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    Summary
    EudraCT Number:2011-001468-23
    Sponsor's Protocol Code Number:TG4010.14
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-07-22
    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 ConcernedUK - MHRA
    A.2EudraCT number2011-001468-23
    A.3Full title of the trial
    A Phase IIb/III randomized, double-blind, placebo-controlled study comparing first-line therapy with or without TG4010 immunotherapy product in patients with stage IV non-small cell lung cancer (NSCLC).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing standard therapy with or without TG4010 in patients with advanced non small cell lung cancer
    A.3.2Name or abbreviated title of the trial where available
    TIME study
    A.4.1Sponsor's protocol code numberTG4010.14
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01383148
    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 SponsorTransgene S.A.
    B.1.3.4CountryFrance
    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 supportTransgene S.A
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTransgene S.A.
    B.5.2Functional name of contact pointTransgene Medical Affairs
    B.5.3 Address:
    B.5.3.1Street AddressBoulevard Gonthier d’Andernach, Parc d’Innovation - CS80166
    B.5.3.2Town/ cityIllkirch Graffenstaden Cedex
    B.5.3.3Post code67405
    B.5.3.4CountryFrance
    B.5.6E-mailclinical.trials@transgene.fr
    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 nameMVA-MUC1-IL2
    D.3.2Product code TG4010
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmesmulogene ancovacivec
    D.3.9.1CAS number 1246525-59-6
    D.3.9.2Current sponsor codeMVATG9931
    D.3.9.3Other descriptive nameMVATG9931
    D.3.10 Strength
    D.3.10.1Concentration unit PFU plaque forming unit
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number37000000 to 250000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    D.8.3Pharmaceutical form of the placeboSuspension for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stage IV non small cell lung cancer (NSCLC)
    E.1.1.1Medical condition in easily understood language
    Advanced non small cell 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 LLT
    E.1.2Classification code 10025055
    E.1.2Term Lung cancer non-small cell stage IV
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10025048
    E.1.2Term Lung cancer non-small cell recurrent
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase IIb part (completed): to prospectively validate the level of
    CD16+CD56+CD69+ lymphocytes, designed as TrPAL, as a predictive biomarker of TG4010's activity by comparing Progression-Free Survival (PFS) between the TG4010 arm (TG4010 + first-line therapy) and the placebo arm (placebo + first-line therapy) in the two subgroups of patients according to their level of TrPAL before randomization (normal and high level of TrPAL).

    Phase III part: To demonstrate that TG4010 improves overall survival (OS) as compared to placebo in stage IV NSCLC patients with non-squamous tumor histology receiving first-line chemotherapy:
    • in the whole study population
    • in the subgroup of patients with non-elevated TrPAL at baseline
    E.2.2Secondary objectives of the trial
    Phase IIb part (completed):
    - Compare the 2 treatment arms with respect to OS, Overall Response Rate (ORR) and Time to Overall Response
    - Describe the Duration of Response (DoR)
    - Evaluate and to compare the safety profiles

    Phase III part:
    - To compare the 2 treatment arms with respect to the following endpoints repeated in the whole study population and in subgroups of patients with non-elevated TrPAL at baseline: PFS based on RECIST 1.1, 9-month PFS, ORR, and DoR
    - Quality of Life and pharmacoeconomic
    - Evaluate safety as assessed based on NCI-CTCAE in the whole study population, in patients with non-elevated TrPAL at baseline, and in patients with elevated TrPAL at baseline.
    - Compare PFS and OS in patients with elevated TrPAL at baseline

    Exploratory objectives of phase III:
    - Assess blood and cellular biomarkers or biomarker “profiles” with potential prognostic and/or predictive value on efficacy outcomes or biomarkers associated with TG4010 mechanism of action.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PBMC isolation and banking – (substudy for 250 patients)
    E.3Principal inclusion criteria
    - Male or female patients, age ≥ 18 years old
    - Histologically confirmed NSCLC. NSCLC Not Otherwise Specified (NOS) are eligible except large cell neuroendocrine carcinoma.
    - Stage IV cancer according to TNM classification
    - Availability of histological material for Immunohistochemistry (IHC) staining on fixed paraffin embedded material; biopsy may come either from the primary tumor or from a metastasis
    - Patient's naïve to first-line therapy for the advanced stage of the disease. Previous neoadjuvant or adjuvant therapy or radiotherapy is allowed for patients who successfully underwent complete radical surgery and if last treatment was administered more than 12 months prior to the start of the study treatment, i.e., D1 of Cycle 1.
    - At least one measurable lesion by computorized tomography scan or magnetic resonance imaging based on RECIST version 1.1 (CT is preferred for the chest exam)
    - Performance status 0 or 1 on the ECOG scale
    - Adequate hematological, hepatic, and renal function:
    * Hemoglobin ≥ 10.0 g/dL
    * White Blood Cells ≥ 3.0x1E+09/L including:
    Neutrophils ≥ 1.5x1E+09/L
    Total lymphocytes count ≥ 0.5x1E+09/L
    * Platelets count ≥ 100x1E+09/L
    * Serum alkaline phosphatase ≤3 x upper limit of normal (ULN) in the absence of liver or bone metastases, and ≤5 ULN in patients with such metastases
    * Serum transaminases alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x ULN in the absence of liver metastases and ≤ 5 x ULN in case of liver metastases
    * Total bilirubin ≤1.5 x ULN
    * Glomerular Filtration Rate ≥ 60 mL/min (according to Modification of the Diet in Renal Disease (MDRD) formula or Cockroft & Gault formula)
    * Serum albumin ≥ 30 g/L
    - Effective contraception during the study period and for 3 months after the last study treatment administration (male and female patient)
    - Signed informed consent
    E.4Principal exclusion criteria
    - NSCLC with predominant squamous cell histology (mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is not eligible). Large cell neuroendocrine carcinoma are excluded
    - Patients having Central Nervous System (CNS) metastases (including leptomeningeal metastases). Patients who have had brain metastases surgically removed or irradiated with no residual disease confirmed by imaging and not treated by corticosteroids are allowed are allowed
    - EGFR activating mutations or ALK rearrangements leading to eligibility for TKI treatment (tests mandatory). Patients with documented ROS1-rearrangement (if already tested) are not eligible
    - Prior history of other malignancy except:
    * Basal cell carcinoma of the skin
    * Cervical intra epithelial neoplasia
    * Other cancer curatively treated with no evidence of disease for at least 5 years
    - Patients under chronic treatment with systemic corticoids or other immunosuppressive drugs (e.g., cyclosporine) for a period of at least 4 weeks and whose treatment was not stopped 1 week prior to the start of the study treatment (i.e., D1 of Cycle 1)
    - Positive serology for Human Immunodeficiency Virus or Hepatitis C Virus; presence in the serum of the antigens HBs
    - Patient with any underlying medical condition that the treating physician considers might be aggravated by treatment or which is not controlled (e.g., elevated troponin or creatinine, uncontrolled diabetes)
    - Patient with major surgery or radiotherapy within 4 weeks prior to the start of the study treatment (i.e., D1 of Cycle 1). However, prior surgery or radiation therapy aimed at local palliation or attempted local disease control is permitted within the 4 weeks before treatment start
    - Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL)
    - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are:
    * women whose sexual orientation precludes intercourse with a male partner
    * women whose partners have been sterilized by vasectomy or other means
    * using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices [IUDs]; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable)
    - Patient with an organ allograft
    - Known allergy to eggs, gentamicin or platinum containing compounds
    - Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment (i.e., D1 of Cycle 1)
    - Patient unable or unwilling to comply with the protocol requirements
    E.5 End points
    E.5.1Primary end point(s)
    Phase IIb part (completed): PFS (time from the date of randomization to the date of first documented tumor progression or death due to any cause, whichever occurs first)

    Phase III part: OS (time from date of randomization to the date of death due to any cause)
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS: tumor progression evaluated by RECIST every 6 weeks from start of treatment until documented progression or for a period of 9 months after start of study treatment, whichever occurs first. Beyond 9 months of treatment, the evaluations will be performed every 12 weeks until documented progression

    OS will be evaluated at the date of a subject's death due to any cause; patients will be followed for survival on a 3-monthly basis
    E.5.2Secondary end point(s)
    Phase IIb part (completed), secondary endpoints:
    - OS: defined in E.5.1
    - ORR: proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST v.1.1
    - Response rate at evaluation #2: proportion of patients having presented a CR or PR (even if not confirmed) at the 2nd tumor assessment after treatment start.
    - TOR: the start date is the date of randomization and the end date is the date of first documented response (CR or PR).
    - DoR: time from the date of first documented response (CR or PR) to the date of first documented disease progression or death due to underlying cancer
    - Safety: Incidence of AEs and SAEs assessed by the NCI CTCAE

    Phase IIb part (completed), exploratory endpoints:
    - Response rate at evaluation #2, change in tumor size over time: tumor size is defined as the sum of the longest diameters for all target lesions as identified at baseline
    - Efficacy and safety in subgroups of patients
    - Peripheral blood parameters: cellular and humoral response, immunophenotyping of lymphocytes, inflammatory and immune cytokines and related proteins, transcriptomics and genomics
    - Blood biomarkers with potential prognostic and/or predictive value on efficacy outcomes or biomarkers associated with TG4010 mechanism of action
    - Viral dissemination: skin swabs analyses by qPCR

    Phase III part, secondary endpoints:
    - PFS: defined in E.5.1
    - ORR, DoR & safety: defined above
    - QoL: questionnaire QLQC30-LC13-EORTC
    - Pharmacoeconomic: Information obtained from the collection of medical care utilization data through eCRF may be combined with other data such as cost data or other clinical parameters

    Phase III part, exploratory endpoint:
    - Immune related biomarker evaluation
    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS & OS: see E.5.1.1
    ORR & DoR: see E.5.1.1
    TOR: 1st response or last tumor assessment
    Safety: evaluated throughout the study
    QoL: every 6 wks starting on D1 of Cycle 1 until end of study treatmnt
    Pharmacoecon. data: separately from CSR
    Change in tumor size over time: same as for PFS; see E.5.1.1
    Peripheral blood parameters (Phase IIb only): at single time points and over time
    The explor. endpoint relating to the identification of biomarkers with potential prognostic and/or predictive value on efficacy outcomes, or associated with TG4010 mechanism of action, may be conducted after patient participation has ended
    Viral dissemination: before & 6 hrs after the 1st IMP injection & before IMP injections on D8, D15 and D22
    Immune rel. biomarker evaluation: on D1 of Cycles 1, 2, 3 & 5
    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 Yes
    E.6.12Pharmacoeconomic Yes
    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) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA112
    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
    Belgium
    Bulgaria
    Canada
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    New Zealand
    Poland
    Romania
    Russian Federation
    Serbia
    South Africa
    Spain
    Ukraine
    United Kingdom
    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
    For the Phase IIb part: after a follow-up of 30 months after last patient
    randomization and providing that all patients have completed the study
    with regard to PFS.
    For the Phase III part: after a follow-up of 48 months from last patient
    randomization.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    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 years9
    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: 309
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 191
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Such subjects will mainly include patients incapable of reading the informed consent due to visual impairment; patients incapable of giving consent personally who are unable to understand study risks (whatever the cause) will not be included.
    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 314
    F.4.2.2In the whole clinical trial 500
    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)
    As per standard of care for this condition
    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 Decision2011-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-05
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