Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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
Brief Summary: The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with Everolimus (Afinitor) on progression-free survival (PFS) and overall survival (OS) in subjects with advanced renal cell cancer that has progressed after prior VEGFR tyrosine kinase inhibitor therapy.


Options:
A: Inclusion Criteria:

* Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up.
* Age ≥ 18 years.
* Histologically confirmed diagnosis of progressive metastatic clear cell renal cell cancer defined as \>10% of the tumor cells having the clear cell phenotype.
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to AJCC staging).
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Measurable disease.
* No prior systemic anti-cancer treatment against clear cell renal carcinoma.
* Adequate organ system function.
* Non-childbearing potential.

Exclusion Criteria:

* Prior malignancy.
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
* Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding.
* Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product.
* Presence of uncontrolled infection.
* Known past or present infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV).
* Corrected QT interval (QTc) \> 480 msecs using Bazett's formula.
* History of one or more of the following cardiovascular conditions within the past 6 months:

  1. Cardiac angioplasty or stenting
  2. Myocardial infarction
  3. Stable or unstable angina pectoris.
  4. Coronary artery bypass graft surgery.
  5. Symptomatic peripheral vascular disease
  6. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
* Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg\].
* History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any nonhealing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Evidence of active bleeding or bleeding diathesis.
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
* Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
* Unable or unwilling to discontinue use of prohibited medications or modify the dosing of interacting drugs for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
* Pregnant or lactating female.
* Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of Pazopanib OR Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy.
B: Inclusion Criteria:

1. Patients with metastatic renal cell carcinoma
2. Patients with at least one measurable lesion
3. Patients with progressive metastatic renal cell carcinoma
4. Patients who had a prior partial or complete nephrectomy
5. Patients with a Karnofsky Performance Status ≥70%.
6. Adequate bone marrow function
7. Adequate liver function
8. Adequate renal function
9. Adequate coagulation profile

Exclusion Criteria:

1. 4 weeks post-major surgery
2. Patients who had radiation therapy within 28 days prior to start of study
3. Patients in need for major surgical procedure during the course of the study.
4. Patients with a serious non-healing wound, ulcer, or bone fracture.
5. Patients with a history of seizure(s) not controlled with standard medical therapy.
6. Patients who have received prior systemic treatment for their metastatic RCC.
7. Patients who received prior therapy with VEGF pathway inhibitor
8. Patients who have previously received systemic mTOR inhibitors
9. Patients with a known hypersensitivity RAD001 (everolimus) or other rapamycins or to its excipients.
10. Patients with history or current central nervous system (CNS) metastases or spinal cord compression.
11. Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment.
12. Patients with proteinuria at screening.
13. Patients with inadequately controlled hypertension
14. Patients receiving ongoing or with recent need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin
15. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent.
16. Patients with a known history of HIV
17. Patients with hypersensitivity to interferon alfa-2a or any component of the product.
18. Patients with an active, bleeding diathesis or coagulopathy or recurrent thromboembolism
19. Patients who have any severe and/or uncontrolled medical conditions or other conditions
20. Left Ventricular Ejection Fraction \< lower limit of institutional normal assessed by ECHO or MUGA
21. Patients who have a history of another primary malignancy ≤ 3 years
22. Female patients who are pregnant or breast feeding
23. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start.
24. Patients unwilling to or unable to comply with the protocol

Other protocol-defined inclusion/exclusion criteria may apply
C: Select Inclusion Criteria:

1. Documented histological or cytological diagnosis of renal cell cancer with a clear-cell component.
2. Measurable disease as determined by the investigator.
3. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib).
4. Recovery from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
5. Adequate organ and marrow function.
6. Sexually active fertile subjects(male and female)must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment.
7. Female subjects of childbearing potential must not be pregnant at screening.

Select Exclusion Criteria:

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 and stable for at least 3 months before randomization.
6. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors.
7. Chronic treatment with corticosteroids or other immunosuppressive agents.
8. Serious illness other than cancer.
9. Major surgery within 3 months before randomization. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery at least 10 days before randomization.
10. Pregnant or lactating females.
11. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low grade tumors.
D: Inclusion Criteria:

* Unresectable advanced or metastatic renal cell carcinoma with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic agents, including treatment in the adjuvant setting
* Measurable disease, as defined by RECIST v1.1
* Karnofsky performance score greater than or equal to (\>/=) 70
* Adequate hematologic and end-organ function as defined by protocol
* Women of childbearing potential and male participants with partners of childbearing potential must agree to use highly effective methods of contraception as defined by protocol

Exclusion Criteria:

Disease-Specific Exclusions:

* Radiotherapy for renal cell carcinoma within 14 days prior to Cycle 1, Day 1 with the exception of single-fraction radiotherapy given for the indication of pain control
* Known active malignancies or metastasis of the brain or spinal cord or leptomeningeal disease, as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Uncontrolled hypercalcemia or symptomatic hypercalcemia
* Malignancies other than renal cell carcinoma within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death, treated with expected curative outcome

General Medical Exclusions:

* Life expectancy of less than (\<) 12 weeks
* Pregnant and lactating women
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* History of autoimmune disease
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Participants with active or chronic hepatitis B, active hepatitis C, Human Immunodeficiency Virus (HIV) positive test, significant cardiovascular disease
* Prior allogeneic stem cell or solid organ transplant

Exclusion Criteria Related to Medications:

* Prior treatment with Cluster of Differentiation 137 (CD137) agonists, anti-Cytotoxic T-Lymphocyte Antigen-4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
* Treatment with systemic immunostimulatory agents for any reason within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
* Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1

Bevacizumab- and Sunitinib-Specific Exclusions:

* Inadequately controlled hypertension
* Prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association Class II or greater congestive heart failure
* History of myocardial infarction or unstable angina, stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1

Answer: C