A Multicenter, Open-Label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination with Everolimus or Pembrolizumab Versus Sunitinib Alone in First Line Treatment of Subjects with Advanced Renal Cell Carcinoma

  • sponsor
    Eisai, Inc.
Updated on 25 March 2021


A Multicenter, Open-Label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination with Everolimus or Pembrolizumab Versus Sunitinib Alone in First Line Treatment of Subjects with Advanced Renal Cell Carcinoma


The primary objective of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]) as first-line treatment in subjects with advanced renal cell carcinoma (RCC).

Condition Renal Cell Carcinoma
Clinical Study IdentifierTX150753
SponsorEisai, Inc.
Last Modified on25 March 2021


Yes No Not Sure

Inclusion Criteria

Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable)
Documented evidence of advanced RCC
At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria
Lymph node (LN) lesion that measures at least 1 dimension as =1.5 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 subjects age ≥18 years (or any age >18 years of age (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 mmHg at Screening and no change in antihypertensive medications within 1 week before the Cycle 1/Day 1
Adequate renal function defined as calculated creatinine clearance =30 mL/min per the Cockcroft and Gault formula
Adequate bone marrow function defined by
Absolute neutrophil count (ANC) ≥1500/mm3
Platelets ≥100,000/mm3
Hemoglobin ≥9 g/dL
Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5 (except for subjects on warfarin therapy where INR must be =3.0 prior to randomization)
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×ULN (in the case of liver metastases ≤5×ULN), unless there are bone metastases. Subjects with ALP values >3 times the ULN and known to have bone metastases can be included
Provide written informed consent
Willing and able to comply with all aspects of the protocol

Exclusion Criteria

Subjects who have received any systemic anticancer therapy for RCC, including anti-VEGF therapy, or any systemic investigational anticancer agent. Prior adjuvant treatment with an investigational anticancer agent is not allowed unless the investigator can provide evidence of subject’s randomization to placebo arm
Subjects with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks 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, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months. Subjects with history of localized & low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no PSA recurrence within the past 5 years
Prior radiation therapy within 21 days prior to 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
Subjects who are using other investigational agents or who had received investigational drugs ≤4 weeks prior to study treatment start
Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed within 30 days of C1D1
Subjects with proteinuria >1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible
Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) and/or fasting triglycerides level >2.5 x ULN. NOTE: these subjects 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 subjects can be included after initiation or adjustment of glucose-lowering medication
Prolongation of QTc interval to >480 ms
Subjects 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, everolimus, and sunitinib
Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels 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 of 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, cardiac arrhythmia associated with significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by MUGA or echocardiogram
Active infection (any infection requiring systemic treatment)
Subjects known to be positive for Human Immunodeficiency Virus (HIV)
Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected)
Known history of, or any evidence of, interstitial lung disease
Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
Any medical or other condition that in the opinion of the investigator(s) would preclude the subject’s participation in a clinical study
Subjects with a diagnosis of immunodeficiency or who are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5 mg/d of prednisone or equivalent) may be approved after consultation with the sponsor
Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-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
do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study 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) OR
do not have a vasectomized partner with confirmed azoospermia
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 dosing]
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
Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to use condom + spermicide OR have a female partner who does not meet the criteria above (ie, is of childbearing potential and not practicing highly effective contraception throughout the study period), starting with the first dose of study therapy through 120 days after the last dose of study therapy, unless sexually abstinent. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
Known intolerance to any of the study drugs (or any of the excipients)
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