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

Eisai Inc.81 enrolled

Overview

This Is a Multicenter, Randomized, Open-Label, Parallel-Group, Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents, and Young Adults with Relapsed or Refractory Osteosarcoma.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Osteosarcoma

Interventions

LenvatinibDRUG

Lenvatinib 14 milligrams per square meter (mg/m\^2) capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until disease progression (PD), development of unacceptable toxicity, participant request, withdrawal of consent, or discontinuation of study by the sponsor. An extemporaneous suspension of lenvatinib capsules may be used for participants unable to swallow capsules.

IfosfamideDRUG

Ifosfamide 3000 milligrams per square meter per day (mg/m\^2/day) intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

EtoposideDRUG

Etoposide 100 mg/m\^2/day intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Eligibility

Sex: ALLMin age: 2 YearsMax age: 25 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma 2. Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments 3. Measurable or evaluable disease per RECIST 1.1. 4. Life expectancy of 12 weeks or more 5. 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 6. Adequate organ function per blood work 7. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) \>=50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan 8. 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 9. 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 1 10. Must have no prior history of lenvatinib treatment Eligibility for optional lenvatinib crossover: 1. Disease progression per RECIST 1.1 (as confirmed by IIR for all participants who crossover prior to the study data-cut) 2. No new systemic anti-cancer medication administered after the last dose of study drugs 3. Meets all safety parameters listed in the inclusion criteria and none listed in the exclusion criteria 4. Study is ongoing Exclusion Criteria: 1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1 (that is, no longer requiring systemic treatment) 2. Participants with central nervous system metastases are not eligible, unless they have completed local therapy (example, whole brain radiation therapy, surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 2 weeks before Cycle 1 Day 1 3. Active second malignancy within 2 years prior to enrollment (\[in addition to osteosarcoma\], but not including definitively treated superficial melanoma, carcinoma-in-situ, basal or squamous cell carcinoma of the skin) 4. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility 5. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT or corrected QT (QTc) interval (example, a repeated demonstration of a QTc interval greater than \[\>\] 480 millisecond \[msec\]) 6. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted 7. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib 8. Pre-existing Grade \>=3 gastrointestinal or non-gastrointestinal fistula 9. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least 1 divided \[/\] by 2 teaspoon) within 3 weeks prior to Cycle 1 Day 1 10. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy 11. History of ifosfamide-related Grade \>=3 nephrotoxicity or encephalopathy 12. Known to be human immunodeficiency virus (HIV) positive 13. Known active Hepatitis B (example, Hepatitis B surface antigen \[HBsAg\] reactive) or Hepatitis C (example, hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected). Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority

Locations (84)

Outcomes

Primary Outcomes

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

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)

Secondary Outcomes

Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment

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

Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment

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

Overall Survival (OS)

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.

Data from ClinicalTrials.gov

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