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    Summary
    EudraCT Number:2021-006812-10
    Sponsor's Protocol Code Number:BBI-20201001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2022-09-14
    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 number2021-006812-10
    A.3Full title of the trial
    Phase 1/2 Study of BDC 1001 as a Single Agent and in Combination with Nivolumab in Patients with Advanced HER2-Expressing Solid Tumors.
    Studio di fase I/II su BDC-1001 in monoterapia e in combinazione con nivolumab in pazienti affetti da tumori solidi avanzati con espressione di HER2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1/2 Study of BDC 1001 as a Single Agent and in Combination with Nivolumab in Patients with Advanced HER2-Expressing Solid Tumors.
    Studio di fase I/II su BDC-1001 in monoterapia e in combinazione con nivolumab in pazienti affetti da tumori solidi avanzati con espressione di HER2.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    N/A
    A.4.1Sponsor's protocol code numberBBI-20201001
    A.5.4Other Identifiers
    Name:IND 142439Number:IND 142439
    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 SponsorBolt Biotherapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBolt Biotherapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBolt Biotherapeutics, Inc.
    B.5.2Functional name of contact pointJonathan Harris
    B.5.3 Address:
    B.5.3.1Street Address900 Chesapeake Drive
    B.5.3.2Town/ cityRedwood City, CA
    B.5.3.3Post code94063
    B.5.3.4CountryUnited States
    B.5.4Telephone number0014158718593
    B.5.6E-mailjharris@boltbio.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 nameBDC-1001
    D.3.2Product code [BDC-1001]
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    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 INNTLR7/8
    D.3.9.2Current sponsor codeA00104
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3500
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.2Current sponsor codeN/A
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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: 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 OPDIVO 10 mg/mL Concentrato per soluzione per infusione
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameOPDIVO 10 mg/mL Concentrato per soluzione per infusione
    D.3.2Product code [N/A]
    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 INNNIVOLUMAB
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 HER2-Expressing Solid Tumors
    tumori solidi avanzati con espressione di HER2
    E.1.1.1Medical condition in easily understood language
    Advanced HER2-Expressing Solid Tumors
    tumori solidi avanzati con espressione di HER2
    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 10075638
    E.1.2Term HER2 protein overexpression
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10075653
    E.1.2Term HER2 gene amplification
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Dose Escalation (Part 1 & 2):
    Define the safety and tolerability of BDC 1001 as monotherapy (Part 1) and in combination with nivolumab (Part 2) in patients with advanced HER2-expressing solid tumors.
    Determine the RP2D for BDC 1001 as monotherapy (Part 1) and in combination with nivolumab (Part 2) in patients with advanced HER2-expressing solid tumors.
    Dose Expansion (Parts 3 & 4):
    Evaluate preliminary antitumor activity of BDC 1001 as monotherapy (Part 3) and in combination with nivolumab (Part 4) in patients with advanced HER2-expressing solid tumors.
    All:
    Evaluate exploratory pharmacodynamic biomarkers of BDC 1001 biological activity as monotherapy (Parts 1 and 3) or in combination with nivolumab (Parts 2 and 4) in tumor tissue and peripheral blood in patients with advanced HER2-expressing solid tumors.
    Explore potential baseline biomarkers associated with BDC 1001 biological activity as monotherapy (Parts 1 and 3) or in combination with nivolumab (Parts 2 and 4).
    Aumento della dose (Parte 1,2):
    Definire la sicurezza e la tollerabilità di BDC-1001 in monoterapia (P.1) e in combinazione con nivolumab (P.2) in pazienti affetti da tumori solidi avanzati HER2+.
    Determinare la RP2D di BDC-1001 in monoterapia (P.1) e in combinazione con nivolumab (P.2) in pazienti affetti da tumori solidi avanzati HER2+
    Espansione della dose (P.3,4):
    Valutare l'attività antitumorale preliminare di BDC-1001 in monoterapia (P.3) e in combinazione con nivolumab (P.4) in pazienti affetti da tumori solidi avanzati HER2+
    Tutte le parti:
    Valutare i biomarcatori farmacodinamici esplorativi dell'attività biologica di BDC-1001 in monoterapia (Parti 1,3) o in combinazione con
    nivolumab (Parti 2, 4) nel tessuto tumorale e nel sangue periferico in pazienti affetti da tumori solidi avanzati HER2+.
    Esplorare i potenziali biomarcatori al basale associati all'attività biologica di BDC-1001 in monoterapia (Parti 1,3) o in combinazione con nivolumab (Parti 2, 4)
    E.2.2Secondary objectives of the trial
    Dose Escalation (Part 1 & 2):
    Part 1:
    To analyze PK characteristics of BDC 1001 in patients with advanced HER2 expressing solid tumors. To evaluate preliminary antitumor activity of BDC 1001 as monotherapy (Part 1) and in combination with nivolumab (Part 2) in patients with advanced HER2-expressing solid tumors.
    To evaluate the immunogenicity of BDC 1001 as monotherapy (Part 1) and in combination with nivolumab (Part 2) in patients with advanced HER2-expressing solid tumors.
    Dose Expansion (Parts 3 & 4):
    To define the safety and tolerability of BDC 1001 as monotherapy (Part 3) and in combination with nivolumab (Part 4) in patients with advanced HER2-expressing solid tumors.
    To verify the exposure of BDC 1001.
    To evaluate the immunogenicity of BDC 1001 as monotherapy (Part 3) or in combination with nivolumab (Part 4) in patients with advanced HER2-expressing solid tumors.
    Aumento della dose (Part1,2):
    Part 1: Analizzare le caratteristiche PK di BDC-1001 in pazienti affetti da tumori solidi avanzati con espressione di HER2.
    Valutare l'attività antitumorale preliminare di BDC-1001 in monoterapia (Parte 1) e in combinazione con nivolumab (Parte 2) in pazienti affetti da tumori solidi avanzati con espressione di HER2.
    Valutare l'immunogenicità di BDC-1001 in monoterapia (Parte 1) e in combinazione con nivolumab (Parte 2) in pazienti affetti da tumori solidi
    avanzati con espressione di HER2
    Espansione della dose (Parti 3 e 4):
    Definire la sicurezza e la tollerabilità di BDC-1001 in monoterapia (Parte 3) e in combinazione con nivolumab (Parte 4) in pazienti affetti da tumori solidi avanzati con espressione di HER2.
    Verificare l'esposizione di BDC-1001.
    Valutare l'immunogenicità di BDC-1001 in monoterapia (Parte 3) o in combinazione con nivolumab (Parte 4) in pazienti affetti da tumori solidi avanzati con espressione di HER2
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.For P.1 and P.2:
    a.Pt has an advanced solid tumor for which approved therapies have been exhausted or for which the Investigator considers the patient ineligible or intolerant of other forms of treatment
    bTumor has documented HER2 expression. At least 1 of the first 3 patients evaluated for DLT in Cohort M2 and all subsequent cohorts in Part 1 requires documented HER2 protein expression in tumor tissue.
    2.For Part 3 and Part 4:
    a.Patient has an advanced solid tumor for which approved therapies have been exhausted or for which the Investigator considers the patient ineligible or intolerant of other forms of treatment and also has the
    following:
    breast cancer HER2+ cohorts (3A and 4A):
    1)Has histologically documented advanced or metastatic HER2+ breast cancer
    2)Has received at least 2 prior treatment regimens with anti-HER2 agents
    For GE cancer cohorts (3B and 4B):
    1)Has histologically documented advanced or metastatic HER2+ GE cancer
    2)Has prior treatment with trastuzumab based therapy For other tumor types cohorts (3C and 4C):
    1)Has histologically documented advanced or metastatic HER2+ cancer other than CRC, endometrial cancer, GE cancer, or breast cancer
    For HER2-low breast cancer cohorts (3D and 4D)
    1)Has histologically documented advanced or metastatic breast cancer
    2)HER2-low tumors are defined as IHC2+ and negative or equivocal gene amplification
    For CRC with HER2+ tumor cohorts (3E and 4E)
    1)Has histologically documented advanced or metastatic HER2+ CRC
    For endometrial cancer with HER2+ tumor cohorts (3F and 4F)
    1)Has histologically documented advanced or metastatic HER2+ endometrial cancer
    3.Age greater than or equal to 18 years old
    4.Mentally competent and able to understand and sign the informed consent form
    5.Eastern Cooperative Oncology Group performance status of 0 or 1
    6.Expected life expectancy of greater than 12 weeks.
    7.Has LVEF = 50% by either echocardiography or multiple-gated acquisition within 28 days before C1D1
    8.Has disease that is measurable by (RECIST) v1.1
    9.Has tumor tissue (archival or collected prior to the study start) available for exploratory biomarker evaluation. A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in paraffin block (preferred) or at least 15 unstained, freshly cut, serial sections (on slides) from an FFPE tumor specimen is required for participation in this study. The specimen must be accompanied by the associated pathology report.
    a.If archival tissue is either insufficient or unavailable, the patient may still be eligible upon discussion with the Medical Monitor if the patient is willing to consent to and undergo a pretreatment tumor biopsy
    collection.
    b.The following specimen types are acceptable: resections, core needle biopsies, excisional, incisional, punch, or forceps biopsies. For core needle biopsy specimens, preferably, at least 3 cores embedded in a
    single paraffin block should be submitted for evaluation. For all specimen types, submitted blocks should have sufficient tissue to generate at least 15 sections, and each section should contain at least 100 viable tumor cells.
    c.Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or cell smears), brushing, cell pellet from pleural effusion, and lavage samples are not acceptable.
    d.Tumor tissue from bone metastases that have been decalcified is not acceptable.
    10.Willing and able to provide blood samples prior to the start of this study.
    11.At least 4 weeks post-op from prior major surgery
    12Laboratory values at Screening must be as follows:
    a.Hematology:
    iAbsolute neutrophil count = 1000 cells/mm3
    ii.Platelet count = 75,000 cells/mm3
    iii.Hemoglobin = 8.5 g/dL
    b.Renal:
    i.Serum creatinine = 1.5 × upper limit of normal (ULN) or creatinine clearance = 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 – age) × (weight in kg) × (0.85 if female) 72 × (serum creatinine in mg/dL)
    1. Per Parte 1 e 2:
    -Il paziente ha tumore solido avanzato per il quale terapie approvate sono state esaurite o per il quale lo Sperim ritiene il paziente non idoneo o intollerante ad altro trattamento
    -tumore ha espressione documentata di HER2. Almeno 1 dei primi 3 pazienti valutati per la DLT nella Coorte M2 e in tutte le coorti successive
    nella P.1 deve avere espressione documentata diHER2 nel tessuto tumorale
    2.per parte 3 e 4:
    -Il pz ha tumore solido avanzato per il quale le terapie approvate sono state esaurite o per il quale lo Sperim ritiene il paziente non idoneo o intollerante ad altro trattamento e ha anche:
    Per carcinoma mammario HER2+ (3A e 4A):
    1.ha carcinoma mammario HER2+ in stadio avanzato o metastatico istologicamente documentato
    2.ha ricevuto almeno 2 precedenti trattamenti con agenti anti-HER2
    Per tumore GE (3B e 4B):
    1.ha tumore GE HER2+ in stadio avanzato o metastatico istologicamente documentato
    2. Precedente terapia a base di trastuzumab
    Per altri tipi di tumore (3C e 4C):
    ha tumore HER2+ in stadio avanzato o metastatico istologicamente documentato diverso da CRC, tumore dell'endometrio, tumore GE o carcinoma mammario
    Per carcinoma mammario HER2-low (3D e 4D)
    1.ha carcinoma mammario metastatico o in stadio avanzato istologicamente documentato
    2.I tumori HER2-low sono definiti come 2+ IHC e amplific genica negativa o ambigua
    Per CRC con tumore HER2+ (3E e 4E)
    1.Ha CRC HER2+ in stadio avanzato o metastatico istologicamente documentato
    3.Età pari o superiore a 18 anni
    4.Mentalmente capace e in grado di capire e firmare il consenso
    5.ECOG pari a 0 o 1
    6.Aspettativa di vita > 12 settimane secondo lo Sperimentatore
    7.ha FEVS = 50% con ecocardiografia o scansione con acquisizione a gate multipli entro 28 giorni prima del C1G1
    8.Ha malattia misurabile in base ai criteri (RECIST) v1.1
    9.Ha tessuto tumorale (d'archivio o raccolto prima dell'inizio dello studio) per la valutazione dei biomarcatori esplorativi. E' necessario un campione tumorale rappresentativo fissato in formalina e incluso in paraffina (FFPE) in blocchetto di paraffina (preferibile) o almeno 15 sezioni seriali non colorate, tagliate al momento (su vetrini) da un campione tumorale FFPE. Il campione deve avere referto patologico
    associato.
    a.Se tessuto d'archivio è insufficiente o non disponibile, il pz può comunque essere idoneo previa discussione con il Medical Monitor nel caso in cui il paziente sia disposto ad acconsentire, e a sottoporsi, a un prelievo di biopsia tumorale pre-trattamento.
    b. Sono accettabili i seguenti campioni: resezioni, carotaggi di agobiopsie, biopsie escissionali, incisionali, con punzone o con forcipe.
    Per quanto riguarda i campioni di carotaggi di agobiopsie, devono essere sottoposti a valutazione, preferibilmente, almeno 3 campioni incorporati in un singolo blocchetto di paraffina. Per tutti i campioni, i blocchetti
    inviati devono avere una quantità di tessuto sufficiente a generar almeno 15 sezioni e ogni sezione deve contenere almeno 100 cellule tumorali vitali.
    c.Non sono accettabili aspirazioni con ago sottile (campioni che non preservano l'architettura tissutale e non producono la sospensione cellulare e/o gli strisci cellulari), raschiamenti, pellet cellulare da versamento pleurico e campioni di lavaggio.
    d.Non è accettabile tessuto tumorale proveniente da metastasi ossee che sono state decalcificate.
    10.Disponibilità e capacità nel fornire campioni di sangue prima dell'inizio di questo studio
    11.Almeno 4 settimane dopo il precedente intervento di chirurgia maggiore
    12.deve avere i seguenti valori di laboratorio allo screening:
    Ematologia:
    Conta assoluta neutrofili=1000 cellule/mm3
    Conta piastrinica=75.000 cellule/mm3
    Emoglobina=8,5 g/dl
    b.Valori renali:
    Creatinina sierica=1,5×ULN o clearance creatinina=30 ml/min sulla base della stima della velocità di filtrazione glomerulare di Cockcroft-Gault: (140 – età) × (peso in kg) × (0,85 se donna) 72 × (creatinina sierica in
    mg/dl)
    E.4Principal exclusion criteria
    1.For Part 2 and Part 4 with BDC 1001 and nivolumab combination therapy:
    a.Patient has a history of immune-mediated colitis
    b.Patient has an active autoimmune disease with the exception of autoimmune endocrinopathies that are stable on hormone replacement therapy
    c.History of allergy or hypersensitivity to nivolumab components
    d.History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 or anti-PD-1/ PD L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, Hypothyroidism)
    2.Cardiovascular exclusions:
    a.Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II IV) or a cardiac arrhythmia that requires treatment
    b.Has a medical history of myocardial infarction or unstable angina within 6 months before C1D1
    c.Has a mean QTcF prolongation of > 450 milliseconds (ms) in males and > 470 ms in females based on a 12 lead electrocardiogram (ECG) in triplicate
    d.Has a medical history of an arterial thrombotic event, stroke, or transient ischemia attack within the past 12 months
    3.Other exclusions:
    a.History of treatment with a toll-like receptor (TLR)7, TLR8, or TLR7/8 agonist
    b.Patient was previously enrolled in this study
    c.Actively enrolled in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up component of an interventional study
    d.Use of another investigational agent or anticancer therapy within 4 weeks prior to C1D1 or within 5 estimated elimination half-lives, whichever is shorter
    e.Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks prior to first study treatment.
    f.Use of another anti-HER2 therapy within 4 weeks prior to C1D1
    g.Use of strong inducers or inhibitors of major human cytochrome P450 (CYP) isoenzymes and transporters within 2 weeks prior to C1D1
    h.History of severe hypersensitivity to any ingredient of BDC-1001, including trastuzumab.
    i.Recent medical concerns and exclusions:
    i.Patient has evidence of active infection and is being treated with intravenous (IV) therapy within 7 days prior to C1D1
    ii.Radiation therapy within 2 weeks of C1D1
    iii.Patient has active uncontrolled bleeding, or a bleeding diathesis within 7 days prior to C1D1
    iv.Patient has an infected wound, fistula, skin ulcer, or non-healing bone fracture within 7 days prior to C1D1
    v.Patient is a lactating mother or pregnant as confirmed by pregnancy tests within 7 days prior to C1D1
    vi.Patient has had a live/attenuated virus vaccine within 30 days prior to C1D1
    vii.Active SARS-CoV-2 infection as determined by viral testing.
    viii.Prior history of pneumonitis (contact Medical Monitor)
    4.Patient has known human immunodeficiency virus (HIV) infection (by antibody test), active hepatitis B infection (by hepatitis B surface antigen [HbsAg] test), or hepatitis C infection (by antibody test followed by confirmatory RNA test if antibody test is positive)
    5.Patient is unwilling to use adequate contraceptive methods (as per Inclusion Section 4.1)
    6.Patient has untreated central nervous system or brain metastasis
    7.Patient taking steroids exceeding 10 mg/day prednisone for a corticosteroids or equivalent dose. Inhaled, intranasal, intraocular, topical, and intraarticular joint injections of corticosteroids are allowed.
    8.Patient has a serious illness considered by the Investigator as incompatible with participating in the protocol
    9.Patient is unwilling or unable to follow protocol requirements
    10.Patient has had an organ transplantation
    1.Per la P.2 e 4 con BDC-1001+nivolumab:
    a.anamnesi di colite immuno-mediata
    b.malattia autoimmune attiva, eccetto endocrinopatie autoimmuni stabili con terapia ormonale sostitutiva
    c.allergia o ipersensibilità ai componenti di nivolumab
    d. tossicità pericolosa per la vita correlata a una precedente terapia immunitaria (es., trattamento anti-CTLA-4 o anti-PD-1/PD-L1 o altro anticorpo o farmaco mirato alla co-stimolazione delle cellule T o alle pathway del checkpoint immunitario) eccetto quelle che è improbabile che si ripresentino con contromisure standard (ad es., ipotiroidismo)
    2.Esclusioni cardiovascolari:
    a.anamnesi medica di insufficienza cardiaca congestizia sintomatica (classe II-IV della New York Heart Association) o aritmia cardiaca che richiede trattamento
    b.anamnesi medica di infarto miocardico o angina instabile nei 6 mesi precedenti il C1G1
    c.prolungamento medio del QTcF > 450 ms nei soggetti di sesso maschile e > 470 ms nei soggetti di sesso femminile in base a un ECG a
    12 derivazioni in triplicato d.anamnesi medica di evento trombotico arterioso, ictus o attacco ischemico transitorio negli ultimi 12 mesi
    3.Altre esclusioni:
    a.trattamento con un agonista del recettore toll-like (TLR)7, TLR8 o TLR7/8
    b.Il paziente precedentemente arruolato in questo studio
    c.Arruolamento attivo in altro studio clinico, a meno che non si tratti di uno studio clinico osservazionale o della parte relativa al follow-up di uno studio interventistico.
    d.Uso di un altro agente sperimentale o terapia antitumorale entro 4 settimane prima del C1G1 o entro 5 emivite di eliminazione stimate, a seconda di quale sia il più breve
    e.Tratt con farmaci complementari (es., integratori a base di erbe o medicine tradizionali cinesi) per trattare la malattia oggetto di studio nelle 2 settimane prima del primo trattamento dello studio.
    f.Utilizzo di altra terapia anti-HER2 nelle 4 sett prima del C1G1
    g.Utilizzo di forti induttori o inibitori dei principali isoenzimi e trasportatori umani del citocromo P450 (CYP) nelle 2 settimane prima del C1G1
    h. grave ipersensibilità a qualsiasi ingrediente di BDC-1001, incluso trastuzumab.
    i.Problematiche mediche recenti:
    i.evidenza di infezione attiva e trattamento con terapia endovenosa (EV) nei 7 gg prima del C1G1
    ii.Radioterapia entro 2 sett dal C1G1
    iii. sanguinamento incontrollato attivo o una diatesi emorragica nei 7 gg precedenti il C1G1
    iv.ferita infetta, una fistola, un'ulcera cutanea o una frattura ossea che non guarisce nei 7 gg precedenti il C1G1
    v.La paziente è una madre che allatta al seno o in gravidanza confermata da test di gravidanza nei 7 giorni precedenti il C1G1
    vi.Il paziente ha ricevuto un vaccino con virus vivo/attenuato nei 30 gg precedenti il C1G1
    vii.Infezione attiva da SARS-CoV-2 determinata mediante test virale.
    viii.Anamnesi pregressa di infiammazione polmonare (contattare il Medical Monitor)
    4.infezione nota da virus HIV (mediante test anticorpale), infezione attiva da epatite B (mediante test dell'antigene di superficie dell'epatite
    B) o infezione da epatite C (mediante test anticorpale seguito da test di conferma su RNA se il test anticorpale è positivo)
    5.Il/La paziente non è disposto/a ad utilizzare metodi contraccettivi adeguati (come in Sezione 4.1 Criteri di inclusione)
    6.metastasi al sistema nervoso centrale o al cervello non trattate
    7.Il pz sta assumendo steroidi superiori a 10 mg/die di prednisone per corticosteroidi o dose equivalente. Sono consentiti corticosteroidi per via inalatoria, intranasale, intraoculare, topica e mediante infiltrazioni intrarticolari.
    8.una malattia seria, considerata incompatibile con la partecipazione al protocollo dallo Sperimentatore
    9.Il paziente non è disposto a, o non è in grado di, seguire i requisiti del protocollo
    10.Il paziente è stato sottoposto a un trapianto d'organo
    E.5 End points
    E.5.1Primary end point(s)
    Dose Escalation (Part 1 and Part 2):
    •Incidence of AEs and SAEs graded according to NCI CTCAE v5.0
    •Incidence and nature of DLTs within a 3 + 3 design
    •Changes from baseline in relevant clinical safety laboratory values and vital signs
    •Incidence of potential-immune related toxicities
    •The MTD or a tolerated dose below MTD (if MTD is not reached)
    •The occurrence of DLTs
    Dose Expansion (Parts 3 and 4):
    •ORR of confirmed CR or PR.
    Aumento della dose (Parte 1 e 2):
    • Incidenza di AE e SAE classificati secondo i criteri NCI-CTCAE v5.0
    • Incidenza e natura delle DLT nell'ambito di un disegno 3 + 3
    • Variazioni rispetto al basale nei valori di laboratorio rilevanti per la
    sicurezza clinica e nei segni vitali
    • Incidenza di potenziali tossicità immuno-correlate
    • La MTD o una dose tollerata inferiore alla MTD (se la MTD non viene raggiunta)
    • Il verificarsi di DLT
    Espansione della dose (Parti 3 e 4)
    • ORR di CR o PR confermata
    E.5.1.1Timepoint(s) of evaluation of this end point
    Related to Parts 1, 2, 3, and 4.
    Correlati alle Parti 1, 2, 3 e 4.
    E.5.2Secondary end point(s)
    Dose Escalation (Part 1 and Part 2):
    Pharmacokinetic variables may include:
    •Cmax
    •Cmin
    •AUC0-t
    •AUC0-inf
    •CL
    •Vz
    •t½
    •ORR using RECIST v1.1
    •DCR of confirmed CR, PR, or stable disease (SD) lasting 4 or more
    weeks following the initiation of BDC 1001
    •DoR
    •PFS
    Exploratory:
    •ORR using iRECIST
    •Incidence of ADAs
    Dose Expansion (Parts 3 and 4):
    •DoR of confirmed CR or PR
    •DCR of confirmed CR, PR, or SD lasting 4 or more weeks following the
    initiation of BDC 1001
    •PFS
    Exploratory
    •OS
    •Incidence of AEs and SAEs graded according to NCI CTCAE v5.0
    •Changes from baseline in relevant clinical safety laboratory values and
    vital signs
    •Incidence of potential-immune related toxicities
    PK variables may include:
    •Cmax
    •Cmin
    •Incidence of ADAs
    All Parts (Parts 1, 2, 3, and 4):
    •Changes in TLR7/8 pathway activation, myeloid and T cell content and
    activation status by gene expression profiling and tissue image analysis
    •Evaluation of changes in additional exploratory biomarkers in tumor
    tissue and blood related to tumor and immune biology by such methods
    as gene expression profiling, mutational, protein and tissue image
    analysis
    •Anti-tumor activity in tumors with different levels of HER2 and PD-L1
    expression
    •Evaluation of BDC 1001 activity in the context of additional exploratory predictive and/or prognostic biomarkers related to tumor and immune biology by such methods as gene expression profiling, mutational,
    protein and tissue image analysis; Aumento della dose (Parte 1 e 2):
    Le variabili farmacocinetiche possono includere:
    • Cmax
    • Cmin
    • AUC0-t
    • AUC0-inf
    • CL
    • Vz
    • t½
    • ORR utilizzando i criteri RECIST v1.1
    • DCR di CR, PR o malattia stabile (SD) confermata della durata di 4 o
    più settimane dopo l'inizio di BDC-1001
    • DoR
    • PFS
    Esplorativi:
    • ORR utilizzando i criteri iRECIST
    • Incidenza di ADA
    Espansione della dose (Parti 3 e 4):
    • DoR di CR o PR confermata
    • DCR di CR, PR o SD confermata della durata di 4 o più settimane dopo
    l'inizio di BDC-1001
    • PFS
    Esplorativi
    • OS
    • Incidenza di AE e SAE classificati secondo i criteri NCI-CTCAE v5.0
    • Variazioni rispetto al basale nei valori di laboratorio rilevanti per la
    sicurezza clinica e nei segni vitali
    • Incidenza di potenziali tossicità immuno-correlate
    Le variabili PK possono includere:
    • Cmax
    • Cmin
    • Incidenza di ADA
    Tutte le parti (Parti 1, 2, 3 e 4):
    • Variazioni nell'attivazione della pathway di TLR7/8, nel contenuto di
    cellule mieloidi e T e nello stato di attivazione mediante profilazione
    dell'espressione genica e analisi delle immagini tissutali
    • Valutazione delle variazioni nei biomarcatori esplorativi aggiuntivi nel
    tessuto tumorale e nel sangue correlate al tumore e alla biologia
    immunitaria mediante metodi quali l'analisi del profilo di espressione
    genica, l'analisi delle immagini mutazionali, proteiche e tissutali
    • Attività antitumorale nei tumori con diversi livelli di espressione di
    HER2 e PD-L1
    • Valutazione dell'attività di BDC-1001 in riferimento a ulteriori biomarcatori predittivi e/o prognostici esplorativi correlata al tumore e alla biologia immunitaria mediante metodi quali l'analisi del profilo di
    espressione genica, l'analisi delle immagini mutazionali, proteiche e tissutali
    E.5.2.1Timepoint(s) of evaluation of this end point
    Related to Parts 1, 2, 3, and 4.
    Correlati alle Parti 1, 2, 3 e 4.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    Aumento della dose
    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 No
    E.8.1.2Open Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Aumento della dose
    Dose escalation
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Nivolumab
    Nivolumab
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Korea, Republic of
    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 definition of the end of the study is when the last patient has completed their safety follow up (SFU). The Sponsor may terminate the study at any time at its discretion
    La definizione della fine dello studio è quando l'ultimo paziente ha completato il follow up di sicurezza (SFU). Lo sponsor può interrompere lo studio in qualsiasi momento a sua discrezione
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 655
    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)
    Upon completion of the study, the Sponsor will follow local regulatory/ICH guidelines for any follow-up treatment provided to patients. Each Investigator is responsible for ensuring that appropriate post-study care is provided for each patient's medical condition.
    Al termine dello studio, lo Sponsor seguirà le linee guida regolatorie/ICH locali per qualsiasi trattamento di follow-up fornito ai pazienti. Ogni sperimentatore è responsabile di garantire che venga fornita un'adeguata assistenza post-studio per le condizioni mediche di ciascun paziente.
    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 Decision2023-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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