Lenvatinib and Everolimus in Renal Cell Carcinoma (RCC)

NCT03324373 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 201710801
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to see what effect the combination of lenvatinib plus everolimus has in local and metastatic renal cell carcinoma to potentially make surgically unresectable tumors resectable.

Conditions

Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Surgical complications as assessed by Clavien-Dindo classification system

  To determine whether there is increased surgical morbidity with lenvatinib and everolimus prior to nephrectomy as assessed by Clavien complications.

  Assessment will be completed at the first post-operative visit within 4-6 weeks after surgery.

Secondary Outcomes (3)

• Treatment related adverse events as assessed by CTCAE criteria, version 4.03

  First treatment through 5 years after Cycle 1, Day 1 or death.

• Changes in overall response rate as assessed by RECIST 1.1

  Screening (within 14 days of Day 1) and pre-surgery (week 9-10). 1) If metastatic disease followup monthly or 2) if no evidence of disease followup every three months until five years or death.

• Comparison of surgical outcomes to historical controls

  Within two years following the last study participant's surgery

Study Arms (1)

Lenvatinib and Everolimus prior to cytoreductive nephrectomy

EXPERIMENTAL

Eligible patients will start treatment with lenvatinib 18 mg PO daily (administered as one 10 mg capsule and two 4 mg capsules) and everolimus 5 mg PO daily for 4 weeks constituting one cycle. Two cycles of treatment will be administered and after 2 weeks wash out period, the patients will go for nephrectomy.

Drug: Lenvatinib; Drug: Everolimus; Procedure: Partial or Radical Cytoreductive Nephrectomy

Interventions

Lenvatinib DRUG

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.

Also known as: LENVIMA®, KISPLYX®

Lenvatinib and Everolimus prior to cytoreductive nephrectomy

Everolimus DRUG

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Also known as: AFINITOR®

Lenvatinib and Everolimus prior to cytoreductive nephrectomy

Partial or Radical Cytoreductive Nephrectomy PROCEDURE

Surgical removal of a kidney. After completion of 8 weeks of therapy and restaging, investigators will require 2 weeks wash out period. The patients will be evaluated by urology oncology team and appropriate surgery will be planned. This includes partial nephrectomy and radical nephrectomy.

Lenvatinib and Everolimus prior to cytoreductive nephrectomy

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed locally advanced or metastatic renal cell carcinoma, clear cell histology that can be considered for partial or complete nephrectomy.
• \- Locally advanced disease is defined as follows:
• Adjacent organs (T4) or vascular invasion (Level III/ IV / IVC thrombus)
• Bulky lymphadenopathy encasing renal or great vessels
• cT1b-T2a Grade (G) 4, cT2b G3/4, c T3-cT4 any grade and any cT with cN1 or M1 disease
• Written and voluntary informed consent.
• Renal function (creatinine level within normal institutional limit, or creatinine clearance \>30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, calculated using the Cockcroft-Gault formula).
• AST/ALT \<2.5 X institutional upper limit of normal
• Adequate hematological lab values including:
• Absolute Neutrophil count (ANC) ≥ 1.0 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 8.0 g/dL
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry on all pre-disease performance without restriction), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work) or 2 (Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours).
• Age of at least 18 years.
• Life expectancy of 12 weeks or more.

You may not qualify if:

• Any other cancer from which the patient has been disease-free for less than 3 years (except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated carcinoma in situ of the cervix, breast, or bladder and treated localized prostate cancer with undetectable PSA for 2 years).
• Symptomatic untreated metastases in the central nervous system.
• Subject that is pregnant or lactating.
• Pre-existing uncontrolled hypertension defined as \>140/90 mm Hg with medication.
• Known HIV or acquired immunodeficiency syndrome-related disease.
• Prolongation of QTc interval (\>480 ms). QTc interval per Bazett formula.
• Uncontrolled diabetes \[fasting glucose \>1.5 × upper limit of normal (ULN)\] (it will be acceptable if labs were done non-fasting and met the fasting requirement (meaning glucose \< 1.5 ULN).
• Fasting total cholesterol \>300 mg/dL and fasting triglyceride levels \>2.5 × ULN (it will be acceptable if labs were done non-fasting and met the fasting requirement (meaning total cholesterol \<300 mg/dL and triglyceride levels \< 2.5 × ULN.
• Proteinuria (defined by urine protein/creatinine ratio (UPC) \>2.0 if urinalysis protein is \>2+)
• Significant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction (d) stroke, or (e) cardiac arrhythmia associated with hemodynamic instability within 6 months of the first dose of study drugs.
• Known history of active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] RNA detected)

Sponsors & Collaborators

• Yousef Zakharia: lead
• Eisai Inc.: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

lenvatinib; Everolimus

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

• Yousef Zakharia, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Assistant Professor

Study Record Dates

• First Submitted: October 20, 2017
• First Posted: October 27, 2017
• Study Start: March 20, 2019
• Primary Completion: September 27, 2023
• Study Completion: August 28, 2024
• Last Updated: April 24, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)