Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase II Study of Afinitor (RAD001) vs. Sutent (Sunitinib) in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN)
Brief Summary: To compare the anti-tumor activity of everolimus and sunitinib in subjects with metastatic renal cell carcinoma (mRCC) with non-clear cell pathology.


Options:
A: 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
B: Inclusion Criteria:

1. Histologically confirmed advanced Renal Cell Carcinoma (RCC), with non-clear cell pathology.
2. RCC tumor tissue available for correlative sciences, from either primary or metastatic site or both.
3. At the time of screening, at least 4 weeks since prior palliative radiation therapy and/or major surgery, and resolution of all toxic effects of prior therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.0) Grade 1.
4. Subject must have radiographic evidence of metastatic disease with at least 1 measurable per RECIST 1.1 criteria (Attachment 1)\].
5. Age \> 18 years.
6. Adequate laboratory values
7. Karnofsky Performance Status ≥ 60 (Attachment 2).
8. Life expectancy of at least 3 months.
9. Written, signed, dated, and witnessed Institutional Review Board (IRB) or Institutional Ethics Committee (IEC) approved informed consent form (ICF) before any screening procedures are performed.

Exclusion Criteria:

1. Subjects with a history of or active central nervous system (CNS) metastases.
2. Prior systemic therapy for RCC, including mTOR and anti-angiogenic therapy, chemotherapy, biologic or experimental therapy.
3. Subjects with collecting duct, medullary, small cell, oncocytoma, or lymphoma-type pathology.
4. Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers.
5. Major surgery, open biopsy, traumatic injury, or radiotherapy within 4 weeks of the screening visit.
6. Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy.
7. Presence of a non-healing wound or ulcer.
8. Grade 3 hemorrhage within the past month.
9. Hypertension with systolic blood pressure of \>180 mm Hg and/or diastolic pressure \>100 mm Hg.
10. Subjects with American Heart Association (AHA) Class 2-4 heart disease or any history of congestive heart failure with an ejection fraction \<50%, or history of unstable angina, myocardial infarction, coronary artery bypass graft, cerebrovascular accident, transient ischemic attack, or pulmonary embolism within 6 months of entry.
11. Diabetes mellitus with glycosylated hemoglobin A1c (HbgA1c) \> 10% despite therapy.
12. A history of interstitial pneumonitis.
13. Subjects with active autoimmune disorder(s) being treated with immunosuppressive agents within 4 weeks prior to the screening visit.
14. Subjects receiving immunosuppressive agents and those with chronic viral/bacterial/fungal illnesses such as human immunodeficiency virus (HIV).
15. Patients who have receive immunization with attenuated live vaccines within one week of study entry or during study period.
16. Patients with active infection(s), active antimicrobial therapy or serious intercurrent illness.
17. History of other prior malignancy in past 5 years.
18. Pregnant or nursing women.
19. Major medical/psychiatric illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study, including inability to absorb oral medications and history of noncompliance to medical regimens.
20. Known hypersensitivity to any of the components in everolimus or sunitinib product
21. Subjects taking agents that significantly prolong the QTc interval are not eligible.
22. Proteinuria with a spot urine protein/creatinine ratio \>2 or 24 hour urine protein \>2 grams per 24 hours.
23. Severely impaired lung function as defined as spirometry and Carbon Monoxide Diffusing Capacity (DLCO) that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air.
24. Advanced liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).
C: 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
D: * INCLUSION CRITERIA:

Patients must have histologically confirmed alveolar soft part sarcoma. Pathology should be confirmed at the Laboratory of Pathology, National Institutes of Health.

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 millimeters with conventional techniques or as greater than or equal to 10 millimeters with spiral computed tomography (CT) scan.

Patients must have metastatic alveolar soft part sarcoma that is not curable by surgery. Patients who have surgically resectable tumors with metastasis will be considered on a case by- case basis.

Any prior therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol and the participant must have recovered to eligibility levels from prior toxicity. Patients should be at least 6 weeks out from nitrosoureas and mitomycin C. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the principal investigator's (PI's) discretion, and should haverecovered to eligibility levels from any toxicities.

Any degree of prior treatment is allowed, including other anti-angiogenic treatments (e.g., vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors or bevacizumab). Patients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgery.

Body surface area (BSA) greater than or equal to 1.04 square meter.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 for adults, Karnofsky performance status greater than or equal to 50% for pediatric patients greater than 10 years of age, and Lansky performance status greater than or equal to 50 for pediatric patients less than or equal to 10 years of age.

Life expectancy of greater than 8 weeks.

Patients must have normal organ and marrow function as defined below:

* absolute neutrophil count greater than or equal to 1,500/microliter
* platelets greater than or equal to 100,000/microliter
* total bilirubin less than 1.5 times institutional upper limit of normal
* Aspartate aminotransferase (AST)(Serum glutamic Oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) less than or equal to 2.5 times institutional upper limit of normal
* creatinine within normal limits based on age as follows:

Age (Years) Maximum Serum Creatinine (milligrams per deciliter)

less than or equal to 5 0.8

5 less than age less than or equal to 10 1.0

10 less than age less than or equal to 15 1.2

greater than 15 1.5

OR

creatinine clearance greater than or equal to 60 milliliter/min for adults or greater than or equal to 60 milliliter/min/1.73m\^2 for children with creatinine levels above institutional upper limit of normal.

Corrected QT interval (QTc) must be less than 500 msec.

Pediatric patients: Normal left ventricular function with ejection fraction greater than 55% or shortening fraction greater than or equal to 27%.

At present, the potential of Cediranib (AZD2171) for clinically significant drug interactions involving the cytochrome P450 (CYP) isozymes is unknown. However, studies of the agent in rats indicated possible suppression of cytochrome P450, family 1, subfamily A (CYP1A) that may be of biological significance. Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity of pharmacokinetics (PK) of AZD2171 will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications one week prior to starting therapy.

AZD2171 has been shown to terminate fetal development in the rat, as expected for a process dependent on vascular endothelial growth factor (VEGF) signaling. For this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Ability to understand and the willingness to sign a written informed consent document.

Patients should not be receiving any other investigational agents.

Prior therapy with anti-angiogenic agents is permitted.

EXCLUSION CRITERIA:

Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to: active or uncontrolled infection, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.

Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, ibuprofen, pentamidine).

Patients who are unable to swallow tablets.

Mean QTc greater than 500 msec (with Bazett's correction) in screening electrocardiogram or history of familial long Q wave, T wave (QT) syndrome.

Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart.

Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with known abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD2171, breastfeeding should be discontinued if the mother is treated with AZD2171.

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with AZD2171.

Adult patients with hypertension not controlled by medical therapy (hypertension defined as systolic blood pressure greater than 150 millimeters of mercury or diastolic pressure greater than 90 millimeters of mercury despite optimal medical management). Pediatric patients must have blood pressure (BP) within normal limits (WNL) for age. NOTE: blood pressure within the upper limit of normal is defined as: blood pressure less than or equal to the 95th percentile for age, height, and gender, and measured, and not be receiving medication for treatment of hypertension.

Answer: B