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

Phase 2

Active, not recruiting

• Conditions: 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
• Interventions: Drug: Cabozantinib; Drug: Everolimus; Other: Questionnaire Administration; Drug: Lenvatinib

• Registration Number: NCT05012371
• Lead Sponsor: 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.

Detailed Description

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVE:

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.

Study Timeline

• Study First Submitted: 2021-08-12
• Study First Submitted QC: 2021-08-12
• Study First Posted: 2021-08-19
• Study Start: 2022-02-16
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-21
• Last Update Posted: 2025-04-23
• Primary Completion: 2025-10-25
• Study Completion: 2025-10-25

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B (cabozantinib)	Cabozantinib	Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Arm B (cabozantinib)	Questionnaire Administration	Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Arm A (lenvatinib, everolimus)	Everolimus	Patients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Arm A (lenvatinib, everolimus)	Lenvatinib	Patients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
Arm A (lenvatinib, everolimus)	Questionnaire Administration	Patients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	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

Name	Time	Method
Disease Control Rate (DCR)	Up to 2 years	Defined as CR + PR + stable disease.
Health-Related Quality of Life (HRQoL)	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).
Incidence of grade 3 or 4 adverse events	Up to 2 years	Defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Overall survival (OS)	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.
Objective Response Rate (ORR)	Up to 2 years	ORR is defined as complete response (CR) plus partial response (PR).

Trial Locations

Locations (3)

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States