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    EudraCT Number:2018-002583-11
    Sponsor's Protocol Code Number:UM2018IMMUNOSABR2RLPL
    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:2021-06-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-002583-11
    A.3Full title of the trial
    Phase II study examining the activity of L19-IL2 immunotherapy and stereotactic ablative radiotherapy in metastatic non-small cell lung cancer
    Studio di fase II sulla combinazione di immunoterapia L19-IL2 e radioterapia (stereotassica ablativa) in pazienti con carcinoma polmonare non a piccole cellule metastatico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC
    Lo studio consisterà in una coorte di pazienti adulti con NSCLC metastatico in stadio IV
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberUM2018IMMUNOSABR2RLPL
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03705403
    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 SponsorMaastricht University
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCommissione Europea
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSillar Clinical bvba
    B.5.2Functional name of contact pointMieke Denys
    B.5.3 Address:
    B.5.3.1Street AddressXavier de Cocklaan 66
    B.5.3.2Town/ cityDeurle
    B.5.3.3Post code9831
    B.5.4Telephone number0032475282974
    B.5.5Fax number003293952365
    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 nameL19-IL2 (L19 Interleukin-2, Darleukin)
    D.3.2Product code [L19-IL2]
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 8000048-25-1
    D.3.9.2Current sponsor codeDARLEUKIN
    D.3.9.4EV Substance CodeSUB14225MIG
    D.3.10 Strength
    D.3.10.1Concentration unit million IU million international units
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number13
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    Patients with progressive lung cancer with a maximum of 10 metastatic lesions will receive Standard Of Care radiotherapy combined with immunotherapy
    Pazienti con carcinoma polmonare progressivo con un massimo di 10 metastasi lesioni riceveranno radioterapia Standard Of Care in combinazione con immunoterapia
    E.1.1.1Medical condition in easily understood language
    The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC
    Lo studio consiste in una coorte di pazienti adulti con NSCLC metastatico al quarto stadio
    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 10025044
    E.1.2Term Lung cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the trial is to test if the combination of (SAB)R and the immunocytokine L19-IL2 has clinical meaningful activity in patients with limited metastatic non-small cell lung cancer (NSCLC): (=10 sites, WHO 0-1). The expected activity is a systemic immune response preventing disease progression and resulting in an improvement of progression-free survival (PFS) 1,5 years after randomisation.
    L'obiettivo principale dello studio è verificare se la combinazione di (SAB)R e l'immunocitochina L19-IL2 ha un'attività clinica significativa in pazienti con carcinoma polmonare non a piccole cellule (NSCLC) metastatico limitato: (= 10 siti, OMS 0- 1). L'attività attesa è una risposta immunitaria sistemica che previene la progressione della malattia e determina un miglioramento della sopravvivenza libera da progressione (PFS) 1,5 anni dopo la randomizzazione.
    E.2.2Secondary objectives of the trial
    • PFS 5 years after randomisation
    • Assesment of the overall survival 1,5 years and 5 years after randomisation
    • Toxicity 1,5 years after randomisation
    • Quality of Life
    • To assess the occurrence of an Out of Field Radio-Immune (OFRI) response 1,5 years after randomisation
    • To assess the occurrence of an In Field Radio-Immune (IFRI) response 1,5 years after randomisation
    • PFS 5 anni dopo la randomizzazione
    • Valutazione della sopravvivenza globale 1,5 anni e 5 anni dopo la randomizzazione
    • Tossicità 1,5 anni dopo la randomizzazione
    • Qualità della vita
    • Valutare il verificarsi di una risposta radioimmune fuori campo (OFRI) 1,5 anni dopo la randomizzazione
    • Valutare il verificarsi di una risposta IFRI (In Field Radio-Immune) 1,5 anni dopo la randomizzazione
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological/Cytological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status.
    2. Previous treatments
    3. Patient received a (last gift) of live vaccine need to wait 8 weeks before they can be randomised and receive aPD(L)1 treatment.
    4. Age of 18 years or older.
    5. WHO performance status 0-1;
    6. Adequate bone marrow function;
    7. Adequate hepatic function and renal function;
    8. Adequate endocrine function;
    9. The patient is capable of complying with study procedures;
    10. Life expectancy of at least 12 weeks;
    11. Negative serum pregnancy test for females of childbearing potential;
    12. Ability to comply with contraception requirements;
    13. Signed and dated written informed consent;
    1. L’Istologico/Citologico ha confermato la presenza di pazienti adulti adulti NSCLC con metastasi limitate, indipendentemente dallo stato di PD-L1.
    2. Trattamento precedente:
    3. Il paziente ha ricevuto un (ultimo dono) di vaccino vivo deve aspettare 8 settimane prima di poter essere randomizzato e ricevere un trattamento di aPD(L)1.
    4. Età pari o superiore a 18 anni.
    5. OMS stato di prestazione 0-1;
    6. Adeguata funzionalità del midollo osseo;
    7. Adeguata funzionalità epatica;
    8. Adeguata funzione endocrina;
    9. Il paziente è in grado di seguire le procedure previste dallo studio;
    10. Aspettativa di vita di almeno 12 settimane;
    11. Test di gravidanza sierico negativo per donne potenzialmente fertili.
    12. Capacità di soddisfare i requisiti di contraccezione;
    13. Consenso informato scritto firmato e datato
    E.4Principal exclusion criteria
    1. More than 10 metastatic lesions
    2. More than 2 brain metastatic lesions
    3. Two brain metastases with a cumulative diameter larger than 5 cm
    4. Patients with non-infectious pneumonitis, uncontrolled thyroidbdisease, pleuritis, pericarditis and peritonitis carcinomatosis or other mild/serious infection at screening that might need antibiotic therapy.
    5. Patients who received live vaccines 30 days or fewer prior to enrolment
    6. Patients who are already actively participating in another interventional study with an investigational product.
    7. Patients who need simultaneous radiation on the primary tumour and metastatic lesion(s).
    8. Patients that need (maintenance) chemotherapy during ImmunoSABR
    9. Whole brain radiotherapy (WBRT) is not allowed, although it is accepted when given at least 4 weeks prior to randomisation or after the treatment period.
    10. Previous radiotherapy to an area that would be re-treated by (SAB)R, resulting in overlap of the high dose areas;
    11. Maintenance therapy with Anti-PD(L)1 treatment combined with chemotherapy is not allowed during treatment ((SAB)R and L19-IL2 cycles).
    12. Other active malignancy or malignancy within the last 2 years (except localised skin basal/squamous cell carcinoma, non-muscle invasive carcinoma of the bladder or in situ carcinoma from any site);
    13. Concomitantly administered glucocorticoids may decrease the activity of IL2 and therefore should be avoided.
    14. History of allergy to intravenously administered L19-IL2/proteins/peptides/antibodies/radiographic contrast media;
    15. HIV positive; active HIV infection, or active hepatitis B or C (assessed in local lab).
    16. Systemic treatment with either corticosteroid (>10 mg daily prednisone equivalents) or Interferon alpha or immunosuppressive medications within 14 days prior to randomisation. Topical or inhalation steroids are allowed.
    17. Prior history of organ transplant, including autologous stem cell transplant.
    18. Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart disease, heart insufficiency NYHA > 2, or irreversible cardiac arrhythmias;
    19. A known impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50 % (or below the study site's lower limit of normal) as measured by MUGA or ECHO.
    20. Uncontrolled hypertensive disease. Uncontrolled and symptomatic hypotensive disease.
    21. History or evidence of active autoimmune disease;
    22. Severe diabetic retinopathy (neoangiogenesis targeted by L19 outside the tumour)
    23. Major trauma.
    24. Any underlying mental, medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results
    25. Unstable or serious concurrent uncontrolled medical conditions.
    26. Pregnancy or breastfeeding
    1. Più di 10 lesioni metastatiche.
    2. Più di 2 lesioni metastatiche cerebrali.
    3. 2 metastasi cerebrali con diametro cumulativo superiore a 5 cm.
    4. Pazienti con polmonite non infettiva, malattia tiroidea non controllata, pleurite, pericardite e carcinomatosi della peritonite o altre infezioni lievi/serie allo screening che potrebbero richiedere una terapia antibiotica.
    5. Pazienti che hanno ricevuto vaccini vivi 30 giorni o meno prima del reclutamento.
    6. Pazienti che partecipano già attivamente a un altro studio interventistico con un prodotto sperimentale.
    7. Pazienti che necessitano di radiazioni simultanee sul tumore primario e sulle lesioni metastatiche.
    8. Pazienti che necessitano di chemioterapia (di mantenimento) durante l’ImmunoSABR
    9. La radioterapia cerebrale intera (WBRT) non è consentita, sebbene sia accettata se somministrata almeno 4 settimane prima della randomizzazione o dopo il periodo di trattamento.
    10. Pregressa radioterapia su un’area che potrebbe essere ritrattata con (SAB)R determinando una sovrapposizione delle aree ad alto dosaggio.
    11. Non è consentita alcuna terapia di mantenimento con trattamento Anti-PD(L)1 in combinazione con chemioterapia durante il trattamento ((SAB)R e cicli di L19-IL2).
    12. Altra neoplasia attiva o neoplasia negli ultimi 2 anni (ad eccezione di carcinoma cutaneo basocellulare/carcinoma a cellule squamose, carcinoma della vescica non muscolo-invasivo o carcinoma in situ da qualsiasi sito).
    13. I glucocorticoidi somministrati in concomitanza possono diminuire l’attività di IL2 e pertanto devono essere evitati.
    14. Anamnesi di allergia a proteine/peptidi/anticorpi/mezzi di contrasto radiografici somministrati per via endovenosa.
    15. Positività all’HIV; infezione da HIV attiva oppure epatite B o C attive (valutate nel laboratorio locale).
    16. Trattamento sistemico con corticosteroidi (equivalenti del prednisone >10 mg al giorno) o interferone alfa o farmaci immunosoppressori nei 14 giorni precedenti la randomizzazione. Sono consentiti steroidi topici o inalatori.
    17. Precedenti di trapianto di organi, compreso il trapianto di cellule staminali autologhe.
    18. Sindromi coronariche acute o sub-acute nel corso dell’ultimo anno, malattia cardiaca infiammatoria acuta, insufficienza cardiaca NYHA > 2 oppure aritmie cardiache irreversibili.
    19. Una nota insufficienza cardiaca definita come frazione di eiezione ventricolare sinistra (LVEF) <50% (o al di sotto del limite inferiore del normale del sito dello studio) misurata mediante MUGA o ECHO.
    20. Malattia ipertensiva incontrollata. Malattia ipotensiva incontrollata e sintomatica.
    21. Anamnesi o evidenza di malattia autoimmune attiva.
    22. Grave retinopatia diabetica (neoangiogenesi individuata da L19 al di fuori del tumore).
    23. Trauma grave.
    24. Qualsiasi condizione mentale, medica o psichiatrica preesistente che a giudizio del ricercatore possa rendere pericolosa la somministrazione del farmaco oggetto dello studio oppure ostacolare l’interpretazione dei risultati dello studio.
    25. Gravi condizioni mediche concomitanti fuori controllo o instabili.
    26. Gravidanza o allattamento.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival (PFS) at 1.5 years after randomisation compared to the Standard of care
    Progression Free Survival (PFS) a 1.5 anni dopo la randomizzazione rispetto allo Standard of Care
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the study
    Alla fine dello studio
    E.5.2Secondary end point(s)
    • PFS
    • Overall survival
    • Toxicity
    • Quality of Life
    • Out of Filed Radio-Immune (OFRI) response
    • In of Filed Radio-Immune (IFRI) response
    • PFS
    • Overall survival
    • Tossicità
    • Qualità della vita
    • Out of Filed Radio-Immune (OFRI) response
    • In of Filed Radio-Immune (IFRI) response
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study
    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 No
    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 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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    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: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 84
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 126
    F.4.2.2In the whole clinical trial 126
    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)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-17
    P. End of Trial
    P.End of Trial StatusOngoing
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