Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)

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. Cytokine unsuitability will be determined by means of a checklist (see appendix 15.1)
2. Age ≥ 18 and ≤ 85 years
3. Karnofsky Index ≥ 70% (see appendix 15.2)
4. MSKCC prognostic score (2004), low or intermediate (see appendix 15.3)
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 neurophil count (ANC)>1,500/µl
   • Platelet count >=100,000/µl
   • Total bilirubin < 1.5x the upper limit of normal (Note: Subjects with Gilbert´s Syndrome are eligible if their total bilirubin is <3.0 X ULN and direct bilirubin is ≤35%)
   • ALAT and ASAT < 2.5x upper limit of normal (Note: concomitant elevations in bilirubin and ASAT/ALAT above 1.0x upper limit of normal are not permitted).
   • Alkaline phosphatase < 4x upper limit of normal
   • PI-INR/PT < 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 or anticoagulation and no prior evidence of underlying abnormality in these parameters exists.]
   • Serum creatinie < 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%, (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. 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. 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, major surgery or trauma within 4 weeks prior to first dose of investigational drug
10. 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 anticoagulating agents for at least 6 weeks are eligible)
11. Corrected QT Interval (QTc) > 480 msecs
12. Untreated hypothyroidism
13. Patients undergoing renal dialysis
14. 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
15. 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 trail
16. Substance abuse, medical, psychological or social conditions that may interfere with the patient´s participation in the study or evaluation of the study results
17. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
18. Patients unable to swallow oral medications
19. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
20. Known allergy to Votrient® or Nexavar® (i.e to active substance or one of the constituents)
21. Anticancer chemo-, cytokine- or targeted therapy for RCC
22. Radiotherapy during study or within 3 weeks or start of study drug (Palliative radiotherapy will be allowed).
23. Major surgery within 4 weeks of start of study (if wound healing is considered to be completed investigator can decide to start with study earlier).
24. Autologous bone marrow transplant or stem cell rescue within 4 months of study
25. Use of biologic response modifiers, such as G-CSF, within 3 weeks 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]
26. Investigational drug therapy outside of this trial during or within 4 weeks of study entry
27. Prior exposure to the study drugs
28. Any St. John´s wort containing remedy
29. Strong CYP3A4 inhibitors during pazopanib therapy
30. Grapefruit juice during pazopnib therapy