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NCT03245151

Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors

Completed Phase 1, PHASE2 Results posted Last updated 30 August 2023
What this trial tests

Phase 1, PHASE2 trial testing Lenvatinib in Recurrent and Refractory Solid Tumors in 64 participants. Completed in 30 September 2022.

Timeline
16 November 2017
Primary endpoint
30 September 2022
30 September 2022

Quick facts

Lead sponsorEisai Inc.
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment64
Start date16 November 2017
Primary completion30 September 2022
Estimated completion30 September 2022
Sites50 locations across Canada, United States

Drugs / interventions tested

Conditions studied

Sponsor

Eisai Inc. — full company profile →

Who can join

Adults 2 to 21, any sex, with Recurrent and Refractory Solid Tumors. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus Primary · Cycle 1 (Each cycle was of 28 days)

MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03.

GroupValue95% CI
Phase 1: Lenvatinib + Everolimus (All Participants)11
Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus Primary · Cycle 1 (Each cycle was of 28 days)

The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03.

GroupValue95% CI
Phase 1: Lenvatinib + Everolimus (All Participants)11
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Primary · From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)

A TEAE was defined as an adverse event that emerged during treatment, 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 the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.

GroupValue95% CI
Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^25
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^218
Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) Primary · From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)

A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.

GroupValue95% CI
Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^22
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^212
Phase 2: Objective Response Rate (ORR) at Week 16 Primary · Week 16

ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as 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 less than (\<) 10 millimeter (mm). PR was defined as at

GroupValue95% CI
Phase 2: Cohort 1, Ewing Sarcoma0.00.0 – 30.8
Phase 2: Cohort 2, Rhabdomyosarcoma10.01.2 – 31.7
Phase 2: Cohort 3, HGG00.0 – 30.8
Phase 1: Objective Response Rate (ORR) Secondary · From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months)

ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as 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.

GroupValue95% CI
Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^20.00.0 – 70.8
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^20.00.0 – 21.8
Phase 2: Objective Response Rate (ORR) Secondary · From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months)

ORR was defined as the percentage of participants with BOR of CR or PR based on investigator assessment according to RECIST version 1.1 for non-HGG cohorts and RANO for HGG cohort. CR was defined as 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.

GroupValue95% CI
Phase 2: Cohort 1, Ewing Sarcoma0.00.0 – 30.8
Phase 2: Cohort 2, Rhabdomyosarcoma10.01.2 – 31.7
Phase 2: Cohort 3, HGG0.00.0 – 30.8
Phase 1: Disease Control Rate (DCR) Secondary · From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)

DCR was defined as percentage of participants with a confirmed CR, PR, or stable disease (SD) (SD duration \>=7 weeks since the first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. 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 su

GroupValue95% CI
Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^220.00.5 – 71.6
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^250.026.0 – 74.0
Phase 2: Disease Control Rate (DCR) Secondary · From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)

DCR was defined as percentage of participants with confirmed CR, PR, or SD (SD duration greater than or equal to \[\>=\] 7 weeks since first dose of study treatment) divided by number of participants in analysis set. DCR was assessed by investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. 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 diame

GroupValue95% CI
Phase 2: Cohort 1, Ewing Sarcoma40.012.2 – 73.8
Phase 2: Cohort 2, Rhabdomyosarcoma40.019.1 – 63.9
Phase 2: Cohort 3, HGG30.06.7 – 65.2
Phase 1: Clinical Benefit Rate (CBR) Secondary · From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months)

CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG participants or RANO for HGG participants. 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 diameter

GroupValue95% CI
Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^220.00.5 – 71.6
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^222.26.4 – 47.6
Phase 2: Clinical Benefit Rate (CBR) Secondary · From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months)

CBR was defined as percentage of participants who had BOR of CR, PR, or durable SD (SD duration \>=23 weeks since the first dose of study treatment) divided by number of participants in analysis set. CBR was assessed by an investigator based on RECIST v1.1 for non-HGG cohorts or RANO for HGG cohort. 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: neit

GroupValue95% CI
Phase 2: Cohort 1, Ewing Sarcoma20.02.5 – 55.6
Phase 2: Cohort 2, Rhabdomyosarcoma10.01.2 – 31.7
Phase 2: Cohort 3, HGG0.00.0 – 30.8
Phase 2: Duration of Response (DOR) Secondary · From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months)

DOR was defined as the time (in months) from the date of first observation of confirmed response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1 for non-HGG cohorts and RANO for HGG cohort, or date of death, whatever the cause. 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 was

GroupValue95% CI
Phase 2: Cohort 2, Rhabdomyosarcoma2.42.1 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: From date of first dose up to 28 days after the last dose of study treatment (Phase 1: Up to 17.5 months; Phase 2: Up to 7.5 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2
Serious: 2/5 (40%)
Deaths: 4/5
Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^2
Serious: 12/18 (67%)
Deaths: 14/18
Phase 2: Cohort 1, Ewing Sarcoma
Serious: 6/10 (60%)
Deaths: 9/10
Phase 2: Cohort 2, Rhabdomyosarcoma
Serious: 8/20 (40%)
Deaths: 17/20
Phase 2: Cohort 3, HGG
Serious: 8/11 (73%)
Deaths: 8/11

Serious adverse events (51 terms)

ReactionSystemPhase 1: Lenvatinib 8 mg/m…Phase 1: Lenvatinib 11 mg/…Phase 2: Cohort 1, Ewing S…Phase 2: Cohort 2, Rhabdom…Phase 2: Cohort 3, HGG
PyrexiaGeneral disorders
SeizureNervous system disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
PainGeneral disorders
Upper respiratory tract infectionsInfections and infestations
Back painMusculoskeletal and connective tissue disorders
PancreatitisGastrointestinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
Febrile neutropeniaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders
DysphagiaGastrointestinal disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Face oedemaGeneral disorders
Pneumonia aspirationInfections and infestations
SepsisInfections and infestations
Tendon ruptureInjury, poisoning and procedural complications
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Musculoskeletal painMusculoskeletal and connective tissue disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
Musculoskeletal chest painMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
Malignant pleural effusionNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Other adverse events (199 terms — click to expand)

ReactionSystemPhase 1: Lenvatinib 8 mg/m…Phase 1: Lenvatinib 11 mg/…Phase 2: Cohort 1, Ewing S…Phase 2: Cohort 2, Rhabdom…Phase 2: Cohort 3, HGG
HypertensionVascular disorders
HypertriglyceridaemiaMetabolism and nutrition disorders
VomitingGastrointestinal disorders
FatigueGeneral disorders
Blood cholesterol increasedInvestigations
Lymphocyte count decreasedInvestigations
HypothyroidismEndocrine disorders
DiarrhoeaGastrointestinal disorders
Platelet count decreasedInvestigations
ProteinuriaRenal and urinary disorders
Abdominal painGastrointestinal disorders
NauseaGastrointestinal disorders
StomatitisGastrointestinal disorders
Aspartate aminotransferase increasedInvestigations
White blood cell count decreasedInvestigations
HypophosphataemiaMetabolism and nutrition disorders
HeadacheNervous system disorders
AnaemiaBlood and lymphatic system disorders
Alanine aminotransferase increasedInvestigations
Neutrophil count decreasedInvestigations
HyponatraemiaMetabolism and nutrition disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
Weight decreasedInvestigations
Decreased appetiteMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
HaematuriaRenal and urinary disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
PyrexiaGeneral disorders
Non-cardiac chest painGeneral disorders
HypoalbuminaemiaMetabolism and nutrition disorders
HypocalcaemiaMetabolism and nutrition disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
Sinus tachycardiaCardiac disorders
Lipase increasedInvestigations
DehydrationMetabolism and nutrition disorders
HyperglycaemiaMetabolism and nutrition disorders
HyperkalaemiaMetabolism and nutrition disorders
HypokalaemiaMetabolism and nutrition disorders

Most-reported serious reactions: Pyrexia, Seizure, Hypoxia, Pain, Upper respiratory tract infections, Back pain, Pancreatitis, Pleural effusion.

Data from ClinicalTrials.gov NCT03245151 adverse events section.

Sponsor's own description

Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Insights into pediatric rhabdomyosarcoma research: Challenges and goals.
    Yohe ME, Heske CM, Stewart E, Adamson PC, et al · · 2019 · cited 65× · PMID 31222885 · DOI 10.1002/pbc.27869
  2. 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)<sup>☆</sup>.
    Gaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, et al · · 2021 · cited 52× · PMID 34562750 · DOI 10.1016/j.esmoop.2021.100250
  3. Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.
    Lake JA, Donson AM, Prince E, Davies KD, et al · · 2020 · cited 49× · PMID 31595628 · DOI 10.1002/pbc.28028
  4. Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors.
    Nemes K, Johann PD, Tüchert S, Melchior P, et al · · 2022 · cited 31× · PMID 35173482 · DOI 10.2147/cmar.s289544
  5. Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma.
    Fleuren EDG, Vlenterie M, van der Graaf WTA. · · 2023 · cited 25× · PMID 36994209 · DOI 10.3389/fonc.2023.1013359
  6. Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma.
    Just MA, Van Mater D, Wagner LM. · · 2021 · cited 23× · PMID 33894051 · DOI 10.1002/pbc.29084
  7. Metabolic landscapes in sarcomas.
    Miallot R, Galland F, Millet V, Blay JY, et al · · 2021 · cited 20× · PMID 34294128 · DOI 10.1186/s13045-021-01125-y
  8. A systematic review of ongoing clinical trials in optic pathway gliomas.
    Hill CS, Devesa SC, Ince W, Borg A, et al · · 2020 · cited 19× · PMID 32556546 · DOI 10.1007/s00381-020-04724-1

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