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- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT01136733
A Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior Vascular Endothelial Growth Factor (VEGF)-Targeted Treatment
7 de febrero de 2019 actualizado por: Eisai Inc.
An Open-Label, Multicenter, Phase 1b/2 Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
This is an open-label, multicenter, Phase 1b/2 study of lenvatinib alone and in combination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted treatment.
Descripción general del estudio
Estado
Terminado
Condiciones
Intervención / Tratamiento
Tipo de estudio
Intervencionista
Inscripción (Actual)
173
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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Brno, Chequia
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Olomouc, Chequia
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Prague, Chequia
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Barcelona, España
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Cordoba, España
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Madrid, España
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Pamplona, España
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Arizona
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Tucson, Arizona, Estados Unidos
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California
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Orange, California, Estados Unidos
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San Diego, California, Estados Unidos
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Florida
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Tampa, Florida, Estados Unidos
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Illinois
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Joliet, Illinois, Estados Unidos
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Kentucky
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Louisville, Kentucky, Estados Unidos
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Maryland
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Annapolis, Maryland, Estados Unidos
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Bethesda, Maryland, Estados Unidos
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Massachusetts
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Boston, Massachusetts, Estados Unidos
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Mississippi
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Tupelo, Mississippi, Estados Unidos
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New York
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New York, New York, Estados Unidos
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Oklahoma
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Tulsa, Oklahoma, Estados Unidos
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South Carolina
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Charleston, South Carolina, Estados Unidos
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Texas
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Dallas, Texas, Estados Unidos
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Gdansk, Polonia
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Lodz, Polonia
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Szczecin, Polonia
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Warsaw, Polonia
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Bristol, Reino Unido
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Cambridge, Reino Unido
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Cardiff, Reino Unido
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Glasgow, Reino Unido
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Guildford, Reino Unido
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Ipswich, Reino Unido
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Leicester, Reino Unido
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London, Reino Unido
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Manchester, Reino Unido
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Southampton, Reino Unido
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Surrey, Reino Unido
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Wirral, Reino Unido
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Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
18 años a 99 años (Adulto, Adulto Mayor)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Descripción
Select Inclusion Criteria:
- Histologically confirmed diagnosis of renal cell carcinoma.
- Phase 2: Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable).
- Documented evidence of unresectable advanced or metastatic RCC. Phase 2: Radiographic evidence of disease progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
- Phase 2: One prior vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) for unresectable advanced or metastatic RCC.
- Phase 2: Measurable disease meeting the following criteria: a.) at least 1 lesion of greater than or equal to 1.5 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 cm in the short axis diameter for a lymph node which is serially measurable according to Modified RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
Select Exclusion Criteria:
Phase 1b or Phase 2 specific per below:
- Phase 1b only: Subjects with untreated or unstable metastasis to the central nervous system (CNS) are excluded. Subjects who have completed local therapy and have discontinued the use of steroids for this indication at least 4 weeks prior to commencing treatment and in whom stability has been proven by at least 2 CT or MRI scans obtained at least 4 weeks apart are eligible for Phase 1b only. Phase 2 only: Subjects with CNS (e.g., brain or leptomeningeal) metastasis are excluded.
- Phase 2 only: More than one prior VEGF-targeted treatment for unresectable advanced or metastatic RCC.
Phase 1b or Phase 2 specific per below:
- Phase 1b only: Prior exposure to lenvatinib. Phase 2 only: Prior exposure to lenvatinib or mammalian target of rapamycin (mTOR) inhibitor.
- Subjects should not have received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anticancer treatment. Major surgery within 3 weeks prior to the first dose of study drug.
- Subjects having greater than 1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria.
- Subjects with urine protein greater than or equal to 1 g/24 hours will be ineligible. Uncontrolled diabetes as defined by fasting serum glucose at 1.5 x ULN.
- Phase 2 only: Active malignancy (except for renal cell carcinoma, melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
- Known intolerance to any of the study drugs (or any of the excipients) and/or known hypersensitivity to rapamycins (e.g., sirolimus, everolimus, temsirolimus) or any of the excipients.
- Phase 1b only: Subjects who discontinued prior tyrosine kinase inhibitor due to toxicity will be ineligible.
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Lenvatinib
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taken orally, once a day
Otros nombres:
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Experimental: Lenvatinib plus Everolimus
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taken orally, once a day
Otros nombres:
taken orally, once a day
Otros nombres:
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Comparador activo: Everolimus
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taken orally, once a day
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)
Periodo de tiempo: First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
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A DLT was defined as either a treatment-related failure to administer greater than or equal to (>=) 75% of the planned dosage of lenvatinib/everolimus or a specific National Cancer Institute Common Toxicity Criteria (NCI CTC) >= Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care daily living activities) hematologic or nonhematologic toxicities considered to be possibly related to lenvatinib and/or everolimus therapy assessed during the first treatment cycle of each dose level.
Higher grade indicates more severe toxicity.
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First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
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Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose
Periodo de tiempo: First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
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The highest dose level resulting in 0 or 1 DLT in 6 participants was to be considered the MTD of Phase 1b.
Once the MTD was established, the participant cohort was expanded to a minimum of 10 participants.
The MTD was confirmed by assessing DLTs during Cycle 1 and intolerable toxicities (i.e., not manageable with dose interruption and/or reduction) during Cycle 2 of therapy.
Once the dose of lenvatinib/everolimus combination to be used in the succeeding Phase 2 part of the study was established, enrollment into Phase 2 was started.
The RP2 dose was the same as the confirmed MTD and was used for the Phase 2 Treatment Arm A of this study.
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First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
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Phase 2: Progression-Free Survival (PFS)
Periodo de tiempo: Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months
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PFS was defined as the time (in months) from the date of first dose of study drug to the first documentation of disease progression or death, whichever occurred first.
Kaplan-Meier (K-M) estimates were used to estimate median PFS, presented with 2-sided 95% confidence intervals (CIs).
Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease using computed tomography (CT) or magnetic resonance imaging (MRI) and scan acquisition techniques (including use or nonuse of intravenous (IV) contrast).
Tumor response was determined at the site by the investigator and radiologist using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in the evaluation of the tumor assessment scans.
The date of objective disease progression was defined as the earliest date of radiological disease progression.
Participants removed from therapy due to clinical progression with no radiologic confirmation were censored at their last radiologic assessment date.
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Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Phase 2: Overall Survival (OS)
Periodo de tiempo: Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months
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OS was defined as the time (in months) from the date of randomization until date of death from any cause.
Median survival time was calculated using K-M estimate for each treatment arm and presented with 2-sided 95% CIs.
Participants who were lost to follow-up or alive at the data cutoff date (10 Dec 2014) were censored at the date the participants were last known to be alive.
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Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months
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Phase 2: Objective Response Rate (ORR)
Periodo de tiempo: Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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The ORR was defined as the percentage of participants who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions.
Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease).
The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study.
CR was defined as disappearance of all target lesions.
Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm.
PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
ORR = CR + PR was calculated with exact 95% CIs using the method of Clopper and Pearson.
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Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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Disease Control Rate (DCR)
Periodo de tiempo: Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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The DCR was defined as the percentage of participants who had a BOR of CR or PR or SD (minimum duration from randomization to SD greater than or equal to 7 weeks).
Assessments were performed every 8 weeks and were based on investigator review data using RECIST 1.1.
The 95% CI was constructed using the method of Clopper and Pearson.
DCR = CR + PR + SD greater than or equal to 7 weeks.
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Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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Durable Stable Disease (SD) Rate
Periodo de tiempo: Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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The durable SD rate was defined as the percentage of participants whose BOR was SD and the duration of SD was greater than or equal to 23 weeks.
The durable SD was based on investigator review data using RECIST 1.1.
The 95% CI was constructed using the method of Clopper and Pearson.
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Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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Clinical Benefit Rate (CBR)
Periodo de tiempo: Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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The CBR was defined as the percentage of participants who had BOR of CR, PR, or durable SD (duration of SD was greater than or equal to 23 weeks) and was based on investigator review data using RECIST 1.1.
The BOR was defined as the best response recorded from the start of study treatment until discontinuation from the study.
There was no requirement for confirmatory measurement of PR or CR to deem either one the BOR.
The 95% CI was constructed using the method of Clopper and Pearson.
CBR = CR + PR + SD greater than or equal to 23 weeks.
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Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
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Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
Periodo de tiempo: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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Blood samples were collected during the Randomization Phase.
Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose).
Plasma concentrations of lenvatinib were measured and concentration data were summarized.
The summary statistics at time points with one or more below the limit of quantitation (BLQ) values were calculated by assigning zero for each BLQ value.
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Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
Periodo de tiempo: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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Blood samples were collected during the Randomization Phase.
Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose).
Whole blood concentrations of everolimus were measured and concentration data were summarized.
The summary statistics at time points with one or more BLQ values were calculated by assigning zero for each BLQ value.
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Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus
Periodo de tiempo: Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
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Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling.
Blood samples were analyzed for study drug using standardized methods.
PK parameters for lenvatinib were derived from lenvatinib concentration data using non-compartmental methods.
Data were compared via descriptive statistics between single agent and combination therapy.
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Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
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Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus
Periodo de tiempo: Phase 2: Cycle 1 Day 15
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Cmax for lenvatinib was defined as the maximum observed concentration of lenvatinib in plasma following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves.
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Phase 2: Cycle 1 Day 15
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Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus
Periodo de tiempo: Phase 2: Cycle 1 Day 15
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Tmax for lenvatinib was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach maximum concentration (Cmax) of lenvatinib in plasma.
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Phase 2: Cycle 1 Day 15
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Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib
Periodo de tiempo: Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
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Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling.
Blood samples were analyzed for study drug using standardized methods.
PK parameters for everolimus were derived from everolimus concentration data using non-compartmental methods.
Data were compared via descriptive statistics between single agent and combination therapy.
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Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
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Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib
Periodo de tiempo: Phase 2: Cycle 1 Day 15
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Cmax for everolimus was defined as the maximum observed concentration of everolimus in blood following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured blood concentration-time curves.
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Phase 2: Cycle 1 Day 15
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Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib
Periodo de tiempo: Phase 2: Cycle 1 Day 15
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Tmax for everolimus was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach the maximum concentration (Cmax) of everolimus in blood.
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Phase 2: Cycle 1 Day 15
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Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
- Lee CH, Motzer RJ, Glen H, Michaelson MD, Larkin J, Minoshima Y, Kanekiyo M, Ikezawa H, Sachdev P, Dutcus CE, Funahashi Y, Voss MH. Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. Br J Cancer. 2021 Jan;124(1):237-246. doi: 10.1038/s41416-020-01092-0. Epub 2020 Oct 7.
- Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9. Epub 2015 Oct 22. Erratum In: Lancet Oncol. 2016 Jul;17 (7):e270. Lancet Oncol. 2018 Oct;19(10):e509.
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio (Actual)
5 de agosto de 2010
Finalización primaria (Actual)
13 de junio de 2014
Finalización del estudio (Actual)
8 de febrero de 2018
Fechas de registro del estudio
Enviado por primera vez
26 de mayo de 2010
Primero enviado que cumplió con los criterios de control de calidad
2 de junio de 2010
Publicado por primera vez (Estimar)
3 de junio de 2010
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
27 de febrero de 2019
Última actualización enviada que cumplió con los criterios de control de calidad
7 de febrero de 2019
Última verificación
1 de enero de 2018
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Neoplasias por tipo histológico
- Neoplasias
- Neoplasias Urológicas
- Neoplasias urogenitales
- Neoplasias por sitio
- Enfermedades Renales
- Enfermedades urológicas
- Adenocarcinoma
- Neoplasias Glandulares y Epiteliales
- Neoplasias Renales
- Carcinoma De Célula Renal
- Carcinoma
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Inhibidores de enzimas
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Inhibidores de la proteína quinasa
- Everolimus
- Lenvatinib
Otros números de identificación del estudio
- E7080-G000-205
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .
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