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    Summary
    EudraCT Number:2013-002609-78
    Sponsor's Protocol Code Number:ETOP4-12/CA184-310
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-06-03
    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 ConcernedGermany - PEI
    A.2EudraCT number2013-002609-78
    A.3Full title of the trial
    A randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after chemo-radiotherapy

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial comparing the standard treatment (chemotherapy and radiotherapy) alone with the standard treatment followed by nivolumab and ipilimumab in patients with lung cancer called “small cell lung cancer (SCLC)” limited to the thorax and not spread into other tissues.
    A.3.2Name or abbreviated title of the trial where available
    STIMULI: Small cell lung carcinoma Trial with nivolumab and IpiliMUmab in LImited disease
    A.4.1Sponsor's protocol code numberETOP4-12/CA184-310
    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 SponsorETOP (European Thoracic Oncology Platform)
    B.1.3.4CountrySwitzerland
    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 International Corporation, Brussels
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationETOP
    B.5.2Functional name of contact pointETOP Coordinating Office
    B.5.3 Address:
    B.5.3.1Street AddressEffingerstrasse 40
    B.5.3.2Town/ cityBern
    B.5.3.3Post code3008
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41 31389 93 91
    B.5.5Fax number+41 31 389 93 92
    B.5.6E-mailSTIMULI@etop-eu.org
    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 nameIpilimumab
    D.3.4Pharmaceutical form 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 INNIPILIMUMAB
    D.3.9.1CAS number 0477202-00-9
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 nameNivolumab
    D.3.4Pharmaceutical form Solution for injection/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.3.9.3Other descriptive nameBMS-936558
    D.3.9.4EV Substance CodeSUB122750
    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 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.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
    limited-stage SCLC

    E.1.1.1Medical condition in easily understood language
    Lung cancer called “small cell lung cancer (SCLC)” limited to the thorax and not spread into other tissues.
    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 PT
    E.1.2Classification code 10041069
    E.1.2Term Small cell lung cancer limited stage
    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 evaluate whether patients treated with chemo-radiotherapy and prophylactic cranial irradiation followed by consolidation treatment (nivolumab plus ipilimumab) have a better outcome in terms of progression-free survival and overall survival, compared to patients treated with chemo-radiotherapy and prophylactic cranial irradiation without consolidation treatment.
    E.2.2Secondary objectives of the trial
    - To evaluate secondary measures of clinical efficacy including, objective response rate (ORR) and time to treatment failure.
    - To assess the safety and the tolerability of the treatment in both arms.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For enrolment:
    - Histologically or cytologically confirmed small cell lung carcinoma
    - Untreated limited stage disease (with the exception of one cycle of chemotherapy given prior to enrolment) as defined by stage I-IIIB based on 7th TNM classification (IASLC classification for SCLC proposal). M0 proven by
    - Whole body FDG-PET CT including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals);
    OR contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) and bone scan;
    AND
    - brain MRI (or contrast enhanced CT of the brain)
    within 28 days before start of chemotherapy
    - Age ≥ 18 years
    - ECOG performance status 0-1
    - Adequate haematological function:
    haemoglobin >9 g/dL
    neutrophils count >1.5×109/L
    platelet count >100 × 109/L
    - Adequate liver function:
    Total bilirubin <2.5 × ULN
    ALT and/or AST <2.5 × ULN
    alkaline phosphatase <5 × ULN.
    - Adequate renal function: Calculated creatinine clearance ≥30 mL/min (Cockroft-Gault).
    - Pulmonary function FEV1 of 1.0L or >40% predicted value and DLCO >40% predicted value.
    - Patient capable of proper therapeutic compliance, and accessible for correct follow-up.
    - Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning of chemotherapy. The test has to be repeated within 7 days before randomisation and then every 6 weeks during consolidation treatment. Pregnancy tests should be repeated at approximately 30 days and approximately 70 days after consolidation treatment stop.
    - All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs.
    - Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment.
    - Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any trial-related intervention for
    a) Chemo-radiotherapy treatment, PCI, and subsequent randomisation, including mandatory biological samples
    b) Optional biological material collection, long-term storage and future use of biological material for translational research
    For randomization:
    - Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, ≥85% of PTV of thoracic radiotherapy, as well as completed, mandatory PCI
    - Non-PD after chemo-radiotherapy and PCI
    - Recovery of all adverse events to a Grade ≤1, except for fatigue, appetite, oesophagitis and renal impairment (where ≤2 is allowed) and alopecia (any grade)
    - Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomisation.
    E.4Principal exclusion criteria
    For enrolment:
    -Patients with mixed small-cell and non-small-cell histologic features
    -Patients with pleural or pericardial effusions proven to be malignant
    - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast (if no RT was involved).
    - Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient’s capacity to participate in the study.
    - Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
    - Known or suspected hypersensitivity to nivolumab or ipilimumab or any of their excipients.
    - Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
    - Documented history of severe autoimmune or immune mediated symptomatic disease that required prolonged (more than 2 months) systemic immunosuppressive treatment (e.g. steroids), such as but not limited to ulcerative colitis and Crohn´s disease, rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, or autoimmune vasculitis (e.g. Wegener’s granulomatosis).
    - Subjects with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment.
    - Interstitial lung disease or pulmonary fibrosis.
    - Women who are pregnant or in the period of lactation.
    - Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
    - Patients with any concurrent anticancer systemic therapy (except for chemotherapy cycle 1).
    - HIV, active Hepatitis B or Hepatitis C infection
    - Previous radiotherapy to the thorax (prior to inclusion), including RT for breast cancer
    - Planned radiotherapy to lung of mean dose >20 Gy or V20 >35%
    - Patients who received treatment with an investigational drug agent during the 3 weeks before enrolment in the study.
    - Prior chemotherapy or radiotherapy for SCLC. Exception: one cycle of chemotherapy (as specified to section 10.2) may be administered prior to enrolment.

    For randomization:
    - Less than 4 cycles of chemotherapy administered, less than 85% PTV of thoracic radiotherapy delivered, or PCI not completed
    - Progressive disease after chemo-radiotherapy and PCI
    E.5 End points
    E.5.1Primary end point(s)
    -Progression-free survival (PFS) by RECIST 1.1Overall survival
    - Overall survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Time from the date of randomisation until death from any cause.
    - PFS: time from the date of randomisation until documented progression or death, if progression is not documented.
    E.5.2Secondary end point(s)
    - Objective Response (ORR) determined by RECIST 1.1
    - Time to treatment failure
    - Adverse events graded according to CTCAE V4.0
    E.5.2.1Timepoint(s) of evaluation of this end point
    - ORR: best overall response (CR or PR) across all assessment time-points during the period from randomisation to termination of trial treatment. Objective response to chemo-radiotherapy determined by tumour assessment around week 15
    - Time to treatment failure: from the date of randomisation to discontinuation of treatment for any reason
    - AEs: day of enrolment until 100 days after final dose of IMP or within 100 days after the last visit in the observation arm.
    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 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 Yes
    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.8.2.3.1Comparator description
    Observation
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA49
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Germany
    Netherlands
    Spain
    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
    Patient accrual is expected to be completed within 3 years. Patients will be followed until death – thus follow-up is estimated up to last up to 4,5 years following the enrolment of the last patient. The trial will end with the preparation of the final report, scheduled for 7.5 years after the inclusion of first patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    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: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 130
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 247
    F.4.2.2In the whole clinical trial 260
    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 are followed until death at 9 week intervals during first 18 months after randomization, then at 12 week intervals and thereafter at six-month intervals (for a maximum of 4.5 years after last patient randomised).

    Trial treatment beyond disease progression will be permitted if patient meets the criteria outlined in the protocol.

    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 Decision2014-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-08
    P. End of Trial
    P.End of Trial StatusOngoing
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