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

NCT01136733 | Completed Phase 1 Results

• 1 other identifier: E7080-G000-205
• Study Type: interventional
• Target: 173
• Locations: 5 countries
• Sites: 37

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.

Conditions

Metastatic Renal Cell Carcinoma

Keywords

Unresectable advanced or metastatic renal cell carcinoma

Outcome Measures

Primary Outcomes (3)

• Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)

  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

  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)

  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

Secondary Outcomes (13)

• Phase 2: Overall Survival (OS)

  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)

  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)

  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

  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)

  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

Study Arms (3)

Lenvatinib

EXPERIMENTAL

Drug: Lenvatinib

Lenvatinib plus Everolimus

EXPERIMENTAL

Drug: Lenvatinib; Drug: Everolimus

Everolimus

ACTIVE COMPARATOR

Drug: Everolimus

Interventions

Lenvatinib DRUG

taken orally, once a day

Also known as: E7080, Lenvima, Kisplyx

Lenvatinib; Lenvatinib plus Everolimus

Everolimus DRUG

taken orally, once a day

Also known as: Afinitor

Everolimus; Lenvatinib plus Everolimus

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (37)

Unknown Facility

Tucson, Arizona, United States

Location

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Orange, California, United States

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San Diego, California, United States

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Tampa, Florida, United States

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Joliet, Illinois, United States

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Louisville, Kentucky, United States

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Annapolis, Maryland, United States

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Bethesda, Maryland, United States

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Boston, Massachusetts, United States

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Tupelo, Mississippi, United States

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New York, New York, United States

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Tulsa, Oklahoma, United States

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Charleston, South Carolina, United States

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Dallas, Texas, United States

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Brno, Czechia

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Olomouc, Czechia

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Prague, Czechia

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Gdansk, Poland

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Lodz, Poland

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Szczecin, Poland

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Warsaw, Poland

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Barcelona, Spain

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Córdoba, Spain

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Madrid, Spain

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Pamplona, Spain

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Bristol, United Kingdom

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Cambridge, United Kingdom

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Cardiff, United Kingdom

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Glasgow, United Kingdom

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Guildford, United Kingdom

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Ipswich, United Kingdom

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Leicester, United Kingdom

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London, United Kingdom

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Manchester, United Kingdom

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Metropolitan Borough of Wirral, United Kingdom

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Southampton, United Kingdom

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Surrey, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 33024271 DERIVED

• 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.

  PMID: 26482279 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

lenvatinib; Everolimus

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Eisai Medical Services
• Organization: Eisai Medical Inc.

1-888-422-4743

Study Officials

• Eisai Medical Services

  Eisai Limited

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2010
• First Posted: June 3, 2010
• Study Start: August 5, 2010
• Primary Completion: June 13, 2014
• Study Completion: February 8, 2018
• Last Updated: February 27, 2019
• Results First Posted: February 27, 2019

Record last verified: 2018-01

Locations

US (14); GB (12); ES (4); PL (4); CZ (3)