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    Summary
    EudraCT Number:2019-001992-35
    Sponsor's Protocol Code Number:MS200647_0055
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-05-24
    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 number2019-001992-35
    A.3Full title of the trial
    A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp alfa (M7824) as First-line Treatment of Biliary Tract Cancer
    Studio di fase II/III, multicentrico, randomizzato, controllato con placebo di gemcitabina più cisplatino con o senza bintrafusp alfa (M7824) come trattamento di prima linea del tumore delle vie biliari
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    1L BTC Phase II/III Gemcitabine Plus Cisplatin With or Without Bintrafusp alfa (M7824)
    Fase II/III di gemcitabina più cisplatino con o senza bintrafusp alfa (M7824) di 1L per BTC
    A.3.2Name or abbreviated title of the trial where available
    1L BTC Phase II/III Gemcitabine Plus Cisplatin With or Without Bintrafusp alfa (M7824)
    FFase II/III di gemcitabina più cisplatino con o senza bintrafusp alfa (M7824) di 1L per BTC
    A.4.1Sponsor's protocol code numberMS200647_0055
    A.5.4Other Identifiers
    Name:IND numberNumber:140345
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMERCK HEALTHCARE KGaA
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+496151725200
    B.5.5Fax number+496151725200
    B.5.6E-mailservice@merckgroup.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2112
    D.3 Description of the IMP
    D.3.1Product namebintrafusp alfa
    D.3.2Product code [M7824]
    D.3.4Pharmaceutical form Concentrate and solvent 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 INNbintrafusp alfa
    D.3.9.2Current sponsor codeM7824
    D.3.9.4EV Substance CodeSUB179957
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameGemcitabina
    D.3.2Product code [.]
    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 INNGemcitabina
    D.3.9.2Current sponsor code.
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namecisplatino
    D.3.2Product code [.]
    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 INNCisplatino
    D.3.9.2Current sponsor code.
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Biliary Tract Cancer
    tumore delle vie biliari
    E.1.1.1Medical condition in easily understood language
    Biliary Tract Cancer
    tumore delle vie biliari
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028982
    E.1.2Term Neoplasm biliary tract
    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 10073077
    E.1.2Term Intrahepatic cholangiocarcinoma
    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 10074879
    E.1.2Term Extrahepatic cholangiocarcinoma
    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 10017614
    E.1.2Term Gallbladder 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 LLT
    E.1.2Classification code 10034442
    E.1.2Term Periampullary 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 LLT
    E.1.2Classification code 10034443
    E.1.2Term Periampullary carcinoma non-resectable
    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 LLT
    E.1.2Classification code 10034445
    E.1.2Term Periampullary carcinoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Open-label Safety Run-in: To assess if bintrafusp alfa 2400 mg Q3W in combination with gemcitabine and cisplatin is safe and tolerable and to confirm this dose as the recommended Phase II dose for the
    randomized, double-blind part of the study
    Randomized, Double-blind Part: To assess Overall Survival (OS) with bintrafusp alfa in combination with gemcitabine plus cisplatin versus placebo with gemcitabine plus cisplatin in participants with advanced or metastatic BTC who have not received chemotherapy/immunotherapy in the advanced/metastatic setting
    Run-in di sicurezza in aperto: valutare se 2400 mg di bintrafusp alfa Q3W in combinazione con gemcitabina e cisplatino siano sicuri e tollerabili e per confermare questa dose come dose raccomandata della fase II per la parte dello studio randomizzata in doppio cieco
    Parte randomizzata in doppio cieco: valutare la sopravvivenza complessiva (OS) con bintrafusp alfa in combinazione con gemcitabina più cisplatino rispetto al placebo con gemcitabina più cisplatino in partecipanti affetti da BTC avanzato o metastatico che non hanno ricevuto chemioterapia/immunoterapia nel contesto avanzato/metastatico
    E.2.2Secondary objectives of the trial
    Open-label, safety Run-in
    •To assess the safety profile of bintrafusp alfa in combination with gemcitabine and cisplatin
    Randomized, Double-blind Part
    • To assess PFS
    •To assess ORR
    •To assess DOR
    •To assess DRR
    •To assess the safety profile of bintrafusp alfa or placebo in combination with gemcitabine plus cisplatin
    •To characterize the PK profile of bintrafusp alfa
    •To evaluate the immunogenicity of bintrafusp alfa and to correlate it to exposure
    Run-in di sicurezza in aperto
    • Valutare il profilo di sicurezza di bintrafusp alfa in combinazione con gemcitabina e cisplatino

    Parte randomizzata in doppio cieco
    • Valutare PFS
    • Valutare ORR
    • Valutare DOR
    • Valutare DRR
    • Valutare il profilo di sicurezza di bintrafusp alfa o placebo in combinazione con gemcitabina più cisplatino
    • Caratterizzare il profilo PK di bintrafusp alfa
    • Valutare l’immunogenicità di bintrafusp alfa e correlarla all’esposizione
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients aged = 18 years of age at the time of signing the informed consent.
    2. Participants with histologically or cytologically confirmed locally advanced or metastatic BTC,
    including intrahepatic CCA, extrahepatic CCA, gallbladder cancer and ampulla of Vater's cancer.
    The histological origin of ampullary carcinomas (intestinal, pancreaticobiliary, or other) will be
    collected.
    3. Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transarterial
    chemo-embolization, transarterial embolization, transarterial infusion) for locally advanced or
    metastatic BTC. Participants whose disease has recurred = 6 months after completion of
    neoadjuvant or adjuvant treatments will be considered eligible.
    4. Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first
    administration of study intervention. Availability of tumor tissue is mandatory except for the safety
    run-in part. Brush cytology, and cell blocks are not acceptable. Tumor tissue (fresh or archival)
    must be suitable for biomarker assessment as described in the Laboratory Manual.
    5. At least 1 measurable lesion according to RECIST 1.1. Participants in the safety run-in part do
    not require a measurable lesion at baseline.
    6. ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.
    7. Life expectancy of = 12 weeks, as judged by the Investigator.
    8. Adequate hematological function defined by white blood cell count = 2.0 × 10^9/Lwith absolute
    neutrophil count = 1.5 × 10^9/L, lymphocyte count = 0.5 × 10^9/L, platelet count = 100 × 10^9/L,
    and hemoglobin (Hgb) = 9 g/dL (participants may have been transfused) at study entry and at
    Week 1 Day 1 prior to dosing. Previously transfused participants are allowed in the study with a
    stable Hgb of = 9 g/dL at the time of study entry.
    9. Adequate hepatic function defined by a total bilirubin level = 1.5 × upper limit of normal (ULN), an
    aspartate aminotransferase level = 3.0 × ULN, and an alanine aminotransferase level = 3.0 ×
    ULN. For participants with liver involvement, aspartate aminotransferase = 5.0 × ULN and
    alanine aminotransferase = 5.0 × ULN are acceptable.
    10. Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min
    according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
    CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine [Crjaffe]) If female, × 0.85
    If creatinine is measured by the enzymatic method, add 0.2 and use as Crjaffe = 0.2 +
    Crenzyme.
    11. Albumin = 2.8 g/dL.
    12. Adequate coagulation function defined as prothrombin time or international normalized ratio =
    1.5 × ULN unless the participant is receiving anticoagulant therapy.
    13. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and
    on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or interferon is not
    allowed) at study entry and with planned monitoring and management including baseline HBV
    DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis
    C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and
    management according to appropriate labeling guidance of approved antiviral.
    1. Pazienti di età =18 anni al momento della firma del consenso informato.
    2. Partecipanti con BTC localmente avanzato o metastatico istologicamente o citologicamente confermato, inclusi CCA intraepatica, CCA extraepatica, tumore della cistifellea e tumore
    dell’ampolla di Vater. Saranno raccolte informazioni sull’origine istologica dei carcinomi ampollari (intestinali, pancreatici o altro).
    3. Naïve a chemioterapia, immunoterapia o trattamento radiologico interventistico (chemioembolizzazione transarteriosa, embolizzazione transarteriosa, infusione transarteriosa) per BTC
    localmente avanzato o metastatico. Saranno considerati idonei i partecipanti la cui malattia si è ripresentata =6 mesi dopo il completamento dei trattamenti neo-adiuvanti o adiuvanti.
    4. Disponibilità di tessuto tumorale (primario o metastatico) (biopsie fresche o d’archivio) prima della prima somministrazione dell’intervento dello studio. La disponibilità di tessuto tumorale è
    obbligatoria, salvo nella parte di run-in di sicurezza. Le citologie per spazzolamento e i cell blocks non sono accettati. Il tessuto tumorale (fresco o d’archivio) deve essere adatto alla
    valutazione dei biomarcatori come descritto nel manuale di laboratorio.
    5. Almeno 1 lesione misurabile secondo i criteri RECIST 1.1. I partecipanti al run-in di sicurezza non necessitano di una lesione misurabile al basale.
    6. PS ECOG pari a 0 o 1 al momento dell’ingresso nello studio e alla Settimana 1, Giorno 1 prima della somministrazione.
    7. Aspettativa di vita =12 settimane a giudizio dello sperimentatore.
    8. Funzione ematologica adeguata, definita da una conta dei globuli bianchi =2,0 x 10^9/l con conta assoluta dei neutrofili =1,5 x 10^9/l, conta linfocitaria =0,5 x 10^9/l, conta piastrinica =100 ×
    10^9/l ed emoglobina (Hgb) =9 g/dl (i partecipanti potrebbero essere stati sottoposti a trasfusione) nel momento dell’ingresso nello studio e alla Settimana 1 Giorno 1 prima della
    somministrazione. I partecipanti precedentemente sottoposti a trasfusione sono ammessi allo studio con Hgb stabile =9 g/dl al momento dell’ingresso nello studio.
    9. Funzione epatica adeguata definita da un livello di bilirubina totale =1,5 x il limite superiore dell’intervallo normale (ULN), livello di aspartato aminotransferasi =3,0 x ULN e di alanina
    aminotransferasi =3,0 x ULN. Per i partecipanti con coinvolgimento epatico, aspartato aminotransferasi =5,0 x ULN e alanina aminotransferasi =5,0 x ULN sono accettabili.
    10. Funzione renale adeguata, definita da una clearance della creatinina (CrCl) stimata >50 ml/min secondo la formula di Cockcroft-Gault o secondo la misurazione della CrCl dalla raccolta delle
    urine delle 24 ore. CrCl (ml/min) = (140-età) x peso (kg) / (72 x creatinina sierica [Crjaffe])
    Se di sesso femminile, x 0,85 Se la creatinina è misurata utilizzando il metodo enzimatico, aggiungere 0,2 e utilizzare come Crjaffe = 0,2 + Crenzima.
    11. Albumina =2,8 g/dl.
    12. Adeguata funzione di coagulazione definita come tempo di protrombina o rapporto internazionale normalizzato =1,5 x ULN, a meno che il partecipante stia ricevendo una terapia
    anticoagulante.
    13. I partecipanti positivi all’acido desossiribonucleico (DNA) del virus dell’epatite B (HBV) devono essere trattati e assumere una dose stabile di antivirali (ad es. entecavir, tenofovir, o
    lamivudina; adefovir o interferone non sono consentiti) al momento dell’ingresso nello studio, con monitoraggio e gestione programmati, inclusa la quantità di HBV-DNA al basale secondo le
    indicazioni riportate in etichetta. I partecipanti che ricevono una terapia per il virus dell’epatite C (HCV) attivo devono assumere una dose stabile del trattamento al momento dell’ingresso nello
    studio, con monitoraggio e gestione programmati secondo le indicazioni riportate in etichetta dell’antivirale approvato.
    E.4Principal exclusion criteria
    1. Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to
    cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in
    mucosal layer.
    2. Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures at study entry and at Week
    1 Day 1 prior to dosing.
    3. Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not
    eligible unless they are judged to have fully recovered from treatment.
    4. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair
    transplant).
    5. Significant acute or chronic infections including:
    - Known history of positive test for HIV or known acquired immunodeficiency syndrome
    - Active tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
    - Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage (PTBD).
    - Active bacterial, fungal or viral infection (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 Day 1 prior to dosing.
    6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
    - Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    - Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses = 10 mg of prednisone
    or equivalent per day.
    - Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intraocular, or inhalation) is acceptable.
    7. History of, or concurrent, interstitial lung disease.
    8. Known history of hypersensitivity reactions to bintrafusp alfa or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade = 3 NCI-CTCAE] Version 5.0), any
    history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
    9. Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to
    enrollment), unstable angina, congestive heart failure (New York Heart Association Classification = Class II), or serious cardiac arrhythmia.
    10. Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past
    year) or active suicidal ideation or behavior.
    11. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
    For further details please refer to the protocol
    1. Tumori precedenti e/o intercorrenti. Ad eccezione di:
    tumori trattati con intento curativo senza recidiva in >3 anni o tumori precoci trattati con intento curativo, tra cui, a titolo esemplificativo ma non esaustivo, carcinoma della cervice in situ, tumore
    superficiale non invasivo della vescica, carcinoma a cellule basali, carcinoma a cellule squamose in situ o tumori gastrointestinali resecati endoscopicamente limitati allo strato della mucosa.
    2. Rapido deterioramento clinico non correlato a malignità che, a giudizio dello sperimentatore, può predisporre all’incapacità di tollerare il trattamento o le procedure dello studio all’ingresso
    nello studio e alla Settimana 1 Giorno 1 prima della somministrazione.
    3. Sono esclusi i partecipanti con metastasi sintomatiche al sistema nervoso centrale (SNC). I partecipanti con anamnesi di metastasi al SNC trattate (con intervento chirurgico o radioterapia)
    non sono idonei a meno che non siano giudicati completamente guariti dal trattamento.
    4. Qualsiasi trapianto di organi, incluso il trapianto allogenico di cellule staminali, con l’eccezione dei trapianti che non richiedono immunosoppressione (ad es. trapianto di cornea, trapianto di
    capelli).
    5. Infezioni acute o croniche significative, comprese:
    - Anamnesi nota di risultato positivo al test dell’HIV o sindrome da immunodeficienza acquisita nota
    - Tubercolosi attiva (presenza di sintomi clinici, riscontri fisici o radiografici di tubercolosi attiva).
    - Infezione biliare non controllata. L’ostruzione del tratto biliare deve essere eliminata tramite stent o drenaggio biliare percutaneo transepatico (PTBD, percutaneous transhepatic biliary
    drainage).
    - Infezione batterica, fungina o virale attiva (ad eccezione dell’epatite B e dell’epatite C) che richiede terapia sistemica al momento dell’ingresso nello studio e alla Settimana 1 Giorno 1 prima
    della somministrazione.
    6. Malattia autoimmune in fase attiva che potrebbe peggiorare durante il trattamento con un agente immunostimolante:
    - Sono idonei i partecipanti con diabete di tipo 1, vitiligine, alopecia, psoriasi, malattia ipo- o ipertiroidea che non richieda un trattamento immunosoppressivo.
    - I partecipanti che richiedono una terapia sostitutiva ormonale con corticosteroidi sono idonei se gli steroidi vengono somministrati soltanto per le finalità della terapia sostitutiva ormonale e a
    dosi =10 mg di prednisone o equivalente al giorno.
    - È consentita la somministrazione di steroidi per altre malattie attraverso una via nota per indurre un’esposizione sistemica minima (topica, intranasale, intraoculare o per inalazione).
    7. Anamnesi di malattia polmonare interstiziale o malattia polmonare interstiziale concomitante.
    8. Anamnesi nota di reazioni di ipersensibilità a bintrafusp alfa o ai suoi prodotti o reazioni note gravi di ipersensibilità ad anticorpi monoclonali (Grado =3 secondo i criteri NCI-CTCAE Versione 5.0), qualsiasi anamnesi di anafilassi o anamnesi recente (entro 5 mesi) di asma incontrollata.
    9. Malattia cardiovascolare/cerebrovascolare clinicamente significativa come segue:
    accidente cerebrovascolare/ictus (<6 mesi prima dell’arruolamento), infarto miocardico (<6 mesi prima dell’arruolamento), angina instabile, insufficienza cardiaca congestizia (di classe =II
    secondo la New York Heart Association) o aritmia cardiaca grave.
    10. Altre condizioni mediche gravi, acute o croniche, tra cui colite autoimmune, malattia infiammatoria intestinale, polmonite autoimmune o condizioni psichiatriche, tra cui recente (nell’ultimo
    anno) pensiero o comportamento suicida attivo.
    11. Esacerbazione di malattia polmonare ostruttiva cronica o altra malattia respiratoria che richieda ricovero o che precluda la somministrazione della terapia dello studio nei 30 giorni prima della
    randomizzazione.
    Per ulteriori dettagli si faccia riferimento ap protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Open-label Safety Run-in
    Occurrence of DLTs during the DLT evaluation period
    Randomized, Double-blind Part
    Overall Survival
    Run-in di sicurezza in aperto
    Comparsa di DLT durante il periodo di valutazione delle DLT
    Parte randomizzata in doppio cieco
    Sopravvivenza complessiva
    E.5.1.1Timepoint(s) of evaluation of this end point
    Open-label Safety Run-in
    From the Occurrence of DLTs during the DLT evaluation period

    Randomized, Double-blind Part
    • Interim analysis at the data cutoff date of 63% of OS events for the primary analysis (210/334
    events), expected at 27 months after randomization
    • Primary analysis when the target number of 334 OS events have occurred in a total of 500
    participants, expected at 40 months after randomization of the first participant
    Run-in di sicurezza in aperto
    Dalla comparsa di DLT durante il periodo di valutazione delle DLT
    Parte randomizzata in doppio cieco
    • Analisi ad interim alla data di cut-off dei dati del 63% degli eventi di OS per l’analisi primaria (210/334 eventi), prevista a 27 mesi dopo la randomizzazione
    • Analisi primaria quando il numero target di 334 eventi di OS si sarà verificato in un totale di 500 partecipanti, atteso a 40 mesi dopo la randomizzazione del primo partecipante
    E.5.2Secondary end point(s)
    Open-label Safety Run-in
    Occurrence of TEAEs and treatment-related AEs
    Occurrence of abnormalities (Grade = 3) in laboratory tests
    Randomized, Double-blind Part
    1. PFS according to RECIST 1.1 as assessed by the investigator
    2. Confirmed objective response according to RECIST 1.1 as assessed by the
    investigator
    3. DOR assessed by confirmed complete response or partial response until death or
    progression of disease according to RECIST 1.1 as assessed by the investigator
    4. Durable confirmed response of at least 6 months according to RECIST 1.1 as
    assessed by the investigator
    5. Occurrence of TEAEs and treatment-related AEs, including adverse events of special
    interest
    6. PK profile of bintrafusp alfa in terms of Ceoi and Ctrough for participants in the
    bintrafusp alfa arm.
    PK profile of bintrafusp alfa in terms of AUC0-t, AUC0-8, Cmax, tmax, and t½ for
    participants in the safety run-in part of the study only
    7. Immunogenicity as measured by antidrug antibody assays at baseline and on-
    treatment for participants in the bintrafusp alfa arm
    Run-in di sicurezza in aperto
    Comparsa di TEAE ed EA correlati al trattamento
    Comparsa di anomalie (Grado =3) negli esami di laboratorio
    Parte randomizzata in doppio cieco
    1. PFS valutata dallo sperimentatore secondo i criteri RECIST 1.1
    2. Risposta obiettiva confermata valutata dallo sperimentatore secondo i criteri RECIST 1.1
    3. DOR valutata dallo sperimentatore in base alla risposta completa o parziale confermata fino al decesso o alla progressione della malattia in base ai criteri RECIST 1.1
    4. Risposta durevole di almeno 6 mesi confermata valutata dello sperimentatore secondo i criteri RECIST 1.1
    5. Comparsa di TEAE ed EA correlati al trattamento, inclusi eventi avversi di interesse speciale
    6. Profilo PK di bintrafusp alfa in termini di Ceoi e Ctrough per i partecipanti nel braccio con bintrafusp alfa.
    Profilo PK di bintrafusp alfa in termini di AUC0-t, AUC0-8, Cmax, tmax e t½ solo per i partecipanti al run-in di sicurezza dello studio
    7. Immunogenicità come misurata mediante analisi di anticorpi anti-farmaco al basale e durante il trattamento per i partecipanti nel braccio bintrafusp alfa
    E.5.2.1Timepoint(s) of evaluation of this end point
    Open-label Safety Run-in
    Multiple and variable timepoints throughout the study - please refer to protocol
    Randomized, Double-blind Part
    Items 1 - 5: Multiple and variable timepoints throughout the study - please refer to protocol
    Items 6 and 7 - multiple timepoints throughout study, please see Protocol table 4, (Schedule of Activities for Biomarkers, PK, and Immunogenicity Sampling: Randomized, Double-blind Part) page 29/168
    Run-in di sicurezza in aperto
    Punti temporali multipli e variabili per tutto lo studio - fare riferimento al protocollo
    Parte randomizzata in doppio cieco
    Voci 1 - 5: Punti temporali multipli e variabili per tutto lo studio - fare riferimento al protocollo
    Voci 6 e 7 - punti temporali multipli durante tutto lo studio, consultare la tabella 4 del protocollo (Programma delle attività per campioni di biomarcatori, PK e immunogenicità: Parte randomizzata in doppio cieco) pagina 29/168
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response 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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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) Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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
    Argentina
    Australia
    Brazil
    Chile
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Poland
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the data cutoff for the primary OS analysis when 334 participants have died. However, if the study does not expand into Phase III but continues as a Phase II study, the end of study is defined accordingly, as the data cutoff date for the primary OS analysis when 60% participants have died.
    La definizione della fine dello studio è la data del cut-off dei dati per l’analisi primaria dell’OS al momento in cui saranno deceduti 334 partecipanti. Tuttavia, se lo studio non si estende nella fase III ma prosegue come uno studio di fase II, la definizione della fine dello studio è, di conseguenza, la data di cut-off dei dati per l’analisi primaria dell’OS al momento in cui il 60% dei partecipanti è deceduto.
    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 months5
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days8
    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: 256
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 256
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 98
    F.4.2.2In the whole clinical trial 524
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants will be followed for survival and AEs as specified in the Schedule of Activities.
    The Sponsor will not provide any additional care to participants after they leave the study because such care would not differ from what is normally expected for patients with BTC.
    I partecipanti saranno seguiti per la sopravvivenza e gli EA come specificato nel Programma delle attività.
    Lo sponsor non fornirà alcuna terapia aggiuntiva ai partecipanti dopo che avranno abbandonato lo studio in quanto tali cure non differirebbero da quanto normalmente previsto per i pazienti con BTC.
    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 Decision2020-11-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-24
    P. End of Trial
    P.End of Trial StatusOngoing
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