Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

Sponsor

Eisai Limited (Industry)

Overall Status

Completed

CT.gov ID

NCT02432274

Collaborator

Merck Sharp & Dohme LLC (Industry)

117

Enrollment

Locations

Arms

90.5

Actual Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib as single-agent, and in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed solid malignancies including differentiated thyroid carcinoma (single agent lenvatinib) and osteosarcoma (single agent and combination lenvatinib).

Condition or Disease	Intervention/Treatment	Phase
Tumors Solid Malignant Tumors Osteosarcoma Differentiated Thyroid Cancer (DTC)	Drug: Lenvatinib Drug: Lenvatinib Drug: Lenvatinib Drug: Lenvatinib Drug: Lenvatinib Drug: Ifosfamide Drug: Etoposide Drug: Ifosfamide Drug: Etoposide	Phase 1/Phase 2

Detailed Description

The study consists of 5 cohorts:

Cohort 1 (Single-Agent Dose-Finding) dose-escalation to find the recommended dose (RD) of lenvatinib using time-to-event continual reassessment method (TiTE-CRM) in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will enroll in parallel.

Cohort 2 (Single-Agent Expansion) will evaluate the efficacy of lenvatinib at the RD in children, adolescents, and young adults with

131 iodine-refractory differentiated thyroid cancer (DTC) [Cohort 2A] or
Relapsed or refractory osteosarcoma [Cohort 2B]

Cohort 3A (Combination Dose-Finding) will determine the RD of lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.

Cohort 3B (Combination Expansion) will evaluate the efficacy of lenvatinib at the RD from Cohort 3A in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Participants with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced progressive disease will also be candidates for enrollment in Cohort 3B.

Lenvatinib will be provided as hard capsules containing 1, 4, or 10 mg lenvatinib. Lenvatinib capsules should be dissolved in water or apple juice for those who are unable to swallow capsules.

Study Design

Study Type:

Interventional

Actual Enrollment :

117 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

Actual Study Start Date :

Dec 29, 2014

Actual Primary Completion Date :

Jul 18, 2019

Actual Study Completion Date :

Jul 14, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Single-Agent Dose-Finding Children and adolescents with relapsed or refractory solid malignant tumors.	Drug: Lenvatinib Cohort 1: Lenvatinib will be administered orally, once daily on Days 1 to 28 of each 28-day cycle at a starting dose of 11 mg/m2. Dose can be de-escalated to 9 mg/m2 or escalated to 14 and 17 mg/m2. Other Names: E7080, lenvatinib
Experimental: Cohort 2A: Single-agent Expansion (DTC) Children and adolescents with 131 iodine-refractory DTC.	Drug: Lenvatinib Cohort 2A: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle. Other Names: E7080, lenvatinib
Experimental: Cohort 2B: Single-agent Expansion (Osteosarcoma) Participants with relapsed or refractory osteosarcoma.	Drug: Lenvatinib Cohort 2B: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle. Other Names: E7080, lenvatinib
Experimental: Cohort 3A: Combination Dose-finding Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.	Drug: Lenvatinib Cohort 3A: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at 20% lower than RD determined in Cohort 1 (starting dose). Lenvatinib dose can be escalated to the RD from Cohort 1 or de-escalated to 40 and 60% lower than the RD from Cohort 1. Other Names: E7080, lenvatinib Drug: Ifosfamide Ifosfamide 3000 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Ifosfamide dose can be de-escalated to 2400 mg/m2/day and 1800 mg/m2/day. Drug: Etoposide Etoposide 100 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Etoposide dose can be de-escalated to 80 mg/m2/day and 60 mg/m2/day.
Experimental: Cohort 3B: Combination Expansion Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.	Drug: Lenvatinib Cohort 3B: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at the RD as determined in Cohort 3A. Other Names: E7080, lenvatinib Drug: Ifosfamide Ifosfamide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Drug: Etoposide Etoposide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Outcome Measures

Primary Outcome Measures

Cohort 1: Recommended Dose (RD) of Lenvatinib [Cycle 1 (28 days)]
RD was defined as the dose that had a dose limiting toxicity (DLT) rate closest to the targeted 20% rate. DLT was an adverse drug reaction and was assessed according to common terminology criteria for adverse events (CTCAE) version (v) 4.03 defined as 1) Grade 4 neutropenia for greater than or equal to (>=) 7 days, 2) Grade >=3 thrombocytopenia with bleeding, or lasting greater than (>) 7 days, 3) Grade >=3 febrile neutropenia, 4) Next course of chemotherapy delayed for >=7 days, 5) Grade >=3 non-hematologic toxicity persisting >7 days optimal supportive care, 6) Grade 4 hypertension, confirmed systolic or diastolic blood pressure >25 millimeters of mercury (mmHg) above the 95th percentile for age, or an elevated diastolic blood pressure (that is, >95th percentile for age) not controlled by a single antihypertensive medication within 14 days of use, 7) Grade 3 proteinuria, 8) Any recurrent Grade 2 non-hematological toxicity requiring >=2 interruption and dose reductions.
Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR) [From date of first dose of study drug until first documentation of PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)]
OR was defined as participants with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for >4 weeks) recorded from the start of the treatment until PD or death whichever occurred first. CR was 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 <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Cohort 2A: Number of Participants With Best Overall Response (BOR) [From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)]
BOR was defined as the best response of CR or PR for >4 weeks or SD for >=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4 [At Month 4]
Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of participants who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: >= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD.
Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide [Cycle 1 (21 days)]
RD of lenvatinib when given in combination with ifosfamide and etoposide was defined as dose that resulted in no more than 1 DLT per 6 participants,or hematologic DLT in 1 participant and nonhematologic DLT in another participant per 6 participants,upon repeating same dose level.DLT was adverse drug reaction and assessed per CTCAE v4.03 defined as 1)Grade 4 neutropenia for >=10 days,2)Grade >=3 thrombocytopenia with bleeding,or lasting >=10 days,3)Grade >=3 febrile neutropenia lasting >=7 days,4)Next course of chemotherapy delayed for >=7 days,5)Grade >=3 nonhematologic toxicity persisting >7 days despite optimal supportive care,6)Grade 4 hypertension,confirmed systolic or diastolic blood pressure >25 mmHg above 95th percentile for age,or elevated diastolic blood pressure(>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7)Grade 3 proteinuria,8)Any recurrent Grade 2 nonhematological toxicity requiring >=2 interruption and dose reductions.

Secondary Outcome Measures

Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR) [From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
BOR: best response of CR or PR for >4 weeks or SD for >=7 weeks from first dose, recorded from start of treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have reduction in their short axis <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Not evaluable (NE) means BOR of NE or SD of <7 weeks duration. Unknown means no data were available on the case report form.
Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR) [From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
ORR was defined as the percentage of participants with a BOR of CR or PR for >4 weeks or SD for >=7 weeks as assessed by investigator based on RECIST v1.1, recorded from start of study treatment until PD or death whichever occurred first. CR was 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 <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. 95% CI of the ORR were calculated according to Clopper and Pearson method.
Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR) [First documentation of CR/PR until first documentation of PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
DOR was defined as time in months from the first documentation confirmed CR or PR until the first documentation of confirmed PD as assessed by investigator based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. 95% CI for the median were calculated according to Brookmeyer and Crowley method.
Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control [From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
Participants were defined as having disease control if they had a BOR of CR or PR for >4 weeks, or SD (minimum duration from first dose to SD >=7 weeks) or if participants had a BOR of CR or Non-CR/Non-PD (minimum duration from first dose to Non-CR/Non-PD >=7 weeks) per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest SOD. Non-CR/Non-PD: persistence of 1 or more non-target lesions, maintenance of tumor marker level above the normal limits.
Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit [From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
Participants were defined as having clinical benefit if they had a BOR of CR or PR for >4 weeks or durable SD (lasting >=23 weeks) or if participants had a BOR of CR or durable Non-CR/Non-PD (lasting >=23 weeks) as per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. Non-CR/Non-PD:persistence of 1 or more non-target lesions and maintenance of tumor marker level above the normal limits.
Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS) [From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
PFS was defined as the time (in months) from the date of first dose of study drug to the date of first documentation of PD or date of death, whichever occurred first, based on RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP) [From first dose of study drug until PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
TTP was defined as the time from the date of first dose of study drug to the date of first documentation of PD based on RECIST 1.1. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS) [From first dose of study drug until death (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
OS was defined as the time from the date of the first dose of study drug until the date of death from any cause. Participants who are lost to follow-up and those who are alive at the date of data cutoff were censored at the date the participant was last known to be alive (or the data cutoff date). 95% CI of median were calculated according to Brookmeyer and Crowley method.
Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
Number of participants with TEAEs (serious and non-serious adverse events) and SAEs were reported based on their safety assessments of hematology, clinical chemistry, proximal tibial growth, fecal occult blood, physical examinations, regular measurement of vital signs and electrocardiogram parameter values.
Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Most Frequent Treatment-emergent Adverse Events (TEAEs) Related to Lenvatinib Exposure [First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)]
TEAEs (serious and non-serious), those occurred most frequently have been reported in this outcome measure. "Palmar-plantar E syndrome" refers to Palmar-plantar erythrodysaesthesia syndrome.
Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib [Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose]
Duration of each cycle for Cohorts 1, 2A, 2B is 28 days. Duration of each cycle for Cohorts 3A, 3B is 21 days.
Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level [Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1 (Duration of each cycle=21 days)]
Serum biomarkers included Fibroblast Growth Factor (FGF) 19, FGF 21, Vascular Endothelial Growth Factor (VEGF). In this outcome measure, percent change from baseline in serum biomarkers level per "PFS-4, Yes" and "PFS-4, No" have been reported. As per assessment of investigator based on RECIST v1.1, "PFS-4, Yes"= participants evaluable for PFS-4 month and alive and without PD at 4 months from the first dose, "PFS-4, No"=participants evaluable for PFS-4 month and not alive or with PD at 4 months from the first dose.
Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Categorized Based on Overall Acceptability Questionnaire Responses for Suspension of Lenvatinib [Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B)]
In acceptability questionnaire, participants were asked to answer the overall acceptability of lenvatinib suspension considering the following elements: taste, appearance, smell and how does it feel in the mouth. Overall acceptability was answered in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. Overall acceptability was the overall acceptance for taste, appearance, smell, and the feeling in mouth. In this measure, number of participants have been reported per their overall acceptability responses.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 25 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of solid malignant tumor.
Cohort 1: Any solid malignant tumor.
Cohort 2A: Differentiated Thyroid Cancer (DTC) with one of the following histological subtypes:

Papillary thyroid cancer (PTC). i.a) Follicular variant. i.b) Other variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hurthle cell variant of papillary carcinoma, or poorly differentiated carcinomas).

Follicular thyroid cancer (FTC). ii.a) Hurthle cell. ii.b) Clear cell. ii.c) Insular.

Cohort 2B, 3A, and 3B: Relapsed or refractory osteosarcoma.

Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer therapy with no available curative options. (Note: Osteosarcoma participants must be in first or subsequent relapse [greater than or equal to first relapse]). Only the osteosarcoma participants enrolled to Cohorts 3A and 3B must be deemed candidates for ifosfamide and etoposide chemotherapy).
Evaluable or measurable disease that meets the following criteria:
Participants must have evaluable or measurable disease based on RECIST 1.1 using computed tomography (CT)/magnetic resonance imaging (MRI).
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must have subsequently grown unequivocally to be deemed a target lesion.
DTC participants must be 131 iodine-refractory/ relapsed as defined by at least one of the following:
One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; or
One or more evaluable or measurable lesions that have progressed based on RECIST 1.1, within 12 months of 131 iodine therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These participants must not be eligible for possible curative surgery; or
Cumulative activity of 131 iodine greater than 400 millicuries (mCi) or 14.8 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
Participants with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone (TSH) should not be elevated (TSH should be less than or equal to 5.50 milliunits per liter (mU/L)). When tolerated by the participant, thyroxine dose should be changed to achieve TSH suppression (TSH less than 0.50 mU/L).
Participants with known central nervous system (CNS) primary tumors or metastases who have completed brain therapy (such as radiotherapy, stereotactic radiosurgery, or surgical resection) and have remained clinically stable, asymptomatic, and off of steroids for 2 weeks prior to Cycle 1 Day 1 will be eligible.
Male or female participants age 2 years to less than18 years and less than or equal to 25 years for osteosarcoma subjects at the time of informed consent.
Lansky play score greater than or equal to 50% or Karnofsky Performance Status score greater than or equal to 50%. Use Karnofsky for participants greater than or equal to 16 years of age and Lansky for participants less than 16 years of age.
Life expectancy greater than or equal to 3 months.
Adequate bone marrow function as evidenced by:
absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^{9/L (for
Cohorts 3A and 3B leucocyte count greater than or equal to 2 x 10}9/L; participants with bone marrow involvement should have ANC greater than or equal to 0.8 x 10^{9/L and leucocyte count greater than or equal to 1 x 10}9/L).
hemoglobin greater than or equal to 8.0 grams/deciliter (g/dL) (a hemoglobin less than 8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before starting lenvatinib).
platelet count greater than or equal to 75 x 10^9/L.
Adequate liver function as evidenced by:
bilirubin less than or equal 1.5 times the upper limit of normal (ULN).
alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN.
Adequate renal function as evidenced by:

Serum creatinine based on age/gender as below. If serum creatinine is greater than maximum serum creatinine for age/gender as shown in the table below, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be greater than 70 milliliter/minute/1.73 square meter (mL/min/1.73 m2).

Maximum Serum Creatinine in milligrams/deciliter (mg/dL) for male:

Age 2 to less than 6 years = 0.8
Age 6 to less than 10 years = 1.0
Age 10 to less than 13 years = 1.2
Age 13 to less than 16 years = 1.5
Age greater than or equal to 16 years = 1.7

Maximum Serum Creatinine (mg/dL) for Female:

Age 2 to less than 6 years = 0.8
Age 6 to less than 10 years = 1.0
Age 10 to less than 13 years = 1.2
Age 13 to less than 16 years = 1.4
Age greater than or equal to 16 years = 1.4

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating glomerular filtration rate using child length and stature data published by the CDC.

Urine dipstick less than 2+ for proteinuria. Participants who have greater than or equal to 2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be Grade less than 2.
No clinical evidence of nephrotic syndrome.

Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) greater than or equal to 50%) at baseline as determined by echocardiography.
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

BP less than 95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1-week prior to Cycle 1/Day 1. Osteosarcoma subjects 18 to 25 years should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day 1.

Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative radiotherapy; 3 months from high-dose chemotherapy and stem cell rescue; 3 weeks from major surgery. Participants must have recovered from the acute toxic effects of all prior anticancer therapy before enrollment into the study.
Written and signed informed consent from the parent(s) or legal representative (guardian) and assent from the minor participant. Written informed consent from subjects ≥18 years.
Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the Investigator.

Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet only Inclusion Criteria Numbers 6 through 17 (after progression in Cohort 2B).

Exclusion criteria:

Any active infection or infectious illness unless fully recovered prior to dosing.
Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.
Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, or radiation therapy) except alopecia, and ototoxicity due to cisplatin not already covered in the inclusion/exclusion criteria, which has not recovered to Grade less than 2 per Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Known hypersensitivity to any component of the product (lenvatinib or ingredients).
Concurrent administration of any other antitumor therapy.
Previous treatment with lenvatinib (except for participants previously enrolled into Cohorts 1 or 2B of this study).
Two or more prior vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) targeted therapies.
Currently receiving any investigational drug or device in another clinical trial or within 30 days preceding informed consent.
A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval greater than 480 msec).
Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.
Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 3 weeks prior to the first dose of study drug.
Active second malignancy within 2 years prior to enrollment ([in addition to the primary tumor types specified by cohort in Inclusion Criterion Number 1], but not including definitively treated superficial melanoma, in-situ, basal or squamous cell carcinoma of the skin).
Previous treatment with ifosfamide and Grade greater than or equal to 3 nephrotoxicity or encephalopathy (Cohorts 3A and 3B).
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.

Cohort 3B (Combination Expansion): Osteosarcoma participants who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Texas Children's Hospital	Houston	Texas	United States	77030
2	CHU Strasbourg - Hopital Hautepierre	Strasbourg	Bas Rhin	France
3	Centre Oscar Lambret Lille	Lille	Rhone	France
4	Centre Leon Berard	Lyon	Rhone	France
5	CHU Nantes - Hopital Mere-Enfant	Nantes		France
6	Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris	Paris		France
7	Institut Gustave Roussy	Paris		France
8	CHU de Toulouse - Hopital des Enfants	Toulouse		France
9	Universitaetsklinikum Muenster	Muenster		Germany
10	Kinderklinik des Olga hospitals	Stuttgart		Germany
11	Istituto Ortopedico Rizzoli	Bologna		Italy
12	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan		Italy
13	Ospedale Pediatrico Bambino Gesu	Roma		Italy
14	Hospital Universitari Vall d'Hebron	Barcelona		Spain
15	Hospital Infantil Universitario Nino Jesus	Madrid		Spain
16	Hospital Universitario y Politecnico La Fe Hospital La Fe Valencia	Valencia		Spain
17	Birmingham Children's Hospital	Birmingham		United Kingdom
18	University College London Hospital	London		United Kingdom
19	Royal Victoria Infirmary	Newcastle		United Kingdom

Sponsors and Collaborators

Eisai Limited
Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Eisai Limited

ClinicalTrials.gov Identifier:

NCT02432274

Other Study ID Numbers:

E7080-G000-207
2013-005534-38

First Posted:

May 4, 2015

Last Update Posted:

Aug 4, 2022

Last Verified:

Sep 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Eisai Limited

Differentiated Thyroid Cancer

Additional relevant MeSH terms:

Isophosphamide mustard

Lenvatinib

Study Results

Participant Flow

Recruitment Details	Participants took part at 19 investigative sites in France, Germany, Italy, Spain, United Kingdom and the United States. Total 117 participants were enrolled and screened, of which 20 participants were screen failures and 97 participants received study treatment.
Pre-assignment Detail	Prior to entering Cohort 1, participants aged 2 to less than (<) 6 years underwent a run-in period and received lenvatinib 5 milligram per square meter (mg/m^2) per body surface area (BSA) as capsules or suspension once daily for 21 days. In this result summary, data has been reported at primary completion date (18 July 2019) of the overall study.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants(age group 2 to<6 years and 6 to<18 years)with relapsed or refractory solid malignant tumors received lenvatinib 11mg/m^2(per BSA, daily dose capped at 24 milligram per day[mg/day])as capsules or suspension(lenvatinib capsules dissolved in water/apple juice for participants who were unable to swallow capsules and given as suspension),orally,once daily on Days 1 to 28 of each treatment cycle until progressive disease(PD),intolerable toxicity,participant noncompliance with safety/efficacy assessments,initiation of another anticancer therapy,voluntary discontinuation by participant at any time,or study termination by sponsor,whichever occurred first. Eligible participants of age group 2 to<6 years first underwent 21days run-in period with lenvatinib 5mg/m^2,once daily before receiving lenvatinib11 mg/m^2 in Cycle1 in Cohort1. Duration of each treatment cycle in Cohort1=28 days.After determining recommended dose(RD)in Cohort1,participants were enrolled in Cohorts 2A,2B and 3A.	Participants (age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Eligible participants of age group 2 to <6 years first underwent 21-days run-in period with lenvatinib 5 mg/m^2, once daily before receiving lenvatinib 14 mg/m^2 in Cycle 1 in Cohort 1. Duration of each treatment cycle in Cohort 1=28 days. After determining RD in Cohort 1, participants were enrolled in Cohorts 2A, 2B and 3A.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days. After determining the RD in Cohort 1, participants were enrolled in Cohorts 2A, 2B and 3A.	Participants with 131 iodine-refractory differentiated thyroid cancer (DTC) received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20 percent [%] lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 milligram per square meter per day (mg/m^2/day) intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, participants were enrolled in Cohort 3B.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, participants were enrolled in Cohort 3B.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Period Title: Overall Study
STARTED	3	9	11	1	31	7	15	20
Underwent Run-in Period	1	1	0	0	0	0	0	0
Treated (Safety Population)	5	11	7	1	31	11	11	20
COMPLETED	0	0	0	0	0	0	0	0
NOT COMPLETED	3	9	11	1	31	7	15	20

Baseline Characteristics

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2	Total
Arm/Group Description	Participants (age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Eligible participants of age group 2 to <6 years first underwent 21-days run-in period with lenvatinib 5 mg/m^2, once daily before receiving lenvatinib 11 mg/m^2 in Cycle 1 in Cohort 1. Duration of each treatment cycle in Cohort 1=28 days. After determining RD in Cohort 1, participants were enrolled in Cohorts 2A, 2B and 3A.	Participants (age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Eligible participants of age group 2 to <6 years first underwent 21-days run-in period with lenvatinib 5 mg/m^2, once daily before receiving lenvatinib 14 mg/m^2 in Cycle 1 in Cohort 1. Duration of each treatment cycle in Cohort 1=28 days. After determining RD in Cohort 1, participants were enrolled in Cohorts 2A, 2B and 3A.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days. After determining the RD in Cohort 1, participants were enrolled in Cohorts 2A, 2B and 3A.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, participants were enrolled in Cohort 3B.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, participants were enrolled in Cohort 3B.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.	Total of all reporting groups
Overall Participants	3	9	11	1	31	7	15	20	97
Age, Customized (Count of Participants)
2 to <6 years	1 33.3%	1 11.1%	0 0%	0 0%	0 0%	0 0%	1 6.7%	0 0%	3 3.1%
6 to <18 years	2 66.7%	8 88.9%	11 100%	1 100%	24 77.4%	5 71.4%	11 73.3%	15 75%	77 79.4%
18 to <=25 years	0 0%	0 0%	0 0%	0 0%	7 22.6%	2 28.6%	3 20%	5 25%	17 17.5%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 55.6%	5 45.5%	0 0%	18 58.1%	2 28.6%	5 33.3%	7 35%	43 44.3%
Male	2 66.7%	4 44.4%	6 54.5%	1 100%	13 41.9%	5 71.4%	10 66.7%	13 65%	54 55.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 33.3%	1 11.1%	2 18.2%	0 0%	4 12.9%	1 14.3%	4 26.7%	3 15%	16 16.5%
Not Hispanic or Latino	1 33.3%	4 44.4%	4 36.4%	0 0%	15 48.4%	5 71.4%	8 53.3%	10 50%	47 48.5%
Unknown or Not Reported	1 33.3%	4 44.4%	5 45.5%	1 100%	12 38.7%	1 14.3%	3 20%	7 35%	34 35.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	2 66.7%	5 55.6%	3 27.3%	1 100%	20 64.5%	6 85.7%	14 93.3%	13 65%	64 66%
More than one race	0 0%	0 0%	1 9.1%	0 0%	2 6.5%	0 0%	0 0%	3 15%	6 6.2%
Unknown or Not Reported	1 33.3%	4 44.4%	7 63.6%	0 0%	9 29%	1 14.3%	1 6.7%	4 20%	27 27.8%

Outcome Measures

1. Primary Outcome

Title	Cohort 1: Recommended Dose (RD) of Lenvatinib
Description	RD was defined as the dose that had a dose limiting toxicity (DLT) rate closest to the targeted 20% rate. DLT was an adverse drug reaction and was assessed according to common terminology criteria for adverse events (CTCAE) version (v) 4.03 defined as 1) Grade 4 neutropenia for greater than or equal to (>=) 7 days, 2) Grade >=3 thrombocytopenia with bleeding, or lasting greater than (>) 7 days, 3) Grade >=3 febrile neutropenia, 4) Next course of chemotherapy delayed for >=7 days, 5) Grade >=3 non-hematologic toxicity persisting >7 days optimal supportive care, 6) Grade 4 hypertension, confirmed systolic or diastolic blood pressure >25 millimeters of mercury (mmHg) above the 95th percentile for age, or an elevated diastolic blood pressure (that is, >95th percentile for age) not controlled by a single antihypertensive medication within 14 days of use, 7) Grade 3 proteinuria, 8) Any recurrent Grade 2 non-hematological toxicity requiring >=2 interruption and dose reductions.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who received any study drug and had at least one post-baseline safety evaluation.

Arm/Group Title	Cohort 1: All Participants
Arm/Group Description	Participants (of age group 2 to <6 years [following the completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 11 mg/m^2, 14 mg/m^2 or 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.
Measure Participants	23
Number [milligram per square meter (mg/m^2)]	14

2. Primary Outcome

Title	Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)
Description	OR was defined as participants with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for >4 weeks) recorded from the start of the treatment until PD or death whichever occurred first. CR was 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 <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time Frame	From date of first dose of study drug until first documentation of PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.
Measure Participants	1
Count of Participants [Participants]	1 33.3%

3. Primary Outcome

Title	Cohort 2A: Number of Participants With Best Overall Response (BOR)
Description	BOR was defined as the best response of CR or PR for >4 weeks or SD for >=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time Frame	From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.
Measure Participants	1
Complete Response	0 0%
Partial Response	1 33.3%
Stable Disease	0 0%

4. Primary Outcome

Title	Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4
Description	Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of participants who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: >= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD.
Time Frame	At Month 4

Outcome Measure Data

Analysis Population Description
PFS-4 evaluable set included all participants treated with study drug for at least 4 months or those who died or radiologically progressed within 4 months after first dose, or received anticancer treatment within 4 months after first dose.

Arm/Group Title	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	28	15
Number (95% Confidence Interval) [percentage of participants]	32.1 1070%	66.7 741.1%

5. Primary Outcome

Title	Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide
Description	RD of lenvatinib when given in combination with ifosfamide and etoposide was defined as dose that resulted in no more than 1 DLT per 6 participants,or hematologic DLT in 1 participant and nonhematologic DLT in another participant per 6 participants,upon repeating same dose level.DLT was adverse drug reaction and assessed per CTCAE v4.03 defined as 1)Grade 4 neutropenia for >=10 days,2)Grade >=3 thrombocytopenia with bleeding,or lasting >=10 days,3)Grade >=3 febrile neutropenia lasting >=7 days,4)Next course of chemotherapy delayed for >=7 days,5)Grade >=3 nonhematologic toxicity persisting >7 days despite optimal supportive care,6)Grade 4 hypertension,confirmed systolic or diastolic blood pressure >25 mmHg above 95th percentile for age,or elevated diastolic blood pressure(>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7)Grade 3 proteinuria,8)Any recurrent Grade 2 nonhematological toxicity requiring >=2 interruption and dose reductions.
Time Frame	Cycle 1 (21 days)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who received any study drug and had at least one post-baseline safety evaluation.

Arm/Group Title	Cohort 3A: All Participants
Arm/Group Description	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1) or 14 mg/m^2, administered per BSA with daily dose capped at 24 mg/day as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle, in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.
Measure Participants	22
Number [milligram per square meter (mg/m^2)]	14

6. Secondary Outcome

Title	Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR)
Description	BOR: best response of CR or PR for >4 weeks or SD for >=7 weeks from first dose, recorded from start of treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have reduction in their short axis <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Not evaluable (NE) means BOR of NE or SD of <7 weeks duration. Unknown means no data were available on the case report form.
Time Frame	From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	10	30	7	14	18
Complete Response	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Partial Response	0 0%	0 0%	0 0%	2 200%	2 6.5%	0 0%	3 20%
Stable Disease	2 66.7%	5 55.6%	4 36.4%	13 1300%	3 9.7%	10 142.9%	9 60%
Progressive Disease	1 33.3%	2 22.2%	4 36.4%	12 1200%	2 6.5%	2 28.6%	4 26.7%
Not Evaluable or Unknown	0 0%	2 22.2%	2 18.2%	3 300%	0 0%	2 28.6%	2 13.3%

7. Secondary Outcome

Title	Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)
Description	ORR was defined as the percentage of participants with a BOR of CR or PR for >4 weeks or SD for >=7 weeks as assessed by investigator based on RECIST v1.1, recorded from start of study treatment until PD or death whichever occurred first. CR was 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 <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. 95% CI of the ORR were calculated according to Clopper and Pearson method.
Time Frame	From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	10	30	7	14	18
Number (95% Confidence Interval) [percentage of participants]	0 0%	0 0%	0 0%	6.7 670%	28.6 92.3%	0 0%	16.7 111.3%

8. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)
Description	DOR was defined as time in months from the first documentation confirmed CR or PR until the first documentation of confirmed PD as assessed by investigator based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. 95% CI for the median were calculated according to Brookmeyer and Crowley method.
Time Frame	First documentation of CR/PR until first documentation of PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening. Here "overall number of participants analyzed, N" signifies participants who were evaluable for this measure. Here, "N" for Cohort 1 (Lenvatinib 11, 14, 17 mg/m^2) and Cohort 3A (Lenvatinib 14 mg/m^2) is zero as there were no events of CR or PR in these arms.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	0	0	0	1	2	2	0	3
Median (95% Confidence Interval) [months]	1.9	4.6	NA	NA

9. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control
Description	Participants were defined as having disease control if they had a BOR of CR or PR for >4 weeks, or SD (minimum duration from first dose to SD >=7 weeks) or if participants had a BOR of CR or Non-CR/Non-PD (minimum duration from first dose to Non-CR/Non-PD >=7 weeks) per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest SOD. Non-CR/Non-PD: persistence of 1 or more non-target lesions, maintenance of tumor marker level above the normal limits.
Time Frame	From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	11	1	31	7	15	20
Count of Participants [Participants]	2 66.7%	5 55.6%	5 45.5%	1 100%	16 51.6%	5 71.4%	11 73.3%	14 70%

10. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit
Description	Participants were defined as having clinical benefit if they had a BOR of CR or PR for >4 weeks or durable SD (lasting >=23 weeks) or if participants had a BOR of CR or durable Non-CR/Non-PD (lasting >=23 weeks) as per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. Non-CR/Non-PD:persistence of 1 or more non-target lesions and maintenance of tumor marker level above the normal limits.
Time Frame	From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	11	1	31	7	15	20
Count of Participants [Participants]	0 0%	3 33.3%	4 36.4%	1 100%	7 22.6%	4 57.1%	5 33.3%	8 40%

11. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)
Description	PFS was defined as the time (in months) from the date of first dose of study drug to the date of first documentation of PD or date of death, whichever occurred first, based on RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
Time Frame	From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	11	1	31	7	15	20
Median (95% Confidence Interval) [months]	3.7	6.3	5.5	5.5	3.0	7.1	12.0	6.9

12. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)
Description	TTP was defined as the time from the date of first dose of study drug to the date of first documentation of PD based on RECIST 1.1. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
Time Frame	From first dose of study drug until PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	11	1	31	7	15	20
Median (95% Confidence Interval) [months]	3.7	6.3	5.5	5.5	3.0	7.1	12.0	6.9

13. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)
Description	OS was defined as the time from the date of the first dose of study drug until the date of death from any cause. Participants who are lost to follow-up and those who are alive at the date of data cutoff were censored at the date the participant was last known to be alive (or the data cutoff date). 95% CI of median were calculated according to Brookmeyer and Crowley method.
Time Frame	From first dose of study drug until death (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Full analysis set included all enrolled participants who did not fail study screening.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	3	9	11	1	31	7	15	20
Median (95% Confidence Interval) [months]	8.1	7.4	7.7	6.1	10.0	13.6	NA	NA

14. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	Number of participants with TEAEs (serious and non-serious adverse events) and SAEs were reported based on their safety assessments of hematology, clinical chemistry, proximal tibial growth, fecal occult blood, physical examinations, regular measurement of vital signs and electrocardiogram parameter values.
Time Frame	First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who received any study drug and had at least one post-baseline safety evaluation.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	5	11	7	1	31	11	11	20
TEAEs	5 166.7%	11 122.2%	7 63.6%	1 100%	29 93.5%	11 157.1%	11 73.3%	20 100%
SAEs	2 66.7%	7 77.8%	5 45.5%	0 0%	21 67.7%	7 100%	9 60%	15 75%

15. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Most Frequent Treatment-emergent Adverse Events (TEAEs) Related to Lenvatinib Exposure
Description	TEAEs (serious and non-serious), those occurred most frequently have been reported in this outcome measure. "Palmar-plantar E syndrome" refers to Palmar-plantar erythrodysaesthesia syndrome.
Time Frame	First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who received any study drug and had at least one post-baseline safety evaluation.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	5	11	7	1	31	11	11	20
Hypothyroidism	3 100%	6 66.7%	3 27.3%	0 0%	13 41.9%	5 71.4%	6 40%	6 30%
Abdominal pain	2 66.7%	2 22.2%	1 9.1%	1 100%	5 16.1%	6 85.7%	5 33.3%	6 30%
Diarrhea	3 100%	5 55.6%	3 27.3%	1 100%	8 25.8%	5 71.4%	5 33.3%	12 60%
Nausea	1 33.3%	2 22.2%	3 27.3%	0 0%	8 25.8%	7 100%	8 53.3%	13 65%
Vomiting	1 33.3%	6 66.7%	3 27.3%	0 0%	7 22.6%	5 71.4%	6 40%	12 60%
Asthenia	2 66.7%	1 11.1%	0 0%	0 0%	8 25.8%	0 0%	0 0%	7 35%
Fatigue	2 66.7%	2 22.2%	3 27.3%	0 0%	8 25.8%	2 28.6%	4 26.7%	3 15%
Alanine aminotransferase increased	0 0%	2 22.2%	1 9.1%	0 0%	1 3.2%	3 42.9%	1 6.7%	4 20%
Blood thyroid stimulating hormone increased	0 0%	0 0%	0 0%	0 0%	9 29%	3 42.9%	0 0%	5 25%
Weight decreased	3 100%	4 44.4%	1 9.1%	0 0%	6 19.4%	5 71.4%	3 20%	4 20%
Decreased appetite	3 100%	5 55.6%	1 9.1%	0 0%	13 41.9%	4 57.1%	2 13.3%	5 25%
Arthralgia	0 0%	2 22.2%	1 9.1%	0 0%	1 3.2%	2 28.6%	4 26.7%	1 5%
Myalgia	1 33.3%	2 22.2%	0 0%	0 0%	1 3.2%	0 0%	0 0%	0 0%
Pain in extremity	0 0%	2 22.2%	1 9.1%	0 0%	0 0%	3 42.9%	1 6.7%	0 0%
Headache	0 0%	1 11.1%	1 9.1%	0 0%	5 16.1%	2 28.6%	4 26.7%	4 20%
Proteinuria	0 0%	3 33.3%	3 27.3%	0 0%	7 22.6%	2 28.6%	5 33.3%	8 40%
Dysphonia	0 0%	0 0%	0 0%	0 0%	5 16.1%	0 0%	0 0%	0 0%
Erythema	1 33.3%	1 11.1%	1 9.1%	0 0%	0 0%	0 0%	0 0%	0 0%
Hair color changes	1 33.3%	1 11.1%	1 9.1%	0 0%	2 6.5%	0 0%	0 0%	0 0%
Palmar-plantar E syndrome	2 66.7%	2 22.2%	0 0%	0 0%	1 3.2%	1 14.3%	2 13.3%	0 0%
Hypertension	2 66.7%	3 33.3%	4 36.4%	1 100%	10 32.3%	1 14.3%	4 26.7%	3 15%
Haematuria	0 0%	0 0%	0 0%	0 0%	0 0%	4 57.1%	1 6.7%	4 20%
Hypokalaemia	0 0%	0 0%	0 0%	0 0%	0 0%	4 57.1%	1 6.7%	2 10%
Hypophosphataemia	0 0%	0 0%	0 0%	0 0%	0 0%	3 42.9%	2 13.3%	2 10%
Platelet count decreased	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	3 20%	11 55%
Back pain	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	2 13.3%	2 10%
Dry skin	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	2 13.3%	0 0%
Oral pain	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	2 13.3%	1 5%
Pneumothorax	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	2 13.3%	1 5%
Dehydration	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	4 20%
Hypoalbuminaemia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	0 0%
Lethargy	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	2 10%
Leukopenia	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	2 13.3%	3 15%
Neutrophil count decreased	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	9 45%
Oral dysaesthesia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	0 0%
Oropharyngeal pain	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	2 13.3%	1 5%
Proctalgia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	1 6.7%	0 0%
Toxic encephalopathy	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	2 13.3%	0 0%
Lymphocyte count decreased	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	4 20%
Abdominal pain upper	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	4 20%
Hyperuricemia	0 0%	0 0%	0 0%	1 100%	0 0%	0 0%	0 0%	0 0%
Insomnia	0 0%	0 0%	0 0%	1 100%	0 0%	0 0%	0 0%	0 0%
Anaemia	0 0%	0 0%	0 0%	0 0%	0 0%	9 128.6%	7 46.7%	15 75%
Neutropenia	0 0%	0 0%	0 0%	0 0%	0 0%	6 85.7%	6 40%	8 40%
Epistaxis	0 0%	0 0%	0 0%	0 0%	0 0%	5 71.4%	4 26.7%	4 20%
Thrombocytopenia	0 0%	0 0%	0 0%	0 0%	0 0%	5 71.4%	4 26.7%	5 25%
Febrile neutropenia	0 0%	0 0%	0 0%	0 0%	0 0%	5 71.4%	3 20%	2 10%
Stomatitis	0 0%	0 0%	0 0%	0 0%	0 0%	4 57.1%	4 26.7%	4 20%
Constipation	0 0%	0 0%	0 0%	0 0%	0 0%	5 71.4%	2 13.3%	2 10%
White blood cell count decreased	0 0%	0 0%	0 0%	0 0%	0 0%	4 57.1%	3 20%	12 60%
Lymphopenia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	0 0%
Haematochezia	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%
Pyrexia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	0 0%
Wound dehiscence	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%
Hypocalcaemia	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	0 0%
Dizziness	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%
Dyspnoea	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	0 0%
Hyperhidrosis	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%

16. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib
Description	Duration of each cycle for Cohorts 1, 2A, 2B is 28 days. Duration of each cycle for Cohorts 3A, 3B is 21 days.
Time Frame	Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose

Outcome Measure Data

Analysis Population Description
Pharmacokinetic (PK) Analysis Set included all participants who had received any study drug and had evaluable PK data. Here "number analyzed, n" signifies participants who were evaluable for this outcome measure at given time points.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	5	11	7	1	31	11	11	20
Cycle 1 Day 1: 0.5-4 hours	295.6 (214.01)	134.8 (145.83)	52.5 (81.40)	11.1 (NA)	177.4 (191.03)	105.2 (131.54)	111.4 (131.47)	209.7 (197.66)
Cycle 1 Day 1: 6-10 hours	212.7 (185.98)	281.9 (137.39)	238.0 (135.87)	188 (NA)	289.4 (200.09)	191.9 (100.69)	148.5 (122.41)	164.8 (73.59)
Cycle 1 Day 15: Pre-dose	46.9 (11.01)	59.1 (29.19)	96.9 (66.10)	56.2 (NA)	67.0 (53.78)
Cycle 1 Day 15: 0.5-4 hours	133.4 (163.37)	226.6 (204.61)	191.8 (190.22)	124 (NA)	168.3 (157.67)
Cycle 1 Day 15: 6-10 hours	351.8 (157.15)	375.8 (121.21)	413.0 (221.47)	247 (NA)	322.9 (138.87)
Cycle 2 Day 1: Pre-dose	58.1 (19.58)	61.6 (60.61)	97.9 (77.08)	59.8 (NA)	66.8 (62.50)	51.7 (44.23)	76.1 (63.25)	50.4 (65.10)
Cycle 2 Day 1: 2-12 hours	502.4 (360.71)	440.7 (229.29)	339.2 (212.44)	102 (NA)	382.4 (217.49)	205.6 (134.66)	237.4 (124.82)	275.3 (135.73)

17. Secondary Outcome

Title	Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level
Description	Serum biomarkers included Fibroblast Growth Factor (FGF) 19, FGF 21, Vascular Endothelial Growth Factor (VEGF). In this outcome measure, percent change from baseline in serum biomarkers level per "PFS-4, Yes" and "PFS-4, No" have been reported. As per assessment of investigator based on RECIST v1.1, "PFS-4, Yes"= participants evaluable for PFS-4 month and alive and without PD at 4 months from the first dose, "PFS-4, No"=participants evaluable for PFS-4 month and not alive or with PD at 4 months from the first dose.
Time Frame	Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1 (Duration of each cycle=21 days)

Outcome Measure Data

Analysis Population Description
PFS-4 evaluable set: all participants treated with study drug for at least 4 months or those who died or radiologically progressed within 4 months after first dose or received anticancer treatment within 4 months after first dose. "N": participants evaluable for this measure. "n": participants who were evaluable for this measure for specific rows.

Arm/Group Title	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle=21 days.
Measure Participants	26	13
C2D1: FGF 19 (PFS-4, Yes)	48.7 (110.78)	172.1 (211.86)
C2D1: FGF 19 (PFS-4, No)	109.9 (139.19)	78.3 (203.30)
C3D1: FGF 19 (PFS-4, Yes)	47.3 (130.42)
C3D1: FGF 19 (PFS-4, No)	194.5 (180.71)
C4D1: FGF 19 (PFS-4, Yes)	237.7 (204.94)
C4D1: FGF 19 (PFS-4, No)	91.9 (NA)
C2D1: FGF 21 (PFS-4, Yes)	-14.9 (68.95)	70.2 (138.90)
C2D1: FGF 21 (PFS-4, No)	134.3 (203.81)	7.2 (48.64)
C3D1: FGF 21 (PFS-4, Yes)	55.0 (125.51)
C3D1: FGF 21 (PFS-4, No)	17.0 (88.92)
C4D1: FGF 21 (PFS-4, Yes)	256.2 (323.34)
C4D1: FGF 21 (PFS-4, No)	-1.5 (NA)
C2D1: VEGF (PFS-4, Yes)	119.9 (309.01)	87.9 (105.60)
C2D1: VEGF (PFS-4, No)	124.2 (212.18)	95.8 (92.53)
C3D1: VEGF (PFS-4, Yes)	64.3 (153.50)
C3D1: VEGF (PFS-4, No)	23.2 (69.67)
C4D1: VEGF (PFS-4, Yes)	84.3 (97.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C2D1: FGF 19 (PFS-4, Yes) vs. C2D1: FGF 19 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.20359
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Comments	C2D1: FGF 19 (PFS-4, Yes) vs. C2D1: FGF 19 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.50068
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C3D1: FGF 19 (PFS-4, Yes) vs. C3D1: FGF 19 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.05512
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Comments	C4D1: FGF 19 (PFS-4, Yes) vs. C4D1: FGF 19 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.50382
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C2D1: FGF 21 (PFS-4, Yes) vs. C2D1: FGF 21 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.04760
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Comments	C2D1: FGF 21 (PFS-4, Yes) vs. C2D1: FGF 21 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.21420
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C3D1: FGF 21 (PFS-4, Yes) vs. C3D1: FGF 21 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.42542
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Comments	C4D1: FGF 21 (PFS-4, Yes) vs. C4D1: FGF 21 (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.73573
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C2D1: VEGF (PFS-4, Yes) vs. C2D1: VEGF (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.35754
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Comments	C2D1: VEGF (PFS-4, Yes) vs. C2D1: VEGF (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=0.59903
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: All Participants
	Comments	C3D1: VEGF (PFS-4, Yes) vs. C3D1: VEGF (PFS-4, No)
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	=1.00000
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

18. Secondary Outcome

Title	Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Categorized Based on Overall Acceptability Questionnaire Responses for Suspension of Lenvatinib
Description	In acceptability questionnaire, participants were asked to answer the overall acceptability of lenvatinib suspension considering the following elements: taste, appearance, smell and how does it feel in the mouth. Overall acceptability was answered in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. Overall acceptability was the overall acceptance for taste, appearance, smell, and the feeling in mouth. In this measure, number of participants have been reported per their overall acceptability responses.
Time Frame	Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B)

Outcome Measure Data

Analysis Population Description
Palatability analysis set included all participants who received oral suspension of lenvatinib and answered at least 1 question in the palatability questionnaire case report form.

Arm/Group Title	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.	Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.	Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
Measure Participants	0	2	1	0	1	0	1	4
Super Good	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Really Good	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Good	0 0%	1 11.1%	0 0%	0 0%	1 3.2%	0 0%	1 6.7%	1 5%
May be Good or May be Bad	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%
Bad	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%
Really Bad	0 0%	1 11.1%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%
Super Bad	0 0%	0 0%	1 9.1%	0 0%	0 0%	0 0%	0 0%	0 0%

Adverse Events

	Lenvatinib 5 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2		Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2		Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2		Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Time Frame	Lenvatinib 5 mg/m^2 (Run-in period): up to 21 days; first dose of study drug until 30 days after last dose (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019)
Adverse Event Reporting Description	Safety analysis set included all participants who received any study drug and had at least one post-baseline safety evaluation.

Arm/Group Title	Lenvatinib 5 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2		Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2		Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2		Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Arm/Group Description	Eligible participants of age group 2 to <6 years first underwent a 21-day run-in period with lenvatinib 5 mg/m^2, once daily as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension) before receiving lenvatinib 11 mg/m^2 or 14 mg/m^2 in Cycle 1 of Cohort 1 (Single-agent Dose-finding).		Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.		Participants (age group 2 to <6 years [following completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by participant at any time, or study termination by sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.		Participants (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA, daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 1=28 days.		Participants with 131 iodine-refractory DTC received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.		Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until PD, intolerable toxicity, participant noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the participant at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.		Participants with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the RD from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.		Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days.		Participants with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for participants who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		2/5 (40%)		7/11 (63.6%)		6/7 (85.7%)		0/1 (0%)		20/31 (64.5%)		6/11 (54.5%)		6/11 (54.5%)		3/20 (15%)
Serious Adverse Events
	Lenvatinib 5 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2		Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2		Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2		Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		2/5 (40%)		7/11 (63.6%)		5/7 (71.4%)		0/1 (0%)		21/31 (67.7%)		7/11 (63.6%)		9/11 (81.8%)		15/20 (75%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Neutropenia	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	5
Febrile neutropenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	5/11 (45.5%)	8	3/11 (27.3%)	4	2/20 (10%)	5
Leukopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Thrombocytopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Anaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	4
Lymphopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Pancytopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Cardiac disorders
Cardiac arrest	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Cardio-respiratory arrest	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Sinus bradycardia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Bradycardia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Cardiac failure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Abdominal pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Colitis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Enterocolitis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Vomiting	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	3	2/20 (10%)	4
Diarrhoea	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	2	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Gingival bleeding	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Intestinal obstruction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Nausea	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Gastritis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0
Stomatitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Anal inflammation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Pancreatitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
General disorders
Gait disturbance	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
General physical health deterioration	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pain	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Facial pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Influenza like illness	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pyrexia	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	1/31 (3.2%)	1	1/11 (9.1%)	1	1/11 (9.1%)	1	2/20 (10%)	2
Hepatobiliary disorders
Cholecystitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0
Infections and infestations
Pneumonia	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Gastroenteritis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Bacteraemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Clostridium difficile infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Influenza	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Urinary tract infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Wound infection bacterial	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Vulvitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Injury, poisoning and procedural complications
Post procedural haemorrhage	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Wound dehiscence	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Accidental overdose	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Allergic transfusion reaction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Transfusion related complication	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Investigations
Amylase increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Blood pressure increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Ejection fraction decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Lipase increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Platelet count decreased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	5	0/11 (0%)	0	0/11 (0%)	0	4/20 (20%)	12
Weight decreased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Neutrophil count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	4/20 (20%)	18
White blood cell count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	5/20 (25%)	15
Metabolism and nutrition disorders
Dehydration	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	2
Hypokalaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Hypophosphataemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Back pain	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/7 (0%)	0	0/1 (0%)	0	4/31 (12.9%)	4	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Pain in extremity	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	2/7 (28.6%)	2	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Intervertebral disc compression	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pathological fracture	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/2 (0%)	0	0/5 (0%)	0	3/11 (27.3%)	3	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Myelodysplastic syndrome	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	3	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Tumour pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	4
Malignant neoplasm progression	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Nervous system disorders
Depressed level of consciousness	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Spinal cord compression	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	4	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Headache	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Ischaemic stroke	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Brain injury	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Toxic encephalopathy	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Renal and urinary disorders
Renal pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Renal failure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Urinary retention	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Respiratory distress	0/2 (0%)	0	1/5 (20%)	2	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Dyspnoea	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	1/11 (9.1%)	2	0/11 (0%)	0	1/20 (5%)	2
Pneumothorax	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	4/31 (12.9%)	7	2/11 (18.2%)	3	2/11 (18.2%)	2	1/20 (5%)	1
Respiratory failure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Cough	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Epistaxis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	1/11 (9.1%)	1	1/20 (5%)	1
Pleuritic pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Vascular disorders
Hypertension	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Arterial thrombosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Lymphoedema	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	1/31 (3.2%)	1	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Hypotension	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Venoocclusive disease	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Lenvatinib 5 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2		Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2		Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2		Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2		Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2		Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		5/5 (100%)		11/11 (100%)		7/7 (100%)		1/1 (100%)		29/31 (93.5%)		11/11 (100%)		11/11 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Anaemia	0/2 (0%)	0	1/5 (20%)	2	2/11 (18.2%)	2	1/7 (14.3%)	1	0/1 (0%)	0	5/31 (16.1%)	7	9/11 (81.8%)	43	7/11 (63.6%)	29	15/20 (75%)	74
Lymphopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	4	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	8	0/11 (0%)	0	2/20 (10%)	3
Neutropenia	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	6/11 (54.5%)	19	6/11 (54.5%)	25	8/20 (40%)	49
Polycythaemia	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Thrombocytopenia	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	7	5/11 (45.5%)	50	4/11 (36.4%)	54	5/20 (25%)	47
Febrile neutropenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Leukopenia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	4	2/11 (18.2%)	21	3/20 (15%)	20
Acquired antithrombin III deficiency	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Cardiac disorders
Pericardial effusion	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Left ventricular dysfunction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Sinus bradycardia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	4/11 (36.4%)	4	0/20 (0%)	0
Tachycardia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	2/20 (10%)	2
Bradycardia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	4
Ventricular dysfunction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	4
Ear and labyrinth disorders
Vertigo	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	3	2/20 (10%)	2
Tinnitus	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Endocrine disorders
Hypothyroidism	1/2 (50%)	1	3/5 (60%)	5	6/11 (54.5%)	10	3/7 (42.9%)	3	0/1 (0%)	0	13/31 (41.9%)	17	6/11 (54.5%)	7	8/11 (72.7%)	11	6/20 (30%)	8
Hyperthyroidism	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Eye disorders
Eye ulcer	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Papilloedema	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Diplopia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Dry eye	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0
Eye pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	0/11 (0%)	0	0/20 (0%)	0
Eyelid oedema	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	4	0/11 (0%)	0	0/20 (0%)	0
Ocular hyperaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Photophobia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Vision blurred	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Eye discharge	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Abdominal pain	1/2 (50%)	1	2/5 (40%)	2	7/11 (63.6%)	9	2/7 (28.6%)	6	1/1 (100%)	1	9/31 (29%)	22	6/11 (54.5%)	20	6/11 (54.5%)	18	7/20 (35%)	19
Abdominal pain upper	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	4/31 (12.9%)	9	0/11 (0%)	0	1/11 (9.1%)	1	4/20 (20%)	7
Anal haemorrhage	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Anal incontinence	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Anal pruritus	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Aphthous ulcer	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Constipation	0/2 (0%)	0	1/5 (20%)	1	2/11 (18.2%)	2	1/7 (14.3%)	1	0/1 (0%)	0	10/31 (32.3%)	14	6/11 (54.5%)	11	5/11 (45.5%)	8	6/20 (30%)	8
Diarrhoea	1/2 (50%)	1	3/5 (60%)	4	5/11 (45.5%)	9	4/7 (57.1%)	8	1/1 (100%)	4	12/31 (38.7%)	27	8/11 (72.7%)	24	6/11 (54.5%)	14	12/20 (60%)	44
Dyspepsia	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	5/31 (16.1%)	5	0/11 (0%)	0	0/11 (0%)	0	3/20 (15%)	6
Flatulence	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Gingival pain	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Mouth ulceration	0/2 (0%)	0	1/5 (20%)	2	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	2/11 (18.2%)	2	0/20 (0%)	0
Nausea	0/2 (0%)	0	3/5 (60%)	7	2/11 (18.2%)	4	3/7 (42.9%)	3	0/1 (0%)	0	12/31 (38.7%)	16	8/11 (72.7%)	28	8/11 (72.7%)	28	13/20 (65%)	42
Odynophagia	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	0/11 (0%)	0	2/11 (18.2%)	2	1/20 (5%)	1
Oral dysaesthesia	0/2 (0%)	0	1/5 (20%)	2	1/11 (9.1%)	6	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	3	1/11 (9.1%)	1	0/20 (0%)	0
Perianal erythema	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Proctalgia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0	0/31 (0%)	0	3/11 (27.3%)	5	2/11 (18.2%)	2	1/20 (5%)	1
Rectal haemorrhage	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	2/20 (10%)	3
Stomatitis	0/2 (0%)	0	1/5 (20%)	2	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	4/31 (12.9%)	5	5/11 (45.5%)	7	3/11 (27.3%)	4	4/20 (20%)	7
Vomiting	0/2 (0%)	0	1/5 (20%)	9	7/11 (63.6%)	20	4/7 (57.1%)	5	0/1 (0%)	0	14/31 (45.2%)	41	9/11 (81.8%)	28	8/11 (72.7%)	20	12/20 (60%)	42
Anal fissure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	5	0/11 (0%)	0	2/11 (18.2%)	2	2/20 (10%)	2
Eructation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Toothache	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0
Abdominal discomfort	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Anal fistula	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Anal inflammation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	1/20 (5%)	1
Anal skin tags	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Diarrhoea haemorrhagic	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Gastritis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	4	0/20 (0%)	0
Gastrooesophageal reflux disease	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Glossitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Haematochezia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	3/11 (27.3%)	3	1/20 (5%)	4
Haemorrhoids	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Hypoaesthesia oral	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Oesophageal obstruction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Oral discomfort	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Oral pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	3/11 (27.3%)	3	1/20 (5%)	1
Proctitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Dry mouth	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Dyschezia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Haematemesis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Noninfective gingivitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Pancreatitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
General disorders
Asthenia	0/2 (0%)	0	2/5 (40%)	4	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	10/31 (32.3%)	13	1/11 (9.1%)	9	2/11 (18.2%)	3	8/20 (40%)	27
Catheter site pain	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	1/20 (5%)	1
Fatigue	1/2 (50%)	1	2/5 (40%)	3	3/11 (27.3%)	4	3/7 (42.9%)	7	0/1 (0%)	0	9/31 (29%)	15	4/11 (36.4%)	8	6/11 (54.5%)	9	4/20 (20%)	4
Non-cardiac chest pain	0/2 (0%)	0	1/5 (20%)	2	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	3/11 (27.3%)	4	1/20 (5%)	1
Oedema peripheral	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	3/31 (9.7%)	3	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pain	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	5	1/7 (14.3%)	1	0/1 (0%)	0	4/31 (12.9%)	4	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Pyrexia	1/2 (50%)	1	2/5 (40%)	8	4/11 (36.4%)	9	4/7 (57.1%)	10	1/1 (100%)	1	11/31 (35.5%)	17	6/11 (54.5%)	6	3/11 (27.3%)	5	6/20 (30%)	9
Catheter site bruise	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Catheter site dermatitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Catheter site swelling	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Chills	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Device related thrombosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Face oedema	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Influenza like illness	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Infusion site irritation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Localised oedema	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Malaise	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	3	0/20 (0%)	0
Swelling	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Axillary pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Chest pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Inflammation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Hepatobiliary disorders
Hepatocellular injury	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Hyperbilirubinaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Infections and infestations
Bronchitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Ear infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Gastroenteritis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Influenza	1/2 (50%)	1	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Localised infection	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Lower respiratory tract infection	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Oral candidiasis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Rhinitis	2/2 (100%)	2	1/5 (20%)	2	2/11 (18.2%)	3	3/7 (42.9%)	3	0/1 (0%)	0	3/31 (9.7%)	3	1/11 (9.1%)	1	1/11 (9.1%)	1	2/20 (10%)	2
Sinusitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Staphylococcal sepsis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Upper respiratory tract infection	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Urinary tract infection	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	3	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	0/11 (0%)	0	2/20 (10%)	2
Viral infection	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Vulvovaginal candidiasis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Nasopharyngitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pharyngitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Clostridium difficile infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Cystitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Device related infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Eye infection bacterial	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Gingivitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Oral herpes	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	2/20 (10%)	2
Osteomyelitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Paronychia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Pseudomonas infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Rash pustular	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	1/20 (5%)	2
Staphylococcal infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Vascular device infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Viral upper respiratory tract infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Cellulitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	2
Eyelid infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	2
Folliculitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Gastrointestinal infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Oesophageal candidiasis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	3
Pneumonia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Sepsis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Vaginal infection	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Injury, poisoning and procedural complications
Contusion	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	0/11 (0%)	0	1/20 (5%)	1
Allergic transfusion reaction	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	0/11 (0%)	0	1/20 (5%)	1
Fall	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	6	1/11 (9.1%)	2	0/20 (0%)	0
Limb injury	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Procedural pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	2/20 (10%)	2
Wound	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Wound complication	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Wound dehiscence	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0
Ligament sprain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Investigations
Alanine aminotransferase increased	0/2 (0%)	0	0/5 (0%)	0	4/11 (36.4%)	6	2/7 (28.6%)	4	0/1 (0%)	0	0/31 (0%)	0	3/11 (27.3%)	3	1/11 (9.1%)	2	5/20 (25%)	13
Aspartate aminotransferase increased	0/2 (0%)	0	0/5 (0%)	0	3/11 (27.3%)	3	2/7 (28.6%)	6	0/1 (0%)	0	2/31 (6.5%)	2	1/11 (9.1%)	1	1/11 (9.1%)	3	3/20 (15%)	12
Blood alkaline phosphatase increased	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	4	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Blood bilirubin increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	3	0/11 (0%)	0	2/20 (10%)	3
Blood creatinine increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	1/11 (9.1%)	1	0/20 (0%)	0
Blood lactate dehydrogenase increased	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Blood urea increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
C-reactive protein increased	0/2 (0%)	0	0/5 (0%)	0	3/11 (27.3%)	3	1/7 (14.3%)	1	0/1 (0%)	0	4/31 (12.9%)	4	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	2
Ejection fraction decreased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	1/11 (9.1%)	1	0/20 (0%)	0
Gamma-glutamyltransferase increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	2	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	4	2/20 (10%)	3
Lipase increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	2/20 (10%)	2
Neutrophil count increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Platelet count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	2/7 (28.6%)	3	0/1 (0%)	0	2/31 (6.5%)	14	2/11 (18.2%)	12	4/11 (36.4%)	16	11/20 (55%)	81
Red blood cell sedimentation rate increased	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Weight decreased	0/2 (0%)	0	3/5 (60%)	13	3/11 (27.3%)	6	3/7 (42.9%)	5	0/1 (0%)	0	11/31 (35.5%)	17	6/11 (54.5%)	8	3/11 (27.3%)	7	4/20 (20%)	7
Thyroglobulin increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	1	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Blood thyroid stimulating hormone increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	9/31 (29%)	13	3/11 (27.3%)	4	0/11 (0%)	0	5/20 (25%)	8
Electrocardiogram QT prolonged	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Blood calcium decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Blood magnesium decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	10	0/11 (0%)	0	0/20 (0%)	0
Blood phosphorus increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Blood potassium decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	1/20 (5%)	4
Haemoglobin decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Lymphocyte count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	4/11 (36.4%)	19	2/11 (18.2%)	5	6/20 (30%)	15
Neutrophil count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	2/11 (18.2%)	5	9/20 (45%)	38
Thyroxine decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Urine output decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0
White blood cell count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	5/11 (45.5%)	8	4/11 (36.4%)	11	13/20 (65%)	84
Amylase increased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	2
Blood phosphorus decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Blood uric acid decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Culture stool positive	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Full blood count decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Lipase decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Decreased appetite	0/2 (0%)	0	4/5 (80%)	11	5/11 (45.5%)	9	3/7 (42.9%)	5	0/1 (0%)	0	15/31 (48.4%)	26	5/11 (45.5%)	8	3/11 (27.3%)	3	7/20 (35%)	12
Hyperkalaemia	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	1/20 (5%)	1
Hypoalbuminaemia	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	4	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	4	1/11 (9.1%)	1	2/20 (10%)	5
Hypokalaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0	0/31 (0%)	0	4/11 (36.4%)	8	1/11 (9.1%)	4	3/20 (15%)	10
Hypomagnesaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	2/11 (18.2%)	4	0/11 (0%)	0	0/20 (0%)	0
Hyponatraemia	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	3/31 (9.7%)	3	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Hypertriglyceridaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	1	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Hyperuricaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	2	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Dehydration	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	1/11 (9.1%)	4	2/20 (10%)	2
Electrolyte imbalance	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	4	0/20 (0%)	0
Hypermagnesaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Hypocalcaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	3	0/11 (0%)	0	0/20 (0%)	0
Hypophosphataemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	3/11 (27.3%)	8	2/11 (18.2%)	13	4/20 (20%)	12
Hypoproteinaemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0
Metabolic acidosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Vitamin D deficiency	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Acidosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Cachexia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Fluid retention	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Hyperphosphataemia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	1/7 (14.3%)	2	0/1 (0%)	0	10/31 (32.3%)	17	6/11 (54.5%)	7	6/11 (54.5%)	8	3/20 (15%)	5
Back pain	0/2 (0%)	0	1/5 (20%)	2	4/11 (36.4%)	8	2/7 (28.6%)	2	1/1 (100%)	2	10/31 (32.3%)	15	6/11 (54.5%)	7	4/11 (36.4%)	6	5/20 (25%)	5
Muscular weakness	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Musculoskeletal chest pain	0/2 (0%)	0	1/5 (20%)	2	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	6/31 (19.4%)	6	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Musculoskeletal pain	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	1/7 (14.3%)	2	0/1 (0%)	0	10/31 (32.3%)	14	2/11 (18.2%)	3	1/11 (9.1%)	1	3/20 (15%)	5
Myalgia	0/2 (0%)	0	2/5 (40%)	10	2/11 (18.2%)	2	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	2/11 (18.2%)	3	1/20 (5%)	1
Pain in extremity	0/2 (0%)	0	2/5 (40%)	4	4/11 (36.4%)	10	3/7 (42.9%)	5	0/1 (0%)	0	9/31 (29%)	10	6/11 (54.5%)	16	5/11 (45.5%)	11	2/20 (10%)	3
Neck pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	1	2/31 (6.5%)	2	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Bone pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	2/11 (18.2%)	3	0/11 (0%)	0	3/20 (15%)	3
Coccydynia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Flank pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Groin pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Joint swelling	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Muscle spasms	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Periostitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Limb mass	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Pain in jaw	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Spinal pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/2 (0%)	0	2/5 (40%)	2	1/11 (9.1%)	2	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	5	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Pericardial effusion malignant	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Tumour pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	3/31 (9.7%)	4	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Malignant pleural effusion	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Nervous system disorders
Cranial nerve paralysis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Dizziness	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	3/31 (9.7%)	3	1/11 (9.1%)	1	3/11 (27.3%)	5	2/20 (10%)	2
Dysaesthesia	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Headache	0/2 (0%)	0	0/5 (0%)	0	6/11 (54.5%)	9	3/7 (42.9%)	6	0/1 (0%)	0	15/31 (48.4%)	20	4/11 (36.4%)	5	7/11 (63.6%)	13	6/20 (30%)	9
Hypoaesthesia	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Lethargy	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	2/11 (18.2%)	2	1/11 (9.1%)	1	2/20 (10%)	2
Monoparesis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Muscle contractions involuntary	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Phantom pain	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Pyramidal tract syndrome	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Sciatica	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Neuralgia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	1/11 (9.1%)	2	1/20 (5%)	1
Somnolence	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	4/31 (12.9%)	5	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Amputation stump pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Generalised tonic-clonic seizure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Migraine	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	8	0/11 (0%)	0	0/20 (0%)	0
Paraesthesia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Presyncope	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Sensory disturbance	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Syncope	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Toxic encephalopathy	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Tremor	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	0/20 (0%)	0
Psychiatric disorders
Anxiety	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	3/31 (9.7%)	3	3/11 (27.3%)	8	1/11 (9.1%)	1	2/20 (10%)	2
Depressed mood	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Depression	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Sleep disorder	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Insomnia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	1	0/31 (0%)	0	3/11 (27.3%)	7	1/11 (9.1%)	1	0/20 (0%)	0
Agitation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0
Confusional state	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Irritability	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Nightmare	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Renal and urinary disorders
Acute kidney injury	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Bladder pain	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Cystitis noninfective	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Dysuria	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	2/11 (18.2%)	3	1/20 (5%)	2
Haematuria	0/2 (0%)	0	0/5 (0%)	0	3/11 (27.3%)	3	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	5/11 (45.5%)	6	1/11 (9.1%)	2	4/20 (20%)	9
Hydronephrosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Pollakiuria	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Proteinuria	0/2 (0%)	0	0/5 (0%)	0	3/11 (27.3%)	16	3/7 (42.9%)	8	0/1 (0%)	0	13/31 (41.9%)	26	3/11 (27.3%)	5	5/11 (45.5%)	13	9/20 (45%)	26
Glycosuria	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	2/20 (10%)	2
Renal impairment	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Renal tubular disorder	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	1/20 (5%)	1
Leukocyturia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	5
Renal failure	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Urine flow decreased	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Reproductive system and breast disorders
Menstruation irregular	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Balanoposthitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Vulvovaginal pruritus	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Genital pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Vaginal haemorrhage	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/2 (50%)	1	2/5 (40%)	3	3/11 (27.3%)	3	2/7 (28.6%)	2	0/1 (0%)	0	9/31 (29%)	10	4/11 (36.4%)	4	4/11 (36.4%)	5	4/20 (20%)	4
Dysphonia	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	6/31 (19.4%)	10	1/11 (9.1%)	2	2/11 (18.2%)	3	1/20 (5%)	1
Dyspnoea	0/2 (0%)	0	2/5 (40%)	2	0/11 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0	6/31 (19.4%)	8	3/11 (27.3%)	3	2/11 (18.2%)	3	2/20 (10%)	3
Epistaxis	0/2 (0%)	0	2/5 (40%)	3	3/11 (27.3%)	3	2/7 (28.6%)	2	0/1 (0%)	0	4/31 (12.9%)	7	5/11 (45.5%)	10	6/11 (54.5%)	8	6/20 (30%)	12
Pleural effusion	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Pneumothorax	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	4	1/11 (9.1%)	1	2/11 (18.2%)	2	0/20 (0%)	0
Productive cough	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Respiratory distress	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Rhinitis allergic	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Dysaesthesia pharynx	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Dyspnoea exertional	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Hypoxia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Nasal congestion	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Oropharyngeal pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	2/11 (18.2%)	2	4/11 (36.4%)	4	4/20 (20%)	7
Pharyngeal inflammation	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	3	0/20 (0%)	0
Pleuritic pain	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Rhinorrhoea	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1
Pneumonitis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	1/11 (9.1%)	1	2/20 (10%)	2
Dry skin	1/2 (50%)	1	1/5 (20%)	1	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	3/11 (27.3%)	4	3/11 (27.3%)	3	0/20 (0%)	0
Eczema	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Erythema	1/2 (50%)	1	1/5 (20%)	1	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	2	0/11 (0%)	0	0/20 (0%)	0
Hair colour changes	0/2 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Hyperhidrosis	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0
Pain of skin	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/2 (0%)	0	2/5 (40%)	4	2/11 (18.2%)	2	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	3/11 (27.3%)	12	0/20 (0%)	0
Pruritus	0/2 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	4	1/7 (14.3%)	1	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	2/11 (18.2%)	3	1/20 (5%)	1
Rash	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	3/11 (27.3%)	3	3/11 (27.3%)	7	2/20 (10%)	4
Rash macular	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Rash maculo-papular	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	2/11 (18.2%)	3	0/20 (0%)	0
Rash papular	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Skin exfoliation	0/2 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Spider naevus	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Acne	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	1/1 (100%)	3	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Dermatitis acneiform	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	2	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Skin ulcer	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	2/31 (6.5%)	3	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Dermatitis bullous	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Scab	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	1/11 (9.1%)	1	0/11 (0%)	0	0/20 (0%)	0
Dermatitis allergic	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Hyperkeratosis	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	2
Night sweats	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Onychalgia	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Rash generalised	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	2/20 (10%)	2
Urticaria	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Vascular disorders
Flushing	0/2 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Hypertension	0/2 (0%)	0	2/5 (40%)	2	3/11 (27.3%)	3	4/7 (57.1%)	12	1/1 (100%)	1	10/31 (32.3%)	12	3/11 (27.3%)	4	5/11 (45.5%)	10	3/20 (15%)	4
Hypotension	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	0/20 (0%)	0
Lymphoedema	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0
Capillary leak syndrome	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Haematoma	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	1
Hot flush	0/2 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/7 (0%)	0	0/1 (0%)	0	0/31 (0%)	0	0/11 (0%)	0	0/11 (0%)	0	1/20 (5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results Point of Contact

Name/Title	Eisai Medical Information
Organization	Eisai Ltd.
Phone	1-888-274-2378
Email	esi_oncmedinfo@eisai.com

Responsible Party:

Eisai Limited

ClinicalTrials.gov Identifier:

NCT02432274

Other Study ID Numbers:

E7080-G000-207
2013-005534-38

First Posted:

May 4, 2015

Last Update Posted:

Aug 4, 2022

Last Verified:

Sep 1, 2021

Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

Study Details

Study Description

Brief Summary

Detailed Description

The study consists of 5 cohorts:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Maximum Serum Creatinine in milligrams/deciliter (mg/dL) for male:

Maximum Serum Creatinine (mg/dL) for Female:

Exclusion criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Statistical Analysis 11

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact