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Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT05012371
Recruitment Status : Recruiting
First Posted : August 19, 2021
Last Update Posted : February 18, 2022
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Cabozantinib Drug: Everolimus Drug: Lenvatinib Other: Questionnaire Administration Phase 2

Detailed Description:


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 16, 2022
Estimated Primary Completion Date : April 25, 2023
Estimated Study Completion Date : April 25, 2023

Arm Intervention/treatment
Experimental: Arm A (lenvatinib, everolimus)
Patients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Drug: Everolimus
Given PO
Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress

Drug: Lenvatinib
Given PO
Other Names:
  • E7080
  • ER-203492-00
  • Multi-Kinase Inhibitor E7080

Other: Questionnaire Administration
Ancillary studies

Active Comparator: Arm B (cabozantinib)
Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib
Given PO

Other: Questionnaire Administration
Ancillary studies

Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: Time from start of study drug until disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed up to 2 years ]
    To be compared between lenvatinib + everolimus versus cabozantinib. Monitored using Bayesian optimal phase 2 (BOP2) design with time-to-event endpoint.

Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Up to 2 years ]
    ORR is defined as complete response (CR) plus partial response (PR).

  2. Disease Control Rate (DCR) [ Time Frame: Up to 2 years ]
    Defined as CR + PR + stable disease.

  3. Health-Related Quality of Life (HRQoL) [ Time Frame: Up to 2 years ]
    Evaluated using standardized questionnaires, including Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19), Patient-Reported Outcomes Measurement Information System (PROMIS)-10, Center for Epidemiologic Studies Depression Scale (CES-D), Social Provisions Scale, and the Finding Meaning in Cancer Scale (FMCS).

  4. Incidence of grade 3 or 4 adverse events [ Time Frame: Up to 2 years ]
    Defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  5. Overall survival (OS) [ Time Frame: Start of study drug to death due to any cause, assessed up to 2 years ]
    OS is compared between lenvatinib + everolimus versus cabozantinib in patients with metastatic renal cell carcinoma who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 cabozantinib.
  • 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%.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT05012371

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Contact: Paul Corn, MD (713) 563-7208

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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Paul Corn, MD    713-563-7208   
Principal Investigator: Paul Corn, MD         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Paul M Corn, MD M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT05012371    
Other Study ID Numbers: 2021-0400
NCI-2021-07429 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2021-0400 ( Other Identifier: M D Anderson Cancer Center )
First Posted: August 19, 2021    Key Record Dates
Last Update Posted: February 18, 2022
Last Verified: February 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action