August 3, 2017
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August 10, 2017
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August 7, 2023
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August 30, 2023
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August 30, 2023
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November 16, 2017
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September 30, 2022 (Final data collection date for primary outcome measure)
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- Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus [ Time Frame: 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.
- Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus [ Time Frame: 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.
- Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) [ Time Frame: 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.
- Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) [ Time Frame: 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.
- Phase 2: Objective Response Rate (ORR) at Week 16 [ Time Frame: 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 least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.
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- Maximum tolerated dose (MTD) of lenvatinib in combination with everolimus [ Time Frame: Cycle 1 (Day 1 to Day 28) of the Treatment Phase ]
The sponsor and Protocol Steering Committee will review all participants' safety and clinical data to determine the MTD of the combination of lenvatinib with everolimus. If 2 or more of a cohort of up to 6 participants experience dose-limiting toxicities (DLTs: side effects that prevent a dose increase) at a given dose level, then the MTD has been exceeded and dose escalation will be stopped.
- Recommended Phase 2 dose (RP2D) of lenvatinib in combination with everolimus [ Time Frame: Cycle 1 (Day 1 to Day 28) of the Treatment Phase ]
The sponsor and Protocol Steering Committee will review all participants' safety and clinical data to determine the MTD of the combination of lenvatinib with everolimus. If 2 or more of a cohort of up to 6 participants experience DLTs (side effects that prevent a dose increase) at a given dose level, then the MTD has been exceeded and dose escalation will be stopped. The RP2D is determined based on the MTD and DLTs.
- Number of participants with any treatment-emergent (TE) serious adverse event (SAE) in Phase 1, as a measure of the safety and toxicity of lenvatinib in combination with everolimus [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2 years ]
An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the adverse event [AE] as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
- Number of participants with any TE adverse event (TEAE) in Phase 1, as a measure of the safety and toxicity of lenvatinib in combination with everolimus [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2 years ]
An AE is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
- Overall Response Rate (ORR) at Week 16 for Phase 2 [ Time Frame: Week 16 ]
ORR is defined as the proportion of participants who have the best overall response (BOR) of complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for Ewing sarcoma/peripheral primitive neuroectodermal tumor [pPNET] and rhabdomyosarcoma) or Response Assessment in Neuro-Oncology (RANO) Criteria (for high grade glioma [HGG]).
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- Phase 1: Objective Response Rate (ORR) [ Time Frame: 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.
- Phase 2: Objective Response Rate (ORR) [ Time Frame: 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.
- Phase 1: Disease Control Rate (DCR) [ Time Frame: 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 sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. 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.
- Phase 2: Disease Control Rate (DCR) [ Time Frame: 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 diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. 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.
- Phase 1: Clinical Benefit Rate (CBR) [ Time Frame: 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 diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. 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.
- Phase 2: Clinical Benefit Rate (CBR) [ Time Frame: 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: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. 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.
- Phase 1: Duration of Response (DOR) [ Time Frame: From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 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 cohorts, 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 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.
- Phase 2: Duration of Response (DOR) [ Time Frame: 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 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.
- Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours]) [ Time Frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) ]
AUC0-t of lenvatinib was quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
- Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax) [ Time Frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) ]
Cmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
- Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax) [ Time Frame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days) ]
Tmax of lenvatinib was quantified using validated liquid LC-MS/MS methods.
- Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib [ Time Frame: Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days) ]
Trough concentrations of everolimus was quantified using validated liquid LC-MS/MS methods.
- Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 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.
- Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE) [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 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.
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- ORR at the time of data cutoff: Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
ORR is defined as the proportion of participants with a BOR of CR or PR per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG).
- ORR at the time of data cutoff: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
ORR is defined as the proportion of participants with a BOR of CR or PR per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- Disease Control Rate (DCR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
DCR is defined as the proportion of participants with a BOR of CR, PR, or stable disease (SD) (SD duration ≥7 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- DCR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
DCR is defined as the proportion of participants with a BOR of CR, PR, or SD (SD duration ≥7 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- Clinical Benefit Rate (CBR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
CBR is defined as the proportion of participants with a BOR of CR, PR, or durable SD (SD duration ≥23 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- CBR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
CBR is defined as the proportion of participants with a BOR of CR, PR, or durable SD (SD duration ≥23 weeks since the first dose of the study treatment) per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- Duration of Response (DOR): Phase 1 [ Time Frame: up to Week 4 of the Treatment Phase; up to 2 years in the Extension Phase ]
DOR is defined as the time from the date of the first documented CR or PR to the date of the disease progression objectively documented or death (whichever occurs first). CR, PR, and disease progression will be defined per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- DOR: Phase 2 [ Time Frame: up to Week 16 of the Treatment Phase; up to 2 years in the Extension Phase ]
DOR is defined as the time from the date of the first documented CR or PR to the date of the disease progression objectively documented or death (whichever occurs first). CR, PR, and disease progression will be defined per RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO Criteria (for HGG only).
- Area under the plasma concentration time course profile (AUC): Phase 1 [ Time Frame: Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22 ]
AUC represents the overall amount of drug in the bloodstream after dosing. AUC will be estimated by non-compartmental methods. Blood samples for plasma concentrations of lenvatinib and whole blood concentrations of everolimus will be collected from all participants.
- AUC: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
AUC represents the overall amount of drug in the bloodstream after dosing. AUC will be estimated by non-compartmental methods. Blood samples for plasma concentrations of lenvatinib and whole blood concentrations of everolimus will be collected from all participants.
- Maximum observed concentration (Cmax): Phase 1 [ Time Frame: Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22 ]
Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.
- Cmax: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
Cmax is the highest concentration of drug in the blood that is measured after a dose. Cmax will be estimated by non-compartmental methods.
- Time from dosing to the maximum observed concentration (Tmax): Phase 1 [ Time Frame: Lenvatinib: Cycle 1 Day 1 (C1D1), C1D2, C1D15, C1D22, C2D1, C3D1; Everolimus: C1D1, C1D2, C1D15, C1D22 ]
Tmax is the time to the highest concentration of drug in the blood that is measured after a dose. Tmax will be estimated by non-compartmental methods.
- Tmax: Phase 2 [ Time Frame: Lenvatinib and everolimus: C1D1, C1D15, Cycles 2 and 3 ]
Tmax is the time to the highest concentration of drug in the blood that is measured after a dose. Tmax will be estimated by non-compartmental methods.
- Number of participants with any TE SAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2.5 years ]
An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the AE as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
- Number of participants with any TEAE in Phase 2, as a measure of the safety and toxicity of lenvatinib in combination with everolimus [ Time Frame: From date of first dose up to 28 days after the last dose of study treatment, up to approximately 2.5 years ]
An AE is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
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Not Provided
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Not Provided
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Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
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A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors
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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.
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Not Provided
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Interventional
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Phase 1 Phase 2
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Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
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Recurrent and Refractory Solid Tumors
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- Drug: Lenvatinib
oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension
- Drug: Everolimus
2 mg, 3 mg, or 5 mg tablets for oral suspension
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- Experimental: Phase 1: Phase 1; Recurrent or refractory solid tumors
During Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions:
- Drug: Lenvatinib
- Drug: Everolimus
- Experimental: Phase 2: Cohort 1, Ewing sarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions:
- Drug: Lenvatinib
- Drug: Everolimus
- Experimental: Phase 2: Cohort 2, Rhabdomyosarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions:
- Drug: Lenvatinib
- Drug: Everolimus
- Experimental: Phase 2: Cohort 3, High Grade Glioma (HGG)
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions:
- Drug: Lenvatinib
- Drug: Everolimus
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Not Provided
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Completed
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64
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132
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September 30, 2022
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September 30, 2022 (Final data collection date for primary outcome measure)
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Inclusion Criteria
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
- Karnofsky performance score ≥50 for participants>16 year of age and Lansky play score ≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
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Prior Therapy
- Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
- Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of agent
- Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody (including checkpoint inhibitors). Toxicity related to prior antibody therapy must be recovered to Grade ≤1
- Corticosteroids: If used to modify immune adverse events related to prior therapy, ≥14 days must have elapsed since last dose of corticosteroid. Participants receiving corticosteroids, who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment, are not eligible
- Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
- Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons or cytokines (other than hematopoietic growth factors)
- Stem cell infusions (with or without total body irradiation): Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocytes infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease; Autologous stem cell infusion including boost infusion: ≥42 days
- Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer cells, dendritic cells, etc)
- Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after total body irradiation, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation.
- Radiopharmaceutical therapy: ≥42 days after systemically administered therapy.
- Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received prior exposure to lenvatinib; May have previously progressed on an mTOR inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only); Must not have received prior VEGF/VEGFR-targeted therapy in combination with an mTOR inhibitor (For Phase 2 only)
- Adequate bone marrow function for participants with solid tumors without known bone marrow involvement
- Adequate bone marrow function for participants with known bone marrow metastatic disease
- Adequate renal function
- Adequate liver function
- Adequate cardiac function
- Adequate neurologic function
- Adequate blood pressure (BP) control with or without antihypertensive medications
- Adequate coagulation
- Adequate pancreatic function
- Adequate metabolic function
- Adequate glycemic control
- Participants must have a minimum body surface area (BSA) of 0.6 m^2 at study entry.
Exclusion Criteria
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Sexes Eligible for Study: |
All |
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2 Years to 21 Years (Child, Adult)
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No
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Contact information is only displayed when the study is recruiting subjects
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Canada, United States
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Palau
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NCT03245151
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E7080-A001-216
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Yes
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Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
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Not Provided
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Eisai Inc.
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Same as current
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Eisai Inc.
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Same as current
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Merck Sharp & Dohme LLC
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Not Provided
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Eisai Inc.
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November 2022
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