Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib Versus Sunitinib in Patients With MET-Driven, Unresectable and Locally Advanced, Or Metastatic Papillary Renal Cell Carcinoma (PRCC)
Brief Summary: This study is designed for patients diagnosed with MET-driven, unresectable and locally advanced or metastatic Papillary Renal Cell Carcinoma. The purpose of this study is to see if an investigational new anti-cancer medication, savolitinib, is effective in treating patients with MET-driven PRCC, how it compares with another medication frequently used to treat this disease called sunitinib, and what side effects it might cause.


Options:
A: Key Inclusion Criteria for Tumor Collection:

1. Diagnosis or clinical signs of advanced RCC
2. Scheduled for cytoreductive or partial nephrectomy

Key Exclusion Criteria for Tumor Collection:

1. Known inability to undergo sunitinib treatment as currently labeled, due to pre-existing medical conditions
2. Requirement for systemic chronic immunosuppressive drugs or corticosteroids
3. Evidence of brain metastases prior to nephrectomy

Key Inclusion Criteria for Treatment Study:

1. Advanced disease, histologically assessed as RCC, with predominantly clear cell histology
2. Metastatic disease (measurable or non-measurable) that can be monitored throughout the course of the study participation per RECIST 1.1
3. Subjects who are candidates for standard first-line therapy initiating with sunitinib
4. Time from diagnosis to treatment \< 1 year
5. Karnofsky performance status (KPS) ≥ 70%
6. Life expectancy of 6 months or greater
7. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to Grade ≤ 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
8. Adequate hematologic, renal, hepatic, and coagulation function
9. Negative serum pregnancy test for female subjects with reproductive potential, and agreement of all male and female subjects of reproductive potential to use a reliable form of contraception during the study and for 12 weeks after the last dose of study drug
10. Normal ECG or clinically non-significant finding(s) at Screening
11. Able to abstain from taking prohibited drugs, either prescription or non-prescription, during the treatment phase of the study
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Key Exclusion Criteria for Treatment Study:

1. Prior systemic therapy (including adjuvant or neoadjuvant) of any kind for RCC, including immunotherapy, chemotherapy, hormonal, or investigational therapy
2. Prior history of malignancy within the preceding 3 years, except for adequately treated in situ carcinomas or non-melanoma skin cancer, adequately treated early stage breast cancer, superficial bladder cancer, and non-metastatic prostate cancer with a normal PSA
3. History of or known brain metastases, spinal cord compression, or carcinomatous meningitis, or evidence of brain or leptomeningeal disease
4. Patients with 4 or more of the following risk factors:

   1. Hgb \< LLN
   2. Corrected calcium \> 10.0 mg/dL
   3. KPS \< 80%
   4. Neutrophils \> ULN
   5. Platelets \> ULN
5. Planned or elective surgical treatment post-nephrectomy for the direct management of RCC, within 28 days before Visit 1 (Week 0)
6. NCI CTCAE Grade 3 hemorrhage \< 28 days before Visit 1 (Day 0)
7. Clinically significant cardiovascular conditions within 3 months prior to Randomization
8. Significant gastrointestinal abnormalities
9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
10. Active autoimmune disease or condition requiring chronic immunosuppressive therapy
11. Clinically significant infections, including human immunodeficiency virus, syphilis, and active hepatitis B or C
12. Current treatment with an investigational therapy on another clinical trial
13. Pregnancy or breastfeeding
14. Any serious medical condition or illness considered by the investigator to constitute an unwarranted high risk for investigational treatment
B: Inclusion Criteria:

* Histologically and/or cytologically confirmed to have advanced renal cell carcinoma (RCC)
* Majority component of conventional clear-cell type is mandatory
* At least 1 measurable lesion (per RECIST)

Exclusion Criteria:

* Prior systemic treatment for RCC
* Evidence of current or prior central nervous system (CNS) metastases
* Cardiovascular disease
* Pregnant or nursing women
* Additional criteria applies
C: 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
D: Inclusion Criteria:

1. Adult males and females: ≥18 years of age.
2. Locally advanced or metastatic, histological confirmed, non-clear cell RCC of all subtypes. Patients must have advanced non-clear cell of one of the following subtypes: papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), or unclassified.
3. Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) If prior palliative radiotherapy to metastatic lesions: ≥ 1 measurable lesion that has not been irradiated.
4. PS 0-2 ECOG
5. Signed written informed consent.
6. White blood cell count (WBC) ≥4x10\*9/L with neutrophils ≥1.5 x 10\*9/L, platelet count ≥100x10\*9/L, hemoglobin ≥9 g/dL.\]
7. Total bilirubin \<2 x upper limit of normal.
8. AST and ALT \<2.5 x upper limit of normal, or \<5 x upper limit of normal in case of liver metastases.
9. Serum creatinine \<2.0 x upper limit of normal.
10. Normal ECG without QT prolongation (QTc \< 450msec).
11. Adequate cardiac function (left ventricular ejection fraction \> 40% as assessed by ECHO.

Exclusion Criteria:

1. Predominant clear-cell RCC
2. Resectability or other curative options
3. Any investigational drug within the 30 days before inclusion.
4. Prior systemic treatment for their RCC.
5. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatments.
6. Radiotherapy within the last 4 weeks.
7. Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.
8. Men or women of child-bearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial.
9. Clinically symptomatic brain or meningeal metastasis. (known or suspected)
10. Cardiac arrhythmias requiring anti-arrhythmics (excluding beta blockers or digoxin).
11. History of any of the following cardiac events within the past 6 months:

    * myocardial infarction (including severe/unstable angina),
    * coronary/peripheral artery bypass graft,
    * congestive heart failure (CHF),
    * cerebrovascular accident,
    * transient ischemic attack,
    * pulmonary embolism.
12. No hemorrhage ≥ grade 3 within the past 4 weeks
13. Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm Hg despite the use of ≥3 anti-hypertensive drugs
14. History of relevant pulmonary hypertension or interstitial lung disease.
15. Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or chronic diarrhea
16. Previous malignancy (other than renal cancer cancer) in the last 5 years except basal cell cancer of the skin, pre-invasive cancer of the cervix or superficial bladder tumor \[Ta, Tis and T1\].
17. History of organ allograft
18. Significant disease which, in the investigator's opinion would exclude the patient from the study
19. Patients with seizure and epileptic disorder or other conditions requiring medication (such as phenytoin, carbamazepin, phenobarbital)
20. Patients under strong inducers or inhibitors to CYP Isoenzymes
21. Patients with hypersensitivity to the antihistamine or patients who cannot receive the antihistamine for other medical reasons
22. Patients requiring long-term cortisone therapy
23. Patients requiring oral anticoagulation treatment, such as marcoumar. (Anticoagulation treatment with heparin or low molecular weight heparin \[LMWH\] is allowed provided that close monitoring is performed).
24. Surgery within at least 2 weeks prior to randomization
25. HIV seropositivity.
26. Abnormal pulmonary function (DLCO \< 50%). \[Pulmonary function tests need only to be performed if abnormal pulmonary function present in medical history\].
27. Poorly controlled diabetes mellitus.
28. Liver cirrhosis, chronic hepatitis
29. Legal incapacity or limited legal capacity
30. Known alcohol or drug abuse.
31. Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent.

Answer: C