A Study to Compare the Efficacy and Safety of Ifosfamide and Etoposide With or Without Lenvatinib in Children, Adolescents and Young Adults With Relapsed and Refractory Osteosarcoma

PFS as assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of PD or date of death (whichever occurred first), as determined using RECIST v1.1. PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.

Time frame: From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first (up to 20.5 months)

Population: FAS included all randomized participants regardless of the treatment actually received.

Health-Related Quality of Life (HRQoL): PedsQL 4.0 Generic Core Scale is a multidimensional scale. It included assessment of 4 dimensions: physical functioning (8 items), emotional functioning (8 items), social functioning (8 items), and school functioning (5 items - children greater than or equal to \[\>=\] 5 years, adults; 3 items - toddlers \[aged 2-4 years\]). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Generic Core Scale total score: sum of all the items divided by the number of items answered across all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL.

Time frame: Baseline and Month 4

Population: HRQoL Analysis Set included all participants who had received at least 1 dose of study drug and had completed at least 1 postbaseline patient-reported outcome (PRO) assessment. Here overall number of participants analyzed, N signifies participants who were evaluable for this outcome measure.

HRQoL: PedsQL 3.0 Cancer Module Scale measured pediatric cancer-specific HRQoL. It included assessment of 8 dimensions: pain and hurt (2 items), nausea (5 items), procedural anxiety (3 items), treatment anxiety (3 items), worry (3 items), cognitive problems (3 items - toddlers \[aged 2-4\], 4 items - young children \[aged 5-7\]; 5 items for children aged \>=8 years, adults), perceived physical appearance (3 items), communication (3 items). Each item was reported using a 5-point Likert scale, items were then reverse-scored and linearly transformed to a 0 to 100 scale. Cancer Module total score: sum of all items divided by the number of items answered on all the scales. Total score ranges from 0 to 100, where higher scores=better HRQoL, lower scores=worse HRQoL.

Time frame: Baseline and Month 4

Population: HRQoL Analysis Set included all participants who had received at least 1 dose of study drug and had completed at least 1 postbaseline PRO assessment. Here overall number of participants analyzed, N signifies participants who were evaluable for this outcome measure.

The palatability and acceptability of lenvatinib oral suspension formulation was assessed using the Palatability Questionnaire. In the questionnaire, participants were asked to answer palatability and acceptability of lenvatinib suspension considering the following elements: taste, appearance, smell, how does it feel in the mouth and overall acceptability in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. In this outcome measure, number of participants have been reported per their overall palatability and acceptability responses.

Time frame: Cycle 1 Day 1 (Cycle length = 21 days)

Population: Palatability and acceptability analysis set included all participants who received oral suspension of lenvatinib in Treatment Arm A and who received an optional lenvatinib suspension in Treatment Arm B and who answered at least 1 question in the palatability questionnaire. As planned, combined data for Lenvatinib from Treatment Arm A and B was reported for this outcome measure. Here overall number of participants analyzed, N signifies participants who were evaluable for this outcome measure.

TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to pretreatment state, when AE was continuous. Serious adverse events (SAE) was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria.

Time frame: From first dose up to 30 days after the last dose of study drug (up to 40.8 months)

Population: Safety Analysis Set included participants who received at least 1 dose of any study drug.

ORR-4m was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST v1.1 within the first 4 months. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<) 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% confidence interval (CI) of ORR was calculated using the method of Clopper and Pearson.

Time frame: Month 4

Population: FAS included all randomized participants regardless of the treatment actually received.

ORR by IIR was defined as the percentage of participants with best overall response of CR or PR determined using RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 95% CI of ORR was calculated using the method of Clopper and Pearson.

Time frame: From the date of randomization to the date of the first documentation of CR or PR (up to 20.5 months)

Population: FAS included all randomized participants regardless of the treatment actually received.

OS was defined as the time from the date of randomization to the date of death from any cause. The median OS was from Kaplan-Meier product-limit estimates and 2-sided 95% CIs from a generalized Brookmeyer and Crowley method.

Time frame: From the date of randomization to the date of death from any cause (up to 37.1 months)

Population: FAS included all randomized participants regardless of the treatment actually received.

OS-1y was defined as the time from the date of randomization to the date of death from any cause assessed up to 1 year. OS was calculated using the Kaplan-Meier method.

Time frame: Month 12 or 1 Year

Population: FAS included all randomized participants regardless of the treatment actually received.

PFS-1y rate as assessed by IIR was defined as the percentage of participants who were alive and without PD at 1 year from randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS-1y rate was estimated using Kaplan-Meier method.

Time frame: Month 12 or 1 Year

Population: FAS included all randomized participants regardless of the treatment actually received.

PFS rate at 4 months as assessed by IIR was defined as the percentage of participants who were alive and without PD at 4 months from the randomization date using RECIST v1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. The PFS-4m was estimated using the Kaplan-Meier method.

Time frame: Month 4

Population: FAS included all randomized participants regardless of the treatment actually received.

Plasma concentration of lenvatinib in participants from Treatment Arm A (Lenvatinib + Ifosfamide + Etoposide) at different time points were reported. As planned, data for this outcome measure was analyzed for treatment arm A only. Lenvatinib concentration in plasma was quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method.

Time frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: Pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: Pre-dose (each Cycle length = 21 days)

Population: Population Pharmacokinetic (PK) Analysis Set included those participants who received at least 1 dose of lenvatinib and had documented dose administration history and measurable plasma concentrations of lenvatinib. Here overall number of participants analyzed, N signifies participants who were evaluable for this outcome measure. Here number analyzed, n signifies participants who were evaluable for this outcome measure at given time points.