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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2019-003696-19
    Trial protocol
    		 FI   SE   ES   GB   AT   DE   FR   BE   IE   NL   IT   CZ  
    Global end of trial date
    17 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-G000-230
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04154189
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    European Knowledge Centre, Mosquito Way Hatfield, Hertfordshire, United Kingdom, AL10 9SN
    Public contact
    EMEA Medical Information, Eisai Ltd., +44 (0)208 600 1400, EUMedInfo@eisai.net
    Scientific contact
    EMEA Medical Information, Eisai Ltd., +44 (0)208 600 1400, EUMedInfo@eisai.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001119-PIP02-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) was superior to ifosfamide and etoposide alone (Arm B) in improving PFS based on IIR assessments (hereafter referred to as “per IIR”) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Mar 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    81
    EEA total number of subjects
    33
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    13
    Adolescents (12-17 years)
    47
    Adults (18-64 years)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 84 investigative sites in Austria, Australia, Belgium, Hong Kong, Korea, New Zealand, Singapore, Taiwan, Czech Republic, Finland, France, Israel, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, United Kingdom, Canada, and the United States.

    Pre-assignment
    Screening details
    		 A total of 99 subjects were screened, 18 failed screening. 81 subjects were enrolled and randomized, out of which 78 received the study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
    Arm description
    		 Subjects received lenvatinib 14 milligrams per square meter (mg/m^2), capsules, orally, once daily, plus ifosfamide 3000 milligrams per square meter per day (mg/m^2/day), intravenously and etoposide 100 mg/m^2/day, intravenously. Ifosfamide and etoposide were administered on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Lenvatinib was administered in continuous 21-day cycles. Treatment continued until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenvatinib 14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received ifosfamide 3000 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles.

    Arm title
    		 Treatment Arm B: Ifosfamide + Etoposide
    Arm description
    		 Subjects received ifosfamide 3000 mg/m^2/day, intravenously and etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Subjects who had PD per RECIST version (v) 1.1 were eligible for an optional lenvatinib treatment (14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first) plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who had PD per RECIST v1.1 were eligible for an optional lenvatinib treatment 14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received ifosfamide 3000 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles.

    Number of subjects in period 1
    		Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Started
    40
    41
    Treated (Safety Analysis Set)
    39
    39
    Optional Lenvatinib (Arm B only)
    0
    16
    Completed
    0
    0
    Not completed
    40
    41
         Consent withdrawn by subject
    4
    6
         Death
    25
    25
         Other
    11
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received lenvatinib 14 milligrams per square meter (mg/m^2), capsules, orally, once daily, plus ifosfamide 3000 milligrams per square meter per day (mg/m^2/day), intravenously and etoposide 100 mg/m^2/day, intravenously. Ifosfamide and etoposide were administered on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Lenvatinib was administered in continuous 21-day cycles. Treatment continued until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first.

    Reporting group title
    Treatment Arm B: Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received ifosfamide 3000 mg/m^2/day, intravenously and etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Subjects who had PD per RECIST version (v) 1.1 were eligible for an optional lenvatinib treatment (14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first) plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.

    Reporting group values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide Total
    Number of subjects
    		 40 41 81
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 4 9 13
        Adolescents (12-17 years)
    		 26 21 47
        Adults (18-64 years)
    		 10 11 21
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.6 ± 3.76 14.3 ± 4.16 -
    Sex: Female, Male
    Units: subjects
        Female
    		 15 20 35
        Male
    		 25 21 46
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 3 5
        Not Hispanic or Latino
    		 38 33 71
        Unknown or Not Reported
    		 0 5 5
    Race
    Units: Subjects
        White
    		 24 26 50
        Black or African American
    		 1 1 2
        Asian
    		 13 7 20
        American Indian or Alaskan Native
    		 0 1 1
        Other
    		 2 4 6
        Missing
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received lenvatinib 14 milligrams per square meter (mg/m^2), capsules, orally, once daily, plus ifosfamide 3000 milligrams per square meter per day (mg/m^2/day), intravenously and etoposide 100 mg/m^2/day, intravenously. Ifosfamide and etoposide were administered on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Lenvatinib was administered in continuous 21-day cycles. Treatment continued until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first.

    Reporting group title
    Treatment Arm B: Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received ifosfamide 3000 mg/m^2/day, intravenously and etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Subjects who had PD per RECIST version (v) 1.1 were eligible for an optional lenvatinib treatment (14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first) plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.

    Subject analysis set title
    Subjects from Treatment Arm A and B: Lenvatinib Suspension
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who were unable to swallow capsules received lenvatinib as an extemporaneous suspension prepared from the capsule. Subjects received lenvatinib 14 mg/m^2 once daily in continuous 21-day cycles until PD, development of unacceptable toxicity, subject request, withdrawal of consent, or discontinuation of study by the sponsor.

    Primary: Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment

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    End point title
    		 Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment
    End point description
    PFS as assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of PD or date of death (whichever occurred first), as determined using RECIST v1.1. PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Primary
    End point timeframe
    From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first (up to 20.5 months)
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: months
        median (confidence interval 95%)
    6.5 (5.7 to 8.2)
    5.5 (2.9 to 6.5)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Statistical analysis description
    Hazard ratio was based on Cox Proportional Hazard Model including treatment group as a factor and stratified by Age (less than [<]18 years, greater than or equal to [>=]18 years) in interactive response technology (IRT).
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0396 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.08
    Notes
    [1] - One-sided P value

    Secondary: Percentage of Subjects with PFS at Month 4 (PFS-4m Rate) by IIR Assessment

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    End point title
    		 Percentage of Subjects with PFS at Month 4 (PFS-4m Rate) by IIR Assessment
    End point description
    PFS rate at 4 months as assessed by IIR was defined as the percentage of subjects who were alive and without PD at 4 months from the randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS-4m rate, and 2-sided 95% confidence intervals (CIs) were calculated using Kaplan-Meier product-limit method and Greenwood Formula. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Month 4
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: percentage of subjects
        number (confidence interval 95%)
    76.3 (59.3 to 86.9)
    66.0 (47.7 to 79.2)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.1683 [3]
    Method
    		 Kaplan-Meier Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    10.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6
         upper limit
    		 31.1
    Notes
    [2] - Difference in PFS rates, and 2-sided 95% CIs: CI and p-value constructed using the difference of the 2 Kaplan-Meier PFS rates (4 months) and the 2 corresponding Greenwood standard errors.
    [3] - One-sided P value

    Secondary: Percentage of Subjects with PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment

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    End point title
    		 Percentage of Subjects with PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment
    End point description
    PFS-1y rate as assessed by IIR was defined as the percentage of subjects who were alive and without PD at 1 year from randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS-1y rate was estimated using Kaplan-Meier method. FAS included all randomized subjects regardless of the treatment actually received. "99999" signifies number and 95% confidence interval data could not be estimated because all subjects had an event or were censored before Month 12.
    End point type
    Secondary
    End point timeframe
    Month 12 or 1 Year
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: percentage of subjects
        number (confidence interval 95%)
    99999 (99999 to 99999)
    14.9 (1.1 to 44.5)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of death from any cause (up to approximately 37.1 months)
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: months
        median (confidence interval 95%)
    12.4 (10.4 to 19.8)
    17.2 (11.1 to 22.3)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Statistical analysis description
    Hazard ratio was based on a Cox Proportional Hazard Model including treatment group as a factor and stratified by Age (<18 years, >=18 years) in IRT. Efron method was used for ties.
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3924
    Method
    		 Stratified Log-rank One-sided Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.62

    Secondary: Percentage of Subjects with Overall Survival at 1 Year or Month 12 (OS-1y)

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    End point title
    		 Percentage of Subjects with Overall Survival at 1 Year or Month 12 (OS-1y)
    End point description
    OS-1y was defined as the time from the date of randomization to the date of death from any cause assessed up to 1 year. OS rate and 2-sided 95% CI were calculated using Kaplan Meier product-limit method and Greenwood Formula. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Month 12 or 1 Year
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: percentage of subjects
        number (confidence interval 95%)
    49.2 (28.5 to 67.0)
    72.1 (54.2 to 83.9)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0352 [5]
    Method
    		 Kaplan Meier Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -22.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.6
         upper limit
    		 1.9
    Notes
    [4] - Difference and 95% CI: difference of 2 Kaplan-Meier OS-1y rates and corresponding Greenwood standard errors.
    [5] - One-sided P value

    Secondary: Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment

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    End point title
    		 Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment
    End point description
    ORR-4m was defined as the percentage of subjects with best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST v1.1 within the first 4 months. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% confidence interval (CI) of ORR was calculated using the method of Clopper and Pearson. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Month 4
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: percentage of subjects
        number (confidence interval 95%)
    15.0 (5.7 to 29.8)
    7.3 (1.5 to 19.9)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 22.3
    Notes
    [6] - Difference calculated as Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide minus Treatment Arm B: Ifosfamide + Etoposide. 2-sided 95% CI: Miettinen-Nurminen (Score) confidence limits, stratified by randomization stratification factor age (<18 and >=18 years).

    Secondary: ORR by IIR Assessment

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    End point title
    		 ORR by IIR Assessment
    End point description
    ORR by IIR was defined as the percentage of subjects with best overall response of CR or PR determined using RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% CI of ORR was calculated using the method of Clopper and Pearson. FAS included all randomized subjects regardless of the treatment actually received.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of the first documentation of CR or PR, whichever occurred first (up to approximately 20.5 months)
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    40
    41
    Units: percentage of subjects
        number (confidence interval 95%)
    15.0 (5.7 to 29.8)
    9.8 (2.7 to 23.1)
    Statistical analysis title
    		 Treatment Arm A versus Treatment Arm B
    Comparison groups
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide v Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 20
    Notes
    [7] - Difference calculated as Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide minus Treatment Arm B: Ifosfamide + Etoposide. 2-sided 95% CI: Miettinen-Nurminen (Score) confidence limits, stratified by randomization stratification factor age (<18 and >=18 years).

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to pretreatment state, when AE was continuous. SAE was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria. Safety Analysis Set included subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after the last dose of study drug (up to 40.8 months)
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    39
    39
    Units: subjects
        Subjects with TEAEs
    38
    39
        Subjects with TESAEs
    30
    20
    No statistical analyses for this end point

    Secondary: Treatment Arm A: Plasma Concentration of Lenvatinib

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    End point title
    		 Treatment Arm A: Plasma Concentration of Lenvatinib [8]
    End point description
    Plasma concentration of lenvatinib in subjects from Treatment Arm A (Lenvatinib + Ifosfamide + Etoposide) at different time points were reported. As planned, data for this endpoint was analyzed for treatment arm A only. Lenvatinib concentration in plasma was quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Population Pharmacokinetic (PK) Analysis Set included those subjects who received at least 1 dose of lenvatinib and had documented dose administration history and measurable plasma concentrations of lenvatinib. Here "number of subjects analyzed" signifies subjects who were evaluable for this endpoint. Here "n" signifies subjects who were evaluable for this endpoint at given time points.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: Pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: Pre-dose (each Cycle length = 21 days)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned for treatment Arm A only.
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
    Number of subjects analysed
    37
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1, Day 1: 0.5-4 hours post-dose (n=37)
    147.9 ± 194.61
        Cycle 1, Day 1: 6-10 hours post-dose (n=35)
    217.8 ± 99.54
        Cycle 1, Day 15: Pre-dose (n=36)
    70.7 ± 43.48
        Cycle 1, Day 15: 0.5-4 hours post-dose (n=37)
    222.3 ± 203.07
        Cycle 1, Day 15: 6-10 hours post-dose (n=35)
    310.9 ± 106.79
        Cycle 2, Day 1: Pre-dose (n=37)
    70.2 ± 67.95
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4

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    End point title
    		 Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4
    End point description
    HRQoL: PedsQL 3.0 Cancer Module Scale measured pediatric cancer-specific HRQoL. It included assessment of 8 dimensions: pain and hurt (2 items), nausea (5 items), procedural anxiety (3 items), treatment anxiety (3 items), worry (3 items), cognitive problems (3 items - toddlers [aged 2-4], 4 items - young children [aged 5-7]; 5 items for children aged >=8 years, adults), perceived physical appearance (3 items), communication (3 items). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Cancer Module total score: sum of all items divided by the number of items answered on all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL. HRQoL Analysis Set included all subjects who had received at least 1 dose of study drug and had completed at least 1 postbaseline PRO assessment. "Number of subjects analyzed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 4
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    16
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    2.66 ± 9.989
    2.08 ± 6.736
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4

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    End point title
    		 Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4
    End point description
    Health-Related Quality of Life (HRQoL): PedsQL 4.0 Generic Core Scale is a multidimensional scale. It included assessment of 4 dimensions: physical functioning (8 items), emotional functioning (8 items), social functioning (8 items), and school functioning (5 items - children greater than or equal to [>=] 5 years, adults; 3 items - toddlers [aged 2-4 years]). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Generic Core Scale total score: sum of all the items divided by the number of items answered across all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL. HRQoL Analysis Set included all subjects who had received at least 1 dose of study drug and had completed at least 1 postbaseline patient-reported outcome (PRO) assessment. Here "number of subjects analyzed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 4
    End point values
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide
    Number of subjects analysed
    15
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    2.61 ± 17.568
    2.65 ± 4.128
    No statistical analyses for this end point

    Secondary: Number of Subjects Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib

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    End point title
    		 Number of Subjects Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib
    End point description
    Palatability and acceptability of lenvatinib oral suspension formulation was assessed using the Palatability Questionnaire. In questionnaire, subjects were asked to answer palatability and acceptability of lenvatinib suspension considering elements: taste, appearance, smell, how does it feel in the mouth and overall acceptability in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. In this endpoint, number of subjects were reported per their overall palatability and acceptability responses. Palatability and acceptability analysis set included all subjects who received oral suspension of lenvatinib in Treatment Arm A and who received an optional lenvatinib suspension in Treatment Arm B and who answered at least 1 question in palatability questionnaire. As planned, combined data for Lenvatinib from Treatment Arm A and B was reported for this endpoint. "Number of subjects analyzed" signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Cycle length = 21 days)
    End point values
    		 Subjects from Treatment Arm A and B: Lenvatinib Suspension
    Number of subjects analysed
    5
    Units: subjects
        Super Bad
    0
        Really Bad
    0
        Bad
    0
        May be Good or May be Bad
    2
        Good
    2
        Really Good
    0
        Super Good
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 30 days after the last dose of study drug (up to 40.8 months)
    Adverse event reporting additional description
    Treatment Arm B safety data for Ifosfamide + Etoposide to Lenvatinib (optional) were reported separately. Deaths in Subject Disposition module versus Adverse Events module are different because deaths in Subject Disposition module are based on Full Analysis Set while deaths in Adverse Events module based on Safety Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received lenvatinib 14 mg/m^2, capsules, orally, once daily, plus ifosfamide 3000 mg/m^2/day, intravenously and etoposide 100 mg/m^2/day, intravenously. Ifosfamide and etoposide were administered on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Lenvatinib was administered in continuous 21-day cycles. Treatment continued until PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first.

    Reporting group title
    Treatment Arm B: Ifosfamide + Etoposide
    Reporting group description
    		 Subjects received ifosfamide 3000 mg/m^2/day, intravenously and etoposide 100 mg/m^2/day, intravenously on Days 1 to 3 of each 21-day cycle for up to 5 cycles. Subjects who had PD per RECIST v1.1 were eligible for an optional lenvatinib treatment (14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first) plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.

    Reporting group title
    Treatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)
    Reporting group description
    		 Eligible subjects from Treatment Arm B: Ifosfamide+Etoposide who had PD per RECIST v1.1 received an optional lenvatinib treatment (14 mg/m^2, capsules, orally, once daily in continuous 21-day cycles until next PD, development of unacceptable toxicity, subject choice, withdrawal of consent or discontinuation of study by the sponsor, whichever occurred first) plus any remaining cycles of chemotherapy if 5 cycles were not completed prior to PD.

    Serious adverse events
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide Treatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 39 (76.92%)
    20 / 39 (51.28%)
    10 / 16 (62.50%)
         number of deaths (all causes)
    24
    25
    12
         number of deaths resulting from adverse events
    5
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to heart
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site ulcer
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 39 (15.38%)
    2 / 39 (5.13%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    5 / 7
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    7 / 39 (17.95%)
    1 / 39 (2.56%)
    4 / 16 (25.00%)
         occurrences causally related to treatment / all
    8 / 12
    0 / 1
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device extrusion
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant spinal cord compression
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    15 / 39 (38.46%)
    7 / 39 (17.95%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    26 / 27
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular injury
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide Treatment Arm B: Ifosfamide + Etoposide Treatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 39 (97.44%)
    39 / 39 (100.00%)
    16 / 16 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    4
    1
    0
    Tumour pain
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    2
    3
    0
    Cancer pain
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Tumour haemorrhage
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 39 (41.03%)
    0 / 39 (0.00%)
    6 / 16 (37.50%)
         occurrences all number
    39
    0
    8
    Hypotension
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    2
    2
    0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    0
    1
    Fatigue
         subjects affected / exposed
    13 / 39 (33.33%)
    9 / 39 (23.08%)
    4 / 16 (25.00%)
         occurrences all number
    28
    11
    8
    Generalised oedema
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    2
    3
    0
    Impaired healing
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    Oedema
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    12 / 39 (30.77%)
    5 / 39 (12.82%)
    2 / 16 (12.50%)
         occurrences all number
    16
    6
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    1
    Early satiety
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Infusion site bruising
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Infusion site swelling
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    12 / 39 (30.77%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    23
    2
    0
    Dyspnoea
         subjects affected / exposed
    4 / 39 (10.26%)
    3 / 39 (7.69%)
    1 / 16 (6.25%)
         occurrences all number
    6
    3
    1
    Dysphonia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    0
    1
    Cough
         subjects affected / exposed
    7 / 39 (17.95%)
    5 / 39 (12.82%)
    1 / 16 (6.25%)
         occurrences all number
    7
    7
    2
    Hypoxia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    4
    1
    2
    Pleural effusion
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumothorax
         subjects affected / exposed
    8 / 39 (20.51%)
    1 / 39 (2.56%)
    3 / 16 (18.75%)
         occurrences all number
    19
    1
    7
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    2 / 16 (12.50%)
         occurrences all number
    4
    1
    4
    Anxiety
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    1
    Confusional state
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 39 (10.26%)
    1 / 16 (6.25%)
         occurrences all number
    6
    5
    1
    Amylase increased
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 39 (17.95%)
    5 / 39 (12.82%)
    3 / 16 (18.75%)
         occurrences all number
    25
    11
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 39 (17.95%)
    4 / 39 (10.26%)
    1 / 16 (6.25%)
         occurrences all number
    27
    11
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 39 (7.69%)
    0 / 16 (0.00%)
         occurrences all number
    0
    7
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    20
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 39 (10.26%)
    1 / 16 (6.25%)
         occurrences all number
    1
    4
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    5 / 39 (12.82%)
    0 / 39 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    6
    0
    3
    Blood creatinine increased
         subjects affected / exposed
    6 / 39 (15.38%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    9
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    5
    0
    1
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 39 (5.13%)
    2 / 16 (12.50%)
         occurrences all number
    18
    11
    2
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    15 / 39 (38.46%)
    13 / 39 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    79
    38
    1
    Platelet count decreased
         subjects affected / exposed
    23 / 39 (58.97%)
    17 / 39 (43.59%)
    3 / 16 (18.75%)
         occurrences all number
    209
    57
    12
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 39 (12.82%)
    7 / 39 (17.95%)
    1 / 16 (6.25%)
         occurrences all number
    28
    32
    4
    Weight decreased
         subjects affected / exposed
    8 / 39 (20.51%)
    4 / 39 (10.26%)
    5 / 16 (31.25%)
         occurrences all number
    13
    4
    10
    Weight increased
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    5
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    5 / 39 (12.82%)
    13 / 39 (33.33%)
    2 / 16 (12.50%)
         occurrences all number
    38
    47
    8
    Blood magnesium decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    Blood pressure increased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Haemoglobin increased
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Procedural pain
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    6
    0
    1
    Muscle rupture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 39 (7.69%)
    0 / 16 (0.00%)
         occurrences all number
    3
    3
    0
    Angina pectoris
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Tremor
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    4
    1
    0
    Headache
         subjects affected / exposed
    14 / 39 (35.90%)
    6 / 39 (15.38%)
    5 / 16 (31.25%)
         occurrences all number
    20
    6
    28
    Toxic encephalopathy
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Dizziness
         subjects affected / exposed
    7 / 39 (17.95%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    8
    4
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Aphasia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 39 (71.79%)
    27 / 39 (69.23%)
    2 / 16 (12.50%)
         occurrences all number
    180
    102
    10
    Leukopenia
         subjects affected / exposed
    5 / 39 (12.82%)
    4 / 39 (10.26%)
    2 / 16 (12.50%)
         occurrences all number
    53
    27
    2
    Lymphopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 39 (10.26%)
    0 / 16 (0.00%)
         occurrences all number
    17
    26
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 39 (10.26%)
    0 / 16 (0.00%)
         occurrences all number
    1
    4
    0
    Neutropenia
         subjects affected / exposed
    9 / 39 (23.08%)
    9 / 39 (23.08%)
    3 / 16 (18.75%)
         occurrences all number
    39
    20
    3
    Thrombocytopenia
         subjects affected / exposed
    6 / 39 (15.38%)
    5 / 39 (12.82%)
    0 / 16 (0.00%)
         occurrences all number
    50
    12
    0
    Pancytopenia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Dry eye
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 39 (17.95%)
    3 / 39 (7.69%)
    3 / 16 (18.75%)
         occurrences all number
    18
    4
    12
    Abdominal pain upper
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 39 (2.56%)
    2 / 16 (12.50%)
         occurrences all number
    6
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    0
    1
    Diarrhoea
         subjects affected / exposed
    14 / 39 (35.90%)
    2 / 39 (5.13%)
    4 / 16 (25.00%)
         occurrences all number
    20
    2
    8
    Gastritis
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Constipation
         subjects affected / exposed
    14 / 39 (35.90%)
    5 / 39 (12.82%)
    4 / 16 (25.00%)
         occurrences all number
    20
    6
    6
    Nausea
         subjects affected / exposed
    23 / 39 (58.97%)
    16 / 39 (41.03%)
    5 / 16 (31.25%)
         occurrences all number
    56
    30
    6
    Mouth ulceration
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 39 (5.13%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    1
    Proctalgia
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    6
    1
    0
    Stomatitis
         subjects affected / exposed
    10 / 39 (25.64%)
    6 / 39 (15.38%)
    1 / 16 (6.25%)
         occurrences all number
    14
    7
    3
    Vomiting
         subjects affected / exposed
    19 / 39 (48.72%)
    11 / 39 (28.21%)
    5 / 16 (31.25%)
         occurrences all number
    44
    17
    12
    Toothache
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    2
    2
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Duodenitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    5
    0
    1
    Cholecystitis acute
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Dry skin
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    6
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 39 (12.82%)
    0 / 39 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    11
    0
    2
    Rash
         subjects affected / exposed
    8 / 39 (20.51%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    13
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    3
    1
    0
    Urticaria
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    7
    1
    0
    Pain of skin
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hair colour changes
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Skin plaque
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    1
    Glycosuria
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 39 (10.26%)
    0 / 16 (0.00%)
         occurrences all number
    2
    7
    0
    Haematuria
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 39 (5.13%)
    0 / 16 (0.00%)
         occurrences all number
    11
    2
    0
    Pollakiuria
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    1
    Proteinuria
         subjects affected / exposed
    21 / 39 (53.85%)
    5 / 39 (12.82%)
    6 / 16 (37.50%)
         occurrences all number
    79
    7
    21
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    Hypothyroidism
         subjects affected / exposed
    35 / 39 (89.74%)
    0 / 39 (0.00%)
    8 / 16 (50.00%)
         occurrences all number
    52
    0
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 39 (38.46%)
    6 / 39 (15.38%)
    4 / 16 (25.00%)
         occurrences all number
    22
    7
    6
    Arthralgia
         subjects affected / exposed
    11 / 39 (28.21%)
    6 / 39 (15.38%)
    3 / 16 (18.75%)
         occurrences all number
    24
    6
    4
    Bone pain
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    5
    1
    1
    Muscular weakness
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    4
    1
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 39 (12.82%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    6
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 39 (2.56%)
    1 / 16 (6.25%)
         occurrences all number
    6
    3
    1
    Myalgia
         subjects affected / exposed
    7 / 39 (17.95%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    15
    0
    0
    Neck pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    9 / 39 (23.08%)
    5 / 39 (12.82%)
    6 / 16 (37.50%)
         occurrences all number
    14
    5
    21
    Trismus
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    8 / 39 (20.51%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    9
    1
    0
    Catheter site infection
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Wound infection
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Rash pustular
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinitis
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Herpes zoster
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Paronychia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    3
    2
    0
    Overgrowth bacterial
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 39 (5.13%)
    1 / 16 (6.25%)
         occurrences all number
    6
    2
    1
    Dehydration
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    3
    1
    0
    Hypervolaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    0
    0
    Decreased appetite
         subjects affected / exposed
    8 / 39 (20.51%)
    5 / 39 (12.82%)
    5 / 16 (31.25%)
         occurrences all number
    10
    6
    10
    Hypocalcaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 39 (10.26%)
    1 / 16 (6.25%)
         occurrences all number
    8
    9
    1
    Hypokalaemia
         subjects affected / exposed
    5 / 39 (12.82%)
    6 / 39 (15.38%)
    1 / 16 (6.25%)
         occurrences all number
    19
    13
    1
    Hypomagnesaemia
         subjects affected / exposed
    6 / 39 (15.38%)
    3 / 39 (7.69%)
    2 / 16 (12.50%)
         occurrences all number
    17
    5
    2
    Hypophosphataemia
         subjects affected / exposed
    6 / 39 (15.38%)
    7 / 39 (17.95%)
    0 / 16 (0.00%)
         occurrences all number
    26
    9
    0
    Hyponatraemia
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 39 (7.69%)
    3 / 16 (18.75%)
         occurrences all number
    4
    3
    3
    Hypercalcaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 39 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2020
    Amendment 01: • Revised definition of adequacy of bone marrow function in inclusion criterion no. 7 Per health authority request, added exclusion criterion no. 20 on contraindication to study drugs • Per health authority request, subjects who received other anticancer therapy, except as specified in the protocol, were required to discontinue study treatment • Optional pharmacodynamic blood sample collection moved from C1D8 to C1D15 to lessen subject burden.
    10 Sep 2020
    Amendment 02: • Revised primary objective and endpoint to PFS, and revised PFS rate at 4 months (PFS-4m) to be a secondary objective and endpoint; analyses updated accordingly • Added ORR as a secondary objective and endpoint • Added Exploratory objective and analysis of the difference in lesion removal between the 2 study arms • Updated and clarified definition for the Randomization Phase • Clarified tumor assessment requirements at the Off- Treatment visit and during Follow-up • Added option for subjects in Arm B to cross over to treatment with lenvatinib in Arm A, provided certain eligibility criteria were met • Updated inclusion criteria nos. 2, 3, 8, 11 and 13 and exclusion criteria nos. 17 and 19 • Added inclusion criterion no. 14: Prior treatment with lenvatinib was not permitted • PK and pharmacodynamic assessments updated per health authorities • Objectives and Endpoints were updated to specify review based on independent and investigator assessment • Added dental examinations to the study assessments • Added sections for the management of fistula formation, GI perforation, and QT prolongation.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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