Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   39363   clinical trials with a EudraCT protocol, of which   6448   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).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2013-005534-38
    Sponsor's Protocol Code Number:E7080-G000-207
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-10-27
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-005534-38
    A.3Full title of the trial
    Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1b/2 trial studying how well lenvatinib works in treating children and adolescents with different types of cancer that are not responding to treatment or have reappeared following an initial recovery
    A.4.1Sponsor's protocol code numberE7080-G000-207
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/040/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEisai Ltd.
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Limited
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEisai Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Europe Ltd
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEuropean Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield, Hertfordshire
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44845676 1400
    B.5.5Fax number+44845676 1401
    B.5.6E-mailEUMedInfo@eisai.net
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1119; EU/3/13/1121
    D.3 Description of the IMP
    D.3.1Product nameLenvatinib
    D.3.2Product code E7080
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenvatinib
    D.3.9.1CAS number 857890-39-2
    D.3.9.2Current sponsor codeE7080
    D.3.9.3Other descriptive nameLENVATINIB MESYLATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1119; EU/3/13/1121
    D.3 Description of the IMP
    D.3.1Product nameLenvatinib
    D.3.2Product code E7080
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenvatinib
    D.3.9.1CAS number 857890-39-2
    D.3.9.2Current sponsor codeE7080
    D.3.9.3Other descriptive nameLENVATINIB MESYLATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1119; EU/3/13/1121
    D.3 Description of the IMP
    D.3.1Product nameLenvatinib
    D.3.2Product code E7080
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenvatinib
    D.3.9.1CAS number 857890-39-2
    D.3.9.2Current sponsor codeE7080
    D.3.9.3Other descriptive nameLENVATINIB MESYLATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 4
    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.2.5The 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.3.4Pharmaceutical form Powder for solution for 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 INNCyclophosphamide
    D.3.9.1CAS number 6055-19-2
    D.3.9.3Other descriptive nameCYCLOPHOSPHAMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB16414MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 5
    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.2.5The 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.3.4Pharmaceutical 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 INNEtoposide
    D.3.9.1CAS number 33419-42-0
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Refractory or relapsed solid malignancies
    tumores sólidos resistentes al tratamiento o recidivantes
    E.1.1.1Medical condition in easily understood language
    Different types of cancer that are not responding to treatment or have reappeared following an initial recovery
    Los diferentes tipos de cáncer que no responden al tratamiento o han reaparecido tras una recuperación inicial
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Cohort 1 (Single-Agent Dose-Finding)
    ? Identify the recommended dose (RD) of lenvatinib as a single agent in children and adolescents with relapsed or refractory solid malignant tumors
    Cohort 2 (Single-Agent Expansion)
    ? Evaluate the activity of lenvatinib in 2 separate malignancy groups:
    o Cohort 2A: 131I- refractory differentiated thyroid cancer: by objective response rate (ORR)
    o Cohort 2B: Relapsed or refractory osteosarcoma: by progression-free survival at 4 months (PFS)-4
    Cohort 3 (Combination Dose-Finding and Expansion)
    ? Cohort 3A (Combination Dose-Finding)
    To identify the RD of lenvatinib in combination with cyclophosphamide (CPM) and etoposide in osteosarcoma subjects
    ? Cohort 3B (Combination Expansion)
    o Evaluate the activity of lenvatinib in combination with CPM and etoposide in osteosarcoma subjects by PFS-4
    E.2.2Secondary objectives of the trial
    Cohort 1
    ? Evaluate the activity of lenvatinib as assessed by best overall response (BOR), ORR, duration of response (DOR), time to progression (TTP), based on RECIST 1.1, and overall survival (OS)
    ? Assess the safety and toxicity profile of lenvatinib in children and adolescents
    Cohort 2
    ? Assess the safety and toxicity profile of lenvatinib in children and adolescents
    ? Evaluate the efficacy of lenvatinib as assessed by BOR, ORR (osteosarcoma only), DOR, TTP, and OS
    Cohort 3
    ? Assess the safety and toxicity of lenvatinib in combination with CPM and etoposide in children and adolescents with relapsed or refractory osteosarcoma
    ? Evaluate the efficacy of lenvatinib as assessed by BOR, ORR, DOR, TTP, and OS
    Cohorts 1,2&3
    ? Examine blood and tumor biomarkers and correlate with clinical response to lenvatinib
    ? Assess bone growth and height during and after discontinuation of treatment with lenvatinib
    ? Determine population-based pharmacokinetic (PK) parameters of lenvatinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Histologically or cytologically confirmed diagnosis of solid malignant
    tumor a.Cohort 1: Any solid malignant tumor b.Cohort 2A: DTC with one histological subtype:i.Papillary thyroid cancer
    1.Follicular variant 2.Other (tall cell, columnar cell, cribriform-morular,solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis,Hürthle cell variant of papillary or poorly differentiated carcinomas)ii.Follicular thyroid cancer 1.Hürthle cell 2.Clear cell 3.Insular2.Relapsed or refractory solid tumor malignancy that has progressed onstandard anticancer therapy with no available curative options3.Evidence of metastases4.Measurable disease that meets the following criteria a.Subjects with osteosarcoma and other tumor types who are in the dose-finding cohorts(Cohort 1 and Cohort 3A) must have evaluable disease based on RECIST1.1 b.Subjects with DTC in Cohort 2A: i.Must have disease meeting the
    following criteria: At least 1 lesion of ?1.0 cm in the longest diameter for a non-lymph node or ?1.5 cm in the short-axis diameter for a lymph node. For Cohort 2, if there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of ?1.5 cm ii.Lesions that have had external beam radiotherapy or locoregional therapies must have subsequently grown unequivocally to be deemed a target lesion 5.DTC subjects must be 131I-refractory/ relapsed as defined by a.One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan OR b.have progressed based on RECIST 1.1 within 12 months of 131I therapy OR c.Cumulative activity of 131I >600 millicuries or 22 gigabecquerels with the last dose administered at least 6 months prior to study entry 6.Subjects with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone should be ?5.50 mU/L).7.Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical
    resection, will be eligible if they have remained clinically stable, asymptomatic and off of steroids for 1 month prior to study entry 8.Male or female subjects age 12 years to <18 years 9.Lansky play score ?70% or ECOG ?1 10.Life expectancy ?3 months
    11.Adequate bone marrow function
    12.Adequate liver function:
    a.bilirubin ?1.5 times the upper limit of normal (ULN)
    b.alkaline phosphatase, alanine aminotransferase, and aspartate
    aminotransferase ? 3 × ULN (in the case of liver metastases ?5 × ULN)
    13.Adequate renal function:
    a.Serum creatinine ?1.5 × ULN for age.
    b.Urine dipstick <2+ for proteinuria.
    c.No clinical evidence of nephrotic syndrome
    14.Adequate cardiac function as evidenced by Fractional Shortening ?
    28% and left ventricular ejection fraction ?50%)
    15.Adequately controlled blood pressure
    a.BP <95th percentile for sex, age, and height/length at screening and
    no change in antihypertensive medications within 1-week prior to Cycle
    1/Day 1
    16.Washout of 3 weeks in case of prior chemotherapy, 6 weeks if
    treatment included nitrosoureas; 4 weeks in case of prior radiotherapy, 3
    months from high-dose chemotherapy and stem cell rescue
    17.Females must not be lactating or pregnant at Screening or Baseline
    18.All post pubertal females will be considered to be of childbearing
    potential unless they have early menopause due to prior treatment
    procedures or have been sterilized surgically
    19.Females of childbearing potential must not have had unprotected
    sexual intercourse within 30 days before study entry and must agree to
    use a highly effective method of contraception throughout the entire
    study period and for 6 months after study drug discontinuation.
    Abstinence is acceptable only when this is in line with the preferred and
    usual lifestyle of the patient. If currently abstinent, the subject must
    agree to use a double barrier method as described above if she becomes
    sexually active during the study period or for 6 months after study drug
    discontinuation. Females who are using hormonal contraceptives must
    have been on a stable dose of the same hormonal contraceptive product
    for at least 4 weeks before dosing and must continue to use the same
    contraceptive during the study and for 6 months after study drug
    discontinuation
    20.If sexually active, male subjects and their female partners must use a
    highly effective method of contraception throughout the study period
    and for 6 months after study drug discontinuation. No sperm donation is
    allowed during the study period and for 6 months after study drug
    discontinuation
    21.Written and signed informed consent from the parent(s) or legal
    guardian and assent from the minor subject
    22.Able to comply with the protocol
    Cohort 3B: Osteosarcoma subjects who progressed in
    Cohort 2B and opt to receive combination therapy:
    23.Osteosarcoma subjects receiving combination therapy of lenvatinib
    with CPM and etoposide should meet only Inclusion Criteria Numbers 9
    through 22 (after progression in Cohort 2B)
    E.4Principal exclusion criteria
    1. Any history or evidence of severe acute or chronic infection or infectious illness unless fully recovered for at least 4 weeks prior to screening
    2. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject?s participation in a clinical study
    3. Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, or radiation therapy) except alopecia, not already covered in the inclusion/exclusion criteria, which has not recovered to Grade <2 per CTCAE v4.0
    4. Known hypersensitivity to any component of the product (lenvatinib or ingredients)
    5. Concurrent administration of any other antitumor therapy
    6. Previous treatment with lenvatinib (except for subjects previously enrolled into Cohort 3B of this study)
    7. Two or more prior VEGF/VEGFR-targeted therapies
    8. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent
    9. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec)
    10. Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib
    11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to the first dose of study drug
    12. Active second malignancy within 2 years prior to enrollment (in addition to the primary tumor types specified by cohort in Inclusion Criterion Number 1), but not including definitively treated melanoma, carcinoma in-situ, basal or squamous cell
    carcinoma of the skin)
    13. Osteosarcoma subjects receiving combination therapy of lenvatinib with CPM and etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6.
    E.5 End points
    E.5.1Primary end point(s)
    Cohort 1 (Single-Agent Dose-Finding)
    ? RD based on the CRM design.
    Cohort 2 (Single-Agent Expansion)
    ? Cohort 2A: DTC Group: ORR (CR + PR) based on RECIST 1.1
    ? Cohort 2B: Osteosarcoma Group: PFS-4, ie, the percentage of subjects who are alive and free of disease progression 4 months after the first dose based on RECIST 1.1
    Cohort 3A (Combination Dose-Finding)
    ? RD of the combination treatment (lenvatinib + etoposide + CPM)
    Cohort 3B (Combination Expansion)
    ? PFS-4, ie, the percentage of subjects who are alive and free of disease progression 4 months after the first dose based on RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohort 1: determination of the RD (either when approximately 18 subjects have been tested, or when futility is declared or when 10 subjects have been treated at the same dose).
    Cohort 2A: all ORR will be based on RECIST 1.1 assessed every 8 weeks. Cohort 2B: PFS-4 based on RECIST 1.1.
    Cohort 3A: the DLT will be assessed to determine the RD of lenvatinib in combination with CPM plus etoposide.
    Cohort 3B: PFS-4 based on RECIST 1.1.
    E.5.2Secondary end point(s)
    Cohort 1 (Single-Agent Dose-Finding):
    Efficacy
    o BOR over the treatment period
    o ORR
    o DOR
    o Disease Control Rate (DCR) defined as the percentage of subjects who have a BOR of CR or PR or stable disease (SD). To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ?7 weeks.
    o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ? 23 weeks
    o Clinical Benefit Rate (CBR) defined as the percentage of subjects who have a BOR of CR or PR or durable SD
    o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
    o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date)
    ? Safety
    o AEs, clinical laboratory values, vital signs, 12-lead ECG, Lansky Play Scores or ECOG performance scores, physical examination findings, and bone growth and height during treatment and follow-up
    ? Plasma lenvatinib exposure
    ? Assessment of blood or tumor biomarkers that correlate with clinical response to lenvatinib treatment or AEs associated with lenvatinib treatment
    Cohort 2:
    Efficacy
    o BOR over the treatment period
    o ORR (osteosarcoma group)
    o DOR
    o DCR defined as the percentage of subjects who have a BOR of CR or PR or SD. To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ?7 weeks.
    o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ? 23 weeks
    o CBR defined as the percentage of subjects who have a BOR of CR or PR or durable SD
    o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
    o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date).
    ? Safety
    o AEs, clinical laboratory values, vital signs, 12-lead ECGs, Lansky play scores or ECOG performance scores, physical examination findings, and bone growth and height during treatment and follow-up
    ? Plasma lenvatinib exposure parameters
    ? Assessment of blood or tumor biomarkers that correlate with clinical response to lenvatinib treatment or AEs associated with lenvatinib treatment.
    Cohort 3A and 3B:
    Efficacy
    o BOR over the treatment period
    o ORR (osteosarcoma group)
    o DOR
    o DCR defined as the percentage of subjects who have a BOR of CR or PR or SD. To be assigned a best overall response of SD, the time from the first administration of study drug until the date of documented SD should be ?7 weeks.
    o Durable SD rate defined as the percentage of subjects who have the duration of SD lasting ? 23 weeks
    o CBR defined as the percentage of subjects who have a BOR of CR or PR or durable SD
    o TTP defined as the time from the date of the first administration of study drug until the date of first documentation of disease progression
    o Time to OS defined as the time from the date of the first administration of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known to be alive (or the data cutoff date).
    ? Safety
    o AEs, clinical laboratory values, vital signs, 12-lead ECGs, Lansky play scores or ECOG performance scores, physical examination findings, and bone growth and height during treatment and follow-up
    ? Plasma lenvatinib exposure parameters
    ? Assessment of blood or tumor biomarkers that correlate with clinical response to
    lenvatinib treatment or AEs associated with lenvatinib treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Median PFS, median OS, and the cumulative probability of PFS at 4, 12, and 24 months and OS at 12 and 24 months
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 No
    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 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.8.2.4Number of treatment arms in the trial5
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    LVLS
    ultima visita, ultimo paciente
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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 Yes
    F.1.1Number of subjects for this age range: 99
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 99
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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
    Adolescents (12 - <18). Parents/legal guardians of subjects must be provided with the informed consent information prior to the Screening Visit to allow adequate time for review and an opportunity to discuss the study with the Investigator/designee.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 99
    F.4.2.2In the whole clinical trial 99
    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 will be followed for survival every 3 months until death or for at least 1 year unless the study is terminated or if the subject discontinues due to withdrawal of consent or is lost to follow-up.
    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 Decision2014-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-14
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA