The Phase 1 part of the study is conducted to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory solid tumors (excluding central nervous system \[CNS\] tumors). The Phase 2 part of the study is conducted to assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and ewing sarcoma (EWS).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
IV infusion
IV infusion
Hopitaux de La Timone
Marseille, Bouches-du-Rhône, France
Centre Oscar Lambret
Lille, Nord, France
Centre Léon Berard
Lyon, Rhône, France
Eisai Trial Site 4
Freiburg im Breisgau, Baden-Wurttemberg, Germany
Eisai Trial Site 2
Frankfurt am Main, Hesse, Germany
Eisai Trial Site 5
Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride
The RP2D was evaluated based on a review of the outcomes of safety (including dose limiting toxicities \[DLTs\]), tumor assessments, and pharmacokinetic (PK) in Phase 1 by investigators and the study team.
Time frame: First dose of study drug up to Cycle 1 (Cycle length=21 days)
Phase 2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants achieving best overall response (BOR) of confirmed partial response (PR) or complete response (CR) determined by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis less than (\<) 10 millimeter (mm). PR was at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment, or reemerged during treatment, having been present at pre-treatment (baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
Time frame: From first dose of study drug up to approximately 2 years 4 months
Number of Participants With Serious Adverse Event (SAE)
SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.
Time frame: Up to approximately 2 years and 4 months
Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38
Half-life for irinotecan and metabolite SN-38 could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 20 mg/m\^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 40 mg/m\^2 arm as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, Total Clearance (CL) of Eribulin and Irinotecan
CL for irinotecan could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 20 mg/m\^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 40 mg/m\^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan
Vz for irinotecan could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 20 mg/m\^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 40 mg/m\^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and Its Active Metabolite SN-38
AUC(0-inf) for irinotecan and metabolite SN-38 could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 20 mg/m\^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m\^2 + irinotecan 40 mg/m\^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Phase 2: Progression Free Survival (PFS)
PFS was defined as the time from date of first dose to the date of disease progression (PD). PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least 20% increase or 5 mm increase in the sum of diameters of target lesions recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
Time frame: From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months
Phase 2: Clinical Benefit Rate (CBR)
CBR was defined as the percentage of participants with BOR of CR, PR, or durable stable disease (SD) based on RECIST 1.1 (durable SD was defined as SD with duration of greater than \[\>\] 11 weeks). CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months
Model Predicted Apparent Total Body Clearance (CL) of Eribulin
Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. The data presented are the CL parameter estimates, with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.
Time frame: Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)
Volume of Distribution Estimates From the Population PK Model for Eribulin
Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. Data presented are the volume of distribution of the central compartment (V1), volume of distribution of the first peripheral compartment (V2), and volume of distribution of the second peripheral compartment (V3) parameter estimates with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.
Time frame: Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)
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Göttingen, Lower Saxony, Germany
Eisai Trial Site 1
Aachen, North Rhine-Westphalia, Germany
Eisai Trial Site 3
Berlin, Germany
Eisai Trial Site 6
Essen, Germany
Aghia Sophia' Children's General Hospital of Athens
Athens, Attica, Greece
...and 29 more locations