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)

Phase III Randomized 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

Sorafenib and pazopanib are both effective and promising treatments for advanced Renal Cell Carcinoma (RCC). Both drugs are registered for this indication. No prospective comparative data in advanced RCC (or other indications) have been published. A search in the clinicaltrials.gov database did not reveal any planned or ongoing studies. As sequential therapy is now the standard of treatment for advanced RCC it is important to evaluate in clinical trials what the value of different sequential strategies is. This needs to be done every time new agents are introduced into the treatment armamentarium. As there are no data yet on the sequential use of sorafenib followed by pazopanib or vice versa, this sequence, however, will most certainly be used in daily practice, it is required to examine efficacy and safety of this sequential approach in a clinical trial in a randomized setting.

Therefore, the investigators have designed an open randomized study in patients not previously treated for advanced RCC. Suitable patients will be randomized (1:1) in 2 groups.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: Sorafenib+Pazopanib; Drug: Pazopanib+Sorafenib

• Study Type: Interventional
• Enrollment (Anticipated): 544
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universität Innsbruck
  • Kufstein, Austria, 6330
    • A. ö. Bezirkskrankenhaus Kufstein
  • Linz, Austria, 4020
    • AKH Linz GmbH
  • Salzburg, Austria, 5020
    • LKH Salzburg
• Germany
  • Aachen, Germany, 51074
    • Universitätsklinikum Aachen, Urologische Klinik
  • Amberg, Germany, 92224
    • Gesundheitszentrum St. Marien GmbH
  • Berlin, Germany, 13055
    • Praxis für Urologie
  • Berlin, Germany, 13353
    • Charite Campus Virchow Klinikum / Klein. Für Innere Med / Onkologie/Hämatologie
  • Bottrop, Germany, 46236
    • Gemeinschaftspraxis Pott / Tirier / Hannig - Onkologie
  • Braunschweig, Germany, 38100
    • Urologie im Schlosscarrée Braunschweig
  • Bremen, Germany, 28177
    • Klinikum Bremen-Mitte gGmbH
  • Chemnitz, Germany, 09130
    • Bethanien Krankenhaus Chemnitz gGmbH
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
  • Dresden, Germany, 01127
    • Onkologische Gemeinschaftspraxis Dörfel/Göhler
  • Duisburg, Germany, 47179
    • Urologische Gemeinschaftspraxis
  • Düren, Germany, 52351
    • Krankenhaus Düren gGmbH
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf
  • Erkrath, Germany, 40699
    • Urologie Neandertal - Ortsübergreifende Gemeinschaftspraxis für Urologie
  • Erlangen, Germany, 91054
    • Waldkrankenhaus St. Marien
  • Eschweiler, Germany, 52249
    • St.-Antonius-Hospital in Eschweiler / Klinik f. Hämatologie und Onkologie
  • Essen, Germany, 45136
    • Hämato-onkologische Gemeinschaftspraxis
  • Freiberg, Germany, 09599
    • Onkozentrum Freiberg
  • Freiburg, Germany, 79106
    • Universitatsklinikum Freiburg
  • Freiburg, Germany, 79106
    • Praxis für interdisziplinäre Onkologie & Hämatologie
  • Fulda, Germany, 36043
    • MVZ Osthessen GmbH
  • Fürth, Germany, 90766
    • Gem.praxis Dres. J. Wilke, H. Wagner - Hämatol.u.intern.Onkol. am Klinikum Fürth
  • Goslar, Germany, 38642
    • Onkologische Schwerpunktpraxis
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Gronau, Germany, 48599
    • St. Antonius-Hospital Gronau GmbH
  • Göttingen, Germany, 37075
    • Universitätsklinikum Göttingen
  • Hamburg, Germany, 22763
    • Asklepios Klinik Altona
  • Hamburg, Germany, 20095
    • Onkologische Schwerpunktpraxis
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg, Klinik für Urologie
  • Heinsberg, Germany, 52525
    • Urologie-Heinsberg
  • Hildesheim, Germany, 331135
    • Onkologische Praxis
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Jena, Germany, 07743
    • Universitätsklinikum Jena, Klinik für Urologie
  • Köln, Germany, 50968
    • Überörtliche Gemeinschaftspraxis
  • Lauenburg, Germany, 21481
    • Praxis für Urologie
  • Leer, Germany, 26789
    • Onkologische Schwerpunktpraxis Leer - Emden
  • Leipzig, Germany, 04103
    • MVZ Mitte/ MVZ Delitzsch GmbH
  • Lutherstadt Eisleben, Germany, 06295
    • Urologische Facharztpraxis
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg A.ö.R
  • Mannheim, Germany, 68167
    • Universitätsklinik Mannheim
  • Marburg, Germany, 35043
    • Philips-Universität-Marburg, Urologie und Kinderurologie
  • Markkleeberg, Germany, 04416
    • Praxis Markkleeberg
  • Mönchengladbach, Germany, 41063
    • Kliniken Maria Hilf
  • Mühlheim, Germany, 45458
    • PUR/R Praxisklinik Urologie Rhein Rhur
  • München, Germany, 81675
    • Klinikum r. d. Isar, Klinik für Urologie
  • Münster, Germany, 48149
    • Universitätsklinikum Münster , Klinik für Urologie
  • Pößneck, Germany
    • Eps- early phase solutions GmbH
  • Regensburg, Germany, 93053
    • Caritas Krankenhaus St. Josef
  • Rostock, Germany, 18107
    • Zentrum für Urologie und Onkologie
  • Rostock, Germany, 18055
    • Universitätsklinikum Rostock
  • Rotenburg (Wümme), Germany, 27356
    • Diakoniekrankenhaus Rotenburg (Wümme) gGmbH
  • Sindelfingen, Germany, 71065
    • Klinikum Sindelfingen-Böblingen
  • Stuttgart, Germany, 70199
    • Marienhospital / Innere Med III Onko Hämato Palliativm
  • Tübingen, Germany, 72076
    • Eberhard-Karls-Universität Tübingen
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
  • Ulm, Germany, 89075
    • Universitätsklinik Ulm
  • Velbert, Germany, 42551
    • Praxis für Hämatologie und Internistische Onkologie
  • Weiden, Germany, 92637
    • Klinikum Nordoberpfalz AG
  • Wiesbaden, Germany, 65191
    • Gesellsch. z. Förd. Von Wissenschaft u.Qualitätssicherung i.d.ambul.Onkologie
  • Wilhelmshaven, Germany, 26389
    • Praxisgemeinschaft für Onkologie und Urologie
  • Wuppertal, Germany, 42103
    • Gemeinschaftspraxis für Urologie
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg
• Netherlands
  • Amsterdam, Netherlands, 1091 HA
    • Onze Lieve Vrouwe Gasthuis
  • Delft, Netherlands, 2600 AG
    • Reinier de Graaf Gasthuis
  • Den Haag, Netherlands, 2545
    • Haga
  • Hoofddorp, Netherlands, 2130 AT
    • Spaarne Ziekenhuis
  • Tilburg, Netherlands, 5042 AD
    • TweeSteden Ziekenhuis
  • Venlo, Netherlands, 5912 BL
    • Viecuri Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sorafenib followed by pazopanib; Sorafenib 400 mg bid orally until progression or intolerable toxicity, followed by pazopanib 800 mg once daily orally until progression or intolerable toxicity. During first- and second-line, treatment visits are scheduled in weeks 0,2,4,8,12, and every 4 weeks thereafter, with tumor assessments and electrocardiogram after every second cycle (every 8 weeks).	Drug: Sorafenib+Pazopanib; Sorafenib (first-line) followed by Pazopanib (second-line)
Experimental: Pazopanib followed by Sorafenib; Pazopanib 800 mg once daily orally until progression or intolerable toxicity, followed by Sorafenib 400 mg bid orally until progression or intolerable toxicity: During first- and second-line, treatment visits are scheduled in weeks, 0,2,4,8,12, and every 4 weeks thereafter, with tumor assessments and electrocardiogram after every second cycle (every 8 weeks).	Drug: Pazopanib+Sorafenib; Pazopanib (first-line) followed by Sorafenib (second-line)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate if progression-free survival from randomization to progression or death during second-line therapy (Total PFS) of sorafenib followed by pazopanib is non-inferior compared to pazopanib followed by sorafenib.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to progression during second-line therapy (total TTP)		1 year
Time to first-line treatment failure (progression, death, discontinuation due to toxicity) descriptively in each arm		1 year
PFS in first-line and second-line treatment, descriptively		4 years
Overall survival, descriptively (data cut-off same as for primary endpoint		4 years
Disease Control Rate (DCR); Response rates in first-line and in second-line (CR, PR, SD according to RECIST criteria)		4 years
Health-related Quality of Life (FACIT-F, FKSI-10)		4 years
Biomarker programme	Circulating tumor cells, Single Nucleotide Polymorphisms, Serum Protein Signatures	4 years
Safety and tolerability	Monitoring of adverse events, summaries and listings of adverse events	4 years

Collaborators and Investigators

• Sponsor: Technical University of Munich
• Investigators: Principal Investigator: Jürgen E. Gschwend, Prof., Klinikum rechts der Isar, TU München

Publications and helpful links

General Publications

• Retz M, Bedke J, Bogemann M, Grimm MO, Zimmermann U, Muller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. doi: 10.1016/j.ejca.2018.11.001. Epub 2018 Dec 7.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): October 30, 2016

Study Registration Dates

• First Submitted: May 4, 2012
• First Submitted That Met QC Criteria: June 6, 2012
• First Posted (Estimate): June 7, 2012

Study Record Updates

• Last Update Posted (Actual): April 20, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: 16037 / AN 33/11; 2011-004396-36 (EudraCT Number)