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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

torstai 7. helmikuuta 2019 päivittänyt: 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.

Tutkimuksen yleiskatsaus

Tila

Valmis

Ehdot

Interventio / Hoito

Opintotyyppi

Interventio

Ilmoittautuminen (Todellinen)

173

Vaihe

  • Vaihe 2
  • Vaihe 1

Yhteystiedot ja paikat

Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.

Opiskelupaikat

  • Espanja
      • Barcelona, Espanja
      • Cordoba, Espanja
      • Madrid, Espanja
      • Pamplona, Espanja
  • Puola
      • Gdansk, Puola
      • Lodz, Puola
      • Szczecin, Puola
      • Warsaw, Puola
  • Tšekki
      • Brno, Tšekki
      • Olomouc, Tšekki
      • Prague, Tšekki
  • Yhdistynyt kuningaskunta
      • Bristol, Yhdistynyt kuningaskunta
      • Cambridge, Yhdistynyt kuningaskunta
      • Cardiff, Yhdistynyt kuningaskunta
      • Glasgow, Yhdistynyt kuningaskunta
      • Guildford, Yhdistynyt kuningaskunta
      • Ipswich, Yhdistynyt kuningaskunta
      • Leicester, Yhdistynyt kuningaskunta
      • London, Yhdistynyt kuningaskunta
      • Manchester, Yhdistynyt kuningaskunta
      • Southampton, Yhdistynyt kuningaskunta
      • Surrey, Yhdistynyt kuningaskunta
      • Wirral, Yhdistynyt kuningaskunta
  • Yhdysvallat
    • Arizona
      • Tucson, Arizona, Yhdysvallat
    • California
      • Orange, California, Yhdysvallat
      • San Diego, California, Yhdysvallat
    • Florida
      • Tampa, Florida, Yhdysvallat
    • Illinois
      • Joliet, Illinois, Yhdysvallat
    • Kentucky
      • Louisville, Kentucky, Yhdysvallat
    • Maryland
      • Annapolis, Maryland, Yhdysvallat
      • Bethesda, Maryland, Yhdysvallat
    • Massachusetts
      • Boston, Massachusetts, Yhdysvallat
    • Mississippi
      • Tupelo, Mississippi, Yhdysvallat
    • New York
      • New York, New York, Yhdysvallat
    • Oklahoma
      • Tulsa, Oklahoma, Yhdysvallat
    • South Carolina
      • Charleston, South Carolina, Yhdysvallat
    • Texas
      • Dallas, Texas, Yhdysvallat

Osallistumiskriteerit

Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.

Kelpoisuusvaatimukset

Opintokelpoiset iät

18 vuotta - 99 vuotta (Aikuinen, Vanhempi Aikuinen)

Hyväksyy terveitä vapaaehtoisia

Ei

Sukupuolet, jotka voivat opiskella

Kaikki

Kuvaus

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.

Opintosuunnitelma

Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.

Miten tutkimus on suunniteltu?

Suunnittelun yksityiskohdat

  • Ensisijainen käyttötarkoitus: Hoito
  • Jako: Satunnaistettu
  • Inventiomalli: Rinnakkaistehtävä
  • Naamiointi: Ei mitään (avoin tarra)

Aseet ja interventiot

Osallistujaryhmä / Arm
Interventio / Hoito
Kokeellinen: Lenvatinibi
Lääke: Lenvatinib
taken orally, once a day
Muut nimet:
  • E7080, Lenvima, Kisplyx
Kokeellinen: Lenvatinib plus Everolimus
Lääke: Lenvatinib
taken orally, once a day
Muut nimet:
  • E7080, Lenvima, Kisplyx
Lääke: Everolimus
taken orally, once a day
Muut nimet:
  • Afinitor
Active Comparator: Everolimus
Lääke: Everolimus
taken orally, once a day
Muut nimet:
  • Afinitor

Mitä tutkimuksessa mitataan?

Ensisijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)
Aikaikkuna: First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
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.
First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose
Aikaikkuna: First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
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.
First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
Phase 2: Progression-Free Survival (PFS)
Aikaikkuna: 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
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.
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

Toissijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Phase 2: Overall Survival (OS)
Aikaikkuna: 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
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.
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
Phase 2: Objective Response Rate (ORR)
Aikaikkuna: 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
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.
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
Disease Control Rate (DCR)
Aikaikkuna: 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
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.
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
Durable Stable Disease (SD) Rate
Aikaikkuna: 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
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.
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
Clinical Benefit Rate (CBR)
Aikaikkuna: 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
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.
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
Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
Aikaikkuna: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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.
Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
Aikaikkuna: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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.
Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
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
Aikaikkuna: 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)
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.
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)
Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus
Aikaikkuna: Phase 2: Cycle 1 Day 15
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.
Phase 2: Cycle 1 Day 15
Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus
Aikaikkuna: Phase 2: Cycle 1 Day 15
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.
Phase 2: Cycle 1 Day 15
Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib
Aikaikkuna: 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)
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.
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)
Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib
Aikaikkuna: Phase 2: Cycle 1 Day 15
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.
Phase 2: Cycle 1 Day 15
Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib
Aikaikkuna: Phase 2: Cycle 1 Day 15
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.
Phase 2: Cycle 1 Day 15

Yhteistyökumppanit ja tutkijat

Täältä löydät tähän tutkimukseen osallistuvat ihmiset ja organisaatiot.

Sponsori

Eisai Inc.

Julkaisuja ja hyödyllisiä linkkejä

Tutkimusta koskevien tietojen syöttämisestä vastaava henkilö toimittaa nämä julkaisut vapaaehtoisesti. Nämä voivat koskea mitä tahansa tutkimukseen liittyvää.

Yleiset julkaisut

Opintojen ennätyspäivät

Nämä päivämäärät seuraavat ClinicalTrials.gov-sivustolle lähetettyjen tutkimustietueiden ja yhteenvetojen edistymistä. National Library of Medicine (NLM) tarkistaa tutkimustiedot ja raportoidut tulokset varmistaakseen, että ne täyttävät tietyt laadunvalvontastandardit, ennen kuin ne julkaistaan ​​julkisella verkkosivustolla.

Opi tärkeimmät päivämäärät

Opiskelun aloitus (Todellinen)

Torstai 5. elokuuta 2010

Ensisijainen valmistuminen (Todellinen)

Perjantai 13. kesäkuuta 2014

Opintojen valmistuminen (Todellinen)

Torstai 8. helmikuuta 2018

Opintoihin ilmoittautumispäivät

Ensimmäinen lähetetty

Keskiviikko 26. toukokuuta 2010

Ensimmäinen toimitettu, joka täytti QC-kriteerit

Keskiviikko 2. kesäkuuta 2010

Ensimmäinen Lähetetty (Arvio)

Torstai 3. kesäkuuta 2010

Tutkimustietojen päivitykset

Viimeisin päivitys julkaistu (Todellinen)

Keskiviikko 27. helmikuuta 2019

Viimeisin lähetetty päivitys, joka täytti QC-kriteerit

Torstai 7. helmikuuta 2019

Viimeksi vahvistettu

Maanantai 1. tammikuuta 2018

Lisää tietoa

Tähän tutkimukseen liittyvät termit

Avainsanat

Muita asiaankuuluvia MeSH-ehtoja

Muut tutkimustunnusnumerot

  • E7080-G000-205

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