Lenvatinib and Everolimus in Renal Cell Carcinoma (RCC)

This is a Phase I interventional clinical trial, with an expansion cohort, at the University
of Iowa Hospitals and Clinics enrolling 15 subjects and lasting approximately 12 months.
Eligible patients will be treated with lenvatinib and everolimus for 8 weeks prior to
cytoreductive nephrectomy. A wash out period of 2 weeks is needed between the end of
treatment and surgery.

Eligible patients will start treatment with lenvatinib 18 milligrams (mg) orally (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.

Inclusion Criteria:

1. Histogically confirmed locally advanced or metastatic renal cell carcinoma, clear cell
histology that can be considered for cytoreductive nephrectomy.

2. The 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

3. Written and voluntary informed consent.

4. 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).

5. AST/ALT <2.5 X institutional upper limit of normal

6. Adequate hematological lab values including:

- Absolute Neutrophil count (ANC) ≥ 1.0 x 109/L

- Platelets ≥ 100 x 109/L

- Hemoglobin ≥ 8.0 g/dL

7. 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).

8. Age of at least 18 years.

9. Life expectancy of 12 weeks or more.

10. Measurable disease per RECIST criteria.

11. Ejection fraction (EF) ≥ 45%

12. 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).

13. 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.

14. Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the patient.

Exclusion Criteria:

1. 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 PSA for 2 years).

2. Symptomatic untreated metastases in the central nervous system.

3. Subject that is pregnant or lactating.

4. Pre-existing uncontrolled hypertension defined as >140/90 mm Hg with medication.

5. Known HIV or acquired immunodeficiency syndrome-related disease.

6. Prolongation of QTc interval (>480 ms). QTc interval per Bazett formula.

7. Uncontrolled diabetes [fasting glucose >1.5 × upper limit of normal (ULN)],

8. Fasting total cholesterol >300 mg/dL and fasting triglyceride levels >2.5 × ULN

9. Proteinuria (defined by >2gm/ 24 hours urine protein if urinalysis is >2+)

10. 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.

12. 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)