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

NCT05012371 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2021-0400NCI-2021-07429
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 3

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.

Conditions

Metastatic Clear Cell Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Advanced Clear Cell Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival (PFS)

  To be compared between lenvatinib + everolimus versus cabozantinib. Monitored using Bayesian optimal phase 2 (BOP2) design with time-to-event endpoint.

  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

Secondary Outcomes (5)

• Objective Response Rate (ORR)

  Up to 2 years

• Disease Control Rate (DCR)

  Up to 2 years

• Health-Related Quality of Life (HRQoL)

  Up to 2 years

• Incidence of grade 3 or 4 adverse events

  Up to 2 years

• Overall survival (OS)

  Start of study drug to death due to any cause, assessed up to 2 years

Study Arms (2)

Arm A (lenvatinib, everolimus)

EXPERIMENTAL

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; Drug: Lenvatinib; Other: Questionnaire Administration

Arm B (cabozantinib)

ACTIVE COMPARATOR

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

Drug: Cabozantinib; Other: Questionnaire Administration

Interventions

Cabozantinib DRUG

Given PO

Arm B (cabozantinib)

Everolimus DRUG

Given PO

Also known as: 42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, Zortress

Arm A (lenvatinib, everolimus)

Lenvatinib DRUG

Given PO

Also known as: E7080, ER-203492-00, Multi-Kinase Inhibitor E7080

Arm A (lenvatinib, everolimus)

Questionnaire Administration OTHER

Ancillary studies

Arm A (lenvatinib, everolimus); Arm B (cabozantinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically or cytologically confirmed metastatic/advanced clear cell RCC, or RCC with a clear cell component, who have received 1 or 2 prior lines of systemic treatment in the advanced or metastatic setting, including a PD-1/PD-L1 checkpoint inhibitor.
• Patients must have previously progressed on or after treatment (at any point after completing prior therapy) with a PD-1/PD-L1-containing regimen. Patients who experienced an immune-mediated adverse event related to their PD-1/PD-L1 containing-regimen and cannot receive additional PD-1/PD-L1 checkpoint inhibitor are permitted, without evidence of progression, if the treating physician intends to change treatment per standard care.
• Patients must have at least one measurable site of disease per RECIST version 1.1. This is defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). For non-lymph node tumor lesions, they must be a minimum size of
• ≥ 10 mm. For malignant lymph node lesions, they must be at least ≥ 15 mm in short axis with conventional techniques or ≥ 10 mm with more sensitive techniques such as MRI or spiral CT scan. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
• ECOG performance status ≤ 2
• Age ≥ 18 years Patients must have adequate organ and marrow function prior to study entry as defined below: Hemoglobina ≥9 g/dl (treatment allowed) Absolute neutrophil count ≥1,000/µL Platelets ≥75,000/µL Total bilirubinb ≤1.5 mg/dL AST(SGOT) or ALT (SGPT) ≤2.5 X institutional ULN, except in known hepatic metastasis, wherein may be \< 5 x ULN Serum CreatinineC ≤1.5 x ULN (as long as patient does not require dialysis) aMay receive transfusion b For patients with Gilbert's disease, total bilirubin should ≤ 3 mg/dL (≤ 51.3 µmol/L). b If creatinine is not \<1.5×ULN, then calculate by Cockcroft-Gault methods or local institutional standard and CrCl must be ≥30 mL/kg/1.73 m2
• \. INR and PT ≤ 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 ofenrollment.
• \. 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 IU/L or equivalent units of HCG) before study entry. Pregnancy test must be repeated if performed \> 14 days before starting study drug. 9. Women must not be breastfeeding. 10. 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. 11. Patients with treated/stable brain metastases are allowed on protocol if they had brain metastases that received CNS-directed therapy, such as surgery or treatment with radiosurgery or Gamma knife, without recurrence for at least 1 month (4 weeks).

You may not qualify if:

• 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 postradiotherapy) 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 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+ Tcell count \< 350 cells/µL. Patients with a history of an AIDS-defining infection can be included if their CD4+ T cell count \> 350 cells/µL 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
• Any underlying medical condition, which in the opinion of the Investigator, will make the administration ofstudy 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 thisstudy.
• 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 orIV
• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (3)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Clear-cell metastatic renal cell carcinoma; Carcinoma, Renal Cell

Interventions

cabozantinib; Everolimus; lenvatinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Andrew W Hahn, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2021
• First Posted: August 19, 2021
• Study Start: February 16, 2022
• Primary Completion (Estimated): October 25, 2027
• Study Completion (Estimated): October 25, 2027
• Last Updated: March 5, 2026

Record last verified: 2026-03

Locations

US (3)