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   38451   clinical trials with a EudraCT protocol, of which   6312   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:2019-003696-19
    Sponsor's Protocol Code Number:E7080-G000-230
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-12-31
    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 ConcernedFinland - Fimea
    A.2EudraCT number2019-003696-19
    A.3Full title of the trial
    A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Children, Adolescents and Young Adults with Relapsed or Refractory Osteosarcoma (OLIE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 trial studying how lenvatinib works in combination with Ifosfamide and Etoposide compared to Ifosfamide and Etoposide in treating Children, Adolescents and Young Adults for a type of cancer that is not responding to treatment or has reappeared following an initial recovery.
    A.4.1Sponsor's protocol code numberE7080-G000-230
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04154189
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/033/2020
    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 Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Ltd
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressMosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4408456761400
    B.5.5Fax number+4408456761401
    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 No
    D.2.5.1Orphan drug designation number
    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 MESILATE
    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 No
    D.2.5.1Orphan drug designation number
    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 MESILATE
    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 No
    D.2.5.1Orphan drug designation number
    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 MESILATE
    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.2.1.1.1Trade name Ifosfamide for injection 1g/vial
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare Corporation
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.2.1.1.1Trade name Etoposide 100mg HEXAL® concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderHexal AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.9.3Other 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.IMP: 6
    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 Etoposide 20 mg/ml Concentrate for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.9.3Other 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
    Relapsed or Refractory Osteosarcoma
    E.1.1.1Medical condition in easily understood language
    Osteosarcoma (a cancer in the bone) which is not responding to treatment or has 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
    To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) rate at 4 months (PFS-4m) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
    E.2.2Secondary objectives of the trial
    1. Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms
    2. Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS between the 2 treatment arms
    3. Compare differences in overall survival (OS) and OS rate at 1 year (OS-1y) between the 2 treatment arms
    4. Compare differences in objective response rate (ORR) at 4 months between the 2 treatment arms
    5. Compare differences in safety and tolerability between the 2 treatment arms
    6. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with ifosfamide and etoposide
    7. Compare differences in health-related quality of life (HRQoL) as assessed by using the the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module between the 2 treatment arms
    8. Assess the palatability and acceptability of the suspension formulation of lenvatinib in pediatric subjects receiving the suspension formulation in the study
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
    2. Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments.
    3. Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
    - Must be accurately measurable with a minimum size (by long axis) of 10 mm using computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be accurately measurable with a minimum size [by short axis] of 15 mm).
    - Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must have subsequently grown unequivocally to be deemed a target lesion.
    4. Aged 2 years to ≤25 years at the time of informed consent.
    5. Life expectancy of 12 weeks or more.
    6. Lansky play score ≥50% or Karnofsky Performance Status score ≥ 50%. Use Karnofsky for subjects ≥16 years of age and Lansky for subjects <16 years of age. Subjects who are unable to walk because of paralysis, but who are up in wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
    7. Adequate bone marrow function as evidenced by:
    a. absolute neutrophil count (ANC) ≥1.5×10^9/L. (subjects with bone marrow involvement should have ANC ≥0.8×10^9/L and leucocyte count ≥1×10^9/L).
    b. hemoglobin ≥8.0 g/dL (a hemoglobin of <8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before Cycle 1 Day 1).
    c. platelet count ≥100×10^9/L.
    8. Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5 unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range of intended use of anticoagulants.
    9. Adequate liver function as evidenced by:
    a. Bilirubin ≤1.5 times the upper limit of normal (ULN).
    b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN).
    10. Adequate renal function as evidenced by:
    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 within the protocol page 5, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be >70 mL/min/1.73 m2.
    b. Urine dipstick <2+ for proteinuria. Subjects who have ≥2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio test that should be Grade <2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible perform a 24-hour urine collection (children and adolescents ≤12 years of age must have ≤500 mg of protein/24 hours and subjects >12 years of age must have ≤1 g of protein/24 hours).
    c. No clinical evidence of nephrotic syndrome.
    11. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50% at baseline as determined by echocardiography.
    12. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:
    a. BP <95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1.
    Subjects >18 years of age should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1.
    13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue. Subjects must have recovered (to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per CTCAE v5.0) from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1.
    14. 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.
    15. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the investigator.
    E.4Principal exclusion criteria
    1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1.
    2. Subjects with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication at least 2 weeks before C1D1
    3. Active second malignancy within 2 years prior to enrollment
    4. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study.
    5. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.
    6. Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and etoposide, or their ingredients).
    7. Currently receiving any investigational drug or device in another clinical study or within 28 days prior to Cycle 1 Day 1.
    8. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).
    9. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.
    10. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
    11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to Cycle 1 Day 1.
    12. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy.
    13. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
    14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments.
    15. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by local authority.
    16. Active viral hepatitis (B or C) as demonstrated by positive serology. Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority.
    17. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ßhCG]) (human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG /hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of any study drug.
    18. Females of childbearing potential* who:
    - Do not agree to use a highly effective method of contraception for the entire study period and for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide discontinuation, ie:
    ◦ total abstinence (if it is their preferred and usual lifestyle)
    ◦ an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
    ◦ A contraceptive implant
    ◦ an oral contraceptive. Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing with study drug and throughout the study and for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide discontinuation .
    OR
    - Do not have a vasectomized partner with confirmed azoospermia.
    * All post pubertal females will be considered to be of childbearing potential unless they have early menopause (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3).
    19. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period and for 28 days after lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide). No sperm donation is allowed during the study period and for 28 days after lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide
    20. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per local prescribing information
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival rate at 4 months (PFS-4m rate) by IIR (independent imaging review) is defined as the percentage of subjects who are alive and without PD at 4 months from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-4m rate is estimated on the full analysis set for this study using the K-M method.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy analyses will be based primarily on the Full Analysis Set.
    All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date (ie, when the last subject has completed 18 cycles of treatment or discontinues before the end of Cycle 18, whichever occurs first), including the analysis of PFS-4m rate. Additional follow-up analysis will be based on the date of data cutoff for the additional follow-up analysis for OS or at the time of last subject last visit, whichever occurs later.
    E.5.2Secondary end point(s)
    1. Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage of subjects who are alive and without PD at 1 year from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-1y rate is estimated on the full analysis set for this study using the K-M method.
    2. Progression-free survival (PFS) by IIR is defined as the time from the date of randomization to the date of the first documentation of PD or death (whichever occurs first) as determined by IIR using RECIST 1.1.
    3. Overall survival (OS) is defined as the time from the date of randomization to 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 alive, or date of data cutoff, whichever occurs first. Overall survival rate at 1 year will be estimated.
    4. Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects who have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1 within the first 4 months.
    5. Safety will be assessed summarising the incidence of TEAEs and SAEs together with all other safety parameters.
    6. Assessment of population-based PK parameters of lenvatinib.
    7. Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer Module. Scores will be calculated for total generic score, total cancer score, each physical function subscale including physical health, psychosocial health, emotional function, social function, school/work function in the Generic Core Scales, and each subscales in the cancer module.
    8. Palatibility and acceptability of the suspension formulation of lenvatinib in subjects receiving the suspension formulation in the study will be assessed using the Palatability Questionnaire (see Appendix 5 within Protocol).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At 1 year
    2. From randomization every cycle until progression disease/death
    3. From randomization to death
    4. During 4 months up to complete response or partial response
    5. Throught the trial
    6. PK C1D1 postdose 0.5-4; C1D15 predose, postdose 0.5-4 and 6-10; C2D1 predose
    7. Baseline, C2D1, C3D1, W18, C8D1, C18D1
    8. C1D1
    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 No
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    ifosfamide and etoposide
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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
    Canada
    Finland
    France
    Germany
    Hong Kong
    Ireland
    Israel
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    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
    The definition of the end of the study is the date of the data cutoff for the final analysis or last subject/last visit, including discontinuation from the study for any reason, whichever occurs later.
    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 months6
    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: 41
    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: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 36
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 31
    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 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 47
    F.4.2.2In the whole clinical trial 72
    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)
    After participation in the trial, at discretion of investigator, patients may receive another anticancer agent
    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 Decision2020-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-21
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA