Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Double-blind Cross-over Patient Preference Study of Pazopanib Versus Sunitinib in Treatment naïve Locally Advanced or Metastatic Renal Cell Carcinoma.
Brief Summary: This is a randomised, double-blind, cross-over study of pazopanib versus sunitinib in patients with locally advanced or metastatic renal cell carcinoma (mRCC) who have received no prior systemic therapy for advanced or metastatic RCC. Approximately 160 eligible patients will be stratified based on the ECOG performance status (0 vs. 1) and number of metastatic sites of disease (0 and 1 vs. \>=2). The study consists of two treatment periods of 10 weeks with a 2-week wash-out period between the two treatment periods. Patients will receive pazopanib and sunitinib treatment sequentially in a double-blinded fashion. The primary objective of the study is to assess how the tolerability and safety differences between pazopanib and sunitinib translate into patient preference, defined by the patient's stated preference for which drug they may prefer to continue treatment with at end of study. The secondary objectives are to evaluate the reason for patient preference as assessed by a patient preference questionnaire; to evaluate fatigue as assessed by FACIT-Fatigue and quality of life as assessed by EuroQoL EQ-5D; to evaluate dose modifications and time to dose modification; and to evaluate safety.


Options:
A: Inclusion Criteria:

* Male or female patients\>= 18 years of age;
* Patients with histological or cytological evidence of metastatic renal cell carcinoma mostly of all type,except for papillary;
* No prior systemic treatment (chemotherapy, immunotherapy, anti-angiogenic drugs, or treatment under evaluation) for metastatic renal cancer;
* No brain metastases revealed by MRI or CT-scan within 28 days prior to randomization. Patients with a history of brain metastases treated by surgery +/- radiation therapy can be included if they have normal brain MRI;
* E.C.O.G performance status =\<2;
* At least one measurable lesion using the RECIST criteria;
* Blood tests and renal and liver functions in the normal range with, in the 7 days prior to study entry, blood or serum values as follows:

Hemoglobin \> 8g/dl; Neutrophil count \> 1500\*10exp9/L; Platelets \> 100\*10exp9/L; Serum creatinine \< 200µmol/L; Total Bilirubin \< 1.5 times upper limit of normal; ALT and AST \< 2.5 times upper limit of normal or \< 5 ULN for patients with liver metastases, PT or INR \< 1.5 times upper limit of normal in the absence of anticoagulant therapy;

* Absence of proteinuria confirmed by urinary dipstick test
* Fertile women must use effective means of contraception
* Mandatory affiliation with a healthy security insurance
* Signed written informed consent.

Exclusion Criteria:

* Patient with pure papillary renal cell carcinoma
* Prior systemic treatment for metastatic renal cancer
* History of other malignancies, other than curatively treated in-situ carcinoma of the cervix or basal cell carcinoma of the skin, or any other curatively treated cancer with no sign of recurrence within 5 years prior to randomization
* Evidence of brain metastasis by computerized tomographic scan or MRI in the 28 days prior to randomization. Patients with history of brain metastases treated by exclusive brain therapy are not allowed to participate, even if brain MRI is normal
* Significant cardiovascular disease or uncontrolled hypertension while receiving appropriate medication (\>= 160 mm Hg systolic and/or \>= 90 mm Hg diastolic)
* Hepatic affection like chronic advanced hepatitis, liver cirrhosis or chronic hepatitis recently treated or in process of treatment by immunosuppressive agents, hepatitis auto-immune or history of auto-immune disease
* Major surgical procedure, open biopsy, or serious non healing wound within 28 days prior to randomization
* Uncontrolled hypercalcemia while receiving appropriate treatment
* Uncontrolled hypercholesterolemia or hypertriglyceridemia
* Patient under anti-vitamin K therapy
* Patient under strong CYP3A4 inhibitors
* Patient with severe neuropsychiatric disorder (or comitial crises)
* Patient included in another clinical trial, except for supportive care trials
* Pregnant or lactating women (mandatory negative serum or urinary pregnancy test at study entry for all women of childbearing potential)
B: 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 treatment. For cytokine- unsuitability at least one of the following criteria must be fulfilled\*:

   * Age 66 to 88 years
   * Non-clear cell histology RCC
   * Intermediate risk according to MSKCC score
   * ECOG ≥ 1 and\> 1 organ metastasis + \< 24 months between diagnosis and establishing indication for interleukin-2-therapy
   * ECOG ≥ 1 and "unable to carry on normal activity or do active work" (Karnofsky Index 70%)
   * Creatinine ≥ 1x ULN and \< 2x ULN
   * Total bilirubin ≥ 1x ULN and \< 1.5x ULN
   * Present autoimmune disease
   * Patients who might require steroids
   * Hypersensitivity against cytokines
   * Severe organic disease, not interfering with other in-/exclusion criteria of the Switch-2 study
   * Non-symptomatic brain metastases
   * Severe lung disease (e.g. PAH, COPD) with Pa O2 \< 60 mmHg on rest
2. Age ≥ 18 and ≤ 85 years
3. Karnofsky Index ≥ 70% (see appendix 15.1)
4. MSKCC prognostic score (2004), low or intermediate (see appendix 15.2)
5. Life expectancy of at least 12 weeks
6. Subjects with at least one uni-dimensional (for RECIST 1.1) 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 µl
   * Platelet count ≥ 100,000 / µl
   * total bilirubin \< 1.5x the upper limit of normal (Note: Subjects with Gilbert' Syndrome are eligible if their total bilirubin is \< 3.0 X ULN and direct bilirubin ≤ 35 %).
   * ALAT and ASAT \< 2.5x upper limit of normal (Note: concomitant elevations in bilirubin ans ASAT/ALAT above 1.0x upper limit of normal are not permitted).
   * Alkaline phosphatase \< 4x upper limit of normal
   * PT-INR/aPTT \< 1.2x 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 their INR is stable and within the recommended range for the desired level of anticoagulation and no prior evidence of underlying abnormality in these parameters exists).
   * Serum creatinine \< 2x 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%, (echocardiography is optional); 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)
2. Uncontrolled hypertension (defined as blood pressure ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic on medication).
3. History of HIV infection or chronic hepatitis B or C
4. 4. Active clinically serious infections (\> grade 2 NCI-CTC version 4.03)
5. 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)
6. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
7. Patients with evidence or history of bleeding diathesis
8. History of organ allograft
9. Major surgery within 4 weeks of start of study
10. Autologous bone marrow transplant or stem cell rescue within 4 months before study start.
11. Any significant condition that increases the risk for bleeding, including, but not limited to active peptic ulcer disease, inflammatory bowel disease, known intraluminal or endobronchial metastatic lesions and/or lesions infiltrating major pulmonary vessels with risk of bleeding, presence of non-healing wound or trauma within 4 weeks prior to first dose of investigational drug
12. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep vein thrombosis (DVT) within the past 6 months (Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible)
13. Corrected QT Interval (QTc) \> 480 msecs
14. Untreated hypothyroidism
15. Patients undergoing renal dialysis
16. 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
17. 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 (with a Pearl Index \< 1) during the course of the trial and 3 months after the completion of trial
18. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
19. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
20. Patients unable to swallow oral medications
21. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
22. Known allergy to Votrient or Nexavar (i.e. to active substance or one of the constituents)
23. Prior exposure to study drugs.
24. Investigational drug therapy within 4 weeks of study entry.
25. Use of biologic response modifiers, such as G-CSF and other hematopoietic growth factors, within 3 weeks of study entry
26. Radiotherapy within 3 weeks of start of study drug and planned radiotherapy during the study
27. Concomitant medication: Any condition at the discretion of the investigator that precludes compliance with concomitant therapy restrictions described below.
C: 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
D: 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.

Answer: D