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    Summary
    EudraCT Number:2013-005534-38
    Sponsor's Protocol Code Number:E7080-G000-207
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-31
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    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 and Young Adults with Osteosarcoma
    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 and young adults 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/282/2014
    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 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 INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    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
    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
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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) for subjects with measurable disease and by best overall response (BOR) for all subjects
    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 ifosfamide and etoposide in osteosarcoma subjects
     Cohort 3B (Combination Expansion)
    o Evaluate the activity of lenvatinib in combination with ifosfamide and etoposide in osteosarcoma subjects by PFS-4
    E.2.2Secondary objectives of the trial
    Cohort 1
    • Evaluate the activity of E7080 as assessed by best overall response (BOR), ORR,DOR,PFS, time to progression(TTP), based on RECIST 1.1
    • Assess the safety & toxicity profile of E7080 in children and adolescents and young adults
    Cohort 2
    • Assess the safety and toxicity of E7080 as for Cohort 1
    • Evaluate the efficacy of E7080 as assessed by BOR,ORR (osteosarcoma only), DOR, TTP, PFS, DCR and CBR
    Cohort 3
    • Assess the safety & toxicity of E7080 in combination with IFO and etoposide in children and adolescents and young adults with relapsed or refractory osteosarcoma
    • Evaluate the efficacy of E7080 as assessed by BOR, ORR, DOR, TTP, PFS, DCR and CBR
    Cohorts 1,2&3
    • Examine blood and tumor biomarkers and correlate with clinical response to E7080
    • Assess bone growth and height during and after discontinuation of treatment with E7080
    • Determine population-based PK parameters of E7080
    Assess the palatability and acceptability of the suspension formulation of E7080
    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 of the following histological subtypes:
    i.Papillary thyroid cancer (PTC)
    1.Follicular variant
    2.Other variants (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 (FTC)
    1.Hürthle cell
    2.Clear cell
    3.Insular
    c. Cohort 2B, 3A and 3B:Relapsed or refractory osteosarcoma
    2.Relapsed or refractory solid tumor malignancy that has progressed on
    standard anticancer therapy with no available curative options.
    3.Evaluable or measurable disease that meets the following criteria
    a. Subjects must have evaluable or measurable disease based on RECIST
    1.1
    b.Lesions that have had external beam radiotherapy (EBRT) or
    locoregional therapies must have subsequently grown unequivocally to
    be deemed a target lesion
    4.DTC subjects must be 131I-refractory/relapsed as defined by at least
    one of the following:
    a.One or more evaluable or measurable lesions that do not demonstrate
    iodine uptake on any radioiodine scan OR
    b.One or more evaluable or measurable lesions that have progressed
    based on RECIST 1.1, within 12 months of 131I therapy, despite
    demonstration of radioiodine avidity at the time of that treatment by
    pre- or post-treatment scanning. These subjects must not be eligible for
    possible curative surgery OR
    c.Cumulative activity of 131I >400 millicuries (mCi) or 14.8
    gigabecquerels (GBq), with the last dose administered at least 6 months
    prior to study entry
    5.Subjects with DTC must be receiving thyroxine suppression therapy
    and levels of thyroid stimulating hormone (TSH) should not be elevated
    (TSH should be ≤5.50 mU/L). When tolerated by the subject, thyroxine
    dose should be changed to achieve TSH suppression (TSH <0.50 mU/L)
    6.Subjects with known CNS primary tumors or metastases who have
    completed brain therapy (such as radiotherapy), stereotactic
    radiosurgery or complete surgical resection, will be eligible if they have
    remained clinically stable, asymptomatic and off of steroids for 4 weeks
    prior to Cycle 1 Day 1.
    7.Male or female subjects age 2 years to <18, (≤25 years for
    osteosarcoma subjects) at the time of informed consent
    8.Lansky play score ≥50% or Karnofsky Performance Status score ≥50%
    9.Life expectancy ≥ 3 months
    10.Adequate bone marrow function
    11.Adequate liver function:
    a.bilirubin :Sl.S times the upper limit of normal (ULN)
    b.alkaline phosphatase, ALT, and AST ≤ 3 x ULN (in the case of liver
    metastases ≤5 x ULN)
    12.Adequate renal function:
    a. Serum creatinine based on age/gender as below. If serum creatinine
    is greater than maximum serum creatinine for age/gender as shown in
    the table below, then creatinine clearance (or radioisotope glomerular
    filtration rate [GFR]) must be >70 mL/min/l.73 m2 (Appendix 6).
    Age Max. Serum Creatinine (mg/dL)
    Male Female
    2 to < 6 years 0.8 0.8
    6 to < 10 years 1 1
    10 to < 13 years 1.2 1.2
    13 to < 16 years 1.5 1.4
    ≥ 16 years 1.7 1.4
    b.Urine dipstick <2+ for proteinuria.
    c.No clinical evidence of nephrotic syndrome
    13. Adequate cardiac function as evidenced by Fractional Shortening ≥
    28% (≥35% for children <3 yrs of age) or left ventricular ejection
    fraction ≥5O%)
    14. Adequately controlled blood pressure (BP) with or without
    antihypertensive medications:
    BP <95th percentile for sex, age, and height/length at screening (as per
    National Heart Lung and Blood Institute guidelines; see Appendix 7 and
    Appendix 8) and no change in antihypertensive medications within 1-
    week prior to Cycle 1/Day 1. Osteosarcoma subjects age lS to 25 years
    should have BP ≤150/90 mm Hg at screening and no change in
    antihypertensive therapy within 1 week prior to Cycle 1 Day 1.
    15.Washout of 3 weeks in case of prior chemotherapy, 6 weeks if
    treatment included nitrosoureas; 4 weeks for definitive radiotherapy and
    2 weeks for palliative radiotherapy, 3 months from high-dose
    chemotherapy and stem cell rescue; 3 weeks from major surgery.
    Subjects must have recovered from the acute toxic effects of all prior
    anticancer therapy before enrollment into the study.
    16.Written and signed informed consent from the parent(s) or legal
    guardian and assent from the minor subject. Written informed consent
    from subjects ≥ 18 years.
    17.Willing and able to comply with the protocol, scheduled follow-up,
    and management of toxicity as judged by the Investigator
    Cohort 3B (Combination Expansion):
    l8.Osteosarcoma subjects receiving combination therapy of lenvatinib
    with ifosfamide and etoposide should meet only Inclusion Criteria
    Numbers: 6 through 17 (after progression in Cohort 2B)
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria will be excluded from
    this study:
    1.Any active infection or infectious illness unless fully recovered prior to
    dosing
    2.Any medical or other condition that in the opinion of the
    investigator(s) would preclude the subject's participation in a clinical
    study
    3.0ther organ toxicity due to prior anticancer therapy (investigational
    agent, chemotherapy, or radiation therapy) except alopecia, and
    ototoxicity due to cisplatin not already covered in the
    inclusion/exclusion criteria, which has not recovered to Grade <2 per CTCAE v4.03
    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 Cohorts 1 or 2B of this study)
    7.Two or more prior VEGF/VEGFR-targeted therapies
    8.Currently receiving any investigational drug or device in another
    clinical trial or 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 superficial
    melanoma, in-situ, basal or squamous cell carcinoma of the skin).
    13.Previous treatment with ifosfamide and grade ≥3 nephrotoxicity or
    encephalopathy (Cohorts 3A and 3B).
    14.Females who are breastfeeding or pregnant at Screening or Baseline
    (as documented by a positive beta-human chorionic gonadotropin [ßhCG]
    (or human chorionic gonadotropin [hCG]) test with a minimum
    sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate
    baseline assessment is required if a negative screening pregnancy test
    was obtained more than 72 hours before the first dose of study drug.
    Females of childbearing potential who:
    •Within 28 days before study entry, did not use a highly effective
    method of contraception, which includes any of the following:
    ototal abstinence (if it is their preferred and usual lifestyle)
    o an intrauterine device or intrauterine hormone-releasing system (IUS)
    o an oral contraceptive. Subject must be on a stable dose of the same
    oral contraceptive product for at least 28 days before dosing and
    throughout the study and for 6 months after study drug
    discontinuation.) .
    o have a vasectomized partner with confirmed azoospermia.
    •Do not agree to use a highly effective method of contraception (as
    described above) throughout the entire study period and for 6 months
    after study drug discontinuation.
    Cohort 3B (Combination Expansion): Osteosarcoma subjects who
    progressed in Cohorts 1 or 2B and opt to receive combination therapy:
    15.Osteosarcoma subjects receiving combination therapy of lenvatinib
    with etoposide and ifosfamide 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 TiTE-CRM design.
    Cohort 2 (Single-Agent Expansion)
     Cohort 2A: DTC Group: ORR (CR + PR) for subjects with measurable disease and BOR for all subjects 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 + ifosfamide)
    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 ifosfamide 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 Karnofsky Performance Status scores, physical examination findings, and bone growth and height (including proximal tibial growth plates)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 Karnofsky Performance Status, physical examination findings, and bone growth and height (including proximal tibial growth plates) 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 Karnofsky Performance Status scores, physical examination findings, and bone growth and height (including proximal tibial growth plates)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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1/2 paediatric study
    E.7.2Therapeutic exploratory (Phase II) No
    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
    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 months
    E.8.9.1In the Member State concerned days
    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: 80
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 12
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 68
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    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 (2 - <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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 108
    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 1 year, whichever occurs first, unless the study is terminated or 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 Decision2014-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-08
    P. End of Trial
    P.End of Trial StatusCompleted
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