Clinical trial 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: Unresectable advanced or metastatic renal cell carcinoma
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2010-06-03
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)
timeFrame: First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
measure: Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose
timeFrame: First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
measure: Phase 2: Progression-Free Survival (PFS)
timeFrame: 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
Secondary outcomes:
measure: Phase 2: Overall Survival (OS)
timeFrame: 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
measure: Phase 2: Objective Response Rate (ORR)
timeFrame: 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
measure: Disease Control Rate (DCR)
timeFrame: 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
measure: Durable Stable Disease (SD) Rate
timeFrame: 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
measure: Clinical Benefit Rate (CBR)
timeFrame: 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
measure: Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
timeFrame: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
measure: Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
timeFrame: Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
measure: 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
timeFrame: 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)
measure: Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus
timeFrame: Phase 2: Cycle 1 Day 15
measure: Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus
timeFrame: Phase 2: Cycle 1 Day 15
measure: Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib
timeFrame: 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)
measure: Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib
timeFrame: Phase 2: Cycle 1 Day 15
measure: Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib
timeFrame: Phase 2: Cycle 1 Day 15
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Orange
country: United States
state: California
city: San Diego
country: United States
state: California
city: Tampa
country: United States
state: Florida
city: Joliet
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: Annapolis
country: United States
state: Maryland
city: Bethesda
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Tupelo
country: United States
state: Mississippi
city: New York
country: United States
state: New York
city: Tulsa
country: United States
state: Oklahoma
city: Charleston
country: United States
state: South Carolina
city: Dallas
country: United States
state: Texas
city: Brno
country: Czechia
city: Olomouc
country: Czechia
city: Prague
country: Czechia
city: Gdansk
country: Poland
city: Lodz
country: Poland
city: Szczecin
country: Poland
city: Warsaw
country: Poland
city: Barcelona
country: Spain
city: Cordoba
country: Spain
city: Madrid
country: Spain
city: Pamplona
country: Spain
city: Bristol
country: United Kingdom
city: Cambridge
country: United Kingdom
city: Cardiff
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Guildford
country: United Kingdom
city: Ipswich
country: United Kingdom
city: Leicester
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Southampton
country: United Kingdom
city: Surrey
country: United Kingdom
city: Wirral
country: United Kingdom
Study officials:
affiliation: Eisai Limited
name: Eisai Medical Services
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.