Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
Brief Summary: The clinical benefits of sunitinib and sorafenib have been demonstrated in patients with cytokine-refractory metastatic renal cell carcinoma. Sunitinib has also been shown to improve progression free survival and overall survival in a comparative study with interferon-alpha. When sunitinib is used as first-line molecular-targeted therapy, switching to sorafenib is one of the treatment options after disease progression. Reversely, when sorafenib is used as first-line molecular-targeted therapy, sunitinib is used as second-line therapy. The goal of cancer treatment is cure, and if cure is not possible, it is to prolong survival. In this study, sunitinib or sorafenib will be administered as first-line molecular-targeted therapy and treatment switched to the other test drug, sorafenib or sunitinib, when disease progression is detected to assess which treatment sequence produces longer progression free survival and offers a better safety profile (causing fewer adverse events). The purpose of this trial is to compare progression free survival of first line sunitinib versus sorafenib, and that of two treatment sequences, i.e. sunitinib followed by sorafenib versus sorafenib followed by sunitinib.


Options:
A: Inclusion Criteria:

* 18 years or older
* Participants with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib.
* Histologically or cytologically confirmed RCC with a clear cell component (participants with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, and unclassified RCC are excluded).
* Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life expectancy ≥ 3 months.

Exclusion Criteria:

* Prior treatment with sorafenib or tivozanib.
* More than 3 prior regimens for metastatic RCC.
* Known central nervous system (CNS) metastases other than stable, treated brain metastases. Participants with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
* Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders.
* Significant serum chemistry abnormalities
* Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure, uncontrolled hypertension, myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug, history of serious ventricular arrhythmia, cardiac arrhythmias requiring anti-arrhythmic medications.
* Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
* Currently active second primary malignancy.
B: 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
C: Inclusion Criteria:

* Age: 20-80 years old, both inclusive
* ECOG performance status of 0, 1, or 2
* MSKCC risk of favorable or intermediate
* Histologically confirmed renal cell carcinoma
* No ischemic heart disease
* Laboratory findings meet the following criteria:

  1. Respiratory function: %VC, 80% and FEV1.0,70%
  2. Hematology: white blood cell count4,000/mm3, platelet count100,000/mm3
  3. Clinical chemistry: GOT and GPT within the normal range of each medical institution; total bilirubin \<1.5 x ULN
  4. Serum creatinin \<2.0mg/dl, blood urea nitrogen (BUN) \<25mg/dl
  5. Echocardiographic estimation of left ventricular ejection fraction is higher than the lower limit of reference range of each medical institution.

Exclusion Criteria:

* History of any other malignancy
* Central nervous system metastases. However, patients who remain asymptomatic, have no new or enlarging lesion in the CNS within 6 months of enrollment in this study, and require no corticosteroids may be enrolled.
* History of cardiac infarction, unstable angina, congestive heart failure, or symptomatic peripheral vascular disease within 12 months of enrollment
* History of cerebrovascular disorder including transient ischemic attack (TIA)
* Pregnancy or possible pregnancy at any time during the study
* Ongoing grade 2 adverse event prior treatment
* Prior treatment with any anticancer therapy including cytokine therapy such as interferon-alpha and interleukin-2
* Prior treatment with mTOR inhibitor
* Prior treatment with sunitinib or sorafenib
* Treatment with an test drug in a clinical research within 4 weeks of enrollment in this study
D: 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

Answer: C