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

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination With Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents and Young Adults With Relapsed or Refractory Osteosarcoma (OLIE)

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Lenvatinib
* Drug: Ifosfamide
* Drug: Etoposide
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of high grade osteosarcoma Refractory 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 1 Must 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 Exclusion Criteria: Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1 (that is, no longer requiring systemic treatment) 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 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) 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 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]) 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 Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib Pre-existing Grade >=3 gastrointestinal or non-gastrointestinal fistula 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 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 History of ifosfamide-related Grade >=3 nephrotoxicity or encephalopathy Known to be human immunodeficiency virus (HIV) positive 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomization Phase: Lenvatinib + Ifosfamide + Etoposide<br>Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide. | Drug: Lenvatinib<br>* 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.<br>* Other names: E7080;Drug: Ifosfamide<br>* 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.<br>Drug: Etoposide<br>* 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.<br>|
| Active Comparator: Randomization Phase: Ifosfamide + Etoposide<br>Participants with relapsed or refractory osteosarcoma will receive ifosfamide with etoposide. Participants with relapsed or refractory osteosarcoma may receive optional lenvatinib plus or minus chemotherapy (Ifosfamide and Etoposide) if disease progression is observed in study. | Drug: Ifosfamide<br>* 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.<br>Drug: Etoposide<br>* 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.<br>Drug: Lenvatinib<br>* Lenvatinib 14 mg/m^2 capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until the next PD (per response evaluation criteria in solid tumors [RECIST] 1.1 as assessed by investigator), development of unacceptable toxicity, participant request, or withdrawal of consent, whichever occurs first.<br>* Other names: E7080;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first (up to 14.2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. Final analysis data was reported for this outcome measure. | 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. Final analysis data was reported for this outcome measure. | Month 12 or 1 Year | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2025). | From the date of randomization to the date of death from any cause (up to approximately 59 months) | 
| Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y) | 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. Final analysis data was reported for this outcome measure. | Month 12 or 1 Year | 
| Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment | 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. Final analysis data was reported for this outcome measure. | Month 4 | 
| ORR by IIR Assessment | 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. Final analysis data was reported for this outcome measure. | From the date of randomization to the date of the first documentation of CR or PR, whichever occurred first (up to approximately 14.2 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to pretreatment state, when AE was continuous. SAE was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria. Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2025). | From date of first dose up to 30 days after the last dose of study drug (up to approximately 60 months) | 
| Treatment Arm A: Plasma Concentration of Lenvatinib | 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. Final analysis data was reported for this outcome measure. | 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) | 
| Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4 | 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. Final analysis data was reported for this outcome measure. | Baseline and Month 4 | 
| Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4 | 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. Final analysis data was reported for this outcome measure. | Baseline and Month 4 | 
| Number of Participants Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib | 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. Final analysis data was reported for this outcome measure. | Cycle 1 Day 1 (Cycle length = 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteosarcoma, Lenvatinib, Ifosfamide, Etoposide, E7080, Relapsed or Refractory Osteosarcoma, Pediatrics, Chemotherapy