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CompletedNCT04154189Updated Jul 22, 2024Results posted

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

A Phase 2 interventional study of Lenvatinib and Ifosfamide in Osteosarcoma, sponsored by Eisai Inc.. Completed at 84 sites in 21 countries. Open to participants aged 2 Years to 25 Years. Per ClinicalTrials.gov, last updated 2024-07-22.

Sponsored by Eisai Inc. · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
81
Allocation
Randomized
Ages
2 Years to 25 Years
Sex
All
01

Study summary

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.

02

Conditions studied

  • Osteosarcoma

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Keywords

  • Osteosarcoma
  • Lenvatinib
  • Ifosfamide
  • Etoposide
  • E7080
  • Relapsed or Refractory Osteosarcoma
  • Pediatrics
  • Chemotherapy
03

In context

Osteosarcoma

437 studies on the registry are indexed under Osteosarcoma; 116 are open to participants now.

This study's enrollment of 81 is above the median of 42 across 325 interventional studies indexed under Osteosarcoma.

Browse Osteosarcoma studies →

Lead sponsor

Eisai Inc. is the lead sponsor of 360 studies on the registry; 7 are open to participants now.

Of its 81 completed or terminated interventional studies of FDA-regulated products, 54 (67%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
2 Years to 25 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
81 participants (actual)

Study arms

  • Experimental
    Randomization Phase: Lenvatinib + Ifosfamide + Etoposide

    Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.

    Drug: Lenvatinib · Drug: Ifosfamide · Drug: Etoposide

  • Active comparator
    Randomization Phase: Ifosfamide + Etoposide

    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 · Drug: Etoposide · Drug: Lenvatinib

Interventions

  • DrugLenvatinib

    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.

    Also known as: E7080

  • DrugIfosfamide

    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.

  • DrugEtoposide

    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.

  • DrugLenvatinib

    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.

    Also known as: E7080

06

What researchers measure

Primary outcomes

  1. 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

  1. 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

  2. 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

  3. 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.

    Time frame: From the date of randomization to the date of death from any cause (up to 37.1 months)

  4. 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.

    Time frame: Month 12 or 1 Year

  5. 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.

    Time frame: Month 4

  6. 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.

    Time frame: From the date of randomization to the date of the first documentation of CR or PR (up to 20.5 months)

  7. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

    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. Serious adverse events (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.

    Time frame: From first dose up to 30 days after the last dose of study drug (up to 40.8 months)

  8. 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.

    Time frame: 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)

  9. 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.

    Time frame: Baseline and Month 4

  10. 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.

    Time frame: Baseline and Month 4

  11. 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.

    Time frame: Cycle 1 Day 1 (Cycle length = 21 days)

07

Results

Posted Aug 7, 2023

Participant flow

Participants took part in the study at 84 investigative sites in Austria, Australia, Belgium, Hong Kong, Korea, New Zealand, Singapore, Taiwan, Czech Republic, Finland, France, Israel, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, United Kingdom, Canada, and the United States.

Participant flow — Overall Study
MilestoneTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Started4041
Treated (safety analysis set)3939
Optional lenvatinib treatment (arm b only)016
Completed00
Not completed4041
Withdrew: Withdrawal by subject46
Withdrew: Survival follow-up discontinued by sponsor810
Withdrew: Participants transitioned to patient access program (pap)10
Withdrew: Participants transitioned to managed access program (map)20
Withdrew: Death2525

Outcome measures

PrimaryProgression-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)
Reported as:
Median · months
Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment
monthsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Progression-free Survival (PFS) by Independent Imaging Review (IIR) Assessment6.5 (5.7 to 8.2)5.5 (2.9 to 6.5)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Log Rank · p = 0.0396 (One-sided P value) · Hazard ratio (hr): 0.54 · 95% CI 0.27 to 1.08Hazard ratio was based on Cox Proportional Hazard Model including treatment group as a factor and stratified by Age (less than \[\<\]18 years, more than or equal to \[\>=\]18 years) in interactive response technology (IRT). Efron method was used for ties.
SecondaryPercentage 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
Reported as:
Number · percentage of participants
Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment
percentage of participantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Percentage of Participants With PFS at Month 4 (PFS-4m Rate) by IIR Assessment76.3 (59.3 to 86.9)66.0 (47.7 to 79.2)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Kaplan-Meier Method · p = 0.1683 (One-sided P value) · Difference in percentage: 10.2 · 95% CI -10.6 to 31.1
SecondaryPercentage 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
Reported as:
Number · percentage of participants
Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR Assessment
percentage of participantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Percentage of Participants With PFS at 1 Year or Month 12 (PFS-1y Rate) by IIR AssessmentNA (NA to NA)14.9 (1.1 to 44.5)
SecondaryOverall 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.

Time frame:
From the date of randomization to the date of death from any cause (up to 37.1 months)
Reported as:
Median · months
Overall Survival (OS)
monthsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Overall Survival (OS)12.4 (10.4 to 19.8)17.2 (11.1 to 22.3)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Stratified Log-rank One-sided Test · p = 0.3924 (Nominal p-value from stratified log-rank test adjusted for the randomization stratification factor, that is, age.) · Hazard ratio (hr): 0.93 · 95% CI 0.53 to 1.62Hazard ratio was based on a Cox Proportional Hazard Model including treatment group as a factor and stratified by Age (\<18 years, \>=18 years) in IRT. Efron method was used for ties.
SecondaryPercentage 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.

Time frame:
Month 12 or 1 Year
Reported as:
Number · percentage of participants
Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y)
percentage of participantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Percentage of Participants With Overall Survival at 1 Year or Month 12 (OS-1y)49.2 (28.5 to 67.0)72.1 (54.2 to 83.9)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Kaplan Meier Method · p = 0.0352 (One-sided P value) · Difference in percentage: -22.9 · 95% CI -47.6 to 1.9
SecondaryObjective 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.

Time frame:
Month 4
Reported as:
Number · percentage of participants
Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment
percentage of participantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Objective Response Rate at Month 4 (ORR-4m) by IIR Assessment15.0 (5.7 to 29.8)7.3 (1.5 to 19.9)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Difference in percentage: 7.7 · 95% CI -6.4 to 22.3
SecondaryORR 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.

Time frame:
From the date of randomization to the date of the first documentation of CR or PR (up to 20.5 months)
Reported as:
Number · percentage of participants
ORR by IIR Assessment
percentage of participantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
ORR by IIR Assessment15.0 (5.7 to 29.8)9.8 (2.7 to 23.1)
Statistical analysis
  • Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide vs Treatment Arm B: Ifosfamide + Etoposide · Difference in percentage: 5.2 · 95% CI -10.3 to 20.0
SecondaryNumber of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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. Serious adverse events (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.

Time frame:
From first dose up to 30 days after the last dose of study drug (up to 40.8 months)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
ParticipantsTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Participants with TEAEs3839
Participants with TESAEs3020
SecondaryTreatment 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.

Time frame:
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)
Reported as:
Mean · nanograms per milliliter (ng/mL)
Treatment Arm A: Plasma Concentration of Lenvatinib
nanograms per milliliter (ng/mL)Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide
Cycle 1, Day 1: 0.5-4 hours post-dose147.9 ± 194.61
Cycle 1, Day 1: 6-10 hours post-dose217.8 ± 99.54
Cycle 1, Day 15: Pre-dose70.7 ± 43.48
Cycle 1, Day 15: 0.5-4 hours post-dose222.3 ± 203.07
Cycle 1, Day 15: 6-10 hours post-dose310.9 ± 106.79
Cycle 2, Day 1: Pre-dose70.2 ± 67.95
SecondaryChange 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.

Time frame:
Baseline and Month 4
Reported as:
Mean · score on a scale
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 4
score on a scaleTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Scale: Generic Core Scale Score at Month 42.61 ± 17.5682.65 ± 4.128
SecondaryChange 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.

Time frame:
Baseline and Month 4
Reported as:
Mean · score on a scale
Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 4
score on a scaleTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + Etoposide
Change From Baseline in PedsQL Scale: Cancer Module Scale Score at Month 42.66 ± 9.9892.08 ± 6.736
SecondaryNumber 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.

Time frame:
Cycle 1 Day 1 (Cycle length = 21 days)
Reported as:
Count of participants · Participants
Number of Participants Categorized Based on Overall Palatability and Acceptability Questionnaire Responses for Suspension of Lenvatinib
ParticipantsAll Participants: Lenvatinib 14 mg/m^2
Super Bad0
Really Bad0
Bad0
May be Good or May be Bad2
Good2
Really Good0
Super Good1

Adverse events

Collected over From first dose up to 30 days after the last dose of study drug (up to 40.8 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Treatment Arm A: Lenvatinib + Ifosfamide + Etoposide25/40 (62.5%)30/39 (76.9%)38/39 (97.4%)
Treatment Arm B: Ifosfamide + Etoposide25/41 (61%)20/39 (51.3%)39/39 (100%)
Treatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)12/16 (75%)10/16 (62.5%)16/16 (100%)
Most frequent serious events
Showing 10 of 83
Most frequent serious events
EventTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTreatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)
Febrile neutropeniaBlood and lymphatic system disorders15/397/390/16
PneumothoraxRespiratory, thoracic and mediastinal disorders7/391/394/16
PyrexiaGeneral disorders6/392/391/16
Malignant pleural effusionNeoplasms benign, malignant and unspecified (incl cysts and polyps)4/391/390/16
Platelet count decreasedInvestigations3/390/390/16
Toxic encephalopathyNervous system disorders3/390/390/16
DiarrhoeaGastrointestinal disorders1/390/391/16
VomitingGastrointestinal disorders0/391/391/16
PneumoniaInfections and infestations2/390/391/16
HypertensionVascular disorders1/390/391/16
Most frequent other events
Showing 10 of 153
Most frequent other events
EventTreatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTreatment Arm B: Ifosfamide+Etoposide to Lenvatinib (Optional)
HypothyroidismEndocrine disorders35/390/398/16
AnaemiaBlood and lymphatic system disorders28/3927/392/16
NauseaGastrointestinal disorders23/3916/395/16
Platelet count decreasedInvestigations23/3917/393/16
ProteinuriaRenal and urinary disorders21/395/396/16
VomitingGastrointestinal disorders19/3911/395/16
HypertensionVascular disorders16/390/396/16
Neutrophil count decreasedInvestigations15/3913/391/16
Back painMusculoskeletal and connective tissue disorders15/396/394/16
Pain in extremityMusculoskeletal and connective tissue disorders9/395/396/16

Baseline characteristics

Full Analysis Set (FAS) included all randomized participants regardless of the treatment actually received.

Age, Continuous
Age, Continuous(years)Treatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTotal
Mean15.6 ± 3.7614.3 ± 4.1614.9 ± 3.99
Sex: Female, Male
Sex: Female, Male(Participants)Treatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTotal
Female152035
Male252146
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Treatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTotal
Hispanic or Latino235
Not Hispanic or Latino383371
Unknown or Not Reported055
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Treatment Arm A: Lenvatinib + Ifosfamide + EtoposideTreatment Arm B: Ifosfamide + EtoposideTotal
White242650
Black or African American112
Asian13720
American Indian or Alaskan Native011
Other246
Missing022
08

Study locations

84 sites
  • Children's of Alabama
    Birmingham, Alabama 35233, United States
  • Loma Linda University Medical Center
    Loma Linda, California 92354, United States
  • Children's Hospital of Orange County
    Orange, California 92868, United States
  • UCSF Benioff Children's Hospitals
    San Francisco, California 94143, United States
  • Childrens Hospital Colorado
    Aurora, Colorado 80045, United States
  • Children's National Medical Center
    Washington, District of Columbia 20010, United States
  • Riley Hospital For Children
    Indianapolis, Indiana 46202, United States
  • Dana Farber Cancer Institute
    Boston, Massachusetts 02215, United States
  • University of Mississippi Medical Center
    Jackson, Mississippi 39216, United States
  • Hackensack University Medical Center
    Hackensack, New Jersey 07601, United States
  • Memorial Sloan Kettering Cancer Center
    New York, New York 10065, United States
  • Cincinnati Children's Hospital Medical Center
    Cincinnati, Ohio 45229, United States
  • Vanderbilt University Medical Center
    Nashville, Tennessee 37232, United States
  • Children's Medical Center Dallas
    Dallas, Texas 75235, United States
  • Cook Children's Health Care System
    Fort Worth, Texas 76104, United States
  • Texas Children's Hospital
    Houston, Texas 77030, United States
  • Chris O'Brien Lifehouse Hospital
    Camperdown, Australia
  • Perth Childrens Hospital
    Nedlands, Australia
  • Royal Children's Hospital Melbourne
    Parkville, Australia
  • Queensland Children's Hospital
    South Brisbane, Australia
  • Children's Hospital at Westmead
    Westmead, Australia
  • St. Anna Kinderspital
    Wien, Austria
  • UZ Gent
    Gent, Belgium
  • Hospital For Sick Children
    Toronto, Canada
  • FN Brno 2 Detska Klinika
    Brno, Czechia
  • Fakultní nemocnice v Motole
    Prague, Czechia
  • Tampereen yliopistollinen sairaala
    Tampere, Länsi-Suomen Lääni FI-33520, Finland
  • Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin
    Bordeaux, France
  • Centre Oscar Lambret
    Lille, France
  • Centre Léon Berard
    Lyon, France
  • Hopitaux de La Timone
    Marseille, France
  • Hôpital de La Mère Et de L'enfant
    Nantes, France
  • CHU de Nice
    Nice, France
  • Hôpital Armand Trousseau
    Paris, France
  • Institut Curie
    Paris, France
  • Hopital de Hautepierre
    Strasbourg, France
  • Hôpital Des Enfants
    Toulouse, France
  • CHRU Nancy
    Vandœuvre-lès-Nancy, France
  • Institut Gustave Roussy
    Villejuif, France
  • Hong Kong Children's Hospital
    Hong Kong, Hong Kong
  • Prince of Wales Hospital
    Hong Kong, Hong Kong
  • Children's Health Ireland at Crumlin
    Dublin, Ireland
  • Schneider Children's Medical Center of Israel
    Petach Tikva, Israel
  • Istituti Ortopedici Rizzoli
    Bologna, Italy
  • Azienda Ospedaliera A Meyer
    Firenze, Italy
  • Istituto Giannina Gaslini
    Genova, Italy
  • Istituto Nazionale Dei Tumori
    Milan, Italy
  • IRCCS Ospedale Pediatrico Bambino Gesù
    Roma, Italy
  • National Cancer Center
    Goyang-si, Korea, Republic of
  • Asan Medical Center
    Seoul, Korea, Republic of
  • Samsung Medical Center
    Seoul, Korea, Republic of
  • Seoul National University Hospital
    Seoul, Korea, Republic of
  • Severance Hospital Yonsei University Health System
    Seoul, Korea, Republic of
  • Princess Maxima Center for Pediatric Oncology
    Utrecht, Netherlands
  • Auckland City Hospital
    Auckland, New Zealand
  • Starship Children's Hospital
    Auckland, New Zealand
  • KK Women's and Children's Hospital
    Singapore, Singapore
  • National Cancer Centre
    Singapore, Singapore
  • National University Hospital
    Singapore, Singapore
  • Hospital Universitario de Cruces
    Barakaldo, Spain
  • Hospital Sant Joan de Deu
    Barcelona, Spain
  • Hospital Universitario Vall d'Hebrón
    Barcelona, Spain
  • Hospital Infantil Universitario Niño Jesus
    Madrid, Spain
  • Hospital Universitario Fundacion Jimenez Diaz
    Madrid, Spain
  • Hospital Universitario La Paz
    Madrid, Spain
  • Hospital Universitario Virgen del Rocio
    Sevilla, Spain
  • Hospital Universitari i Politecnic La Fe de Valencia
    Valencia, Spain
  • Drottning Silvias Barn Och Ungdomssjukhus
    Göteborg, Sweden
  • Skanes Universitetssjukhus Lund
    Lund, Sweden
  • Karolinska Universitetssjukhuset Solna
    Stockholm, Sweden
  • Centre Hospitalier Universitaire Vaudois
    Lausanne, Switzerland
  • Kinderspital Zürich - Eleonorenstiftung
    Zürich, Switzerland
  • National Taiwan University Hospital
    Taipei, Taiwan
  • Taipei Veterans General Hospital
    Taipei, Taiwan
  • Birmingham Children's Hospital
    Birmingham, United Kingdom
  • The Royal Hospital for Children
    Bristol, United Kingdom
  • Royal Hospital for Children
    Glasgow, United Kingdom
  • Leeds Children Hospital
    Leeds, United Kingdom
  • Alder Hey Children's Hospital
    Liverpool, United Kingdom
  • UCL Cancer Institute
    London, United Kingdom
  • Royal Manchester Childrens Hospital
    Manchester, United Kingdom
  • The Christie NHS Foundation Trust
    Manchester, United Kingdom
  • Royal Victoria Infirmary
    Newcastle, United Kingdom
  • John Radcliffe Hospital
    Oxford, United Kingdom
09

References and documents

Publications

  • Gaspar N, Venkatramani R, Hecker-Nolting S, Melcon SG, Locatelli F, Bautista F, Longhi A, Lervat C, Entz-Werle N, Casanova M, Aerts I, Strauss SJ, Thebaud E, Morland B, Nieto AC, Marec-Berard P, Gambart M, Rossig C, Okpara CE, He C, Dutta L, Campbell-Hewson Q. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021 Sep;22(9):1312-1321. doi: 10.1016/S1470-2045(21)00387-9. Epub 2021 Aug 17. PubMed 34416158 ↗
  • Gaspar N, Campbell-Hewson Q, Huang J, Okpara CE, Bautista F. OLIE, ITCC-082: a Phase II trial of lenvatinib plus ifosfamide and etoposide in relapsed/refractory osteosarcoma. Future Oncol. 2021 Nov;17(32):4249-4261. doi: 10.2217/fon-2021-0743. Epub 2021 Aug 12. PubMed 34382412 ↗

Related links

Study documents

  • Study protocol · Sep 10, 2020
  • Statistical analysis plan · Jun 15, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jul 22, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04154189
Lead sponsor
Eisai Inc.
Collaborators
Merck Sharp & Dohme LLC
Responsible party
Sponsor
First posted
Nov 6, 2019
Start date
Mar 23, 2020
Primary completion
Jun 22, 2022
Completion
Aug 17, 2023
Results posted
Aug 7, 2023
Last update
Jul 22, 2024

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jul 2024. You cannot join it, but the record below documents what was studied.

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