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    Summary
    EudraCT Number:2020-002202-20
    Sponsor's Protocol Code Number:213400
    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:2021-06-15
    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 number2020-002202-20
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants Whose Disease has Remained Stable or Responded to First-Line Platinum-Based Chemotherapy with Pembrolizumab forStage IIIB or IV Non-Small Cell Lung Cancer.
    Studio multicentrico di fase 3, randomizzato, in doppio cieco, controllato con placebo, volto a confrontare niraparib più pembrolizumab rispetto al placebo più pembrolizumab come terapia di mantenimento nei partecipanti la cui malattia è rimasta stabile o ha risposto alla chemioterapia di prima linea a base di platino con pembrolizumab per il carcinoma del polmone non a piccole cellule di stadio IIIB o IV.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Niraparib Ph 3 – 1L Maintenance Non-Small Cell Lung Cancer with Niraparib in combination with pembrolizumab Simplified Title for public to understand

    Niraparib in combinazione con pembrolizumab nel carcinoma del polmone non a piccole cellule di stadio IIIB o IV
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code number213400
    A.5.4Other Identifiers
    Name:naNumber:na
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/313/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGLAXOSMITHKLINE RESEARCH AND DEVELOPMENT
    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 supportGlaxoSmithkline R&D
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & development Ltd
    B.5.2Functional name of contact pointClinical Trials Help Desk
    B.5.3 Address:
    B.5.3.1Street Address980 Great West Road
    B.5.3.2Town/ cityBrentford, Middlesex
    B.5.3.3Post codeTW8 9GS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00442089904466
    B.5.5Fax number000000
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 nameNiraparib
    D.3.2Product code [GSK3985771]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNiraparib
    D.3.9.1CAS number 1038915-60-4
    D.3.9.2Current sponsor codeGSK3985771
    D.3.9.4EV Substance CodeSUB177208
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerckSharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code [MK-3475]
    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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Yes
    D.3.11.13.1Other medicinal product typePembrolizumab è un anticorpo monoclonale umanizzato anti PD-1 (isotipo IgG4 / kappa con un'alterazione della sequenza stabilizzante nella regione Fc).
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-small Cell Lung Cancer
    Carcinoma del polmone non a piccole cellule
    E.1.1.1Medical condition in easily understood language
    Lung Cancer
    Carcinoma del polmone
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To compare PFS as assessed by BICR using RECIST v1.1 of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy

    -To compare OS of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy
    • Confrontare la sopravvivenza libera da progressione (PFS) valutata da un comitato di revisione centrale indipendente in cieco (BICR) tramite i criteri di valutazione della risposta nei tumori solidi (RECIST, versione 1.1) di niraparib più pembrolizumab rispetto al placebo più pembrolizumab come terapia di mantenimento

    • Confrontare la sopravvivenza globale (OS) di niraparib più pembrolizumab rispetto al placebo più pembrolizumab come terapia di mantenimento
    E.2.2Secondary objectives of the trial
    -To evaluate and compare the TTP in the CNS as assessed by BICR using RANO-BM criteria

    -To evaluate PFS as assessed by the Investigator using RECIST v1.1

    -To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by PD-L1 status (PDL1 TCs <1% versus =1%)

    -To evaluate and compare TTD, defined as time from randomization to meaningful deterioration on a composite endpoint of
    dyspnea, chest pain, and cough, from the EORTC QLQ-LC13

    -To evaluate changes from baseline in HRQoL and symptoms as assessed by the EORTC QLQ-C30 and the EORTC QLQ-LC13 total and domain scores

    -To evaluate safety and tolerability in participants treated with niraparib plus pembrolizumab compared to placebo plus pembrolizumab

    -To evaluate population PK of niraparib when given in combination with pembrolizumab
    Valutare e confrontare il tempo alla progressione a livello di SNC in base al giudizio del BICR formulato utilizzando i criteri RANO-BM.Valutare la PFS sulla base del giudizio dello sperimentatore tramite i criteri RECIST 1.1. Valutare la PFS in base al giudizio del BICR tramite i criteri RECIST 1.1 e la OS in base allo stato del PD-L1 <1% vs =1%.Valutare e confrontare il tempo al peggioramento dei sintomi polmonari, definito come tempo dalla rand. al peggioramento su un endpoint composito di dispnea, dolore toracico e tosse, tramite il questionario EORTC QLQ-LC13.Valutare le variazioni rispetto al basale della qualità della vita correlata alla salute(HRQoL)e dei sintomi valutati tramite il questionario EORTC QLQ-C30 e l’EORTC QLQ-LC13. Valutare la sicurezza e la tollerabilità nei partecipanti trattati con niraparib più pembrolizumab rispetto al placebo più pembrolizumab.Valutare la farmacocinetica di popolazione di niraparib quando è somministrato in associazione a pembrolizumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants will be eligible for study entry if all of the following criteria are met:
    1. Participants must be >= 18 years of age.
    2. Participants must have a histologically or cytologically confirmed diagnosis of NSCLC without known targetable driver alteration (either non-squamous or squamous histology; mixed histology is allowed).
    3. Participants must have advanced (Stage IIIB not amenable to definitive chemoradiotherapy) or metastatic (Stage IV) NSCLC as defined by the AJCC 8th Edition Staging Manual.
    4. Participants must have completed at least 4 but no more than 6 cycles of platinum-based first-line induction chemotherapy with pembrolizumab (according to standard of care defined by NCCN and/or ESMO Clinical Practice Guidelines for NSCLC).
    Note: Participants may be randomized directly after completing the induction period or, under the Investigator’s discretion, they may be randomized within 6 weeks of the last dose of chemotherapy. If the 6-week recovery period is used, pembrolizumab, in the absence of chemotherapy, must continue in the cycle immediately following the last cycle of induction and in accordance with standard prescribing directions. Up to 7 weeks recovery from last dose of chemotherapy may be granted upon Sponsor approval.
    5. Participants must have SD, PR, or CR of their NSCLC per Investigator’s assessment after completion of 4 to 6 cycles of pembrolizumab plus platinum-based first-line induction chemotherapy.
    Note: Baseline imaging may be done as part of first-line induction period so long as imaging is within 28 days of randomization. If baseline imaging falls outside of this 28-day window, then new imaging will be needed (CT [preferred] or MRI scan [if clinically indicated] of the chest and abdomen, and MRI [preferred; CT if MRI not possible] of the CNS).
    6. Participants must have an ECOG performance status of 0 or 1.
    7. Participants must have a life expectancy of at least 12 weeks.
    8. Participants must have adequate organ and bone marrow function defined as:
    Absolute neutrophil count: >=1,500/µL
    Platelets: >=100,000/µL
    Hemoglobin: >=9 g/dL or 5.6 mmol/L
    Serum creatinine: <2 × ULN
    Total bilirubin: <=1.5 × ULN (except in participants with Gilbert’s syndrome.
    Participants with Gilbert’s syndrome: isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
    AST and ALT: <= 2.5 × ULN (unless liver metastases are present, in which casethey must be <=5 × ULN)
    Note: CBC test should be obtained without transfusion or receipt of colony stimulating factors within 4 weeks prior to obtaining sample. Participants with current active liver or biliary disease are excluded (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per Investigator assessment).
    9. Participants must submit FFPE tumor specimens preferably collected after being diagnosed with metastatic disease and prior to initiating induction therapy (chemotherapy or radiation) (ie, collected at time of diagnosis of advanced [Stage IIIB] or metastatic [Stage 4] NSCLC), from location(s) not irradiated prior to biopsy. Either tissue block or freshly cut slides (minimum of 5 slides; <30 days from the date of sectioning) are acceptable.
    10. Participants with toxicity from induction therapy must have recovered to Grade 1. (A participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study.)
    11. Participants must be able to swallow and retain orally administered study treatment.
    Please see study protocol section 5.1 Inclusion Criteria pp 42-44 for a complete list of Inclusion Criteria.
    1. Età >=18 anni.
    2. Diagnosi di NSCLC istologicamente o citologicamente confermata senza un’alterazione driver nota per cui sia disponibile una terapia
    3. NSCLC avanzato (stadio IIIB non idoneo a chemioradioterapia definitiva)o metastatico (stadio IV)
    4. Devono aver completato almeno 4 ma non più di 6 cicli di chemioterapia di induzione di prima linea a base di platino con pembrolizumab.
    5. Devono avere SD, PR o CR dell’NSCLC in base alla valutazione dello sperimentatore dopo il completamento di 4-6 cicli di pembrolizumab più chemioterapia di induzione di prima linea a base di platino
    6. Devono avere un performance status ECOG pari a 0 o 1
    7. Aspettativa di vita minima di 12 settimane.
    8. Adeguata funzionalità d’organo e del midollo osseo definita come segue: Conta assoluta dei neutrofili: >=1.500/µL, Piastrine: >=100.000/µL, Emoglobina: >=9 g/dL o 5,6 mmol/L,Creatinina sierica: <2 × il limite superiore della norma (ULN), Bilirubina totale: <=1,5 × ULN (tranne nei partecipanti con la sindrome di Gilbert.Partecipanti con la sindrome di Gilbert: un valore di bilirubina isolata >1,5 x ULN è accettabile se la bilirubina è frazionata e la bilirubina diretta è <35%).Aspartato aminotransferasi (AST) e alanina aminotransferasi (ALT): <= 2,5 × ULN (a meno che non siano presenti metastasi, nel qual caso devono essere <= 5 × ULN.
    9. Devono inviare dei campioni di tumore FFPE prelevati preferibilmente dopo la diagnosi di malattia metastatica e prima dell’inizio della terapia di induzione
    10. I partecipanti con tossicità da terapia di induzione devono essersi ripresi fino al grado 1.
    11. Devono essere in grado di deglutire e trattenere il trattamento sperimentale somministrato per via orale.
    12. Le donne sono eleggibili alla partecipazione se non sono in gravidanza o in allattamento e se le condizioni indicate nel protocollo sono rispettate.
    13. I soggetti di sesso maschile sono eleggibili per la partecipazione se acconsentono a non donare sperma, astenersi da rapporti eterosessuali per il periodo di trattamento e per almeno 180 giorni dopo l’ultima dose di trattamento sperimentale, oppure acconsentire all’uso di un metodo contraccettivo.
    14. Devono essere in grado di comprendere le procedure dello studio e acconsentire a partecipare allo studio fornendo il proprio consenso informato scritto.
    Per la lista completa dei criteri di inclusione si faccia riferimento alla sezione del protocollo 5.1 Criteri di inclusione (pp 42-44)
    E.4Principal exclusion criteria
    1. Participants have mixed small cell lung cancer or sarcomatoid variant NSCLC.
    2. Participants have received prior PARP inhibitor(s) in prior lines of treatment.
    3. Participants have systolic BP >140 mmHg and/or diastolic BP >90 mmHg.
    4. Participants have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
    5. Participants have leptomeningeal disease, carcinomatous meningitis, symptomatic BM, or radiologic signs of CNS hemorrhage.
    6. Participants have received colony-stimulating factors within 4 weeks prior to the first dose of study treatment.
    7. Participants have active or previously documented autoimmune or inflammatory disorder: refer to the page 54-55 for more details.
    8. Participants are receiving chronic systemic steroids (prednisone >20 mg per day). Participants with asthma who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
    9. Participants have previously or are currently participating in a treatment study of an investigational agent within 4 weeks of the first dose of first-line induction therapy preceding the study.
    10. Participants have received prior systemic cytotoxic chemotherapy, biological therapy (including checkpoint inhibitor), or hormonal therapy for cancer, or received thoracic radiation therapy of >30 Gy within 6 months of the first dose of the start of first-line induction therapy.
    11. Participants have received live vaccine within 30 days of planned start of study randomization.
    12. Participants have known hypersensitivity to the components of niraparib, placebo, or pembrolizumab or their formulation excipients.
    13. Participants have undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery.
    14. Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy.
    15. Participants have any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the participants in this study.
    16. Participants have any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures.
    17. Participants have high medical risk due to a serious, uncontrolled medical disorder; non-malignant systemic disease; or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
    18. Participant is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
    19. Participants have presence of hepatitis B surface antigen or a positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, participants with presence of hepatitis B core antibody should also be excluded.
    20. Participants have a known history of MDS or AML.
    21. Participants have a known history of active tuberculosis.
    22. Participants have current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment.
    1. Hanno un’istologia mista di carcinoma del polmone a piccole cellule o una variante sarcomatoide di NSCLC. 2. Hanno ricevuto in precedenza degli inibitori di PARP come prima linea di trattamento. 3. Presentano BP sistolica >140 mmHg e/o BP diastolica >90 mmHg. 4. Hanno una qualsiasi anomalia gastrointestinale clinicamente significativa che potrebbe alterare l’assorbimento, come la sindrome da malassorbimento, o hanno subito una resezione maggiore dello stomaco e/o dell’intestino. 5. Hanno la malattia leptomeningea, la meningite carcinomatosa, metastasi cerebrali sintomatiche o segni radiologici di emorragia SNC. 6. Hanno ricevuto fattori stimolanti le colonie di granulociti e macrofagi o l’eritropoietina ricombinante nelle 4 settimane precedenti la prima dose di trattamento. 7. Hanno un disturbo infiammatorio o autoimmune precedentemente documentato in atto,tra cui: Infezione attiva, diagnosi nota di immunodeficienza o assunzione in corso di una terapia sistemica cronica a base di steroidi (ad es.>30 giorni) o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose di trattamento, patologia autoimmune in corso che abbia richiesto un trattamento sistemico negli ultimi 2 anni. Anamnesi di trapianto d’organo. 8. Attualmente assumono una terapia sistemica cronica a base di steroidi (prednisone >20mg al giorno). I partecipanti asmatici che richiedono l’uso intermittente di broncodilatatori, steroidi per via inalatoria o iniezioni locali di steroidi non saranno esclusi dallo studio. 9. Hanno partecipato o stanno partecipando a uno studio di trattamento su un IP nelle 4 settimane che precedono la prima dose della terapia di induzione di prima linea. 10. Hanno ricevuto in precedenza la chemioterapia citotossica sistemica, terapia biologica o una terapia ormonale per il carcinoma, oppure sono stati sottoposti a radioterapia toracica di >30 Gy nei 6 mesi dalla prima dose di inizio della terapia di induzione di prima linea. 11. Hanno ricevuto un vaccino vivo nei 30 giorni precedenti la randomizzazione. 12. Hanno un’ipersensibilità nota ai componenti di niraparib, placebo o pembrolizumab o agli eccipienti contenuti nelle loro formulazioni. 13. Sono stati sottoposti a un intervento chirurgico maggiore nelle 4 settimane precedenti la prima dose di trattamento o non si sono ripresi da uno o più effetti di un intervento chirurgico. 14. Hanno un altro tumore maligno concomitante che giustifichi una terapia sistemica, biologica od ormonale. 15. Hanno una qualsiasi malattia o condizione concomitante clinicamente significativa che potrebbe interferire con lo svolgimento dello studio o che, a giudizio dello sperimentatore, determinerebbe un rischio inaccettabile per i partecipanti 16. Hanno una qualsiasi condizione psicologica, familiare, sociologica o geografica che potrebbe ostacolare il rispetto dei requisiti dello studio e/o delle procedure di follow-up. 17. Presentano un rischio elevato dovuto a un disturbo serio e non controllato; malattia sistemica non maligna; un’infezione non controllata in atto. 18. È in gravidanza, in allattamento o intende concepire durante l’assunzione del trattamento nei 180 giorni successivi all’ultima dose di farmaco 19. Presentano l’antigene di superficie dell’epatite B o un risultato positivo al test per la ricerca degli anticorpi diretti contro il virus dell’epatite C al momento dello screening o nei 3 mesi precedenti la prima dose del trattamento sperimentale. Per gli agenti immunosoppressori potenti, devono essere esclusi anche i partecipanti con anticorpi contro l’antigene “core” del virus dell’epatite B. 20. Hanno un’anamnesi nota o una diagnosi attuale di sindrome mielodisplastica (MDS) o leucemia mieloide acuta (AML).
    Per la lista completa dei criteri di esclusione si faccia riferimento alla sezione del protocollo 5.2 Criteri di esclusione (pp 44-46)
    E.5 End points
    E.5.1Primary end point(s)
    Compare progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors Version 1.1 of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy. Compare overall survival (OS) of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy. To evaluate and compare the time to progression (TTP) in the central nervous system (CNS) as assessed by BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
    Questo studio ha un duplice endpoint di efficacia primario: PFS e OS. Lo studio avrà raggiunto il suo obiettivo primario se niraparib più pembrolizumab sarà superiore al placebo più pembrolizumab in termini di PFS o OS all’analisi ad interim o finale. La PFS è definita come il tempo intercorrente tra la data della randomizzazione e la data della prima osservazione di progressione radiografica secondo il giudizio del BICR o la data del decesso per qualsiasi causa in assenza di progressione, a seconda di quale evento si verifichi per primo. La progressione sarà valutata dal BICR tramite i criteri RECIST versione 1.1. La OS è definita come il tempo dalla randomizzazione alla data del decesso per qualsiasi causa. I partecipanti in vita saranno censurati alla data dell’ultimo contatto.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Three interim analysis are planned. First being when approximately 241 OS events have occurred (22 months from FPFD) Second IA to occur when 321 events have occurred (29 months from FSFD), final analysis when 401 events have occurred (39 months from FSFD)
    Sono previste tre analisi intermedie. La prima quando si sono verificati circa 241 eventi OS (22 mesi dalla FPFD), la seconda analisi intermedia quando si sono verificati 321 eventi (29 mesi dalla FSFD), l'analisi finale quando si sono verificati 401 eventi (39 mesi dalla FSFD).
    E.5.2Secondary end point(s)
    To evaluate PFS as assessed by the Investigator using RECIST v1.1. Evaluate PFS as assessed by BICR using RECIST v1.1 and OS by programmed cell death ligand (PD-L1) status (PD-L1 tumor cells [TCs] <1% versus =1%). To evaluate and compare time to deterioration in lung symptoms (TTD), defined as time from randomization to meaningful deterioration on a composite endpoint of dyspnea, chest pain, and cough, from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 13-item lung cancer-specific module (EORTC QLQ-LC13). To evaluate changes from baseline in health-related quality of life (HRQoL) and symptoms as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core module (EORTC QLQ-C30) and the EORTC QLQ-LC13 total and domain scores. To evaluate safety and tolerability in participants treated with niraparib plus pembrolizumab compared to placebo plus pembrolizumab. To evaluate population pharmacokinetics (PK) of niraparib when given in combination with pembrolizumab.
    Verranno valutati i seguenti principali endpoint di efficacia secondari:
    • TTP nel SNC, definito come il tempo dalla data della randomizzazione alla prima data di PD documentata a livello di SNC, sulla base della valutazione espressa dal BICR basata sui criteri RANO-BM
    Endpoint di efficacia secondari
    Verranno valutati i seguenti endpoint di efficacia secondari:
    • PFS, secondo i criteri RECIST versione 1.1 sulla base del BICR e OS per stato PD-L1 (PD-L1 TC <1% vs =1%)
    • TTD, definito come il tempo dalla randomizzazione al peggioramento significativo su un endpoint composito di dispnea, dolore toracico e tosse, tramite il questionario EORTC QLQ-LC13
    • Variazione rispetto al basale dei domini EORTC QLQ-C30 e EORTC QLQ-LC13
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ongoing throughout trial
    Durante tutto lo 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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Exploratory biomarker analysis of plasma samples will be carried out to identify the important
    factors to predict the sensitivity to niraparib plus pembrolizumab, and to explore potential
    mechanisms of either de novo or treatment-emergent resistance.
    Verrà effettuata un'analisi esplorativa sui biomarcatori dai campioni di plasma per identificare i fattori importanti per prevedere la sensibilità al niraparib più pembrolizumab, e per esplorare i potenziale meccanismi di resistenza de novo o di resistenza emergente da trattamento.
    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 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) No
    E.8.2.2Placebo Yes
    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 concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA99
    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
    Colombia
    Denmark
    France
    Germany
    Hungary
    Italy
    Japan
    Mexico
    Netherlands
    Norway
    Peru
    Romania
    Russian Federation
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    LVLS
    ultima visita ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned 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 months3
    E.8.9.2In all countries concerned by the trial days30
    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: 390
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 260
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 251
    F.4.2.2In the whole clinical trial 650
    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)
    Treatment with niraparib/placebo will continue until radiographic PD or another treatment discontinuation criterion is met, or for up to 3 years. Participants with evidence of disease at 3 years who, in the opinion of the treating physician may derive further benefit from continuous treatment, may be treated beyond 3 years. If available, participants continuing niraparib treatment at the time of final analysis may be offered the option to continue in a rollover study.
    Il trattamento con niraparib/placebo proseguirà fino a progressione o al raggiungimento di un altro criterio di interruzione del trattamento o per un massimo di 3 anni.
    I pazienti con evidenza di malattia a 3 anni che nell'opinione del medico evidenzino beneficio dal trattamento, possono essere trattati per più di 3 anni. Se disponibile, ai pazienti, che al momento dell'analisi finale saranno ancora in trattamento, potrà essere data loro l'opzione di continuare in uno studio di proseguimento.
    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 Decision2020-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-29
    P. End of Trial
    P.End of Trial StatusOngoing
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