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

Histologically or cytologically confirmed diagnosis of high grade osteosarcomaRefractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments Measurable or evaluable disease per RECIST 1.1. Life expectancy of 12 weeks or more Lansky play score greater than or equal to (>=) 50 Percent (%) or Karnofsky Performance Status score >=50%. Use Karnofsky for participants >=16 years of age and Lansky for participants less than (<)16 years of age. Participants who are unable to walk because of paralysis, but who are able to perform activities of daily living while wheelchair bound, will be considered ambulatory for the purpose of assessing the performance score Adequate organ function per blood work Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) >=50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan

Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

BP <95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Participants >18 years of age should have BP less than or equal to (<=) 150/90 millimeters of Mercury at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1

Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue. For all other anti-cancer therapies, washout before Cycle 1 Day 1 of at least 5 half-lives (or at least 28 days, whichever is shorter). Participants must have recovered [to Grade <=1, except for alopecia, ototoxicity, and Grade <=2 peripheral neuropathy, per common terminology criteria for adverse events (CTCAE) v5.0] from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1Must have no prior history of lenvatinib treatment

Eligibility for optional lenvatinib crossover:

Disease progression per RECIST 1.1 (as confirmed by IIR for all participants who crossover prior to the study data-cut)No new systemic anti-cancer medication administered after the last dose of study drugs Meets all safety parameters listed in the inclusion criteria and none listed in the exclusion criteria Study is ongoing