Relapsed or Refractory Osteosarcoma MedDRA version: 21.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 100000004864
Conditions
Sponsors
Eisai Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma. 2. Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments. 3. Measurable or evaluable disease per RECIST 1.1 that meets the following criteria: - Must be accurately measurable with a minimum size (by long axis) of 10 mm using computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be accurately measurable with a minimum size [by short axis] of 15 mm). - 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. 4. Aged 2 years to =25 years at the time of informed consent. 5. Life expectancy of 12 weeks or more. 6. Lansky play score =50% or Karnofsky Performance Status score = 50%. Use Karnofsky for subjects =16 years of age and Lansky for subjects 70 mL/min/1.73 m2. b. Urine dipstick 12 years of age must have =1 g of protein/24 hours). c. No clinical evidence of nephrotic syndrome. 11. Adequate cardiac function as evidenced by left ventricular ejection fraction =50% at baseline as determined by echocardiography. 12. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a. BP 18 years of age should have BP =150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1. 13. 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 rad
Exclusion criteria
Exclusion criteria: 1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1. 2. Subjects with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication at least 2 weeks before C1D1 3. Active second malignancy within 2 years prior to enrollment 4. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study. 5. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. 6. Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and etoposide, or their ingredients). 7. Currently receiving any investigational drug or device in another clinical study or within 28 days prior to Cycle 1 Day 1. 8. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec). 9. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib. 10. Pre-existing Grade =3 gastrointestinal or non-gastrointestinal fistula. 11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to Cycle 1 Day 1. 12. 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. 13. History of ifosfamide-related Grade =3 nephrotoxicity or encephalopathy. 14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments. 15. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by local authority. 16. Active viral hepatitis (B or C) as demonstrated by positive serology. Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority. 17. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ßhCG]) (human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG /hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of any study drug. 18. Females of childbearing potential* who: - Do not agree to use a highly effective method of contraception for the entire study period and for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide discontinuation, ie: ? total abstinence (if it is their preferred and usual lifestyle) ? an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) ? A contraceptive implant ? an oral contraceptive. Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing with study drug and throughout the study and for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide discontinuation . OR - Do not have a vasectomized partner with confirmed azoosper
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) rate at 4 months (PFS-4m) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.;Secondary Objective: 1. Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms 2. Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS between the 2 treatment arms 3. Compare differences in overall survival (OS) and OS rate at 1 year (OS-1y) between the 2 treatment arms 4. Compare differences in objective response rate (ORR) at 4 months between the 2 treatment arms 5. Compare differences in safety and tolerability between the 2 treatment arms 6. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with ifosfamide and etoposide 7. Compare differences in health-related quality of life (HRQoL) as assessed by using the the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module between the 2 treatment arms 8. Assess the palatability and acceptability of the suspension formulation of lenvatinib in pediatric subjects receiving the suspension formulation in the study;Primary end point(s): Progression-free survival rate at 4 months (PFS-4m rate) by IIR (independent imaging review) is defined as the percentage of subjects who are alive and without PD at 4 months from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-4m rate is estimated on the full analysis set for this study using the K-M method.;Timepoint(s) of evaluation of this end point: Efficacy analyses will be based primarily on the Full Analysis Set. All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date (ie, when the last subje | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage of subjects who are alive and without PD at 1 year from the randomization date as determined by IIR of radiological imaging using RECIST 1.1. The PFS-1y rate is estimated on the full analysis set for this study using the K-M method. 2. Progression-free survival (PFS) by IIR is defined as the time from the date of randomization to the date of the first documentation of PD or death (whichever occurs first) as determined by IIR using RECIST 1.1. 3. Overall survival (OS) is defined as the time from the date of randomization to the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff will be censored at the date the subject was last known alive, or date of data cutoff, whichever occurs first. Overall survival rate at 1 year will be estimated. 4. Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects who have best overall response of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1 within the first 4 months. 5. Safety will be assessed summarising the incidence of TEAEs and SAEs together with all other safety parameters. 6. Assessment of population-based PK parameters of lenvatinib. 7. Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer Module. Scores will be calculated for total generic score, total cancer score, each physical function subscale including physical health, psychosocial health, emotional function, social function, school/work function in the Generic Core Scales, and each subscales in the cancer module. 8. Palatibility and acceptability of the suspension formulation of lenvatinib in subjects receiving the suspension formulation in the study will be assessed using the Palatability Questionnaire (see Appendix 5 within Protocol).;Timepoint(s) of evaluation of this end point: | — |
Countries
Australia, Austria, Belgium, Canada, Czech Republic, Finland, France, Germany, Hong Kong, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Singapore, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
Public ContactMedical Information
Eisai Ltd
Outcome results
None listed