta al SNC o dosi crescenti di corticosteroidi entro le 2 settimane precedenti la prima dose del trattamento dello studio. Pazienti con metastasi del cervello sottoposte a trattamento a meno che neurologicamente stabili (per 4 settimane dopo il trattamento e prima dell’arruolamento nello studio) e senza steroidi per almeno 2 settimane prima della prima dose di trattamento dello studio
    2. Anamnesi di gravi reazioni di ipersensibilità ad altri anticorpi monoclonali (mAb) e/o ai rispettivi eccipienti
    3. Presenza nota di anticorpi neutralizzanti anti-atezolizumab (per i pazienti precedentemente trattati con atezolizumab)
    4. Presenza di valori di laboratorio al di fuori del range (creatinina, bilirubina, alanina aminotransferasi [ALT], aspartato aminotransferasi [AST], conteggio assoluto dei neutrofili, conteggio delle piastrine, emoglobina)
    5. Compromissione della funzione cardiaca o cardiopatia clinicamente significativa, compresa una qualsiasi tra le seguenti condizioni:
    - Cardiopatia clinicamente significativa e/o non controllata, come insufficienza cardiaca congestizia che richiede un trattamento, ipertensione non controllata o aritmia clinicamente significativa
    - Intervallo QT corretto con la formula di Fridericia (QTcF) >470 msec all’ECG di screening o sindrome congenita del QT lungo
    - Infarto miocardico acuto o angina pectoris instabile <3 mesi prima della prima dose di trattamento dello studio
    6. Nota infezione da virus dell’immunodeficienza umana (HIV), virus dell’epatite B (HBV) attiva o virus dell’epatite C (HCV) attiva.
    7. Malattia maligna diversa da quella oggetto di trattamento nel presente studio.
    8. Qualsiasi condizione medica che, a giudizio dello sperimentatore, impedirebbe la partecipazione del/della paziente allo studio clinico a causa di problemi di sicurezza, la conformità alle procedure dello studio clinico o interpretazione dei risultati di studio
    9. Malattia autoimmune attiva o anamnesi documentata di malattia autoimmune
    10. I/Le pazienti precedentemente esposti/e al trattamento anti-PD-(L)1, non adeguatamente trattati/e per eruzione cutanea o per i/le quali non sia stata disponibile alcuna terapia sostitutiva in caso di endocrinopatie, devono essere esclusi/e
    11. Pazienti con una anamnesi di polmonite farmaco-indotta o polmonite in corso
    12. Terapia steroidea sistemica o qualsiasi terapia immunosoppressiva. Gli steroidi topici, da inalazione, nasali e oftalmici non sono proibiti
    13. Sono proibiti i preparati/farmaci a base di erbe (che includono, a titolo meramente esemplificativo: iperico, kava, efedra (Ma Huang), gingko biloba, deidroepiandrosterone, yohimbina, saw palmetto e ginseng) dal momento in cui i/le pazienti entrano nel periodo di screening (almeno 7 giorni precedenti la prima dose di trattamento dello studio) fino all’ultima dose di trattamento dello studio (3 settimane per l’iperico)
    14. Sono proibiti warfarin e altri tipi di anticoagulanti ad azione prolungata nelle 4 settimane precedenti la prima dose di trattamento dello studio e i/le pazienti che necessitano del trattamento anticoagulante devono passare all’eparina a basso peso molecolare
    15. Uso di vaccini vivi attenuati contro malattie infettive nelle 4 settimane precedenti la prima dose di trattamento dello studio
    16. Terapia antitumorale sistemica nelle 2 settimane precedenti la prima dose di trattamento dello studio. Per gli agenti citotossici che presentano tossicità maggiori ritardate, è indicato un periodo di washout di 4 settimane
    17. Intervento chirurgico maggiore nelle 2 settimane precedenti la prima dose di trattamento dello studio
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    - Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and electrocardiograms (ECGs)
    - Tolerability: Dose interruptions, reductions and dose intensity
    - The incidence of DLTs with KY1044 as single agent during the first 21 days of treatment
    - The incidence of DLTs with KY1044 in combination with atezolizumab during the first 21 days of treatment

    Phase 2
    - ORR per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    Fase 1:
    - Sicurezza: Incidenza e gravità di EA e SAE, comprese variazioni nei parametri di laboratorio, nei segni vitali e negli ECG
    - Tollerabilità: Interruzioni e riduzioni della dose e intensità della dose
    - Incidenza di tossicità limitanti la dose (DLT) con KY1044 come agente singolo durante i primi 21 giorni di trattamento
    - Incidenza di DLT con KY1044 in combinazione con atezolizumab durante i primi 21 giorni di trattamento

    Fase 2:
    - Tasso di risposta complessiva (ORR) secondo i criteri RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1
    Safety evaluation and assessment of AEs throughout the study

    Phase 2
    Tumor Imaging RECIST 1.1: at screening, every 8 weeks (±7 days) after the start of treatment for the first 16 weeks, after that every 12 weeks (±7 days) till the end of 24 months of treatment or until objective disease progression
    Fase 1
    Valutazione della sicurezza e valutazione degli eventi avversi durante lo studio

    Fase 2
    Imaging RECIST del tumore 1.1: allo screening, ogni 8 settimane (± 7 giorni) dopo l'inizio del trattamento per le prime 16 settimane, successivamente ogni 12 settimane (± 7 giorni) fino alla fine di 24 mesi di trattamento o fino alla progressione obiettiva della malattia
    E.5.2Secondary end point(s)
    Efficacy measures:
    - Best Overall Response (BOR), PFS and Duration of Response (DOR) per RECIST 1.1;
    - ORR and PFS per immune-related (i)RECIST (Phase 1 and Phase 2)
    - ORR per RECIST 1.1 (Phase 1 only)
    - Survival rate at 12 and 24 months

    Safety:
    - Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs (Phase 2)
    - Tolerability: Dose interruptions, reductions and dose intensity (Phase 2)

    PK measures:
    - KY1044 PK measures (e.g., Cmax, half-life); Serum concentration vs. time profiles

    Anti-drug antibodies:
    - Presence and/or concentration of anti-KY1044 and anti-atezolizumab antibodies

    Biomarkers
    Misure di efficacia
    - Migliore risposta complessiva (BOR), sopravvivenza libera da progressione (PFS) e durata della risposta (DOR) secondo i criteri RECIST 1.1
    - ORR e PFS secondo i criteri iRECIST (Fase 1 e Fase 2)
    - ORR secondo i criteri RECIST 1.1 (solo Fase 1)
    - Tasso di sopravvivenza a 12 e 24 mesi

    Sicurezza:
    - Incidenza e gravità di EA e SAE, comprese variazioni nei parametri di laboratorio, nei segni vitali e negli ECG (Fase 2)
    - Tollerabilità: Interruzioni e riduzioni della dose e intensità della dose (Fase 2)

    Misure PK:
    - Misure della PK di KY1044 (per es. concentrazione massima [Cmax], emivita); profili di concentrazione sierica vs tempo
    ADA:
    - Presenza e/o concentrazione di anticorpi anti-KY1044 e anti-atezolizumab

    Biomarcatori
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy measures:
    - Tumor Imaging RECIST 1.1: at screening, every 8 weeks after the start of treatment for the first 16 weeks, after that every 12 weeks till the end of 24 months of treatment or until objective disease progression
    Safety:
    - Safety evaluation and assessment of AEs throughout the study
    - Tolerability assessed throughout the study
    PK measures; PK samples will be taken pre- and post-dose during all cycles and unscheduled at any time, when clinically indicated
    Anti-drug antibodies; ADA samples are collected at every cycle at pre-dose on Day 1 and unscheduled at any time, when clinically indicated
    Biomarkers
    Misure di efficacia:
    - Tumor Imaging RECIST 1.1: allo screening, ogni 8 settimane dopo l'inizio del trattamento per le prime 16 settimane, successivamente ogni 12 settimane fino alla fine di 24 mesi di trattamento o fino alla progressione obiettiva della malattia
    Sicurezza:
    - Valutazione della sicurezza e valutazione degli eventi avversi durante lo studio
    - Tollerabilità valutata durante lo studio
    Misure PK; I campioni di PK saranno prelevati prima e dopo la dose durante tutti i cicli e non programmati in qualsiasi momento, quando clinicamente indicato
    Anticorpi anti-droga; I campioni ADA vengono raccolti ad ogni ciclo al momento della pre-dose il primo giorno e non programmati in qualsiasi momento, quando clinicamente indicato
    biomarkers
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) No
    E.8.2.2Placebo No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Germany
    Italy
    Spain
    Taiwan
    United Kingdom
    United States
    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 completion of the study is defined as the last visit for the last patient on treatment (for patients, who stopped treatment earlier follow-up will be ended at this point).
    Il completamento dello studio è definito come l'ultima visita per l'ultimo paziente in trattamento (per i pazienti che hanno interrotto in precedenza il trattamento il follow-up sarà terminato a questo punto)
    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 months8
    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 months4
    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: 82
    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 state82
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 412
    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)
    Additional provisions for treatment continuation will be made for patients who are ongoing on treatment and having clinical benefit at 24 months.
    Ulteriori disposizioni per il proseguimento del trattamento saranno fatte per i pazienti in corso di trattamento e con beneficio clinico a 24 mesi.
    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 Decision2019-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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