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    Summary
    EudraCT Number:2020-002719-23
    Sponsor's Protocol Code Number:BT8009-100
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database: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 number2020-002719-23
    A.3Full title of the trial
    Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT8009 in Patients with Nectin-4 Expressing Advanced Malignancies
    Studio di fase I/II sulla sicurezza, la farmacocinetica e l'attività clinica preliminare di BT8009 in pazienti affetti da neoplasie maligne avanzate che esprimono la Nectina-4.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II clinical study to investigate the safety and effectiveness of BT8009 in patients with advanced malignancies
    Studio clinico di fase I / II per valutare la sicurezza e l'efficacia di BT8009 in pazienti con neoplasie avanzate
    A.3.2Name or abbreviated title of the trial where available
    n.a
    n.a
    A.4.1Sponsor's protocol code numberBT8009-100
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04561362
    A.5.4Other Identifiers
    Name:Sarah Cannon Development Innovations, LLCNumber:REFMAL 669
    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 SponsorBicycleTx 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 supportBicycleTx Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSarah Cannon Development Innovations
    B.5.2Functional name of contact pointDebra Haynes
    B.5.3 Address:
    B.5.3.1Street Address1100 Dr Martin L. King Jr. Blvd., Suite 800
    B.5.3.2Town/ cityNashville, Tennessee
    B.5.3.3Post code37203
    B.5.3.4CountryUnited States
    B.5.4Telephone number9318354
    B.5.6E-maildebra.haynes@sarahcannon.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 nameBT8009
    D.3.2Product code [BT8009]
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeBT8009
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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) No
    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 10mg/mL concentrato per soluzione per infusione (flaconcino 24 mL)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Myers-Squibb Pharma EEIG
    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 10mg/mL concentrato per soluzione per infusione (flaconcino 24 mL)
    D.3.2Product code [SUB122750]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor coden.a.
    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
    Nectin-4 Expressing Advanced Malignancies.
    Neoplasie avanzate che espirmone Nectina-4
    E.1.1.1Medical condition in easily understood language
    Advanced cancer of a type that has an abundance of surface receptors called Nectin-4 on the tumour cells.
    Tipo di cancro avanzato avente una abbondanza di recettori di superficie chiamati nectina-4 sulle cellule tumorali.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objectives of the escalation and renal cohorts (Parts A-1, A-2, Part C) are:

    • To assess safety and tolerability of BT8009 in patients with advanced solid tumor malignancies associated with Nectin-4 expression as a monotherapy (Part A-1) or in combination with nivolumab (Part A-2) or in patients with advanced solid tumor malignancies having renal insufficiency (Part C).

    • To define the maximum tolerated dose (MTD) of BT8009, if observed, and determine a recommended Phase II dose (RP2D) as a monotherapy and in combination with nivolumab (Parts A-1 and A-2).

    The primary objective of the expansion cohort (Parts B-1 and B-2) is:

    • To assess the clinical activity of BT8009 in patients with solid tumor indications associated with Nectin-4 expression as a monotherapy (Part B-1) and in combination with nivolumab (Part B-2) using RECIST 1.1.
    Obiettivi primari delle coorti di incremento della dose e della coorte dei pazienti con insufficienza renale (rispettivamente Parti A-1, A- 2 e Parte C) sono:
    - Valutare la sicurezza e la tollerabilità di BT8009 in pazienti con neoplasie tumorali solide avanzate associate all'espress. di Nectina-4 in monoterapia (Parte A-1) o in comb. con nivolumab (Parte A-2) o in pazienti con neoplasie tumorali solide avanzate e insufficienza renale (Parte C).
    - Definire la dose max tollerata (Maximum Tolerated Dose, MTD) di BT8009, se osservata e determinare una dose raccomandata per la fase 2 (Recommended Phase II Dose, RP2D) sia quando usato in monoterapia sia quando usato in comb. con nivolumab (Parti A-1 e A-2).
    L'obiettivo primario delle coorti di espansione (Parti B-1 e B-2) è:
    - Valutare l'attività clinica di BT8009 in pazienti con indicazioni di tumore solido associato all'espress. di Nectina-4 come monoterapia (Parte B-1) e in comb. con nivolumab (Parte B-2) usando i criteri RECIST 1.1
    E.2.2Secondary objectives of the trial
    Secondary objectives of Parts A-1 and A-2 and renal cohorts (Part C) are:
    1. Assess signals of anti-tumor activity in pts. with advanced solid tumor malignancies associated with Nectin-4 as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2) or in pts. with advanced solid tumor malignancies having renal insufficiency (Part C).
    2. Determine PK parameters of BT8009 and MMAE in pts. with advanced solid tumor malignancies associated with Nectin-4 as a monotherapy and in combination with nivolumab (Part A-2) or in patients with advanced solid tumor malignancies having renal insufficiency (Part C).
    3. Determine incidence of anti-drug antibody (ADA) development.
    Secondary objectives of the expansion cohorts (Parts B-1 and B-2) are: 1) assess safety and tolerability of BT8009 in patients with solid tumors as monotherapy (Part B-1) and in combination with nivolumab (Part B-2); 2) Determine PK parameters of BT8009 and MMAE; 3) determine incidence of ADA development
    Obiettivi sec. Parti A-1 e A-2 e Parte C:
    Valutare i segnali preliminari dell'attività antitumorale ottenuti con la somm. di BT8009 in pazienti con neoplasie tumorali solide avanzate associate a Nectina-4 in monoterapia (Parte A-1) e in comb. con nivolumab (Parte A-2) o in pazienti con neoplasie tumorali solide avanzate e insufficienza renale (Parte C)
    Determinare i parametri di Pk di BT8009 e MMAE in pazienti con neoplasie tumorali solide avanzate associate alla Nectina-4 in monoterapia (Parte A-1) e in comb. con nivolumab (Parte A-2) o in pazienti con neoplasie tumorali solide avanzate e insufficienza renale (Parte C)
    Determinare l'incidenza dello sviluppo di ADA
    Obiettivii sec. Parti B-1 e B-2:
    Valutare la sicurezza e la tollerabilità di BT8009 in pazienti con indicazioni di tumori solidi associati a Nectina-4 in monoterapia (Parte B-1) e in comb. con nivolumab (Parte B-2)
    Determinare i parametri PK di BT8009 e MMAE
    Determinare l'incidenza dello sviluppo di ADA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1 Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
    2 At least 18 years-of-age at the time of signature of the informed consent form.
    3 ECOG Performance Status score of 0 or 1.
    4Patients must have measurable disease per RECIST v1.1.
    5Acceptable organ function, as evidenced by the following laboratory data:
    a Renal function, as follows: creatinine clearance of =50 mL/min by the Cockcroft-Gault equation or equivalent.
    b Total bilirubin =1.5 × ULN
    cSerum albumin =2.5 g/dL
    d AST =2.5 × ULN or =5 × ULN in the presence of liver metastases
    e ALT =2.5 × ULN or =5 × ULN in the presence of liver metastases
    f INR <1.3 or = institutional ULN
    6 Acceptable hematologic function:
    a Hemoglobin =9 g/dL
    b ANC=1500 cells/mm3
    c Platelet count =75,000 cells/mm3
    7 Negative pregnancy test for WOCBP
    8 Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening.
    9 Life expectancy =12 weeks
    10 Must be willing and able to comply with the protocol
    11 Must have exhausted all standard treatment options
    Additional Inclusion Criteria – Part A Only
    12 Patients with the following advanced, histologically confirmed malignant solid tumors that recurred after or have been refractory to previous therapy: a) urothelial (transitional cell) carcinoma (fresh biopsy or an archived sample must be submitted); or b) having pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumor tissue (fresh biopsy or an archived sample) testing positive for Nectin-4 expression.
    Exceptions: single-subject accelerated cohorts may enroll patients with advanced solid tumors not-restricted to the above definitions, unless the SRC views otherwise. The Sponsor may require a) or b) at any time during the enrollment; eligibility will be confirmed by the Medical Monitor. The Sponsor and/or SRC may decide to require enrollment of specific tumor (sub)types at any point during the escalation to enrich the evaluation of biomarkers, safety, anti-tumor activity, or PK.
    Additional Inclusion Criteria – Part B-1 and B-2
    13 Patients with solid tumor metastatic recurrent disease confirmed as Nectin-4 positive on fresh biopsy or archived tissue must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. If patient’s tumor has been demonstrated to contain a therapeutically targetable somatic or driver mutation, therapy must be given with appropriate locally-approved therapy, then therapy must have been given based on local standard standards of care. If platinum therapy is applicable, then FDA-approved or appropriate locally-approved therapy must have been given based on local standard guidelines. If prior immunotherapy, the last dose must have been at least 28 days prior to the first dose. The Sponsor and/or SRC may decide to require or limit enrollment of specific tumor (sub)types meeting the above definition at any point during the expansion to enrich the population for anti-tumor activity.
    14 At least 6 patients per cohort must have at least 1 tumor lesion amenable to biopsy and must be willing to undergo a biopsy prior to first dose and following any dose in Cycle 1.
    Additional Inclusion Criteria – Part C renal insufficiency cohort
    15 Patients with solid tumor advanced disease are eligible as follows: 1) 6 patients with a GFR (by CG or by 24-hour urine) 40-50 mL/min (or equivalent units) to be enrolled and evaluated first followed by; 2) 6 patients with a GFR 30-40 mL/min (or equivalent units). Sponsor may opt to specify tumor (sub)type or Nectin-4 selected.
    1. Consenso informato scritto, firmato e datato prima dell'esecuzione di procedure.
    2. Età minima pari a 18 anni.
    3. ECOG pari a 0 o 1
    4. Malattia misurabile secondo RECIST v1.1
    5. Funzionalità organica accettabile:
    a. Funzionalità renale: clearance della creatinina =50 ml/min
    b. Bilirubina totale =1,5 x ULN;
    c. Albumina sierica =2,5 g/dl;
    d. AST =2,5 x l'ULN o =5 x l'ULN in presenza di metastasi epatiche;
    e. ALT =2,5 x l'ULN o =5 x l'ULN in presenza di metastasi epatiche;
    f. INR <1,3 o = l'ULN
    6. Funzionalità ematologica accettabile:
    a. Emoglobina =9 g/dl;
    b. ANC =1.500 cellule/mm3;
    c. Conta piastrinica =75.000 cellule/mm3.
    7. Test di gravidanza negativo per le donne potenzialmente fertili.
    8. Disponibilità di campioni tumorali d'archivio o disponibilità a fornire un campione bioptico tumorale fresco durante lo screening.
    9. Aspettativa di vita =12 settimane
    10. Disponibilità e capacità di rispettare il protocollo
    11. Esaurimento di tutte le opzioni di trattamento standard

    Criteri di inclusione aggiuntivi - Solo Parte A

    12. Pazienti con i seguenti tumori solidi maligni avanzati e confermati istologicamente, con recidiva dopo la terapia precedente o ad essa refrattari:
    a) carcinoma uroteliale o
    b) presenza di tessuto di tumore pancreatico, mammario, gastrico, esofageo, della testa e del collo, ovarico o carcinoma polmonare non a piccole cellule che risulti positivo per l'espressione della Nectina-4.
    Eccezioni: nelle coorti accelerate a soggetto singolo possono essere arruolati pazienti con tumori solidi avanzati non limitati alle definizioni di cui sopra, a meno di diverso parere del SRC. Lo Sponsor può richiedere a) o b) in qualsiasi momento durante l'arruolamento; lo Sponsor e/o l'SRC possono decidere di richiedere l'arruolamento di specifici (sotto) tipi di tumore in qualsiasi momento durante l'incremento della dose al fine di approfondire la valutazione di biomarcatori, sicurezza, attività antitumorale o PK.

    Criteri di inclusione aggiuntivi - Parte B-1 e B-2

    13. I pazienti affetti da malattia oncologica solida recidivante metastatica con conferma della presenza di Nectina-4 alla biopsia fresca o al campione di tessuto d'archivio devono aver avuto il fallimento di almeno una linea terapeutica precedente con evidenza di progressione radiografica alla linea di terapia più recente. Se è stato dimostrato che il tumore del paziente contiene una mutazione driver o somatica su cui è possibile agire a livello terapeutico, il trattamento deve essere somministrato mediante un'appropriata terapia approvata localmente, e la terapia deve essere stata somministrata sulla base degli standard di cura locali. Se la terapia con platino è applicabile, la terapia approvata dalla FDA o approvata localmente deve essere stata somministrata in base alle linee guida standard locali. In caso di immunoterapia precedente, l'ultima dose deve essere somministrata almeno 28 giorni prima della prima dose di BT8009. Lo Sponsor e/o l'SRC possono decidere di richiedere o limitare l'arruolamento di specifici (sotto) tipi di tumore conformi alla definizione di cui sopra in qualsiasi momento durante l'espansione della dose al fine di incrementare la popolazione per l'attività antitumorale.

    14. Almeno 6 pazienti per coorte devono presentare almeno una lesione tumorale suscettibile di biopsia e devono essere disposti a sottoporsi a una biopsia prima della prima dose di BT8009 e dopo ogni dose nel Ciclo 1.

    Criteri di inclusione aggiuntivi - coorte di pazienti con insufficienza renale

    15. 1) 6 pazienti con un GFR pari a 40-50 ml/min da arruolare e valutare per primi;
    2) 6 pazienti con un GFR pari a 30-40 ml/min
    Lo Sponsor può scegliere di specificare il (sotto) tipo di tumore o la caratteristica relativa alla Nectina-4 selezionati
    E.4Principal exclusion criteria
    1. Chemotherapy treatments within 14 days prior to first dose, other anticancer treatments, treatment within 28 days or 5 terminal half-lives, whichever is shorter. Prior toxicities must have resolved to G1 CTCAE v5.0 (except alopecia, which must be no greater than G2).
    2. Experimental treatments within 4 weeks of first dose
    3. Prior treatment with Nectin-4 targeted therapy
    4. Current treatment with strong inhibitors or strong inducers of CYP3A4 or strong inhibitors of P-gp, including herbal- or food-based.
    5. Known sensitivity to any of the ingredients of BT8009 or monomethyl auristatin E
    6. BSA >2.21 m2
    7. Significant condition, including but not limited to eye (dry eye, corneal opacities or keratitis), skin (rash ), life-threatening illness, active uncontrolled infection or organ system dysfunction, or other reasons in the Investigator opinion. Prior = Grade 2 thyroid endocrinopathy is allowed, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy
    8. relevant troponin elevation.
    9. Uncontrolled diabetes(HbA1c =8%)
    10. Major surgery (excluding placement of vascular access) within 4 weeks and recovered adequately prior to 1st dose
    11. Receipt of live or attenuated vaccine within 30 days of 1st dose
    12. Uncontrolled, symptomatic brain metastases
    13. Patients with uncontrolled hypertension ( Systolic BP =160 mmHg or diastolic BP =100 mmHg) prior to first dose
    14. History or current evidence of any condition that might confound the study result, interfere with the patient’s participation, or is not in the best interest of the patient, including but not limited to:
    - Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of Class III-IV (NYHA)within 6 months prior to first dose or:
    a. QT interval (QTcF) >470 msec
    b. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
    c. Any important abnormalities in rhythm, conduction, or morphology of resting ECGs
    15. Known HIV/) AIDS
    16. Known HBV and/or anti-HBV core antibody.
    17. Active HCV infection with positive viral load if HCV antibody positive (, not applicable if antibody is negative). HCV infected patients can be included if they have sustained virologic response of =12 weeks.
    18. History of another malignancy within 3 years before the first dose, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast)
    19. Systemic IV anti-infective treatment, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of BT8009
    20. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the Investigator
    21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol
    Additional Exclusion Criteria Part A-2 and B-2 Nivolumab Combination Cohorts
    22. Prior intolerance to immune checkpoint inhibitor
    23. Known hypersensitivity to checkpoint inhibitor therapy
    24. Prior organ transplant (including allogeneic)
    25. Diagnosis of clinically relevant immunodeficiency
    26. Active systemic infection in therapy
    27. More than 10 mg daily prednisone equivalent or other strong immunosuppressant
    28. History of autoimmune disease except type I DM well controlled on insulin, alopecia or vitiligo
    29. History of interstitial lung disease
    1. Trattamenti chemioterapici entro 14 gg prima della 1° dose, altri trattamenti antitumorali, trattamento entro 28 gg o 5 emivite terminali, a seconda del periodo più breve. Le tossicità precedenti devono essersi risolte al G1 secondo CTCAE v5.0 (tranne l'alopecia, che non deve essere superiore al G2)
    2. Trattamenti sperimentali entro 4 sett. dalla 1° dose
    3. Trattamento precedente con terapia mirata alla nectina-4
    4. Trattamento attuale con forti inibitori o forti induttori del CYP3A4 o forti inibitori della P-gp, inclusi a base di erbe o alimenti
    5. Sensibilità nota a uno qualsiasi degli ingredienti del BT8009 o alla monometil auristatina E
    6. BSA >2,21 m2
    7. Condizioni significative tra cui, a titolo non esaustivo: oculari (secchezza oculare, opacità corneali o cheratite), cutanee (eruzioni), malattie potenzialmente letali, infezione attiva non controllata o disfunzione del sistema organo (come ascite, coagulopatia, encefalopatia) o altri motivi secondo l'opinione dello sperimentatore. È consentita una precedente endocrinopatia tiroidea di grado =2, se adeguatamente controllata con ormone tiroideo e stabile per almeno 2 mesi in terapia
    8. Aumento della troponina rilevante.
    9. Diabete non controllato (HbA1c =8%)
    10. Intervento chirurgico maggiore (escluso il posizionamento dell'accesso vascolare) entro 4 sett dalla 1ºdosee il paziente ripreso adeguatamente prima di iniziare la 1° dose
    11. Ricezione di un vaccino vivo o attenuato entro 30 gg dalla 1° dose
    12. Metastasi cerebrali sintomatiche non controllate
    13. Pazienti con ipertensione non controllata (PAsistolica =160 mm Hg o PA diastolica =100 mm Hg) prima della 1° dose.
    14. Anamnesi o evidenza attuale di qualsiasi condizione, terapia o anomalia di laboratorio che potrebbe confondere i risultati, interferire con la partecipazione del paziente o la partecipazione non è nel migliore interesse del paziente, come nei seguenti casi esemplificativi:
    a. - anamnesi di un evento cerebrovascolare (ictus o attacco ischemico transitorio), angina instabile, infarto del miocardio, insufficienza cardiaca congestizia o sintomi di classe III-IV (NYHA) entro 6 mesi prima della 1º dose - IntervalloQTcF >470 msec;
    b. Qualsiasi fattore che aumenti il rischio di prolungamento del QTc o il rischio di eventi aritmici
    c. Qualsiasi anomalia importante,del ritmo, della conduzione o della morfologia degli ECG a riposo
    15. Presenza del HIV/AIDS.
    16. Presenzadell'HBV e/o agli anticorpi anti-core dell'HBV.
    17. Infezione da HCV attiva con carica virale positiva in caso di positività agli anticorpi (non è applicabile in caso di negativo anticoprale) HCV. possono essere inclusi se presentano una risposta virologica costante di =12 sett.
    18. Anamnesi di altra neoplasia maligna entro 3 anni prima della 1° dose o evidenza di malattia residua associata a una neoplasia maligna in precedenza (tranne carcinoma basocellulare, carcinoma cutaneo a cellule squamose, neoplasia intraepiteliale della cervice/carcinoma della cervice in situ o melanoma in situ o carcinoma duttale in situ della mammella)
    19. Trattamento antinfettivo sistemico per via e.v. o febbre non attribuibile a un tumore maligno sottostante negli ultimi 14 gg prima della 1° dose
    20. Sospetto di recente sindrome virale sistemica pertinente o necessità di quarantena/isolamento
    21. Condizioni psicologiche, familiari, sociologiche o geografiche che non consentono il rispetto del protocollo.
    EC aggiuntivi - PartiA-2 e B-2
    22. Precedente intolleranza all'inibitore del checkpoint immunitario
    23. Ipersensibilità nota alla terapia con inibitori del checkpoint
    24. Trapianto d'organo precedente (incluso allogenico)
    25. Diagnosi di immunodeficienza rilevante
    26. Infezione sistemica attiva in terapia.
    27. Trattamento con più di 10 mg di prednisone equivalente al gg o altri immunosoppressori forti.
    28. Anamnesi di malattia autoimmune, ad eccezione del DM I ben controllato, alopecia o vitiligine
    29. Anamnesi di malattia polmonare interstiziale
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measures for Parts A and C will be:

    1) The incidence of treatment-emergent adverse events (TEAEs), including laboratory, ECG, and vital sign abnormalities.

    2) The incidence of dose-limiting toxicites.

    The primary outcome measures for Part B will be:

    1) Objective response rate (ORR)

    2) Duration of response (DOR)

    3) Clinical benefit rate (CR + PR + SD = 6 weeks)

    4) Time to tumor progression (TTP)

    5) Progression-free survival time (PFS)

    6) Rate of PFS at 6 months

    7) Rate of Overall Survival (OS) at 12 months all assessed per RECIST v1.1 criteria
    Gli Outcome primari per le parti A e C saranno:

    1) L'incidenza di eventi avversi emergenti dal trattamento (TEAEs), comprese anomalie di laboratorio, ECG e dei segni vitali.

    2) L'incidenza di tossicità dose-limitante.

    Gli Outcome primati per la parte B saranno:

    1) Tasso di risposta obiettiva (ORR)

    2) Durata della risposta (DOR)

    3) Tasso di beneficio clinico (CR + PR + SD = 6 settimane)

    4) Tempo di progressione del tumore (TTP)

    5) Tempo di sopravvivenza libera da progressione (PFS)

    6) Tasso di PFS a 6 mesi

    7) Tasso di sopravvivenza globale (OS) a 12 mesi, tutti valutati in base ai criteri RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary outcome measures will be assessed at pre-specified time points throughout the duration of the study (approximately 3 years).
    Gli Outcome primari verranno valutati in momenti prestabiliti per tutta la durata dello studio (circa 3 anni).
    E.5.2Secondary end point(s)
    The secondary outcome measures for Parts A and C will be:

    1) Objective response rate (ORR)

    2) Duration of response (DOR)

    3) Clinical benefit rate (CR + PR + SD = 6 weeks)

    4) Time to tumor progression (TTP)

    5) Progression-free survival time (PFS)

    6) Rate of PFS at 6 months

    7) Rate of Overall Survival (OS) at 12 months all assessed per RECIST v1.1 criteria

    The secondary outcome measures for Part B will be:

    1) The incidence of treatment-emergent adverse events (TEAEs), including laboratory, ECG, and vital sign abnormalities.

    Secondary endpoints applicable to all parts of the study include:

    1) Plasma concentrations of BT8009 with derivations including Cmax, Cmin, AUC, and elimination half-life t(1/2).
    2) Measurement of ADA
    Gli Outcome secondari per le parti A e C saranno:

    1) Tasso di risposta obiettiva (ORR)

    2) Durata della risposta (DOR)

    3) Tasso di beneficio clinico (CR + PR + SD = 6 settimane)

    4) Tempo di progressione del tumore (TTP)

    5) Tempo di sopravvivenza libera da progressione (PFS)

    6) Tasso di PFS a 6 mesi

    7) Tasso di sopravvivenza globale (OS) a 12 mesi, tutti valutati in base ai criteri RECIST v1.1

    Gli Outcome secondari per la parte B saranno:

    1) L'incidenza di eventi avversi emergenti dal trattamento (TEAE), comprese anomalie di laboratorio, ECG e dei segni vitali.

    Gli endpoint secondari applicabili a tutte le parti dello studio includono:

    1) Concentrazioni plasmatiche di BT8009 con derivazioni comprendenti Cmax, Cmin, AUC ed emivita di eliminazione t (1/2).
    2) Misurazione dell'ADA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary outcome measures will be assessed at pre-specified time points throughout the duration of the study (approximately 3 years)
    Gli Outcome secondari verranno valutati in momenti prestabiliti per tutta la durata dello studio (circa 3 anni).
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans 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 trial5
    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 EEA12
    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
    Canada
    Hong Kong
    Korea, Republic of
    United States
    Belgium
    France
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 97
    F.4.2.2In the whole clinical trial 146
    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)
    After a subject has ended his or her participation in the trial they may receive treatment for their disease according to expected normal protocols at the institution where they are being treated.
    Dopo che un soggetto ha terminato la sua partecipazione alla sperimentazione, può ricevere un trattamento per la sua malattia secondo i normali protocolli previsti presso l'istituto in cui viene trattato.
    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 Decision2021-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-10
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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