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    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   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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    Summary
    EudraCT Number:2015-004633-27
    Sponsor's Protocol Code Number:CA209384
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-28
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2015-004633-27
    A.3Full title of the trial
    A Dose Frequency Optimization, Phase IIIB/IV Trial of Nivolumab 240 mg Every 2 Weeks vs Nivolumab 480 mg Every 4 Weeks in Subjects with Advanced or Metastatic Non-small Cell Lung Cancer who Received 4 Months of Nivolumab at 3 mg/kg or 240 mg Every 2 Weeks
    Etude de phase IIIB/IV d’optimisation de la fréquence de la dose, évaluant le Nivolumab 240 mg toutes les deux semaines versus le Nivolumab 480 mg toutes les 4 semaines chez les patients atteints d’un cancer bronchique non à petites cellules avancé ou métastatique ayant reçu un traitement par le Nivolumab à une dose de 3 mg/kg ou 240 mg toutes les deux semaines pendant 4 mois
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Dose Frequency Optimization Study with Nivolumab Every 2 Weeks vsNivolumab Every 4 Weeks in advanced NSCLC patients Who Received 4 Months of Nivolumab Every 2 Weeks
    A.3.2Name or abbreviated title of the trial where available
    CheckMate 384: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 384
    A.4.1Sponsor's protocol code numberCA209384
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1175-6838
    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 SponsorBristol-Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointGCT-SU
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    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 nameNivolumab
    D.3.2Product code BMS-936558
    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.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    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
    Advanced or Metastatic Non-small Cell Lung Cancer
    E.1.1.1Medical condition in easily understood language
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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 coprimary objectives are to compare Progression Free Survival rate at 6 months after randomization and PFS rate at 1 year after randomization, as measured by investigator-assessed response using Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, of nivolumab 240 mg every 2 weeks (Arm 1) and nivolumab 480 mg every 4 weeks (Arm 2) in subjects with advanced/metastatic (Stage IIIb/IV) NSCLC (non-Sq and Sq).
    E.2.2Secondary objectives of the trial
    - To compare PFS rate in Arms 1 and 2 at 1 year after randomization by tumor histology and by response criteria before randomization
    - To compare PFS rate at 2 years after randomization in Arms 1 and 2
    - To compare the overall survival rate at 1 year after randomization and up to 5 years after randomization in Arms 1 and 2, in all treated subjects, by tumor histology, and by response criteria before randomization
    - To assess safety and tolerability of nivolumab, as measured by the incidence and severity of AEs and specific laboratory abnormalities, in all treated subjects, in Arms 1 and 2, by tumor histology, and response criteria before randomization
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Written Informed Consent
    a) Subjects must have signed and dated an 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.
    b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,laboratory tests, and other requirements of the study.
    2. Target Population
    a) Subjects with histologically or cytologically documented Sq- or non-SqNSCLC who present with Stage IIIB/Stage IV disease (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or with recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemoradiotherapy for locally advanced disease).
    b) Subjects must have received and tolerated nivolumab 3 mg/kg or 240 mg every 2 weeks for approximately 4 months (16 weeks ± 2 weeks). Subjects may continue to receive pre-study nivolumab treatment during screening assessments as noted in Table 5.1-2 of the protocol.
    c) Subjects must have at least 2 tumor assessments after the start of nivolumab and must demonstrate CR, PR, or SD to the pre-study nivolumab treatment on the latest scan within 28 days prior to randomization.
    d) Subjects must have had measurable disease by CT or MRI per RECIST 1.1 criteria at the time of starting first dose of pre-study nivolumab treatment.
    e) As of Amendment 01, this criterion is no longer applicable.
    f) ECOG PS 0-2
    g) Subjects with stable CNS metastases if CNS metastases are treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent).
    h) All baseline laboratory requirements will be assessed and should be obtained within 14 days (unless otherwise specified in Table 5.1-1) of first dose of randomized nivolumab. Screening laboratory values must meet the following criteria:
    i) WBCs ≥ 2000/μL
    ii) Neutrophils ≥ 1500/μL
    iii) Platelets ≥ 100 x 10³/μL
    iv) Hemoglobin ≥ 9.0 g/dL
    v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40 mL/minute (using cockcroft/Gault formula)
    vi) AST ≤ 3X ULN
    vii) ALT ≤ 3X ULN
    viii) Total bilirubin ≤ 1.5X ULN (except subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
    i) Palliative radiotherapy must be completed at least 2 weeks prior to enrollment.
    j) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has not been treated). If re-enrolled, the subject must be re-consented.
    3. Age and Reproductive Status
    a) Males and Females, ≥ 18 years of age.
    b) 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.
    c) Women must not be breastfeeding.
    d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (125 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days or 23 weeks post-treatment completion.
    e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (125 days) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion. In addition, male subjects must be willing to refrain from sperm donation during this time.
    f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.
    Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
    E.4Principal exclusion criteria
    1. Target Disease Exceptions
    a) Subjects with carcinomatous meningitis.
    b) Subjects with untreated, symptomatic central nervous system (CNS) metastases are excluded.
    2. Medical History and Concurrent Diseases
    Subjects with interstitial lung disease (eg, sarcoidosis) that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. Subjects with chronic obstructive pulmonary disease whose disease is controlled at study entry are allowed.
    b) Subjects with an active, known or suspected autoimmune disease. Subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first randomized dose of study drug with the exception of the subjects allowed to enroll with treated or active CNS metastases requiring steroids. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    d) Subjects who received prior therapy with an anti-CTLA-4, anti-PD-L1, or anti-PD-L2, anti-CT137 (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, except pre-study nivolumab) or subject is expected to require any other form of systemic antineoplastic therapy while receiving nivolumab.
    e) Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit the subject’s ability to comply with the study requirements, substantially increase the risk to the subject, or impact the interpretability of study results.
    f) Other active malignancy requiring concurrent intervention.
    g) 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 with the exception of anti-estrogen/androgen therapy or bisphosphonates.
    h) All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
    i) 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.
    j) As of Amendment 01, this criterion has been moved to 3b.
    3. Physical and Laboratory Test Findings
    a) Positive for Hepatitis B virus or Hepatitis C virus indicating acute or chronic infection.
    b) Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated by local regulation
    4. Allergies and Adverse Drug Reaction
    a) History of severe hypersensitivity reactions to other monoclonal antibodies.
    5. Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply, and Bristol-Myers Squibb approval is required.)
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
    E.5 End points
    E.5.1Primary end point(s)
    The coprimary objectives of this trial will be assessed by PFS rate at 6 months after randomization and PFS rate at 1 year after randomization. PFS is defined as the time from the date of randomization to the date of first documented tumor progression determined by the investigator or death, whichever is earlier. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment. The PFS rate at 6 months is the rate from KM estimate 6 months after randomization; PFS rate at 1 year is the rate from KM estimate at 1 year after randomization.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months and 1 year after randomization
    E.5.2Secondary end point(s)
    Secondary objectives will be assessed by:
    - PFS rate at 1 year after randomization by tumor histology and by response criteria
    - PFS rate at 2 years after randomization
    - OS rate at 1 year and OS up to 5 years by arm, histology, and response status at randomization.OS is defined as time from the date of randomization to the date of death. Subjects who did not die by the end of the study will be censored at the last known date alive. OS rate at 1 year is the rate from KM estimated at one year after randomization.
    - Safety and tolerability of nivolumab, as measured by incidence and severity of AEs and specific laboratory abnormalities
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor assessment - every 8 weeks (±1 week) for the first year of the study, then every 3 months for the second year of the study, followed by the local standard of care afterwards

    OS assessment - once per cycle. For subjects receiving nivolumab 240 mg every 2 weeks, cycle= each 14-day dosing period. For subjects receiving nivolumab 480 mg every 4 weeks, cycle=each 28-day dosing period.

    The collection of non serious AE information should begin at initiation of study drug. Nonserious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects

    Laboratory tests conducted at every cycle with the exception of thyroid and pregnancy tests (see protocol for details)
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    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.8.3 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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Australia
    Austria
    Canada
    France
    Germany
    Ireland
    Italy
    Spain
    United States
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 372
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 248
    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 state124
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 307
    F.4.2.2In the whole clinical trial 620
    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)
    Subjects who continue to demonstrate clinical benefit at the conclusion of the study will be eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the study, a rollover study requiring approval by responsible health authority and ethics committee or through another mechanism at the discretion of BMS.
    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 Decision2016-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-01-18
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