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    The EU Clinical Trials Register currently displays   43839   clinical trials with a EudraCT protocol, of which   7280   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2018-002583-11
    Sponsor's Protocol Code Number:UM2018IMMUNOSABR2RLPL
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-05-13
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    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
    Fase II-studie naar de activiteit van L19-IL2-immunotherapie en stereotactisch ablatieve radiotherapie bij metastatische niet-kleincellige longkanker
    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
    Deelnemers zijn patiënten met stadium IV niet-kleincellig longkanker met maximaal 10 uitzaaiingen
    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 Medical Centre
    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 supportEuropean Commission
    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 / 3
    B.5.3.2Town/ citySint-Maartens-Latem
    B.5.3.3Post code9831
    B.5.4Telephone number329395 23 62
    B.5.5Fax number329395 23 65
    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.3.4Pharmaceutical 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.3.8INN - Proposed INNINTERLEUKIN-2
    D.3.9.1CAS number 8000048-25-1
    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 No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    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
    The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC
    E.1.1.1Medical condition in easily understood language
    Patients with progressive lung cancer with a maximum of 10 metastatic lesions will receive Standard Of Care combined with immunotherapy
    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).
    E.2.2Secondary objectives of the trial
    • Assesment of the overall survival
    • Toxicity
    • Quality of Life
    • To assess the occurrence of an Out of Field Radio-Immune (OFRI) response
    • To assess the occurrence of an In Field Radio-Immune (IFRI) response
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A.Oligometastatic disease (≤5 metastasis):
    1.Histological/cytological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status.
    oMax. of 5 metastatic lesions, max. 2 brain lesions with a total cumulative diameter of 5 cm is allowed: SOC baseline imaging e.g MRI and/or PET-CT and CT-brain or MRI brain and/or CT-scan with at least covering thorax-upper abdomen-brain, within 6 weeks < randomisation, If a patient has unclear lesions in the liver or brain an MRI would be advised following the ESMO guidelines. o In patients with 2 lung tumours, it can be unclear if the patient has 2 concurrent primary tumours or a primary lung tumour with 1 metastasis. In this case, it is according to the decision of the local multidisciplinary tumour board whether the patient has an M1 disease or not. 2.Previous treatment: patient inclusion is allowed from 4 w following the last chemo- and/or immunotherapy infusion (first line or second line, exc. aPD(L)1 treatment. In case of maintenance chemotherapy, this can continue during the C-arm and not allowed in the E-arm. 3. Patient received a (last gift) of live vaccine need to wait 8 weeks before they can be randomised and reciev a PD(L)1 treatment. 4.Age of 18 years or older. 5.WHO performance status 0-1; 6.Adequate bone marrow function (evaluated in the local lab): Absolute Neutrophil Count (ANC) of > or equal to 1.0 x 109 /L, platelet count > or equal to 100 x 109/L, Hb greater or equal 6.0 mmol/L (or 9.67 g/dL) (it is allowed to give a blood transfusion if Hb is initially too low; 7.Adequate hepatic function (evaluated in the local lab): total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN for the institution or <= 5 in case of liver metastasis); 8.Adequate renal function (evaluated in the local lab): creatinine clearance of at least 40 ml/min; 9.Adequate endocrine function: TSH based on local laboratory guidelines, FT4 based on local laboratory guidelines. Make sure lower/higher values are not the cause of medication (e.g. heparin i.v. amiodarone, lithium). 10.The patient is capable of complying with study procedures; 11.Life expectancy of at least 12 weeks; 12.Negative serum pregnancy test for women of childbearing potential. 13.Ability to comply with contraception requirements:
    Non-sterilised, sexually active male patient with a female partner who is of child-bearing age, must use two acceptable birth control methods like a condom combined with spermicidal cream or gel and a partner who is WOCBP must use effictive contraception as definied for WOCBP who are participants in the study as per the next paragraph. From the first dose of study medicine, during the study and at least up to 12 weeks after the last administration of the study medicine and up to 5 months after the last dose of the medicine with anti-PDL)1 as an action mechanism (if you get this product besides the study medicine), as an addition to the use, by the female partner, of as described in the following section: Women of childbearing potential (WOCBP) and WOCBP partners of male patients must be using, from the screening to three months following the last study drug administration and 5 months after last dose of anti-PD(L)1 maintenance treatment, effective contraception methods, (a) IUD (IUD) or intrauterine hormone delivery system (IUS), b) combined (with estrogen and progesterone) hormonal contraception associated with ovulation inhibition (oral, intravaginal, transdermal), c) hormonal contraception with progesterone only associated with ovulation inhibition (oral, injectable, implantable). 14.Signed and dated written informed consent;

    B) Poly-metastatic disease (6 to 10 metastasis) 1.Histological/Cytological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status.
    o A minimum of 6 and maximum of 10 metastatic lesions, maximum two brain lesions with a total cumulative diameter of 5 cm is allowed  SOC baseline imaging e.g MRI and/or PET-CT and CT-brain or MRI brain and/or CT-scan with at least covering thorax-upper abdomen-brain, within 6 weeks prior to randomisation. If a patient has unclear lesions in the liver or brain an MRI would be advised following the ESMO Guidelines. o at least one measurable lesion (according to RECIST 1.1) that has no overlap with the PTV of the lesion subjected to radiotherapy. 2.Previous treatment: oThe time between the last administration of chemo and/or immunotherapy (given as first or second line standard of care treatment) and the randomisation must be at least 4 weeks. In case of maintenance chemotherapy, this therapy will only be started after the end of the L19-IL2 treatment or only in case of Anti-PD(L)1 treatment, during L19-IL2 therapy. Inclusion criteria 3 to 14 are identical to the oligometastatic patients.
    E.4Principal exclusion criteria
    For both groups; oligometastatic disease and poly-metastatic disease:
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    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 thyroid disease, pleuritis, pericarditis and peritonitis carcinomatosis. Or other mild/serious infection at screening that might need antibiotic therapy. (First treat infection, so patient can still participate after it is cleared.)
    5.Patients who are already actively participating in another interventional study with an investigational product.
    6.Patients who need simultaneous radiation on the primary tumour and metastatic lesion(s). For these patients it might be an option to treat the primary tumour first although this is not mandatory for this study. There must be minimal 4 weeks between last treatment and randomisation.
    7.SABR to more than one brain metastasis or 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. Patients with stable brain metastases are not excluded.
    8.Previous radiotherapy to an area that would be re-treated by (SAB)R, resulting in overlap of the high dose areas;
    9.Maintenance therapy with anti-PD(L)1 treatment combined with chemotherapy is not allowed during treatment ((SAB)R and L19-IL2 cycles).
    10.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);
    11.Concomitantly administered glucocorticoids may decrease the activity of IL2 and therefore should be avoided. However, patients who develop life-threatening signs or symptoms may be treated with dexamethasone until toxicity resolves or reduces to an acceptable level (generally grade 1 and 2, however must be based at the research physician’s discretion).
    12.History of allergy to intravenously administered L19-IL2 / proteins / peptides / antibodies / radiographic contrast media;
    13.HIV positive; active HIV infection, or active hepatitis B or C (assessed in local lab).
    o For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBCAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV RNA indicating no current infection are eligible.
    14.Systemic treatment with either corticosteroid (>10 mg daily prednisone equivalents) or Interferon aplpha or immunosuppressive medications within 14 days prior to randomisation. Topical or inhalation steroids are allowed. If a patient needs to take unexpectedly immunosuppressive medication during the trial, it will be allowed but decreasing the dose as soon as possible is strongly advised.
    15.Prior history of organ transplant, including autologous stem cell transplant.
    16.Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart disease, heart insufficiency NYHA > 2, or irreversible cardiac arrhythmias;
    17.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.
    18.Uncontrolled hypertensive disease; (systolic BP (SBP) ≥160 or diastolic BP ≥100 mm Hg during two measurements)
    19.Uncontrolled and symptomatic hypotensive disease; (systolic blood pressure (SBP) <85 or diastolic blood pressure (DBP) <55 mm Hg during two measurements).
    20.History or evidence of active autoimmune disease;
    21.Severe diabetic retinopathy (neoangiogenesis targeted by L19 outside the tumour)
    22.Major trauma, including oncologic surgery, but excluding smaller procedures like the placement of porth-à-cath or surgical biopsy, within 4 weeks prior to randomisation (neoangiogenesis targeted by L19 outside a tumour)
    23.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
    24.Pregnancy or breastfeeding; it is well known that ED-B, the target of both L19-IL2, is expressed in a variety of fetal tissues. Furthermore, anti-PD(L)1 treatment may increase the risk of immune-mediated disorders. Therefore, it will be contra-indicated for pregnant or lactating women
    24.Patients who received live vaccines 30 days or fewer prior to enrolment.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    • Progression Free Survival (PFS) at 1.5 years after randomisation compared to the Standard of care
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the study
    E.5.2Secondary end point(s)
    Secondary endpoints:
    • 5 years PFS
    • 1,5 years and 5 years Overall survival
    • 1,5 years toxicity, Quality of Life, Out of Filed Radio-Immune (IFRI) response and in field Radio-Immune (IFRI) response

    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study
    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 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 concerned3
    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 No
    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 sponsor will notify the Ethics Committee / Competent Authority of the end of the study within 90 days. The end of the study is defined as the last patient’s last visit.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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) No
    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 state33
    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 Decision2019-01-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-03
    P. End of Trial
    P.End of Trial StatusOngoing
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