Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomized Sequential Open-Label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Sunitinib Versus Sunitinib Followed by Sorafenib in the Treatment of First-Line Advanced / Metastatic Renal Cell Carcinoma
Brief Summary: Primary:

To evaluate if progression-free survival from first treatment to progression or death during second-line therapy (total PFS) of sorafenib followed by sunitinib is superior compared to sunitinib followed by sorafenib.

Secondary:

1. Time from first treatment to progression during second-line therapy (total TTP)
2. Time to first-line treatment failure (progression, death, discontinuation due to toxicity) descriptively in each arm
3. PFS in first-line and second-line treatment, descriptively
4. Overall survival, descriptively (data cut-off same as for primary endpoint)
5. Disease Control Rate (DCR); Response rates in first-line and in second-line (CR, PR, SD according to RECIST criteria)
6. Cardiotoxicity analysis by means of echocardiography and NT-pro BNP with an interim analysis after 100 patients of each arm have completed the study
7. Safety and tolerability


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:

* Written informed consent
* Histologically confirmed RCC of clear cell histology
* Confirmed metastatic RCC
* Age \>=18 years
* ECOG performance status of 0 or 1
* Life expectancy \>=3 months
* Prior nephrectomy
* Measurable disease, as defined by RECIST
* Use of an acceptable means of contraception (potentially fertile men and women)

Exclusion Criteria:

* RCC with predominantly sarcomatoid features
* Prior systemic or adjuvant therapy for RCC
* Prior radiotherapy for RCC within 28 days prior to Day 0, with the exception of single fraction radiotherapy given for the indication of pain control
* Treatment with Avastin, Tarceva, or other agents, either investigational or marketed, that act by either EGFR inhibition or anti-angiogenesis mechanisms
* 24-hour urine collection with \>=1 g of protein
* INR \>=1.5, except for subjects receiving warfarin therapy
* Serum creatinine \>2.0 mg/dL
* Serum calcium \>10 mg/dL (corrected)
* Absolute neutrophil count (ANC) \<1500/uL
* Platelet count \<75,000/uL
* Total bilirubin \>2.0 mg/dL
* AST or ALT \>5× the upper limit of normal (ULN) for subjects with documented liver metastases; \>2.5 × ULN for subjects without evidence of liver metastases
* LDH \>1.5× ULN
* Hemoglobin \<9 gm/dL (may be transfused or receive epoetin alfa \[e.g., Epogen\] to maintain or exceed this level)
* History of serious systemic disease, including myocardial infarction within the last 6 months, uncontrolled hypertension (blood pressure \>160/110 mmHg on medication), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia, are eligible), or Grade II or greater peripheral vascular disease
* History of acute stroke within 6 months prior to randomization
* Patients on dialysis
* Other invasive malignancies, including bladder cancer and low-grade endometrial cancer, within 5 years of randomization (other than squamous or basal cell carcinoma of the skin)
* Pregnancy or breast feeding
* Inability to comply with study and/or follow-up procedures
* History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications
* Serious, non-healing wound, ulcer, or bone fracture
* Evidence of bleeding diathesis or coagulopathy
* History or clinical evidence of central nervous system or brain metastases
* History of bowel or gastric perforation
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study

  * Fine needle aspirations or core biopsies within 7 days prior to Day 0
C: Inclusion Criteria:

* Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
* Has locally advanced/metastatic disease (i.e., newly diagnosed Stage IV RCC per American Joint Committee on Cancer) or has recurrent disease
* Has measurable disease per RECIST 1.1 as assessed by the investigator/site radiologist
* Has received no prior systemic therapy for advanced RCC.
* Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
* Has Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to randomization.
* If receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to randomization.
* Demonstrates adequate organ function.
* Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.
* Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.

Exclusion Criteria:

* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization.
* Has had major surgery within 4 weeks, received radiation therapy within 2 weeks prior to randomization, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
* Has had prior treatment with any anti-programmed cell death (anti-PD-1), or programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
* Has received prior systemic anti-cancer therapy for RCC with vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) or mechanistic target of rapamycin (mTOR) targeting agents.
* Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to axitinib or sunitinib.
* Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to randomization, except in the case of central nervous system (CNS) metastases.
* Has an active autoimmune disease requiring systemic treatment with in the past 2 years OR a documented history of clinically severe autoimmune disease. Note: Participants with vitiligo, Sjøgren's syndrome, Type 1 diabetes, resolved childhood asthma/atopy, hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement, are not excluded.
* Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are acceptable if they have undergone potentially curative therapy.
* Has known active CNS metastases and/or carcinomatous meningitis.
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* Has an active infection requiring systemic therapy.
* Has a known history of Human Immunodeficiency Virus (HIV).
* Has known active Hepatitis B or Hepatitis C infection.
* Has received a live virus vaccine within 30 days of randomization.
* Has a clinically significant gastrointestinal (GI) abnormality including:
* Malabsorption, total gastric resection
* Or any condition that might affect the absorption of orally taken medication
* Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy
* Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation
* Has QT interval corrected for heart rate (QTc) ≥480 msec.
* Has a history of any of the following cardiovascular conditions within 12 months of randomization:
* Myocardial infarction
* Unstable angina pectoris
* Cardiac angioplasty or stenting
* Coronary/peripheral artery bypass graft
* Class III or IV congestive heart failure per New York Heart Association
* Cerebrovascular accident or transient ischemic attack
* Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening.
* Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg.
* Has evidence of inadequate wound healing.
* Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization.
* Has hemoptysis within 6 weeks prior to randomization.
* Has current use (within 7 days of randomization) or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors.
* Has current use (within 7 days of randomization) or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort; or drugs that are known with proarrhythmic potential.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
* Has had a prior solid organ transplant.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
D: Inclusion Criteria:

1. Patients with metastatic / advanced RCC (all histologies), who are not suitable for cytokine therapy and for whom study medication constitutes first-line therapy
2. Age \>= 18 ans \<= 85years
3. ECOG Performance Status of 0 or 1
4. MSKCC prognostic score, low or intermediate
5. Life expectancy of at least 12 weeks.
6. Subjects with at least one uni-dimensional (for RECIST) measurable lesion. Lesions must be measured by CT/MRI-scan.
7. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of therapy:

   * Hemoglobin \>= 9.0 g/dl
   * Absolute neutrophil count (ANC) \>= 1,500/mm³
   * Platelet count \>= 100,000/μl
   * Total bilirubin \<= 1.5 times the upper limit of normal
   * ALT and AST \<= 2.5 x upper limit of normal (\<= 5 x upper limit of normal for patients with liver involvement of their cancer)
   * Alkaline phosphatase \< 4 x upper limit of normal
   * PT-INR/PT \< 1.5 x upper limit of normal \[Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.\]
   * Serum creatinine \<= 2 x upper limit of normal.
8. Written Informed Consent

Exclusion Criteria:

1. History of cardiac disease: congestive heart failure \>NYHA class 2 or with LVEF at baseline echocardiography \< 50%; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension (defined as blood pressure \>= 160 mmHg systolic and/or \>= 90 mmHG diastolic on medication).
2. History of HIV infection or chronic hepatitis B or C
3. Active clinically serious infections (\> grade 2 NCI-CTC version 3.0)
4. Symptomatic metastatic brain or meningeal tumors (unless the patient is \> 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry)
5. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
6. History of organ allograft
7. Patients with evidence or history of bleeding diathesis
8. untreated hypothyrosis
9. Patients undergoing renal dialysis
10. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors \[Ta, Tis \& T1\] or any cancer curatively treated \> 3 years prior to study entry.
11. Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 3 months after the completion of trial.
12. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
13. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
14. Patients unable to swallow oral medications
15. Known allergy to sunitinib or sorafenib or one of its constituents

Excluded therapies and medications, previous and concomitant:

1. Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry.
2. Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed). Major surgery within 4 weeks of start of study
3. Autologous bone marrow transplant or stem cell rescue within 4 months of study
4. Use of biologic response modifiers, such as G-CSF, within 3 week of study entry.

   \[G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction.\] \[Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study\]
5. Investigational drug therapy outside of this trial during or within 4 weeks of study entry
6. Prior exposure to the study drug.
7. Any St. John's wort containing remedy

Answer: D