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Lenvatinib and Everolimus before Surgery in Treating Patients with Locally Advanced or Metastatic Kidney Cancer

Trial Status: Active

This phase I trial studies how well lenvatinib and everolimus before surgery work in treating patients with kidney cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic). Lenvatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lenvatinib and everolimus may cause kidney cancer to shrink more than either drug taken alone, thus potentially making it possible to remove the tumor with surgery.

Inclusion Criteria

  • Histologically confirmed locally advanced or metastatic renal cell carcinoma, clear cell histology that can be considered for partial or complete nephrectomy.
  • cT1b-T2a Grade (G) 4, cT2b G3/4, cT3-cT4 any grade and any cT with cN1 or M1 disease
  • 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
  • Written and voluntary informed consent.
  • Renal function (creatinine level within normal institutional limit, or creatinine clearance > 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, calculated using the Cockcroft-Gault formula).
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal.
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L.
  • Platelets >= 100 x 10^9 /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).
  • Life expectancy of 12 weeks or more.
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
  • Ejection fraction (EF) >= 45%.
  • Female patients of childbearing potential, as defined in this protocol, must have a negative urine or serum pregnancy test within 72 hours prior to taking the first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative then a serum test is required which must be negative for the patient to enroll. Women of childbearing potential (WOCBP) must be willing to use 2 medically acceptable methods of contraceptive from day 1 through 120 days after the last dose of trial treatment. The 2 medically acceptable birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or guidelines. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents).
  • Male patients of childbearing potential, as described in this protocol, must agree to use an adequate method of contraception from day 1 through 120 days after the last dose of trial treatment.
  • Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

Exclusion Criteria

  • Any other cancer from which the patient has been disease-free for less than 5 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 prostate specific antigen [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 human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related disease.
  • Prolongation of corrected QT (QTc) interval (> 480 ms). QTc interval per Bazett formula.
  • Uncontrolled diabetes (fasting glucose > 1.5 x 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 x 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 > 2 gm/ 24 hours urine protein if urinalysis 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] ribonucleic acid [RNA] detected).


Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: ACTIVE
Contact: Yousef Zakharia
Phone: 319-384-8076


I. To estimate the rate of surgical morbidity with lenvatinib and everolimus prior to nephrectomy as assessed by Clavien complications.


I. To assess whether patients will tolerate the combination of lenvatinib and everolimus with same rate of toxicities as seen on prior phase 2 clinical trials.

II. To evaluate the overall response rate (defined as the proportion of patients with a best overall response of complete or partial response).

III. To assess surgical outcomes and determine whether operating on locally advanced tumors was easier after administering lenvatinib and everolimus.


Patients receive lenvatinib orally (PO) once daily (QD) and everolimus PO QD. Cycles repeat every 4 weeks for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo partial or complete cytoreductive nephrectomy after a 2-week wash out period after completion of lenvatinib and everolimus treatment.

After completion of study treatment, patients are followed up 4-6 weeks after surgery and every 3 months for the first year or until disease progression and then every 6 months for up to 5 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Iowa / Holden Comprehensive Cancer Center

Principal Investigator
Yousef Zakharia

  • Primary ID 201710801
  • Secondary IDs NCI-2019-01916
  • ID NCT03324373