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.

This is a pilot interventional clinical trial at the University of Iowa Hospitals and Clinics, enrolling 15 subjects and lasting approximately 12 months. 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 (8 weeks) will be administered followed by a 1-week wash out period during which time patients will be evaluated by the urology oncology team and appropriate surgery will be planned. The wash out period is for drug to be eliminated prior to surgery, to avoid bleeding/wound healing effects. This includes partial nephrectomy or radical nephrectomy. Following surgery, patients with no evidence of disease will have active surveillance. Patients who continue to have disease following surgery will receive further systemic treatment for metastatic disease.

INCLUSION CRITERIA Inclusion criteria

• 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.

• Measurable disease per 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 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)