cancer in the bone relapsed or refractory osteosarcoma
Conditions
Interventions
Test Arm (Arm A): Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg
Sponsors
Eisai
Eligibility
Age
2 Years to 99 Years
Inclusion criteria
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 that meets the following criteria: - Measurable disease is defined as a lesion 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. - Any other non-measurable lesions will be considered evaluable disease. 4. Aged 2 years to =50% or Karnofsky Performance Status score >= 50%. Use Karnofsky for subjects >=16 years of age and Lansky for subjects =1.5×10^9/L. (subjects with bone marrow involvement should have ANC >=0.8×10^9/L and leucocyte count >=1×10^9/L). b. hemoglobin >=8.0 g/dL (a hemoglobin of =100×10^9/L. 8. Adequate blood coagulation function defined by International Normalized ratio or prothrombin time (INR/PT) and activated partial thromboplastin time or partial thromboplastin time (aPTT/PTT) 70 mL/min/1.73 m2. b. Urine dipstick =2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio test that should be Grade 12 years of age must have =50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan. 12. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a. BP <95th perce
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. 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. 10. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib. 11. Pre-existing Grade >=3 gastrointestinal or non-gastrointestinal fistula. 12. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least * teaspoon) within 3 weeks prior to Cycle 1 Day 1. 13. 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. 14. History of ifosfamide-related Grade >=3 nephrotoxicity or encephalopathy. 15. 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. 16. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by local authority. 17. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected). Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority. 18. 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. 19. 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 disco
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PFS (progression-free survival) 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. | — |
Secondary
| Measure | Time frame |
|---|---|
| -PFS-4m rate (progression-free survival rate at 4 months) by IIR 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 using the Kaplan-Meier (K-M) method. -PFS-1y rate (progression-free survival rate at 1 year) 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 using the K-M method. -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 for the primary analysis, will be censored at the date the subject was last known to be alive, or date of data cutoff for the primary analysis, whichever occurs first. Overall survival rate at 1 year (OS-1y) will be estimated using the K-M method. -Objective response rate by IIR at 4 months (ORR-4m) 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. -Objective response rate (ORR) by IIR 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. -Safety will be assessed summarizing the incidence of treatment-emergent adverse events (TEAEs) and SAEs together with all other safety parameters. -Assessment of population-based PK parameters of lenvatinib. -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 | — |
Countries
Netherlands
Outcome results
None listed