A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell Carcinoma that has Progressed after Prior VEGFR Tyrosine Kinase Inhibitor Therapy

1. Documented histological or cytological diagnosis of renal cell cancer with a clear-cell component.
2. Measurable disease per RECIST 1.1 as determined by the investigator.
3. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib).
Prior treatment with other anticancer therapies including cytokines (eg, interleukin-2,
interferon-alfa), monoclonal antibodies, (eg, bevacizumaband cytotoxic
chemotherapy is allowed (except Exclusion Criterion #1).
4. For the most recently received VEGFR-targeting TKI the following criteria must apply:
a. Must have radiographically progressed during treatment, or been treated for at least 4 weeks and radiographically progressed within 6 months after the last dose.
Radiographic progression is defined as unequivocal progression of existing tumor
lesions or developing new tumor lesions as assessed by the investigator on CT or MRI scans.
b. The last dose must have been within 6 months before the date of randomization.
5. Recovery to baseline or <= Grade 1 CTCAE v.4.0 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
6. Age eighteen years or older on the day of consent.
7. Karnofsky Performance Status (KPS) score of >= 70%.
8. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before randomization:
a. Absolute neutrophil count (ANC) >= 1500/mm3 (>= 1.5 GI/L).
b. Platelets >= 100,000/mm3 (>= 100 GI/L).
c. Hemoglobin >= 9 g/dL (>= 90 g/L).
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal.
e. Total bilirubin <= 1.5 × the upper limit of normal. For subjects with Gilbert*s disease <= 3 mg/dL (<= 51.3 µmol/L).
f. Fasting serum triglycerides <= 2.5 × upper limit of normal AND total cholesterol <= 300 mg/dL (<= 7.75 mmol/L). Lipid-lowering medication is allowed.
g. HbA1c <= 8%. For subjects with a condition (eg, hemoglobin variant)
that affects the interpretation of HBA1c results, a fasting glucose <=
160mg/dL (<=8.9 mmol/L).
h. Serum creatinine <= 2.0 × upper limit of normal or calculated creatinine clearance
>= 30 mL/min (>= 0.5 mL/sec) using the Cockroft-Gault equation (see Table 5-2 for
Cockroft-Gault formula).
i. Urine protein-to-creatinine ratio (UPCR) <= 1 mg/mg (<= 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g.

1. Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT
inhibitor (eg, temsirolimus), or cabozantinib.
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase
inhibitor) within 2 weeks before randomization.
3. Receipt of any type of anticancer antibody (including investigational antibody) within 4
weeks before randomization.
4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy
within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks
before randomization. Subjects with clinically relevant ongoing complications from prior
radiation therapy are not eligible.
5. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before
randomization. Eligible subjects must be neurologically asymptomatic and without
corticosteroid treatment at the time of randomization.
6. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin,
direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose
warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are
permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12
weeks before randomization, and who have had no complications from a thromboembolic
event or the anticoagulation regimen.
7. Chronic treatment with corticosteroids or other immunosuppressive agents (with the
exception of inhaled or topical corticosteroids or corticosteroids with a daily dosage
equivalent <= 10 mg prednisone if given for disorders other than renal cell cancer). Subjects
with brain metastases requiring systemic corticosteroid are not eligible.
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not
limited to, the following conditions:
a. Cardiovascular disorders:
i. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac
arrhythmias.
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or
> 100 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including TIA), myocardial infarction, or other ischemic event, or
thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6
months before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation
or fistula formation:
i. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel
disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute
pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet
obstruction.
ii. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before randomization.
Note: Complete healing of an intra-abdominal abscess must be confirmed before
randomization.
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml)
of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within
3 months before randomization.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e. Lesions invading major pulmonary blood vessels.
f. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, infection with human
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-
related illness, or chronic hepatitis B or C infection.
ii. Serious non-healing wound/ulcer/bone fracture.
iii. Malabsorption syndrome.
iv. Uncompensated/symptomatic hypothyroidism.
v. Moderate to severe hepatic impairment (Child-Pugh B or C).
vi. Requirement for hemodialysis or peritoneal dialysis.
vii. History of solid organ transplantation.
9. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 2 months before
randomization. Complete wound healing from major surgery must have occurred 1 month
before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Subjects with clinically relevant ongoing complications from
prior surgery are not eligible.
10. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 10 days before randomization (see Section 5.5.4 for Fridericia formula).
Three ECGs must be performed. If the average of these three consecutive results for QTcF is
<= 500 msec, the subject meets eligibility in this regard.
11. Pregnant or lactating females.
12. Inability to swallow tablets or capsules.
13. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
14. Diagnosis of another malignancy within 2 years before randomization, except for superficial
skin cancers, or localized, low grade tumors deemed cured and not treated with systemic
therapy.