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    Summary
    EudraCT Number:2017-004261-26
    Sponsor's Protocol Code Number:MM-398-01-03-04
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-02-20
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-004261-26
    A.3Full title of the trial
    RESILIENT: A Randomized, Open Label Phase 3 Study of Irinotecan Liposome Injection
    (ONIVYDE®) versus Topotecan in Patients with Small Cell Lung Cancer Who Have Progressed on or after Platinum-based First-Line Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open label Phase 3 study of Irinotecan liposome injection versus Topotecan in patients with small cell lung cancer
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberMM-398-01-03-04
    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 SponsorIpsen Bioscience, Inc
    B.1.3.4CountryUnited States
    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 supportIpsen Bioscience, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen Bioscience, Inc
    B.5.2Functional name of contact pointGlobal Drug Development
    B.5.3 Address:
    B.5.3.1Street Address650 East Kendall Street
    B.5.3.2Town/ cityCambridge, Massachusetts
    B.5.3.3Post codeMA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number001617679 8000
    B.5.5Fax number001617679 8752
    B.5.6E-mailct-application@ipsen.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 Yes
    D.2.1.1.1Trade name Onivyde
    D.2.1.1.2Name of the Marketing Authorisation holderBaxalta Innovations GmbH
    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 nameirinotecan liposome
    D.3.2Product code MM-398
    D.3.4Pharmaceutical form Injection
    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 INNIRINOTECAN
    D.3.9.1CAS number 97682-44-5
    D.3.9.2Current sponsor codeMM-398
    D.3.9.3Other descriptive nameliposomal irinotecan
    D.3.9.4EV Substance CodeSUB08295MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.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 Yes
    D.2.1.1.1Trade name Onivyde
    D.2.1.1.2Name of the Marketing Authorisation holderBaxalta Innovations GmbH
    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 nameirinotecan liposome
    D.3.2Product code MM-398
    D.3.4Pharmaceutical form Injection
    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 INNIRINOTECAN
    D.3.9.1CAS number 97682-44-5
    D.3.9.2Current sponsor codeMM-398
    D.3.9.3Other descriptive nameliposomal irinotecan
    D.3.9.4EV Substance CodeSUB08295MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Information not present in EudraCT
    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 nameTopotecan
    D.3.4Pharmaceutical form Injection
    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 INNTOPOTECAN
    D.3.9.1CAS number 123948-87-8
    D.3.9.4EV Substance CodeSUB11191MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10041067
    E.1.2Term 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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective Part I

    -Describe the safety and tolerability of irinotecan liposome injection
    monotherapy administered every 2 weeks
    - To determine the irinotecan liposome injection monotherapy dose (85 mg/m2
    or 70 mg/m2 administered every 2 weeks) for Part 2 of this study

    Primary Objective Part II

    To compare overall survival following treatment with irinotecan liposome injection with overall survival following treatment with IV topotecan.
    E.2.2Secondary objectives of the trial
    secondary Objective Part I:

    To assess the preliminary efficacy of irinotecan liposome injection (at either the
    85 mg/m2 dose level or the 70 mg/m2 dose level as determined by:
    Objective response rate (ORR)
    Progression free survival (PFS)
    Overall survival (OS)

    Secondary Objective Part II

    To compare the following between the treatment arms:
     Progression free survival (PFS)
     Objective response Rate (ORR)
     Proportion of patients with improvement in symptoms as measured by the
    European Organization for Research and Treatment of Cancer Quality of Life
    Questionnaire Core 30 (EORTC QLQ-C30) and European Organization for
    Research and Treatment of Cancer Quality of Life Questionnaire Lung
    Cancer 13 (EORTC QLQ-LC13)
     Safety profile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General Inclusion Criteria
    1. At least 18 years of age
    2. Able to understand and provide the study informed consent
    3. ECOG performance status of 0 or 1
    4. Life expectancy ≥12 weeks
    Disease Specific Inclusion Criteria
    5. Histopathologically or cytologically confirmed small cell lung cancer according
    to the International Association for the Study of Lung Cancer (IASLC)
    histopathological classification. Mixed or combined subtypes according to the
    IASLC are not allowed.
    6. Evaluable disease as defined by RECIST Version 1.1 guidelines (patients with
    non-target lesions only are eligible)
    7. Radiologically confirmed progression on or after first-line platinum based
    chemotherapy (carboplatin or cisplatin) or chemo-radiation including platinumbased chemotherapy for treatment of limited or extensive stage small cell lung cancer
    8. Recovered from the effects of any prior chemotherapy, surgery, radiotherapy or other anti-neoplastic therapy (recovered to grade 1 or better, with the exception of alopecia) Hematologic, Biochemical and Organ Function Inclusion Criteria
    9. During the Screening period, adequate bone marrow reserves as evidenced by:
    a. Absolute neutrophil count > 1,500 cells/μL (1.5 x 109/L) without the use
    of hematopoietic growth factors within the immediately preceding 14
    days; and
    b. Platelet count > 100,000 cells/μL (100 x 109/L); and
    c. Hemoglobin > 9 g/dL; transfusions are allowed
    10. Adequate hepatic function as evidenced by:
    a. Serum total bilirubin within normal range for the institution
    b. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper
    limit of normal (ULN) (≤ 5 x ULN is acceptable if liver metastasis is
    present)
    c. Serum albumin ≥3.0 g/dL (≥30 g/L)
    11. Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x ULN and
    creatinine clearance ≥40 mL/min. Actual body weight should be used for
    calculating creatinine clearance using the Cockcroft-Gault Equation (except for
    patients with body mass index > 30 kg/m2 when lean body weight should be used instead):
    Serum Creatinine (mg/min)= (140-Age (years)×(Weight(kg)) ×Sex
    72× Serum Creatinine (mg/dL)
       
    where Sex 1 for males and 0.85 for females.

    12. Electrocardiogram during the Screening period without any clinically significant findings, per the investigator’s assessment
    E.4Principal exclusion criteria
    General Exclusion Criteria
    1. Any medical or social condition deemed by the investigator to be likely to
    interfere with a patient’s ability to sign informed consent, cooperate and
    participate in the study, or interfere with the interpretation of the results
    2. Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a highly effective method of birth control, during the study and for 4 months following the last dose of study drug.
    Disease Specific Exclusion Criteria
    3. Patients with large cell neuroendocrine carcinoma
    4. Patients who received any of the following treatments:
    a. Prior treatment regimens with irinotecan, topotecan or any other
    topoisomerase I inhibitor including investigational topoisomerase I
    inhibitors.
    b. Retreatment of the same platinum-based after relapse.
    c. Any antibody-drug conjugates or molecular targeted agents (e.g. poly
    ADP-ribose polymerase inhibitors), either alone or in combination
    with other treatments.
    d. More than one line of immunotherapy (e.g. nivolumab, pembrolizumab, ipilimumab, atezolizumab, tremelimumab and/or durvalumab).
    One line of immunotherapy is allowed, which is defined as the following: monotherapy or combination of immunotherapy agents given as either (i) in combination with chemotherapy followed by immunotherapy maintenance in the first line setting, (ii) only as a maintenance following response to first-line chemotherapy or (iii) immunotherapy given as second line treatment
    following progression.
    e. Any other additional regimen of prior cytotoxic chemotherapy, not
    described above.
    5. Patients with a history of immunotherapy induced colitis or pneumonitis, based on clinical assessment and/or confirmed by biopsy
    6. Patients with the following CNS metastasis:
    a. Patients who developed new or progressive brain metastasis following prophylactic and/or therapeutic cranial radiation (whole brain or stereotactic radiation)
    b. Patients with symptomatic CNS metastasis (a patient with brain metastasis who received cranial radiotherapy is eligible if asymptomatic for neurological symptoms for ≥2 weeks after cranial radiotherapy and is off corticosteroids for treatment of CNS metastasis). Patients with asymptomatic brain metastasis are eligible to be enrolled directly to the study
    c. Patients with carcinomatous meningitis
    7. Unable to discontinue the use of strong CYP3A4 or UGT1A1 inhibitors at least
    1 week or strong CYP3A4 inducers at least 2 weeks prior to receiving the first
    dose of irinotecan liposome injection
    8. Have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis [carcinoma in situ]) or any previous cancer curatively treated >3 years ago without evidence of recurrence.
    9. Investigational therapy administered within 4 weeks, or within a time interval
    less than at least 5 half-lives of the investigational agent, whichever is less, prior
    to the first scheduled day of dosing in this study
    Hematologic, Biochemical and Organ Function Exclusion Criteria
    10. Severe cardiovascular and pulmonary disease (e.g. myocardial infarction,
    unstable angina pectoris, coronary angioplasty or stenting, deep vein thrombosis,
    stroke, pulmonary fibrosis, active uncontrolled bleeding, or a known bleeding
    diathesis) less than 6 months before inclusion
    11. New York Heart Association Class III or IV congestive heart failure, ventricular
    arrhythmias or uncontrolled blood pressure
    12. Active infection (e.g. acute bacterial infection, tuberculosis, active hepatitis B/C or active human immunodeficiency virus) which in the investigator’s opinion
    might compromise the patient’s participation in the trial or affect the study
    outcome
    13. Known hypersensitivity to any of the components of irinotecan liposome
    injection, other liposomal products, or topotecan
    14. Clinically significant gastrointestinal disorder including hepatic disorders,
    bleeding, inflammation, occlusion, or diarrhea > grade 1
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy end point is Overall Survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    Overall survival is defined as the number of months from the date of the first dose of study drug in Part 2 to the date of death.
    E.5.2Secondary end point(s)
    Secondary efficacy end points are Progression free survival, objective response rate and proportion of patients with improvement in patient-reported outcomes.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the final overall survival analyis
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Biomarkers
    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) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    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) Yes
    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 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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Belgium
    France
    Germany
    Spain
    Taiwan
    United States
    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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 286
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 486
    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)
    None
    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 Decision2018-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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