Trial to Assess Safety and Efficacy of Lenvatinib in Combination With Everolimus in Participants With Renal Cell Carcinoma

Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:August 21, 2017
End Date:September 15, 2019
Contact:Eisai Medical Information

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A Randomized, Open-Label (Formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment

Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial
conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination
with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective
response rate [ORR] at 24 weeks [ORR24W]) with an improved safety profile compared to
lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable
Grade 2, or any ≥ Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Inclusion Criteria:

- Histological or cytological confirmation of predominant clear cell renal cell
carcinoma (RCC) (original tissue diagnosis of RCC is acceptable)

- Documented evidence of advanced RCC

- One prior disease progression episode on or after vascular endothelial growth factor
(VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib,
pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib)
administered for the treatment of RCC. Prior programmed cell death protein 1
(PD-1)/programmed death-ligand 1 (PD-L1) treatment in addition to 1 prior
VEGF-targeted treatment is allowed.

- At least 1 measurable target lesion according to Response Evaluation Criteria in Solid
Tumors (RECIST 1.1) meeting the following criteria:

- Lymph node (LN) lesion that measures at least 1 dimension as ≥1.5 centimeter (cm)
in the short axis;

- Non-nodal lesion that measures ≥1.0 cm in the longest diameter;

- The lesion is suitable for repeat measurement using computerized
tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external
beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence
of disease progression based on RECIST 1.1 to be deemed a target lesion.

- Male or female participants age ≥18 years (or any age ≥18 years if that age is
considered to be an adult per the local jurisdiction) at the time of informed consent

- Karnofsky Performance Status (KPS) of ≥70

- Adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP ≤150/90 millimeters of mercury (mmHg) at Screening and no
change in antihypertensive medications within 1 week before Cycle 1/Day 1

- Adequate renal function defined as calculated creatinine clearance ≥30 milliliters per
minute (mL/min) per the Cockcroft and Gault formula

- Adequate bone marrow function defined by:

- Absolute neutrophil count (ANC) ≥1500/millimeters cubed (mm^3) (≥1.5 ×
10^9/Liters [L]);

- Platelets ≥100,000/mm^3 (≥100 × 10^9/L);

- Hemoglobin ≥9 grams per deciliter (g/dL)

- Adequate blood coagulation function defined by International Normalized Ratio (INR)
≤1.5 (except for participants on warfarin therapy where INR must be ≤3.0 prior to

- Adequate liver function defined by:

- Total bilirubin ≤1.5 times the upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia of Gilbert's syndrome;

- Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤3× the ULN (in the case of liver metastases ≤5× the ULN).
Participants with bone metastases with ALP values greater than 3 times can be

- Participant must voluntarily agree to provide written informed consent

- Participant must be willing and able to comply with all aspects of the protocol

Exclusion Criteria:

- More than 1 prior VEGF-targeted treatment for advanced RCC

- Participants with Central Nervous System (CNS) metastases are not eligible, unless
they have completed local therapy for at least 4 weeks and have discontinued the use
of corticosteroids for this indication or are on a tapering regimen of corticosteroids
(defined as ≤10 milligrams [mg] prednisolone equivalent) before starting treatment in
this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable
for at least 4 weeks before starting study treatment.

- Active malignancy (except for RCC or definitively treated basal or squamous cell
carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past
24 months

- Any anti-cancer treatment (except for radiation therapy) within 21 days, or any
investigational agent within 30 days prior to the first dose of study drug;
participants should have recovered from any toxicity related to previous anti-cancer
treatment to Common Toxicity Criteria (CTC) grade 0 or 1.

- Prior radiation therapy within 21 days prior to the start of study treatment with the
exception of palliative radiotherapy to bone lesions, which is allowed if completed 2
weeks prior to study treatment start

- Known intolerance to study drug (or any of the excipients) and/or known
hypersensitivity to rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the

- Participants with proteinuria >1+ on urinalysis will undergo 24-hour urine collection
for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24
hour will be ineligible.

- Fasting total cholesterol ˃300 mg/dL (or ˃7.75 millimoles [mmol]/L) and/or fasting
triglycerides level ˃2.5 × the ULN. Note: these participants can be included after
initiation or adjustment of lipid-lowering medication.

- Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. Note: these
participants can be included after initiation or adjustment of glucose-lowering

- Prolongation of QT corrected (QTc) interval to >480 milliseconds (ms)

- Participants who have not recovered adequately from any toxicity and/or complications
from major surgery prior to starting therapy

- Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
that might affect the absorption of lenvatinib or everolimus

- Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The
degree of tumor invasion/infiltration of major blood vessels (eg, carotid artery)
should be considered because of the potential risk of severe hemorrhage associated
with tumor shrinkage/necrosis following lenvatinib therapy.

- Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first
dose of study drug

- Significant cardiovascular impairment within 6 months prior to the first dose of study
drug; history of congestive heart failure greater than New York Heart Association
(NYHA) Class II, unstable angina, myocardial infarction or stroke, or cardiac
arrhythmia associated with significant cardiovascular impairment or left ventricular
ejection fraction (LVEF) below the institutional normal range as determined by
screening multigated acquisition (MUGA) scan or echocardiogram.

- Active infection (any infection requiring systemic treatment)

- Any medical or other condition that in the opinion of the investigator(s) would
preclude the participant's participation in a clinical study

- Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin
[hCG]) test with a minimum sensitivity of 25 International Units per Liter [IU/L] or
equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a
negative screening pregnancy test was obtained more than 72 hours before the first
dose of study drug.

- Females of childbearing potential who (Note: all females will be considered to be of
childbearing potential unless they are postmenopausal [amenorrheic for at least 12
consecutive months, in the appropriate age group, and without other known or suspected
cause] or have been sterilized surgically [ie, bilateral tubal ligation, total
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before

- do not agree to use a highly effective method of contraception for the entire
study period and for up to 8 weeks after study drug discontinuation, ie:

- total abstinence (if it is their preferred and usual lifestyle)

- an intrauterine device (IUD) or hormone releasing system (IUS)

- a contraceptive implant

- an oral contraceptive (with additional barrier method) (Note: Participants
must be on a stable dose of the same oral hormonal contraceptive product for
at least 4 weeks before dosing with study drug and for the duration of the
study.) OR

- do not have a vasectomized partner with confirmed azoospermia

For sites outside of the European Union, it is permissible that if a highly effective
method of contraception is not appropriate or acceptable to the participant, then the
participant must agree to use a medically acceptable method of contraception, ie double
barrier methods of contraception, such as condom plus diaphragm or cervical/vault cap with
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626-256-HOPE (4673)
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1001 12th Avenue
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Honolulu, Hawaii 96819
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9299 Southwest 88th Avenue
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200 Lothrop St
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Plainville, Connecticut
Plainville, CT
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Southington, Connecticut 06489
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12697 East 51st Street South
Tulsa, Oklahoma 74146
Tulsa, OK
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Whittier, California 90603
Whittier, CA
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808 North 39th Avenue
Yakima, Washington 98902
Yakima, WA
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