Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma

• ClinicalTrials.gov Identifier: NCT02432274
• Recruitment Status: Completed
• First Posted: May 4, 2015
• Results First Posted: September 17, 2020
• Last Update Posted: December 19, 2022
• Sponsor: Eisai Limited
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Limited )

Study Description

Brief Summary:

This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib as single-agent, and in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed solid malignancies including differentiated thyroid carcinoma (single agent lenvatinib) and osteosarcoma (single agent and combination lenvatinib).

Condition or disease	Intervention/treatment	Phase
Tumors; Solid Malignant Tumors; Osteosarcoma; Differentiated Thyroid Cancer (DTC)	Drug: Lenvatinib; Drug: Ifosfamide; Drug: Etoposide	Phase 1; Phase 2

Detailed Description:

The study consists of 5 cohorts:

Cohort 1 (Single-Agent Dose-Finding) dose-escalation to find the recommended dose (RD) of lenvatinib using time-to-event continual reassessment method (TiTE-CRM) in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will enroll in parallel.

Cohort 2 (Single-Agent Expansion) will evaluate the efficacy of lenvatinib at the RD in children, adolescents, and young adults with

1. 131 iodine-refractory differentiated thyroid cancer (DTC) [Cohort 2A] or
2. Relapsed or refractory osteosarcoma [Cohort 2B]

Cohort 3A (Combination Dose-Finding) will determine the RD of lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.

Cohort 3B (Combination Expansion) will evaluate the efficacy of lenvatinib at the RD from Cohort 3A in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Participants with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced progressive disease will also be candidates for enrollment in Cohort 3B.

Lenvatinib will be provided as hard capsules containing 1, 4, or 10 mg lenvatinib. Lenvatinib capsules should be dissolved in water or apple juice for those who are unable to swallow capsules.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 117 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma
• Actual Study Start Date: December 29, 2014
• Actual Primary Completion Date: July 18, 2019
• Actual Study Completion Date: July 20, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: Single-Agent Dose-Finding; Children and adolescents with relapsed or refractory solid malignant tumors.	Drug: Lenvatinib; Cohort 1: Lenvatinib will be administered orally, once daily on Days 1 to 28 of each 28-day cycle at a starting dose of 11 mg/m2. Dose can be de-escalated to 9 mg/m2 or escalated to 14 and 17 mg/m2.; Other Name: E7080, lenvatinib
Experimental: Cohort 2A: Single-agent Expansion (DTC); Children and adolescents with 131 iodine-refractory DTC.	Drug: Lenvatinib; Cohort 2A: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.; Other Name: E7080, lenvatinib
Experimental: Cohort 2B: Single-agent Expansion (Osteosarcoma); Participants with relapsed or refractory osteosarcoma.	Drug: Lenvatinib; Cohort 2B: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle.; Other Name: E7080, lenvatinib
Experimental: Cohort 3A: Combination Dose-finding; Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.	Drug: Lenvatinib; Cohort 3A: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at 20% lower than RD determined in Cohort 1 (starting dose). Lenvatinib dose can be escalated to the RD from Cohort 1 or de-escalated to 40 and 60% lower than the RD from Cohort 1.; Other Name: E7080, lenvatinib; Drug: Ifosfamide; Ifosfamide 3000 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Ifosfamide dose can be de-escalated to 2400 mg/m2/day and 1800 mg/m2/day.; Drug: Etoposide; Etoposide 100 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Etoposide dose can be de-escalated to 80 mg/m2/day and 60 mg/m2/day.
Experimental: Cohort 3B: Combination Expansion; Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.	Drug: Lenvatinib; Cohort 3B: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at the RD as determined in Cohort 3A.; Other Name: E7080, lenvatinib; Drug: Ifosfamide; Ifosfamide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.; Drug: Etoposide; Etoposide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Outcome Measures

Primary Outcome Measures :

1. Cohort 1: Recommended Dose (RD) of Lenvatinib [ Time Frame: Cycle 1 (28 days) ]
   RD was defined as the dose that had a dose limiting toxicity (DLT) rate closest to the targeted 20% rate. DLT was an adverse drug reaction and was assessed according to common terminology criteria for adverse events (CTCAE) version (v) 4.03 defined as 1) Grade 4 neutropenia for greater than or equal to (>=) 7 days, 2) Grade >=3 thrombocytopenia with bleeding, or lasting greater than (>) 7 days, 3) Grade >=3 febrile neutropenia, 4) Next course of chemotherapy delayed for >=7 days, 5) Grade >=3 non-hematologic toxicity persisting >7 days optimal supportive care, 6) Grade 4 hypertension, confirmed systolic or diastolic blood pressure >25 millimeters of mercury (mmHg) above the 95th percentile for age, or an elevated diastolic blood pressure (that is, >95th percentile for age) not controlled by a single antihypertensive medication within 14 days of use, 7) Grade 3 proteinuria, 8) Any recurrent Grade 2 non-hematological toxicity requiring >=2 interruption and dose reductions.
2. Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR) [ Time Frame: From date of first dose of study drug until first documentation of PD or death, whichever occurred first (until the data cut-off date, 31 May 2019) ]
   OR was defined as participants with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for >4 weeks) recorded from the start of the treatment until PD or death whichever occurred first. CR was 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 <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
3. Cohort 2A: Number of Participants With Best Overall Response (BOR) [ Time Frame: From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019) ]
   BOR was defined as the best response of CR or PR for >4 weeks or SD for >=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
4. Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4 [ Time Frame: At Month 4 ]
   Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of participants who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: >= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD.
5. Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide [ Time Frame: Cycle 1 (21 days) ]
   RD of lenvatinib when given in combination with ifosfamide and etoposide was defined as dose that resulted in no more than 1 DLT per 6 participants,or hematologic DLT in 1 participant and nonhematologic DLT in another participant per 6 participants,upon repeating same dose level.DLT was adverse drug reaction and assessed per CTCAE v4.03 defined as 1)Grade 4 neutropenia for >=10 days,2)Grade >=3 thrombocytopenia with bleeding,or lasting >=10 days,3)Grade >=3 febrile neutropenia lasting >=7 days,4)Next course of chemotherapy delayed for >=7 days,5)Grade >=3 nonhematologic toxicity persisting >7 days despite optimal supportive care,6)Grade 4 hypertension,confirmed systolic or diastolic blood pressure >25 mmHg above 95th percentile for age,or elevated diastolic blood pressure(>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7)Grade 3 proteinuria,8)Any recurrent Grade 2 nonhematological toxicity requiring >=2 interruption and dose reductions.

Secondary Outcome Measures :

1. Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR) [ Time Frame: From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   BOR: best response of CR or PR for >4 weeks or SD for >=7 weeks from first dose, recorded from start of treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have reduction in their short axis <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Not evaluable (NE) means BOR of NE or SD of <7 weeks duration. Unknown means no data were available on the case report form.
2. Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR) [ Time Frame: From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   ORR was defined as the percentage of participants with a BOR of CR or PR for >4 weeks or SD for >=7 weeks as assessed by investigator based on RECIST v1.1, recorded from start of study treatment until PD or death whichever occurred first. CR was 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 <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. 95% CI of the ORR were calculated according to Clopper and Pearson method.
3. Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR) [ Time Frame: First documentation of CR/PR until first documentation of PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   DOR was defined as time in months from the first documentation confirmed CR or PR until the first documentation of confirmed PD as assessed by investigator based on RECIST v1.1. CR: 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 <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. 95% CI for the median were calculated according to Brookmeyer and Crowley method.
4. Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control [ Time Frame: From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   Participants were defined as having disease control if they had a BOR of CR or PR for >4 weeks, or SD (minimum duration from first dose to SD >=7 weeks) or if participants had a BOR of CR or Non-CR/Non-PD (minimum duration from first dose to Non-CR/Non-PD >=7 weeks) per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest SOD. Non-CR/Non-PD: persistence of 1 or more non-target lesions, maintenance of tumor marker level above the normal limits.
5. Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit [ Time Frame: From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   Participants were defined as having clinical benefit if they had a BOR of CR or PR for >4 weeks or durable SD (lasting >=23 weeks) or if participants had a BOR of CR or durable Non-CR/Non-PD (lasting >=23 weeks) as per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. Non-CR/Non-PD:persistence of 1 or more non-target lesions and maintenance of tumor marker level above the normal limits.
6. Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS) [ Time Frame: From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   PFS was defined as the time (in months) from the date of first dose of study drug to the date of first documentation of PD or date of death, whichever occurred first, based on RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
7. Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP) [ Time Frame: From first dose of study drug until PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   TTP was defined as the time from the date of first dose of study drug to the date of first documentation of PD based on RECIST 1.1. PD was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the baseline SOD of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method.
8. Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS) [ Time Frame: From first dose of study drug until death (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   OS was defined as the time from the date of the first dose of study drug until the date of death from any cause. Participants who are lost to follow-up and those who are alive at the date of data cutoff were censored at the date the participant was last known to be alive (or the data cutoff date). 95% CI of median were calculated according to Brookmeyer and Crowley method.
9. Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
   Number of participants with TEAEs (serious and non-serious adverse events) and SAEs were reported based on their safety assessments of hematology, clinical chemistry, proximal tibial growth, fecal occult blood, physical examinations, regular measurement of vital signs and electrocardiogram parameter values.
10. Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Most Frequent Treatment-emergent Adverse Events (TEAEs) Related to Lenvatinib Exposure [ Time Frame: First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019) ]
    TEAEs (serious and non-serious), those occurred most frequently have been reported in this outcome measure. "Palmar-plantar E syndrome" refers to Palmar-plantar erythrodysaesthesia syndrome.
11. Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib [ Time Frame: Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose ]
    Duration of each cycle for Cohorts 1, 2A, 2B is 28 days. Duration of each cycle for Cohorts 3A, 3B is 21 days.
12. Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level [ Time Frame: Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1 (Duration of each cycle=21 days) ]
    Serum biomarkers included Fibroblast Growth Factor (FGF) 19, FGF 21, Vascular Endothelial Growth Factor (VEGF). In this outcome measure, percent change from baseline in serum biomarkers level per "PFS-4, Yes" and "PFS-4, No" have been reported. As per assessment of investigator based on RECIST v1.1, "PFS-4, Yes"= participants evaluable for PFS-4 month and alive and without PD at 4 months from the first dose, "PFS-4, No"=participants evaluable for PFS-4 month and not alive or with PD at 4 months from the first dose.
13. Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Categorized Based on Overall Acceptability Questionnaire Responses for Suspension of Lenvatinib [ Time Frame: Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B) ]
    In acceptability questionnaire, participants were asked to answer the overall acceptability of lenvatinib suspension considering the following elements: taste, appearance, smell and how does it feel in the mouth. Overall acceptability was answered in terms of 7 responses: Super good, really good, good, may be good or may be bad, bad, really bad, super bad. Overall acceptability was the overall acceptance for taste, appearance, smell, and the feeling in mouth. In this measure, number of participants have been reported per their overall acceptability responses.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 25 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of solid malignant tumor.

   1. Cohort 1: Any solid malignant tumor.
   2. Cohort 2A: Differentiated Thyroid Cancer (DTC) with one of the following histological subtypes:

   i) Papillary thyroid cancer (PTC). i.a) Follicular variant. i.b) Other variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hurthle cell variant of papillary carcinoma, or poorly differentiated carcinomas).

   ii) Follicular thyroid cancer (FTC). ii.a) Hurthle cell. ii.b) Clear cell. ii.c) Insular.

   c) Cohort 2B, 3A, and 3B: Relapsed or refractory osteosarcoma.

2. Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer therapy with no available curative options. (Note: Osteosarcoma participants must be in first or subsequent relapse [greater than or equal to first relapse]). Only the osteosarcoma participants enrolled to Cohorts 3A and 3B must be deemed candidates for ifosfamide and etoposide chemotherapy).

3. Evaluable or measurable disease that meets the following criteria:

   1. Participants must have evaluable or measurable disease based on RECIST 1.1 using computed tomography (CT)/magnetic resonance imaging (MRI).
   2. 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. DTC participants must be 131 iodine-refractory/ relapsed as defined by at least one of the following:

   1. One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; or
   2. One or more evaluable or measurable lesions that have progressed based on RECIST 1.1, within 12 months of 131 iodine therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These participants must not be eligible for possible curative surgery; or
   3. Cumulative activity of 131 iodine greater than 400 millicuries (mCi) or 14.8 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
5. Participants with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone (TSH) should not be elevated (TSH should be less than or equal to 5.50 milliunits per liter (mU/L)). When tolerated by the participant, thyroxine dose should be changed to achieve TSH suppression (TSH less than 0.50 mU/L).
6. Participants with known central nervous system (CNS) primary tumors or metastases who have completed brain therapy (such as radiotherapy, stereotactic radiosurgery, or surgical resection) and have remained clinically stable, asymptomatic, and off of steroids for 2 weeks prior to Cycle 1 Day 1 will be eligible.
7. Male or female participants age 2 years to less than18 years and less than or equal to 25 years for osteosarcoma subjects at the time of informed consent.
8. Lansky play score greater than or equal to 50% or Karnofsky Performance Status score greater than or equal to 50%. Use Karnofsky for participants greater than or equal to 16 years of age and Lansky for participants less than 16 years of age.
9. Life expectancy greater than or equal to 3 months.

10. Adequate bone marrow function as evidenced by:

    1. absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^9/L (for Cohorts 3A and 3B leucocyte count greater than or equal to 2 x 10^9/L; participants with bone marrow involvement should have ANC greater than or equal to 0.8 x 10^9/L and leucocyte count greater than or equal to 1 x 10^9/L).
    2. hemoglobin greater than or equal to 8.0 grams/deciliter (g/dL) (a hemoglobin less than 8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before starting lenvatinib).
    3. platelet count greater than or equal to 75 x 10^9/L.

11. Adequate liver function as evidenced by:

    1. bilirubin less than or equal 1.5 times the upper limit of normal (ULN).
    2. alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN.

12. Adequate renal function as evidenced by:

    a) Serum creatinine based on age/gender as below. If serum creatinine is greater than maximum serum creatinine for age/gender as shown in the table below, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be greater than 70 milliliter/minute/1.73 square meter (mL/min/1.73 m2).

    Maximum Serum Creatinine in milligrams/deciliter (mg/dL) for male:

    i. Age 2 to less than 6 years = 0.8

    ii. Age 6 to less than 10 years = 1.0

    iii. Age 10 to less than 13 years = 1.2

    iv. Age 13 to less than 16 years = 1.5

    v. Age greater than or equal to 16 years = 1.7

    Maximum Serum Creatinine (mg/dL) for Female:

    vi. Age 2 to less than 6 years = 0.8

    vii. Age 6 to less than 10 years = 1.0

    viii. Age 10 to less than 13 years = 1.2

    ix. Age 13 to less than 16 years = 1.4

    x. Age greater than or equal to 16 years = 1.4

    The threshold creatinine values in this Table were derived from the Schwartz formula for estimating glomerular filtration rate using child length and stature data published by the CDC.

    b) Urine dipstick less than 2+ for proteinuria. Participants who have greater than or equal to 2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be Grade less than 2.

    c) No clinical evidence of nephrotic syndrome.

13. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) greater than or equal to 50%) at baseline as determined by echocardiography.

14. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

    BP less than 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. Osteosarcoma subjects 18 to 25 years should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day 1.

15. Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative radiotherapy; 3 months from high-dose chemotherapy and stem cell rescue; 3 weeks from major surgery. Participants must have recovered from the acute toxic effects of all prior anticancer therapy before enrollment into the study.
16. Written and signed informed consent from the parent(s) or legal representative (guardian) and assent from the minor participant. Written informed consent from subjects ≥18 years.

17. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the Investigator.

    Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

18. Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet only Inclusion Criteria Numbers 6 through 17 (after progression in Cohort 2B).

Exclusion criteria:

1. Any active infection or infectious illness unless fully recovered prior to dosing.
2. Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.
3. Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, or radiation therapy) except alopecia, and ototoxicity due to cisplatin not already covered in the inclusion/exclusion criteria, which has not recovered to Grade less than 2 per Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
4. Known hypersensitivity to any component of the product (lenvatinib or ingredients).
5. Concurrent administration of any other antitumor therapy.
6. Previous treatment with lenvatinib (except for participants previously enrolled into Cohorts 1 or 2B of this study).
7. Two or more prior vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) targeted therapies.
8. Currently receiving any investigational drug or device in another clinical trial or within 30 days preceding informed consent.
9. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval greater than 480 msec).
10. Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib.
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 3 weeks prior to the first dose of study drug.
12. Active second malignancy within 2 years prior to enrollment ([in addition to the primary tumor types specified by cohort in Inclusion Criterion Number 1], but not including definitively treated superficial melanoma, in-situ, basal or squamous cell carcinoma of the skin).
13. Previous treatment with ifosfamide and Grade greater than or equal to 3 nephrotoxicity or encephalopathy (Cohorts 3A and 3B).

14. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.

    Cohort 3B (Combination Expansion): Osteosarcoma participants who progressed in Cohorts 1 or 2B and opt to receive combination therapy.

15. Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6.

Contacts and Locations

Locations

United States, Texas

Texas Children's Hospital

Houston, Texas, United States, 77030

France

CHU Strasbourg - Hopital Hautepierre

Strasbourg, Bas Rhin, France

Centre Oscar Lambret Lille

Lille, Rhone, France

Centre Leon Berard

Lyon, Rhone, France

CHU Nantes - Hopital Mere-Enfant

Nantes, France

Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris

Paris, France

Institut Gustave Roussy

Paris, France

CHU de Toulouse - Hopital des Enfants

Toulouse, France

Germany

Universitaetsklinikum Muenster

Muenster, Germany

Kinderklinik des Olga hospitals

Stuttgart, Germany

Italy

Istituto Ortopedico Rizzoli

Bologna, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

Ospedale Pediatrico Bambino Gesu

Roma, Italy

Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Hospital Infantil Universitario Nino Jesus

Madrid, Spain

Hospital Universitario y Politecnico La Fe Hospital La Fe Valencia

Valencia, Spain

United Kingdom

Birmingham Children's Hospital

Birmingham, United Kingdom

University College London Hospital

London, United Kingdom

Royal Victoria Infirmary

Newcastle, United Kingdom

Sponsors and Collaborators

Eisai Limited

Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Eisai Inc. ( Eisai Limited ):

Study Protocol  [PDF] November 22, 2019

Statistical Analysis Plan  [PDF] March 26, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, Venkatramani R, Hecker-Nolting S, Gambart M, Bautista F, Thebaud E, Aerts I, Morland B, Rossig C, Canete Nieto A, Longhi A, Lervat C, Entz-Werle N, Strauss SJ, Marec-Berard P, Okpara CE, He C, Dutta L, Casanova M. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆. ESMO Open. 2021 Oct;6(5):100250. doi: 10.1016/j.esmoop.2021.100250. Epub 2021 Sep 22.

Rutkowski P. Antiangiogenic agents combined with systemic chemotherapy in refractory osteosarcoma. Lancet Oncol. 2021 Sep;22(9):1206-1207. doi: 10.1016/S1470-2045(21)00422-8. Epub 2021 Aug 17. No abstract available.

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.

Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

• Responsible Party: Eisai Limited
• ClinicalTrials.gov Identifier: NCT02432274
• Other Study ID Numbers: E7080-G000-207; 2013-005534-38 ( EudraCT Number )
• First Posted: May 4, 2015
• Results First Posted: September 17, 2020
• Last Update Posted: December 19, 2022
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc. ( Eisai Limited ):

E7080; Lenvatinib; Solid malignancies; Osteosarcoma; Differentiated Thyroid Cancer

Additional relevant MeSH terms:

Neoplasms; Thyroid Neoplasms; Osteosarcoma; Thyroid Diseases; Endocrine System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma; Etoposide; Etoposide phosphate; Ifosfamide; Isophosphamide mustard; Lenvatinib; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors