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    Summary
    EudraCT Number:2016-005187-34
    Sponsor's Protocol Code Number:CCR4644
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-07-19
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-005187-34
    A.3Full title of the trial
    Stereotactic body radiotherapy with immunotherapy in early stage non-small cell lung cancer: tolerability and lung effects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stereotactic body radiotherapy with immunotherapy in early stage non-small cell lung cancer: tolerability and lung effects
    A.3.2Name or abbreviated title of the trial where available
    STILE version 1.0
    A.4.1Sponsor's protocol code numberCCR4644
    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 SponsorThe Royal Marsden NHS Foundation Trust
    B.1.3.4Country
    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 supportNIHR Royal Marsden
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportBristol-Myers Squibb
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Royal Marsden NHS Foundation Trust
    B.5.2Functional name of contact pointMs Andrea Pejenaute
    B.5.3 Address:
    B.5.3.1Street AddressDowns Road
    B.5.3.2Town/ citySutton
    B.5.3.3Post codeSM2 5PT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02089156667
    B.5.5Fax number02089156762
    B.5.6E-mailandrea.pejenaute@rmh.nhs.uk
    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 Nivolumab
    D.2.1.1.2Name of the Marketing Authorisation holderBMS-936558-01
    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.3.4Pharmaceutical form 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 INNNivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10 to 1
    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) Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    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) Stage: T1-3( ≤5cm)N0M0)
    E.1.1.1Medical condition in easily understood language
    Non small cell lung cancer that is smaller than 5cm with no evidence of spread to the lymph nodes or other part in the body.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the lung toxicity of nivolumab after stereotactic body radiotherapy (SBRT) for early stage non small-cell lung cancer (NSCLC) (T1-3 (≤5cm) N0M0).
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    To assess the overall safety of nivolumab after SBRT
    To assess the tolerability of nivolumab after SBRT
    To assess local, local-regional and distant disease relapse rates
    To assess the overall survival rates at 6, 12 and 24 months
    To assess the disease free survival (DFS) rates at 6, 12 and 24 months
    To measure health related quality of life (HRQoL)


    Exploratory Objectives:
    To describe the relationship between lung function and the tolerability of nivolumab after SBRT
    To assess relapse rates and survival rates in relation to tumour PD-L1 status
    To assess relapse rates and survival rates according to squamous versus non-squamous histology
    To assess tumour biology and immune function changes with treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subjects must have signed and dated an Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
    - Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory tests
    - ECOG Performance status (PS) 0-2
    - Minimum of first 5 patients to be PS 0-1
    - PS 2 patients to be enrolled only following approval by the Independent Data Monitoring Committee (IDMC)
    - Patients with histological diagnosis of NSCLC, all histological sub-types are eligible
    - Tumour stage T1-3 (≤5cm), N0 M0 (UICC v.7) as determined by the local MDT based on minimum investigations of CT performed within 8 weeks of 1st dose of SBRT and FDG-PET performed within 6 weeks of 1st dose of SBRT. Where the radiological nodal status is equivocal then only eligible if possible nodal disease is subsequently confirmed as pathologically negative with mediastinoscopy or endoscopic bronchial or oesophageal ultra-sound biopsy as necessary
    - Not suitable for surgery because of medical co-morbidity, lesion is technically inoperable or patient declines surgery after surgical assessment (or option of assessment)
    - Peripheral lesions i.e. outside a 2cm radius of main airways and proximal bronchial tree. This is defined as 2cm from the bifurcation of the second order bronchus e.g. where the right upper lobe bronchus splits (See Appendix 4)
    - Screening laboratory values must meet the following criteria prior to commencement of treatment:
    i) WBCs ≥ 2000/μL
    ii) Neutrophils ≥1500/μL
    iii) Platelets ≥ 100 X10³/μL
    iv) Haemoglobin ≥ 9.0 g/dL
    v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl)/glomerular filtration rate (GFR) > 40 mL/minute (using Cockcroft/Gault formula or as assessed by local practice)
    (1). Female CrCl= [(140- age in years) X weight in kg X 0.85) ÷ (72 X serum creatinine in mg/ dL)]
    (2). Male CrCl= [(140- age in years) X weight in kg X 1.00) ÷ (72 X serum creatinine in mg/ dL)]
    vi) AST ≤ 3 X ULN
    vii) ALT ≤ 3 X ULN
    viii) Total bilirubin ≤ 1.5 X ULN (except subjects with Gilbert Syndrome, who must have total bilirubin < 50micrml/L)
    - No prior adjuvant or foreseen neo-adjuvant or adjuvant chemotherapy is allowed
    - Males and Females ≥ 18 years of age
    - Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
    - Women must not be breastfeeding during the study treatment and for a period up to 23 weeks post treatment completion (See Appendix 1)
    - WOCBP must agree to follow instructions for method(s) of contraception during the study treatment and for a total of 23 weeks post treatment completion (See Appendix 1)
    - Males who are sexually active with WOCBP must agree to follow instructions for method(s) for contraception for a total of 31 weeks post treatment completion
    E.4Principal exclusion criteria
    - Any tumour that is not clinically definable on the treatment planning CT scan e.g. surrounded by consolidation or atelectasis
    - Subjects with active, known autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
    - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease
    - Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period
    - Patient with known interstitial lung disease or active, non-infectious pneumonitis
    - Previous radiotherapy to the chest or mediastinum. Patients who have had previous breast radiotherapy may be eligible at the discretion of the principal investigator
    - Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy
    - All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE v.4.0) or baseline before administration of study drug
    - Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment
    - Subjects who received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or who have previously taken part in a randomized BMS clinical trial for nivolumab or ipilimumab
    - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    - Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection
    - Patients with a positive HCV antibody but no detection of HCV RNA indicating no current infection are eligible
    - Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment
    - History of allergy to study drug components
    E.5 End points
    E.5.1Primary end point(s)
    Rate of grade ≥ 3 pneumonitis with nivolumab after stereotactic body radiotherapy (SBRT) within 6 months of the final fraction of SBRT. A rate that exceeds 20% will be deemed unacceptable and will lead to a rejection of the null hypothesis. Further details are provided in the sample size justification
    E.5.1.1Timepoint(s) of evaluation of this end point
    The rate of grade ≥ 3 pneumonitis events observed within the 6 month period from the final fraction of radiotherapy. This will be analysed when the final recruited patient has completed 6 months from their final fraction of SBRT
    E.5.2Secondary end point(s)
    Secondary Endpoints
    - Frequency of treatment related adverse events of all grades and grade ≥ 3 as per CTCAE v. 4
    - The proportion of patients receiving at least 1, 2, 3, 4, 5 and 6 doses within 16 weeks of commencing nivolumab after SBRT
    - Local, loco-regional and distant rates of relapse at 3, 6, 12 and 24 months
    - Overall survival rate (OS) of the 31 patients at 6, 12 and 24 months
    - Disease Free Survival (DFS) rate of the 31 patients at 6, 12 and 24 months
    - Estimation of the health related quality of life (HRQoL) score at each time point of analysis

    Exploratory Endpoints
    - Assessment of rates of toxicity within percentage of predicted FEV1 bands
    - Assessment of rates of toxicity within percentage of predicted DLCO bands
    - OS and DFS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)
    - OS and DFS rates in squamous and non-squamous subgroups Analysis of research blood and biopsy samples
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary Endpoints
    - The overall safety and tolerability of treatment will be assessed for the entire duration of the treatment.
    - The proportion of patients receiving at least 1, 2, 3, 4, 5 and 6 doses within 16 weeks of commencing adjuvant nivolumab after SBRT will be calculated.
    - OS rate: in the overall population at 6, 12 and 24 months
    - DFS rate in the overall population at 6, 12 and 24 months
    - Local, loco-regional and distant rates of relapse at 3, 6, 12 and 24 months

    Exploratory Endpoints will be analysed at the end of the 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 No
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Use of IMP with Stereotactic body radiotherapy
    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 No
    E.8.1.2Open No
    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.8.3 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 concerned2
    E.8.5The trial involves multiple Member States No
    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 No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study definition is defined as last patient last visit.
    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 months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 21
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 31
    F.4.2.2In the whole clinical trial 31
    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)
    Patients will receive the combination of SBRT and nivolumab for up to 12 months unless disease progresses or patients permanently stop treatment for another reason e.g. intolerable side effects or withdraw the consent. When the research study stops, a doctor will assess the disease status and recommend an alternative treatment or follow up as appropriate. This would be normal follow-up/treatment. Nivolumab will not be continued for longer than 12 months.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-08-17
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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