A Phase II Study of Lenvatinib Plus Everolimus Versus Cabozantinib in Patients With Metastatic Renal Cell Carcinoma That Progressed on A PD-1/PD-L1 Checkpoint Inhibitor

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    M.D. Anderson Cancer Center
Updated on 27 October 2022


This phase II trial compares the effects of lenvatinib given in combination with everolimus to the effects of cabozantinib given alone in treating patients with renal cell cancer (RCC) that has spread to other parts of the body (metastatic) and that got worse on a previous PD-1/PD-L1 checkpoint inhibitor. Lenvatinib, everolimus, and cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.



I. To compare the efficacy of lenvatinib plus everolimus versus cabozantinib in patients with mRCC who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.


I. To compare tumor responses to lenvatinib plus everolimus versus cabozantinib in patients with mRCC who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.

II. To compare health-related quality of life (HRQoL) and safety of lenvatinib plus everolimus versus cabozantinib in patients with mRCC who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.

III. To compare overall survival (OS) with lenvatinib plus everolimus versus cabozantinib in patients with mRCC who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.


I. To assess whether alterations to c-MET, VEGF, mTOR, and FGFR are associated with response to therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive lenvatinib orally (PO) once daily (QD) and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Condition Advanced Clear Cell Renal Cell Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Treatment questionnaire administration, Everolimus, Cabozantinib, Lenvatinib
Clinical Study IdentifierNCT05012371
SponsorM.D. Anderson Cancer Center
Last Modified on27 October 2022


Yes No Not Sure

Inclusion Criteria

Patients with histologically or cytologically confirmed metastatic/advanced clear cell renal cell cancer (RCC), or RCC with a clear cell component, who have received 1 or 2 prior lines of treatment in the advanced or metastatic setting, and the most recent treatment must include a PD-1/PD-L1 checkpoint inhibitor
There must be evidence of progression on or after treatment (at any point after completing prior therapy) with a PD-1/PD-L1-containing regimen as the last treatment received within 6 months of enrollment
Patients must have at least one measurable site of disease, defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) and measures >= 15 mm with conventional techniques or >= 10 mm with more sensitive techniques such as magnetic resonance imaging (MRI) or spiral computed tomography (CT) scan. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
Karnofsky performance status >= 70
Age >= 18 years
Hemoglobin >= 9 g/dL (treatment/transfusion allowed)
Absolute neutrophil count (ANC) >= 1,000/microliter
Platelets >= 75,000/microliter
Total bilirubin =< 1.5 mg/dL (for patients with Gilbert's disease, total bilirubin should be =< 3 mg/dL [=< 51.3 micromoles/L])
Aspartate aminotrasferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN), except in known hepatic metastasis, wherein may be =< 5 x ULN
Serum creatinine =< 1.5 x ULN (as long as patient does not require dialysis); if creatinine is not < 1.5 x ULN, then calculate by Cockcroft-Gault methods or local institutional standard and creatinine clearance must be >= 30 mL/kg/1.73 m^2
International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN prior to study entry. Therapeutic anticoagulation is permitted if: on a stable dose of low molecular weight heparin (LMWH) for > 2 weeks (14 days) at the time of enrollment or on a direct oral anticoagulant (DOAC) for > 2 weeks at time of enrollment
Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test (minimum sensitivity 25 international units/L or equivalent units of human chorionic gonadotropin [HCG]) before study entry. Pregnancy test must be repeated if performed > 14 days before starting study drug
Women must not be breastfeeding
Patients with a history of major psychiatric illness must be judged (by the treating physician) able to fully understand the investigational nature of the study and the risks associated with the therapy
Patients with treated/stable brain metastases are allowed on protocol if they had brain metastases that received central nervous system (CNS)-directed therapy, such as surgery or treatment with radiosurgery or gamma knife, without recurrence or edema for 1 month (4 weeks)

Exclusion Criteria

Prior receipt of lenvatinib, a c-MET inhibitor, such as cabozantinib or sitravatinib, or an mTOR inhibitor, such as everolimus or temsirolimus
Patients must not have any other malignancies within the past 3 years except for in situ carcinoma of any site, adequately treated (without recurrence post-resection or post- radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or active non-threatening second malignancy that would not, in the investigator's opinion, potentially interfere with the patient's ability to participate and/or complete this trial. Examples include but are not limited to: urothelial cancer grade Ta/T1 or adenocarcinoma of the prostate treated with active surveillance
Patients currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks (14 days) from enrollment into this study (including chemotherapy and targeted therapy) are excluded. Also, patients who have completed palliative radiation therapy more than 14 days prior to the first dose of lenvatinib plus everolimus or cabozantinib are eligible
Patients who had a major surgery or significant traumatic injury (injury requiring > 28 days to heal) within 28 days of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia), or patients that are expected to require major surgery during the course of the study
Active or documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
Immunocompromising conditions, as follows
Known acute or chronic human immunodeficiency virus (HIV) infection with CD4+ T cell count < 350 cells/microliter. Patients with a history of an acquired immunodeficiency syndrome (AIDS)-defining infection can be included if their CD4+ T cell count > 350 cells/microliter and have not had an AIDS-defining infection within prior 12 months. If patients are on antiretroviral therapy (ART), it must be started at least 4 weeks prior to trial enrollment and the HIV viral load should be < 400 copies/mL. Medication interactions with ART should be screened prior to enrollment
History of primary immunodeficiency
History or allogeneic transplant
Current or prior use of immunosuppressive medication within 28 days before the first dose of study treatment, with the exception of topical, ocular, intranasal, and inhaled corticosteroids, or systemic corticosteroids
Any underlying medical condition, which in the opinion of the investigator, will make
the administration of study drug hazardous or obscure the interpretation of
adverse events, such as a condition associated with frequent diarrhea
uncontrolled nausea, vomiting, malabsorption syndrome or small bowel resection
that may significantly alter the absorption of lenvatinib, everolimus, or
Patients receiving any concomitant systemic therapy for renal cell cancer are excluded
Patients must not be scheduled to receive another experimental drug while on this study
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as
Symptomatic congestive heart failure of New York Heart Association class III or IV
Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
Severely impaired lung function as defined as oxygen saturation that is 88% or less at rest on room air
Uncontrolled diabetes as defined by a hemoglobin A1C >= 8%
Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement) despite appropriate antibiotics or other treatment
Liver disease, such as cirrhosis or chronic active hepatitis as defined here. For hepatitis B virus (HBV), a positive test using HBV surface antigen (HBsAg) test. For hepatitis C virus (HCV), patients with a positive HCV antibody test and HCV ribonucleic acid (RNA) positive are excluded. If a patient is receiving HCV curative treatment, they must complete therapy and have HCV RNA below level of detection. For patients with a history of HCV infection, they are eligible if they have completed curative therapy and have HCV viral load below the level of detection
Uncontrolled blood pressure (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) in spite of optimized regimen of antihypertensive medications
Subjects having > 1+ proteinuria on urine dipstick testing unless a spot urine protein to creatinine ratio is =< 1 mg/mg
Patients must not have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable
suspicion of a disease or condition that contraindicates the use of
lenvatinib, everolimus, or cabozantinib or that might affect the
interpretation of the results of the study or render the subject at high risk
from treatment complications
Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of blood vessels should be considered because of the risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib treatment
Any patients who cannot be compliant with the appointments required in this protocol must not be enrolled in this study
Severe hypersensitivity (>= grade 3) to lenvatinib and/or any of its excipients
Patients with left ventricular ejection fraction < 40%
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