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    Summary
    EudraCT Number:2019-001025-28
    Sponsor's Protocol Code Number:NuTide:121
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-27
    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 number2019-001025-28
    A.3Full title of the trial
    A Phase III Open-Label, Multi-Centre, Randomised Study Comparing NUC-1031 plus Cisplatin to Gemcitabine plus Cisplatin in Patients with Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer
    Studio di fase III, multicentrico, randomizzato, in aperto volto a confrontare NUC-1031 più cisplatino con gemcitabina più cisplatino in pazienti affetti da carcinoma del tratto biliare localmente avanzato o metastatico precedentemente non trattato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of NUC-1031 plus Cisplatin versus Gemcitabine plus Cisplatin in Previously Untreated Biliary Tract Cancer
    Studio su NUC-1031 più Cisplatino rispetto a Gemcitabina più Cisplatino in Tumore del tratto biliare precedentemente non trattato
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberNuTide:121
    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 SponsorNuCana plc
    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 supportNuCana plc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNuCana plc
    B.5.2Functional name of contact pointNuCana Clinical Study Information
    B.5.3 Address:
    B.5.3.1Street Address3 Lochside Way
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH12 9DT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00441313571111
    B.5.6E-mailinfo@nucana.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 nameAcelarin
    D.3.2Product code [NUC-1031]
    D.3.4Pharmaceutical form Concentrate 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 INNFosgemcitabine palabenamide
    D.3.9.1CAS number 1562406-27-2
    D.3.9.2Current sponsor codeNUC-1031
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) 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 Gemcitabina
    D.2.1.1.2Name of the Marketing Authorisation holderSun Pharmaceutical Industries Europe B.V
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameGemcitabine
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Powder 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 INNGemcitabine
    D.3.9.1CAS number 95058-81-4
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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.2.1.1.1Trade name Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holderEBEWE Pharma Ges.m.b.H Nfg. KG
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameCisplatin
    D.3.2Product code [NA]
    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 INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB07483MIG
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally advanced, unresectable or metastatic.
    Adenocarcinoma istologicamente o citologicamente confermato del tratto biliare (compresi cistifellea, dotti biliari intra ed extra-epatici e tumori ampollari) localmente avanzato, non resecabile o metastatico.
    E.1.1.1Medical condition in easily understood language
    Cancer of the biliary tract
    Tumore del tratto biliare
    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 10008594
    E.1.2Term Cholangiocarcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare NUC-1031/cisplatin (Arm A) to the gemcitabine/cisplatin standard of care (Arm B) and to detect a clinically meaningful improvement in Overall Survival and Objective Response Rate.
    Confrontare NUC-1031 / cisplatino (braccio A) con lo standard di cura gemcitabina / cisplatino (braccio B) e rilevare un miglioramento clinicamente significativo del tasso di risposta globale di sopravvivenza e obiettivo.
    E.2.2Secondary objectives of the trial
    To compare the following between the two treatment arms:
    - Progression-free survival (PFS) based on BICR
    - Duration of response (DoR) based on BICR
    - 18- and 12-month survival
    - Disease control rate (DCR)
    To assess the safety and tolerability of NUC-1031
    To explore the pharmacokinetics of NUC-1031
    To assess changes in patient-reported quality of life
    Per confrontare quanto segue tra i due bracci di trattamento:
    - Sopravvivenza libera da progressione (PFS) basata sul BICR
    - Durata della risposta (DoR) basata sul BICR
    - Sopravvivenza di 18 e 12 mesi
    - Tasso di controllo delle malattie (DCR)
    Per valutare la sicurezza e la tollerabilità di NUC-1031
    Per esplorare la farmacocinetica di NUC-1031
    Per valutare i cambiamenti nella qualità della vita riferita dal paziente
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent and authorisation to use and disclose health information.

    2. Ability to comprehend and willingness to comply with the requirements of this protocol, including the QoL questionnaires.

    3. Female or male patients aged =18 years.

    4. Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally advanced, unresectable or metastatic. Patients with measurable (as per RECIST v1.1 criteria) or non-measurable disease are permitted.

    5. Life expectancy =16 weeks.

    6. ECOG performance status 0 or 1.

    7. Adequate biliary drainage with no evidence of ongoing infection. If applicable, treatable and clinically-relevant biliary duct obstruction has been relieved by internal endoscopic drainage/stenting at least 2 weeks previously or by palliative bypass surgery or percutaneous drainage prior to study entry, and the patient has no active or suspected uncontrolled infection. Patients fitted with a biliary stent should be clinically stable and free of signs of infection for =2 weeks prior to study entry. Patients with improving biliary function who meet all other inclusion criteria may be re-tested during the screening window.

    8. Adequate bone marrow, hepatic, and renal function, as evidenced by:
    • Absolute neutrophil count (ANC) =1,500/µL without colony-stimulating factor support.
    • Platelet count =100,000/µL.
    • Haemoglobin =10 g/dL without need for haematopoietic growth factor or transfusion
    support in prior 2 weeks.
    • Total bilirubin <2 × upper limit of normal (ULN); does not apply to patients with Gilbert's
    syndrome. Consistent with inclusion criterion 7, patients whose whole bilirubin and biliary
    function is recovering may be re-tested during the screening period.
    • ALT and/or AST <5 × ULN
    • Serum creatinine =1.5 × ULN or creatinine clearance =45 mL/min actual or calculated by
    the Cockcroft-Gault method.
    • International normalised ratio (INR) <1.5 and partial thromboplastin time (PTT)
    <1.5 × ULN; does not apply to patients on an anti-coagulant with stable dose 28 days prior to first dose.

    9. QTc interval <450 msec (males) or <470 msec (females), in the absence of bundle branch block. In the presence of bundle branch block with consequent QTc prolongation, patients may be enrolled based on a careful risk-benefit assessment.

    10. Human Immunodeficiency Virus-infected patients who are healthy and have a low risk of Acquired Immune Deficiency Syndrome-related outcomes may be included in this study.

    11.Female patients of child-bearing potential (i.e., all women except those who are post-menopausal for =1 year or who have a history of hysterectomy or surgical sterilisation) must have a negative pregnancy test within 3 days prior to the first study drug administration. All patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method of contraception, from the time of screening until 6 months after the last dose of study medication.

    12. Male patients with a female partner must either have had a successful vasectomy or they and their female partner meet the criteria above (not of childbearing potential or practicing highly effective contraceptive methods).
    1. Consenso informato scritto e autorizzazione all'utilizzo e alla divulgazione di informazioni sanitarie.

    2. Capacità di comprensione e disponibilità a rispettare i requisiti del presente protocollo, inclusi i questionari QoL.

    3. Pazienti di sesso maschile o femminile di età = 18 anni.

    4. Adenocarcinoma istologicamente o citologicamente confermato del tratto biliare (compresi cistifellea, dotti biliari intra ed extra-epatici e tumori ampollari) localmente avanzato, non resecabile o metastatico. Sono ammessi pazienti con malattia misurabile (secondo i criteri RECIST v1.1) o non misurabile.

    5. Speranza di vita = 16 settimane.

    6. Stato delle prestazioni ECOG 0 o 1.

    7. Drenaggio biliare adeguato senza evidenza di infezione in corso. Se applicabile, l'ostruzione del dotto biliare trattabile e clinicamente rilevante è stata alleviata da drenaggio / stenting endoscopico interno almeno 2 settimane prima o da un intervento chirurgico di bypass palliativo o drenaggio percutaneo prima dell'ingresso nello studio e il paziente non ha infezione incontrollata attiva o sospetta. I pazienti muniti di uno stent biliare devono essere clinicamente stabili e privi di segni di infezione per = 2 settimane prima dell'ingresso nello studio. I pazienti con miglioramento della funzione biliare che soddisfano tutti gli altri criteri di inclusione possono essere testati nuovamente durante la finestra di screening.

    8. Adeguata funzionalità del midollo osseo, epatico e renale, come evidenziato da:
    • Conta assoluta dei neutrofili (ANC) = 1.500 / µL senza supporto del fattore stimolante le colonie.
    • Conta piastrinica = 100.000 / µL.
    • Emoglobina = 10 g / dL senza necessità di fattore di crescita ematopoietica o trasfusione
    supporto nelle precedenti 2 settimane.
    • Bilirubina totale <2 × limite superiore della norma (ULN); non si applica ai pazienti con Gilbert
    sindrome. Coerentemente con il criterio di inclusione 7, pazienti con bilirubina intera e biliare
    la funzione in fase di recupero può essere testata nuovamente durante il periodo di screening.
    • ALT e / o AST <5 × ULN
    • Creatinina sierica = 1,5 × ULN o clearance della creatinina = 45 ml / min effettivi o calcolati da
    il metodo Cockcroft-Gault.
    • Rapporto internazionale normalizzato (INR) <1,5 e tempo parziale di tromboplastina (PTT)
    <1,5 × ULN; non si applica ai pazienti in trattamento con anticoagulanti con dose stabile 28 giorni prima della prima dose.

    9. Intervallo QTc <450 msec (maschi) o <470 msec (femmine), in assenza di blocco di branca. In presenza di branca ramificata con conseguente prolungamento dell'intervallo QTc, i pazienti possono essere arruolati in base a un'attenta valutazione del rapporto rischio-beneficio.

    10. In questo studio possono essere inclusi pazienti con infezione da virus dell'immunodeficienza umana sani e con un basso rischio di esiti correlati alla sindrome da immunodeficienza acquisita.

    11. I pazienti femminili in età fertile (ovvero, tutte le donne tranne quelle che sono in post-menopausa per = 1 anno o che hanno una storia di isterectomia o sterilizzazione chirurgica) devono sottoporsi a un test di gravidanza negativo entro 3 giorni prima del primo studio somministrazione di droghe. Tutti i pazienti in età fertile devono concordare di praticare la vera astinenza o di utilizzare due forme di contraccezione altamente efficaci, una delle quali deve essere un metodo contraccettivo di barriera, dal momento dello screening fino a 6 mesi dopo l'ultima dose del farmaco in studio.

    12. I pazienti maschi con un partner femminile devono aver avuto una vasectomia di successo oppure loro e il loro partner femminile soddisfano i criteri sopra indicati (non in termini di potenziale fertile o di metodi contraccettivi altamente efficaci).
    E.4Principal exclusion criteria
    1. Combined or mixed hepatocellular/cholangiocarcinoma.

    2. Prior systemic therapy for advanced or metastatic biliary tract cancer. However, prior chemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunction with radiotherapy in the adjuvant setting and completed at least 6 months prior to enrolment is permitted. The following prior interventions are allowed provided the patient has fully recovered:
    • Surgery: non-curative resection with macroscopic residual disease or palliative bypass surgery. Patients who have previously undergone curative surgery must now have evidence of non-resectable disease requiring systemic chemotherapy.
    • Radiotherapy: prior radiotherapy (with or without radio-sensitising low-dose chemotherapy) for localised disease and there is now clear evidence of disease progression requiring systemic chemotherapy.• Photodynamic therapy: prior photodynamic therapy for localised disease with no evidence of metastatic disease or for localised disease to relieve biliary obstruction in the presence of metastatic disease provided there is now clear evidence of disease progression requiring systemic chemotherapy.
    • Palliative radiotherapy: palliative radiotherapy provided that all AEs have resolved and the patient has measurable disease outside the field of radiation.

    3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin or other platinum-based agents or history of allergic reactions attributed to the excipients contained in NUC-1031 or diluent solution (dimethylacetamide [DMA], Kolliphor ELP, Tween 80).

    4. Symptomatic central nervous system or leptomeningeal metastases.

    5. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, low grade prostate cancer not requiring treatment or other solid tumours curatively treated with no evidence of disease for =3 years.

    6. Concurrent serious (as deemed by the Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.

    7. Other acute or chronic medical, neurological, or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

    8. Prior exposure to another investigational agent within 28 days prior to randomisation.

    9. Major surgery within 28 days prior to randomisation; patient must have completely recovered from any prior surgical or other procedures.

    10. Pregnant or breastfeeding.

    11. Residual toxicities from prior treatments or procedures which have not regressed to Grade =1 severity (CTCAE v5.0), except for alopecia or =Grade 1 peripheral neuropathy.

    12. Concomitant use of drugs at doses known to cause clinically relevant prolongation of QT/QTc interval.

    13. Administration of a live vaccination within 28 days prior to randomisation.

    14. Ongoing or recent (=6 months) hepatorenal syndrome.
    1. Epatocellulare / colangiocarcinoma combinato o misto.

    2. Terapia sistemica preventiva per carcinoma del tratto biliare avanzato o metastatico. Tuttavia, è consentita la chemioterapia precedente in ambiente adiuvante o la chemioterapia a basso dosaggio somministrata insieme alla radioterapia in ambiente adiuvante e completata almeno 6 mesi prima dell'arruolamento. Sono consentiti i seguenti interventi precedenti a condizione che il paziente si sia completamente ripreso:
    • Chirurgia: resezione non curativa con malattia macroscopica residua o intervento chirurgico di bypass palliativo. I pazienti che sono stati precedentemente sottoposti a chirurgia curativa devono ora avere evidenza di patologie non resecabili che richiedono la chemioterapia sistemica.
    • Radioterapia: precedente radioterapia (con o senza chemioterapia a basse dosi radio-sensibilizzanti) per la malattia localizzata e ora ci sono evidenti prove di progressione della malattia che richiedono la chemioterapia sistemica • Terapia fotodinamica: precedente terapia fotodinamica per la malattia localizzata senza evidenza di malattia metastatica o per la malattia localizzata per alleviare l'ostruzione biliare in presenza di malattia metastatica, a condizione che ora ci sia chiara evidenza della progressione della malattia che richiede la chemioterapia sistemica.
    • Radioterapia palliativa: radioterapia palliativa a condizione che tutti gli eventi avversi si siano risolti e che il paziente abbia una malattia misurabile al di fuori del campo delle radiazioni.

    3. Trattamento precedente con o nota ipersensibilità a NUC-1031, gemcitabina, cisplatino o altri agenti a base di platino o storia di reazioni allergiche attribuite agli eccipienti contenuti in NUC-1031 o soluzione diluente (dimetilacetamide [DMA], Kolliphor ELP, Tween 80 ).

    4. Sistema nervoso centrale sintomatico o metastasi leptomeningee.

    5. Anamnesi di altri tumori maligni, ad eccezione del carcinoma cutaneo non melanoma adeguatamente trattato, del carcinoma in situ della cervice trattato in modo curativo, del carcinoma prostatico di basso grado che non richiede trattamento o di altri tumori solidi curati curativamente senza evidenza di malattia per = 3 anni.

    6. Condizioni mediche concomitanti gravi (come ritenuto dall'Investigatore), tra cui, a titolo esemplificativo, insufficienza cardiaca congestizia di classe III o IV della New York Heart Association, anamnesi di sindrome congenita prolungata del QT, infezione incontrollata, epatite B o C attiva, oppure altre condizioni di comorbilità che, secondo l'opinione dell'Investigatore, comprometterebbero la partecipazione o la cooperazione allo studio.

    7. Altre condizioni mediche, neurologiche o psichiatriche acute o croniche o anomalie di laboratorio che possono aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del prodotto sperimentale o possono interferire con l'interpretazione dei risultati dello studio e, a giudizio dello sperimentatore, renderebbero paziente inappropriato per l'ingresso in questo studio.

    8. Prima esposizione a un altro agente investigativo entro 28 giorni prima della randomizzazione.

    9. Chirurgia maggiore entro 28 giorni prima della randomizzazione; il paziente deve essersi completamente ripreso da qualsiasi precedente intervento chirurgico o altre procedure.

    10. Incinta o allattamento.

    11. Tossicità residua da precedenti trattamenti o procedure che non sono regrediti alla gravità di Grado = 1 (CTCAE v5.0), eccetto per l'alopecia o = Neuropatia periferica di Grado 1.

    12. Uso concomitante di farmaci a dosi note per causare un prolungamento clinicamente rilevante dell'intervallo QT / QTc.

    13. Somministrazione di una vaccinazione viva entro 28 giorni prima della randomizzazione.

    14. Sindrome epatorenale in corso o recente (= 6 mesi).
    E.5 End points
    E.5.1Primary end point(s)
    OS, defined as the time from randomisation to the time of death from any cause.

    ORR, defined as the percentage of patients achieving a confirmed complete or partial response to treatment as assessed by BICR according to RECIST v1.1 criteria. This will be assessed only in patients with measurable disease at baseline.
    OS, definito come il tempo dalla randomizzazione al momento della morte per qualsiasi causa.

    ORR, definito come la percentuale di pazienti che raggiungono una risposta confermata completa o parziale al trattamento valutata dal BICR secondo i criteri RECIST v1.1. Questo sarà valutato solo nei pazienti con malattia misurabile al basale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Interim Analysis 1 - approx 25.5 months or 418 patients with measurable disease randomised. This will assess ORR for demonstration of efficacy, and assess OS for futility.

    Interim Analysis 2 - approx 33.1 months or approx 425 deaths. This will assess ORR and OS for demonstration of efficacy.

    Interim Analysis 3 - approx 40 months or 541 deaths. This will assess OS for efficacy.

    Final Analysis - approx 48 months or 637 deaths.
    Analisi intermedia 1 - circa 25,5 mesi o 418 pazienti con malattia misurabile randomizzati. Ciò valuterà ORR per la dimostrazione dell'efficacia e valuterà l'OS per la futilità.

    Analisi intermedia 2 - circa 33,1 mesi o circa 425 decessi. Ciò valuterà ORR e OS per la dimostrazione dell'efficacia.

    Analisi intermedia 3 - circa 40 mesi o 541 decessi. Ciò valuterà l'efficacia del sistema operativo.

    Analisi finale - circa 48 mesi o 637 decessi.
    E.5.2Secondary end point(s)
    Progression Free Survival
    • PFS, based on BICR according to RECIST v1.1 criteria, defined as the time from randomisation to the first observation of objective tumour progression or death from any cause. For patients with non-measurable disease at baseline, refer to the protocol criteria for disease progression.

    Efficacy
    • DoR, as assessed by BICR, defined as the time from initial clinical response (partial response [PR] or complete response [CR] that is subsequently confirmed) to the first observation of tumour progression or death from any cause
    • 18-month survival
    • 12-month survival
    • DCR, based on BICR according to RECIST v1.1 criteria, defined as the percentage of patients demonstrating CR, PR, or stable disease (SD)

    Safety
    Safety and tolerability will be assessed by evaluation of the following:
    • Treatment-emergent AEs (TEAEs), including TEAEs by severity grade using Common Terminology Criteria for Adverse Events (CTCAE) v5.0
    • Serious TEAEs (SAEs)
    • Deaths due to TEAEs
    • Treatment discontinuations due to TEAEs
    • Clinically-significant changes in laboratory parameters
    • Changes in Eastern Cooperative Oncology Group (ECOG) status, physical exam, electrocardiogram (ECG) and vital signs

    A robust QT analysis substudy will be carried out to assess the effect of the NUC-1031 + cisplatin combination on QT interval prolongation in a subset of patients.

    Pharmacokinetics of NUC-1031
    Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of infusion, 2 hours after the end of infusion, and 6 hours after the end of infusion, to capture Ctrough and Cmax plasma levels.

    Patient-Reported Quality of Life
    Patient-reported quality of life will be assessed using the European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ-C30) with the QLQ-BIL21 module and the 5-level EuroQol five-dimension scale (EQ-5D-5L).
    Sopravvivenza libera da progressione
    • PFS, basato sul BICR secondo i criteri RECIST v1.1, definito come il tempo che intercorre tra la randomizzazione e la prima osservazione della progressione tumorale oggettiva o della morte per qualsiasi causa. Per i pazienti con malattia non misurabile al basale, fare riferimento ai criteri di protocollo per la progressione della malattia.

    Efficacia
    • DoR, come valutato dal BICR, definito come il tempo dalla risposta clinica iniziale (risposta parziale [PR] o risposta completa [CR] che è successivamente confermata) alla prima osservazione della progressione del tumore o della morte per qualsiasi causa
    • sopravvivenza a 18 mesi
    • Sopravvivenza di 12 mesi
    • DCR, basato sul BICR secondo i criteri RECIST v1.1, definito come percentuale di pazienti che manifestano CR, PR o malattia stabile (SD)

    Sicurezza
    La sicurezza e la tollerabilità saranno valutate valutando quanto segue:
    • Eventi avversi emergenti dal trattamento (TEAE), inclusi i TEAE per livello di gravità utilizzando Common Terminology Criteria for Adverse Events (CTCAE) v5.0
    • TEAE gravi (SAE)
    • Morti dovute a TEAE
    • Interruzioni del trattamento a causa di TEAE
    • Cambiamenti clinicamente significativi dei parametri di laboratorio
    • Cambiamenti nello stato del gruppo cooperativo di oncologia orientale (ECOG), esame fisico, elettrocardiogramma (ECG) e segni vitali

    Verrà effettuato un solido sottostudio di analisi QT per valutare l'effetto della combinazione NUC-1031 + cisplatino sul prolungamento dell'intervallo QT in un sottogruppo di pazienti.

    Farmacocinetica di NUC-1031
    Il campionamento di PK sparse verrà effettuato nel Ciclo 1 Giorno 1 alla fine dell'infusione, 2 ore dopo la fine dell'infusione e 6 ore dopo la fine dell'infusione, per catturare i livelli plasmatici di Ctrough e Cmax.

    Qualità della vita riferita dal paziente
    La qualità della vita riferita dai pazienti sarà valutata utilizzando il questionario sulla qualità della vita dell'Organizzazione europea per la ricerca e il trattamento (EORTC) (QLQ-C30) con il modulo QLQ-BIL21 e la scala a cinque dimensioni EuroQol a 5 livelli (EQ-5D- 5L).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression Free Survival - end the end of the study.

    Efficacy (DoR, 18/12-month survival, DCR) - at the end of the study.

    Safety - after 50 patients have been randomised in total, at every 6 months and at the end of the study.

    QTc analysis - after 40 patients have been enrolled into the QT substudy.

    Pharmacokinetics of NUC-1031 - end of the study.

    Patient-Reported Quality of Life - at the end of the study.
    Sopravvivenza libera da progressione - termina la fine dello studio.

    Efficacia (DoR, sopravvivenza a 18/12 mesi, DCR) - alla fine dello studio.

    Sicurezza: dopo 50 pazienti sono stati randomizzati in totale, ogni 6 mesi e alla fine dello studio.

    Analisi QTc - dopo che 40 pazienti sono stati arruolati nel sottostudio QT.

    Farmacocinetica di NUC-1031 - fine dello studio.

    Qualità della vita riferita dal paziente - alla fine dello studio.
    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 Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Assessment of archival tumour sample characteristics that may further an understanding of the mechanism(s) through which the clinical activity of NUC-1031 is achieved.
    Valutazione delle caratteristiche del campione di tumore archivistico che possono approfondire la comprensione dei meccanismi attraverso i quali viene raggiunta l'attività clinica della NUC-1031.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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 EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Czechia
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Russian Federation
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study date is defined as the time when 637 deaths have occurred, unless the results for OS meet the pre-specified criterion at an interim analysis to stop for early demonstration of efficacy, or unless the study is terminated early on safety grounds on the recommendation of the IDMC.

    Patients who are still receiving benefit from study treatment at the end of study date may continue study treatment until disease progression.
    Fare riferimento alla sezione E.8.12.EN
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial 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: 704
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 124
    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 state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 392
    F.4.2.2In the whole clinical trial 828
    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)
    Following participation in the NuTide:121 study patients will be referred back to their oncologist and GP, according to local practice.

    Patients who are still receiving benefit from study treatment at the end of study date may continue study treatment until disease progression.
    A seguito della partecipazione al NuTide: 121 pazienti dello studio saranno rinviati al loro oncologo e medico di famiglia, secondo la pratica locale.

    I pazienti che stanno ancora ricevendo benefici dal trattamento in studio alla fine della data dello studio possono continuare il trattamento in studio fino alla progressione della malattia.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR Clinical Research Network Portfolio
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-11
    P. End of Trial
    P.End of Trial StatusOngoing
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