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    Summary
    EudraCT Number:2019-002478-29
    Sponsor's Protocol Code Number:CA224-063
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-07-09
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2019-002478-29
    A.3Full title of the trial
    Neoadjuvant nivolumab combination treatment in resectable non-small cell lung cancer patients: Defining optimal combinations and determinants of immunological response (NEOpredict-Lung)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NEOpredict-Lung is a clinical study in subjects with histologically or cytologically confirmed, early stage or locally advanced non-small cell lung cancer (NSCLC) eligible for curative resection. This study will determine the feasibility of two cycles of preoperative immunotherapy with nivolumab or as combination nivolumab plus relatlimab.
    A.3.2Name or abbreviated title of the trial where available
    NEOpredict-Lung
    A.4.1Sponsor's protocol code numberCA224-063
    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 SponsorUniversity Hospital Essen
    B.1.3.4CountryGermany
    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 supportBristol-Myers Squibb
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsmedizin Essen - Studienzentrum GmbH
    B.5.2Functional name of contact pointStudy Coordination
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstr. 26
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45147
    B.5.3.4CountryGermany
    B.5.4Telephone number+49020172377411
    B.5.5Fax number+4902017239477411
    B.5.6E-mailume-studienzentrum@uk-essen.de
    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 Yes
    D.2.1.1.1Trade name OPDIVO®
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameNivolumab
    D.3.2Product code BMS-936558
    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.3.11 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameRelatlimab
    D.3.2Product code BMS-986016
    D.3.4Pharmaceutical form Concentrate for 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 INNRELATLIMAB
    D.3.9.2Current sponsor codeBMS986016
    D.3.9.4EV Substance CodeSUB191011
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    non-small cell lung cancer (NSCLC) of clinical stages IB, II and selected stage III A
    E.1.1.1Medical condition in easily understood language
    early stage non-small lung cancer
    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 10061873
    E.1.2Term Non-small cell lung cancer
    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
    The primary objective of this study is to determine the feasibility of four weeks of preoperative immunotherapy with nivolumab, and nivolumab plus relatlimab in patients with early stage or locally advanced non-small cell lung cancer eligible for curative resection.
    E.2.2Secondary objectives of the trial
    • Estimation of pathological tumor response rate (rate of complete pathological responses defined as absence of viable tumor cells on routine hematoxylin and eosin staining of resected tumors and lymph nodes; rate of major pathological responses defined as 10% or less viable tumor cells on routine hematoxylin and eosin staining of resected tumors)
    • Estimation of complete (R0) resection rate
    • Assessment of radiologic response on computed tomography per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    • Assessment of disease-free survival rate at 12 months per RECIST version 1.1
    • Assessment of overall survival rate at 12 months
    • Assessment of safety and tolerability of preoperative immunotherapy
    • Estimation of morbidity and mortality within 90 days of surgery
    • Exploratory translational analyses for investigation of immunomodulatory and anticancer activity of preoperative treatment with nivolumab and nivolumab/relatlimab combination therapy
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Translational Research Project
    E.3Principal inclusion criteria
    • Patients with histologically (core biopsy) or cytologically (e.g. bronchoscopy-guided biopsy) confirmed non-small cell lung cancer (NSCLC) eligible for anatomic resection, with the following specifications:
    o Clinical stages I B, II and selected stage III A (T3 N1, T4 with satellite nodule in the same lung N0/N1, selected T1a-T2b N2 cases considered suitable for primary surgical approach by the multidisciplinary tumor board) according to UICC 8th edition
    • Males and females, ages  18 years, inclusive
    o Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment.
    o Women of childbearing potential (WOCBP) must agree to follow instructions for highly effective method(s) of contraception for the duration of treatment with study medication plus 5 half-lives of study treatment plus 30 days (duration of ovulatory cycle) post treatment completion for a total of 165 days (approximately 24 weeks) (Appendix IV). This applies to both treatment arms, nivolumab monotherapy and nivolumab/relatlimab combination therapy.
    o Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception and fetal protection (Appendix IV) for the duration of treatment with study medication plus 5 half-lives of the study treatment plus 90 days (duration of sperm turnover) for a total of 225 days (approximately 33 weeks) post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time. This applies to both treatment arms, nivolumab monotherapy and nivolumab/relatlimab combination therapy.
    • ECOG ≤ 1
    • Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3) by PET/CT and/or invasive mediastinal lymph node staging by EBUS-TBNA and/or staging mediastinoscopy as indicated by current guidelines.
    • Exclusion of distant metastases by standard of care imaging studies, which include but are not limited to PET/CT or PET/MRI, or CT or MRI of thorax, abdomen, pelvis, and bone scan. Asymptomatic brain metastases will be excluded by MRI or contrast-enhanced CT as indicated by current guidelines.
    • Measurable target tumor prior to immunotherapy using standard imaging techniques.
    • Sufficient pulmonary function to undergo curative lung cancer surgery, ppFEV1>30%, ppDLCO>30%, ppVO2max  10 ml/min/kg (if CPET was mandated per local guidelines)
    • Adequate hematological, hepatic and renal function parameters:
    • Sufficient cardiac left ventricular defined as LVEF ≥ 50% documented either by echocardiography or MUGA (echocardiography preferred test, MUGA not used in German site) within 6 months before first administration of study drug
    • Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
    E.4Principal exclusion criteria
    • Active or history of autoimmune disease or immune deficiency
    • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
    • Subjects who have undergone organ transplant or allogeneic stem cell transplantation.
    • ppFEV1<30%, ppDLCO<30%, ppVO2max < 10 ml/min/kg (if CPET was mandated per local guidelines)
    • Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
    o Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
    o Uncontrolled angina within the 3 months prior to consent
    o Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
    o QTc prolongation > 480 msec
    o Pulmonary hypertension (sPAP >35 mmHg)
    • History of other clinically significant cardiovascular disease
    • Cardiovascular disease-related requirement for daily supplemental oxygen
    • History of two or more myocardial infarctions or two or more coronary revascularization procedures
    • Subjects with history of myocarditis, regardless of etiology
    • Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are within ULN. If TnT or TnI levels are >1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee.
    • Patients with active neurological disease should be excluded.
    • Active malignancy or a prior malignancy within the past 3 years.
    • Known history of positive test for human immunodeficiency virus (HIV-1 and HIV-2) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV-1 and HIV-2 must be performed at screening.
    • Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative).
    • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
    • Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication
    • Peripheral polyneuropathy NCI CTCAE Grade ≥ 2
    • History of gastric perforation or fistulae in past 6 months
    • Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.
    • The patient has undergone major surgery within 28 days prior to enrollment except staging mediastinoscopy, diagnostic VATS or implantation of a venous port-system.
    • Any other concurrent preoperative antineoplastic treatment including irradiation
    • Pregnant women
    • Breastfeeding women
    • Insufficient cardiac left ventricular function defined as LVEF<50% by echocardiography (outside Germany: or MUGA scan)
    • A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
    • Subjects with history of severe toxicity or life-threatening toxicity (grade 3 or 4) related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy.
    • Subjects with history of severe or life-threatining (grade 3 or 4) infusion-related reactions to prior immune therapy
    • Prior treatment with LAG-3 targeting agent
    E.5 End points
    E.5.1Primary end point(s)
    Primary variable is the number of patients undergoing curatively intended surgery of non-small cell lung cancer within 43 days of initiation of study therapy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcome is continuously assessed for each study arm
    E.5.2Secondary end point(s)
    • Objective response rate (RECIST 1.1)
    • Pathological response rate (complete pathological responses defined as absence of viable tumor cells on routine hematoxylin and eosin staining of resected tumors and lymph nodes; rate of major pathological responses defined as 10% or less viable tumor cells on routine hematoxylin and eosin staining of resected tumors)
    • R0 resection rate
    • Radiomorphologic response per RECIST 1.1
    • Disease-free survival rate at 12 months per RECIST version 1.1
    • Overall survival rate at 12 months
    • Safety and tolerability of preoperative immunotherapy
    • Morbidity and mortality within 90 days of curative surgery
    E.5.2.1Timepoint(s) of evaluation of this end point
    as indicated in E.5.1.1
    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.7.1.3.1Other 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 No
    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 No
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    LVLS
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    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 the end of treatment evaluation or the end of study for any other cause, patients will be treated and followed according to the Standard of Care in Belgium.
    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 Decision2020-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-04
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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