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:

1. Histologically confirmed PRCC, which is unresectable/locally advanced or metastatic with measurable disease as per RECIST 1.1. Patients with papillary urothelial carcinoma or renal pelvis cancer of the kidney are not considered PRCC and are not eligible.
2. Confirmation of MET-driven PRCC without co-occurring FH or VHL mutations from an FFPE tumour sample using the sponsor-designated central laboratory validated NGS assay
3. Patients who have received no prior systemic therapy as well as those who have received prior systemic therapy for PRCC in the advanced setting.\* Patients can be treatment-naïve, or previously treated, but cannot have previously received sunitinib or a MET inhibitor. Patients who have received prior systemic therapy must have had disease progression in soft tissue disease or bone within 6 months of the last dose of the most recent systemic therapy
4. Adequate haematological, renal, cardiac and liver functions
5. Karnofsky performance status ≥ 80

Exclusion Criteria:

1. Most recent cytotoxic chemotherapy, immunotherapy, chemo-immunotherapy, or investigational agents \<28 days from the date of randomisation. Most recent non cytotoxic targeted therapy \<14 days from the date of randomisation.
2. Prior treatment with a MET inhibitor (e.g. foretinib, crizotinib, cabozantinib, onartuzumab or previous savolitinib) or sunitinb.
3. Treatment with strong inducers or inhibitors of CYP3A4 or strong inhibitors of CYP1A2, taken within 2 weeks or not possible to be stopped for at least 2 week before the date of randomisation. Herbal medications cannot be taken within 7 days of the date of randomisation (3 weeks for St John's wort).
4. Wide field radiotherapy administered ≤28 days or limited field radiation for palliation ≤7 days prior to the date of randomisation
5. Major surgical procedures ≤28 days of randomisation or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement.
6. Previously untreated brain metastases
7. Serious active infection or gastrointestinal disease
8. Presence of other active cancers, or history of treatment for invasive cancer within the last 5 years.
9. Mean resting QTcF \>470 msec for women and \>450 msec for men on the Part 2 screening triplicate ECGs or factors that may increase the risk of QTcF prolongation such as chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, or family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes
B: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Histological confirmation of renal cell carcinoma (RCC) with a clear-cell component
* Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
* No prior systemic therapy for RCC with the following exception:

  1. One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy

     * Karnofsky Performance Status (KPS) of at least 70%
     * Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
     * Tumor tissue \[formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition\] must be received by the central vendor (block or unstained slides) in order to randomize a subject to study treatment. (Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable for submission)

Exclusion Criteria:

* Any history of or current central nervous system (CNS) metastases. Baseline imaging of the brain is required within 28 days prior to randomization
* Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, Pazopanib, Axitinib, Tivozanib, and Bevacizumab)
* Prior treatment with an anti-programmed death (PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
* Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\>10 mg daily Prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll
* Any condition requiring systemic treatment with corticosteroids (\>10 mg daily Prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \>10 mg daily Prednisone equivalents are permitted in the absence of active autoimmune disease
C: 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).
D: Inclusion Criteria:

* Evidence of histologically confirmed renal cell carcinoma (RCC) with metastases with a component of clear (conventional) cell histology
* A diagnosis of metastatic renal cell carcinoma (RCC) and have not received prior treatment with systemic (adjuvant or neoadjuvant) therapy for renal cell carcinoma (RCC) (including targeted therapy such as tyrosine kinase inhibitors or bevacizumab, immunotherapy, chemotherapy, hormonal, or investigational therapy)
* Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed within 4 weeks prior to study entry
* Participants who have or have not had their primary tumor removed by nephrectomy are allowed. Participants who have not had a nephrectomy should not be considered to need a nephrectomy as part of their overall therapy at the time of enrollment
* Performance status score of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
* Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements, to be conducted within seven days prior to treatment: (upper limit of normal/lower limit of normal \[ULN/LLN\])

  * hemoglobin (greater than) \>8.0 g/dL (grams per deciliter)
  * absolute neutrophil count (ANC) (greater than or equal to) ≥1.5 × 10\^9/L (liter)
  * platelet count (greater than or equal to) ≥100 × 10\^9/L (liter)
  * total bilirubin (less than or equal to) ≤ 1.5 × ULN (upper limit of normal)
  * serum creatinine (less than or equal to) ≤2 × ULN (upper limit of normal)
  * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (less than or equal to) ≤2.5 × ULN (upper limits of normal) \[or (less than or equal to) ≤5 × ULN (upper limits of normal) for patients with liver involvement of their cancer\]
  * Prothrombin Time (PT) or International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) (less than or equal to) ≤1.5 x ULN (upper limit of normal)
* For women: Must be surgically sterile (surgical procedure: bilateral tubal ligation, hysterectomy, bilateral oophorectomy), post-menopausal (at least 12 consecutive months of amenorrhea), or have a negative pregnancy test. Women of childbearing potential should be compliant with a medically approved contraceptive regimen (intrauterine device \[IUD\], birth control pills, or barrier device) during and for 3 months after the treatment period; must have a negative serum pregnancy test within 7 days before study enrollment, and must not be breastfeeding
* For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after the treatment period
* Estimated life expectancy of at least 12 weeks
* Provide written informed consent/assent prior to any study-specific procedures
* No prior malignancies with the exception of stage 1 cancers definitively treated, carcinoma in situ (any primary site), treated non-melanoma skin cancer, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated 5 or more years prior to study entry
* Capable and willing to learn to self-administer LY2510924, or have a caregiver who is willing to learn and able to administer LY2510924 by subcutaneous (SC) injection and are able to swallow tablets
* Left ventricular ejection fraction (LVEF) greater than or equal to LLN as defined by the institution performing the scan, as assessed by Multiple Gated Acquisition (MUGA) scan, or from echocardiogram to be performed within 28 days prior to start of treatment

Exclusion Criteria:

* Received prior treatment with sunitinib or LY2510924
* Received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
* History of active cardiovascular disease within the previous 12 months, including any of the following:

  * Myocardial infarction
  * Unstable angina
  * Coronary artery/peripheral artery bypass graft
  * Congestive heart failure
  * Malignant hypertension
  * Cerebrovascular accident or transient ischemic attack
  * Symptomatic cardiac arrhythmias (Patients with chronic, stable, rate- controlled atrial fibrillation are eligible)
* Exhibit uncontrolled hypertension ( \[greater than\] \>150/100 \[millimeters of mercury\] mm/Hg despite optimal medical therapy), or history of poor compliance with antihypertensive treatment
* Evidence of bleeding diathesis, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 hemorrhage (less than) \<4 weeks of starting the study treatment, coagulopathy, or thromboembolic event
* Significant surgery (less than) \<4 weeks of starting study treatment or a minor surgical procedure (less than) \< 7 days prior to study treatment (Placement of a portacath or other venous access device does not require a waiting period)
* Suffer from medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
* Known or suspected allergy to any agent given in association with this trial
* Prior palliative radiotherapy to metastatic lesion(s) is/are permitted, provided there is at least 1 measurable lesion that has not been irradiated. Radiotherapy must have been completed (greater than) \>2 weeks prior to starting study treatment, and radiation-related side effects must have resolved
* Pregnant or lactating women
* Impairment of the gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sunitinib
* Current or recent (within 10 days of first dose of study treatment) daily use of aspirin ( \[greater than\] \>325 \[milligram\] mg/day )
* Serious nonhealing wounds, acute or nonhealing ulcers, or bone fractures

Answer: C