Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Phase II Study Comparing Cabozantinib (NSC #761968) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Metastatic Renal Cell Carcinoma
Brief Summary: This randomized phase II trial studies how well cabozantinib-s-malate works compared to sunitinib malate in treating patients with previously untreated kidney cancer that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Cabozantinib-s-malate and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cabozantinib-s-malate is more effective than sunitinib malate in treating patients with kidney cancer.


Options:
A: Inclusion Criteria:

* Confirmation of metastatic or recurrent renal cell carcinoma

Exclusion Criteria:

* Certain types of previous anti-cancer therapy for Renal Cell Carcinoma
* Patients with type I insulin-dependent diabetes or poorly-controlled type II insulin-independent diabetes
* Patients with a history of poorly controlled high blood pressure
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:

* Patients must provide written informed consent prior to performance of any study-specific procedures or assessments and must be willing to comply with treatment and follow up. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging study) and obtained prior to signing of informed consent may be utilised for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
* Received no prior systemic therapy (including interleukin-2, interferon-alpha, chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or metastatic RCC. Patients who received adjuvant treatment with a cancer vaccine are eligible.
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma of any histology (equivalent to Stage IV RCC according to AJCC staging). Patients with non-measurable disease are allowed if metastatic disease can be confirmed.
* ECOG PS of 0 or 1
* Age \>= 18 years
* A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e. physiologically incapable of becoming pregnant) Childbearing potential, including any female who has had a negative serum pregnancy test within two weeks prior to the first dose of study treatment, preferably as close to the first dose as possible and agrees to use adequate contraception.

* Adequate organ system functions
* Total serum calcium concentration \<12.0mg/dL
* Left ventricular ejection fraction (LVEF) \>=lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan. The same modality used at baseline must be applied for subsequent evaluations.
* Patient is able to swallow and retain oral tablets

Exclusion Criteria:

* Poor MSKCC risk group
* History of another malignancy. Note: Patients who have had another malignancy and have been disease-free for 3 years or patients with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
* History or clinical evidence of central nervous system (CNS) metastases.

Note: Patients who have previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

* Are asymptomatic,
* Have had no evidence of active CNS metastases for \>=6 months prior to enrolment ,
* Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC).
* Any clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding or affect absorption of investigational product including, but not limited to:
* Malabsorption syndrome
* Major resection of the stomach or small bowel that could affect the absorption of study drug
* Active peptic ulcer disease
* Inflammatory bowel disease
* Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
* History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
* Presence of uncontrolled infection.
* 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:
* Cardiac angioplasty or stenting
* Myocardial infarction
* Unstable angina
* Coronary artery bypass graft surgery
* Symptomatic peripheral vascular disease
* 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 \> 150mmHg or diastolic blood pressure (DBP) of \> 90mmHg) at baseline.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour within a visit. The mean SBP/DBP values from each blood pressure assessment must be \<=150/90mmHg in order for a patient to be eligible for the study.

- History of cerebrovascular accident (CVA) including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Evidence of active bleeding or bleeding diathesis.
* Significant haemoptysis within 6 weeks prior to first dose of study drug.
* Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with patient's safety, obtaining informed consent or compliance to the study.
* Use any prohibited medications within 14 days of the first dose of study medication.
* Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
* Radiation therapy, surgery or tumour embolisation within 14 days prior to the first dose of study treatment.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or sunitinib.
* Pregnant or lactating female Female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
D: Inclusion Criteria:

* Renal cell carcinoma with some component of clear cell histology; histologic documentation of metastatic disease is not required
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma (RCC) (equivalent to stage IV RCC, according to American Joint Committee on Cancer \[AJCC\] staging)
* Eligible patients must be intermediate/poor risk, per the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (Heng) criteria; patients must therefore have as one or more of the following six factors:

  * Time from diagnosis of RCC to systemic treatment \< 1 year

    * Note: systemic treatment refers to the initiation of A031203 protocol treatment
  * Hemoglobin \< the lower limit of normal (LLN)
  * Corrected calcium \> the upper limit of normal (ULN)
  * Karnofsky performance status \< 80%
  * Neutrophil count \> ULN
  * Platelet count \> ULN
* No radiographic evidence of cavitating pulmonary lesion(s)
* No tumor invading the inferior vena cava (IVC) or superior vena cava (SVC) blood vessels
* No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days prior to registration
* No prior systemic treatment for RCC; supportive therapies such as bisphosphonates (zoledronic acid) or denosumab are permitted
* Patients must not have had a major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; however, patients who have had a nephrectomy may be enrolled 4 weeks after surgery, providing there are no wound-healing complications; the following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures
* Radiation:

  * To the brain, thoracic cavity, abdomen, or pelvis must be completed at least 90 days before registration;
  * To bone must be completed at least 14 days before registration; and
  * To any other sites must be completed at least 28 days before registration In all cases, there must be complete recovery and no ongoing complications from prior radiation therapy
* No chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors; patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration
* Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 2 cm with conventional techniques or as \>= 1 cm with spiral computed tomography (CT) scan
* No active brain metastases; patients with treated, stable brain metastases for at least three months are eligible as long as they meet the following criteria:

  * Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or CT); (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator \[LINAC\], or equivalent) or a combination as deemed appropriate by the treating physician; patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to registration are not eligible
  * Baseline brain imaging (MRI/CT) is required
* No serious non-healing wound, ulcer, or bone fracture requiring intervention within 28 days prior to registration
* No arterial thrombotic events within 6 months prior to registration, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in the 6 months prior to registration, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection), or any other arterial thrombotic event are ineligible
* No history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6 months prior to registration; note: patients with recent DVT who have been treated with therapeutic anticoagulation with low molecular weight heparin for at least 6 weeks are eligible; patients receiving therapeutic warfarin (\> 2 mg/day) are not eligible; patients on warfarin may be switched to low molecular weight heparin at the discretion of the treating physician
* No inadequately controlled hypertension (defined as a blood pressure of \>= 150 mmHg systolic and/or \>= 90 mmHg diastolic), or any prior history of hypertensive crisis or hypertensive encephalopathy
* No New York Heart Association (NYHA) class \>= 2 congestive heart failure
* Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) \> 50%
* No corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 28 days before randomization; note: if initial QTcF is found to be \> 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =\< 500 ms, the subject meets eligibility in this regard
* No history of congenital QT syndrome
* No unstable cardiac arrhythmia within 6 months prior to registration
* No evidence of any of the following:

  * Clinically-significant gastrointestinal bleeding within 6 months before registration; or
  * Hemoptysis of \>= 0.5 teaspoon (2.5 mL) of red blood within 3 months before registration; or
  * Any other signs indicative of pulmonary hemorrhage within 3 months before registration
* No history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 6 months prior to registration and complete healing/resolution prior to registration; no percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration
* No active peptic ulcer disease, within 28 days before registration
* No inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis within 28 days before registration
* No malabsorption syndrome within 28 days before registration
* No uncompensated hypothyroidism; patients with hypothyroidism on therapy are required to have thyroid stimulating hormone (TSH) within normal limits
* No radiologic or clinical evidence of pancreatitis
* No history of organ transplant
* Patients with active infection requiring systemic treatment within 28 days prior to registration are not eligible
* Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:

  * Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea \>= 12 consecutive months)
  * Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35m IU/mL
  * Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)
* Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2
* Archival tissue must be available for submission, though it is optional for patients to choose to participate in the correlative sub studies
* Absolute neutrophil count (ANC) \>= 1,500/uL
* Platelet count \>= 100,000/uL
* Hemoglobin \>= 9 g/dL; patients may not have had a transfusion within 7 days prior to screening assessment
* Total bilirubin =\< 1.5 x upper limits of normal
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x ULN
* Albumin \>= 2.8 g/dL
* Serum creatinine =\< 1.5 x ULN, OR calculated creatinine clearance \>= 30 mL/minute (modified Cockcroft and Gault formula)
* Urine protein to creatinine (UPC) ratio \< 1.0; if UPC \>= 1, then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour urine protein value \< 1 g
* Total serum calcium \< 12 mg/dL
* International normalized ratio (INR) =\< 1.2 x ULN; subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation
* TSH within normal limits (WNL); TSH only required for patients on thyroid supplementation

Answer: D