Clinical trial NCT01613846: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
First posted: 2012-06-07
Enrollment: 544
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 4 years
Secondary outcomes:
measure: Time from randomization to progression during second-line therapy (total TTP)
timeFrame: 1 year
measure: Time to first-line treatment failure (progression, death, discontinuation due to toxicity) descriptively in each arm
timeFrame: 1 year
measure: PFS in first-line and second-line treatment, descriptively
timeFrame: 4 years
measure: Overall survival, descriptively (data cut-off same as for primary endpoint
timeFrame: 4 years
measure: Disease Control Rate (DCR); Response rates in first-line and in second-line (CR, PR, SD according to RECIST criteria)
timeFrame: 4 years
measure: Health-related Quality of Life (FACIT-F, FKSI-10)
timeFrame: 4 years
measure: Biomarker programme
timeFrame: 4 years
measure: Safety and tolerability
timeFrame: 4 years
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Kufstein
country: Austria
facility: A. ö. Bezirkskrankenhaus Kufstein
city: Linz
country: Austria
facility: AKH Linz GmbH
city: Salzburg
country: Austria
facility: LKH Salzburg
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, Urologische Klinik
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien GmbH
city: Berlin
country: Germany
facility: Praxis für Urologie
city: Berlin
country: Germany
facility: Charite Campus Virchow Klinikum / Klein. Für Innere Med / Onkologie/Hämatologie
city: Bottrop
country: Germany
facility: Gemeinschaftspraxis Pott / Tirier / Hannig - Onkologie
city: Braunschweig
country: Germany
facility: Urologie im Schlosscarrée Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte gGmbH
city: Chemnitz
country: Germany
facility: Bethanien Krankenhaus Chemnitz gGmbH
city: Dresden
country: Germany
facility: Onkologische Gemeinschaftspraxis Dörfel/Göhler
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
city: Duisburg
country: Germany
facility: Urologische Gemeinschaftspraxis
city: Düren
country: Germany
facility: Krankenhaus Düren gGmbH
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erkrath
country: Germany
facility: Urologie Neandertal - Ortsübergreifende Gemeinschaftspraxis für Urologie
city: Erlangen
country: Germany
facility: Waldkrankenhaus St. Marien
city: Eschweiler
country: Germany
facility: St.-Antonius-Hospital in Eschweiler / Klinik f. Hämatologie und Onkologie
city: Essen
country: Germany
facility: Hämato-onkologische Gemeinschaftspraxis
city: Freiberg
country: Germany
facility: Onkozentrum Freiberg
city: Freiburg
country: Germany
facility: Praxis für interdisziplinäre Onkologie & Hämatologie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Fulda
country: Germany
facility: MVZ Osthessen GmbH
city: Fürth
country: Germany
facility: Gem.praxis Dres. J. Wilke, H. Wagner - Hämatol.u.intern.Onkol. am Klinikum Fürth
city: Goslar
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Gronau
country: Germany
facility: St. Antonius-Hospital Gronau GmbH
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
city: Hamburg
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Klinik für Urologie
city: Heinsberg
country: Germany
facility: Urologie-Heinsberg
city: Hildesheim
country: Germany
facility: Onkologische Praxis
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Urologie
city: Köln
country: Germany
facility: Überörtliche Gemeinschaftspraxis
city: Lauenburg
country: Germany
facility: Praxis für Urologie
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis Leer - Emden
city: Leipzig
country: Germany
facility: MVZ Mitte/ MVZ Delitzsch GmbH
city: Lutherstadt Eisleben
country: Germany
facility: Urologische Facharztpraxis
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg A.ö.R
city: Mannheim
country: Germany
facility: Universitätsklinik Mannheim
city: Marburg
country: Germany
facility: Philips-Universität-Marburg, Urologie und Kinderurologie
city: Markkleeberg
country: Germany
facility: Praxis Markkleeberg
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf
city: Mühlheim
country: Germany
facility: PUR/R Praxisklinik Urologie Rhein Rhur
city: München
country: Germany
facility: Klinikum r. d. Isar, Klinik für Urologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster , Klinik für Urologie
city: Pößneck
country: Germany
facility: Eps- early phase solutions GmbH
city: Regensburg
country: Germany
facility: Caritas Krankenhaus St. Josef
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock
city: Rostock
country: Germany
facility: Zentrum für Urologie und Onkologie
city: Rotenburg (Wümme)
country: Germany
facility: Diakoniekrankenhaus Rotenburg (Wümme) gGmbH
city: Sindelfingen
country: Germany
facility: Klinikum Sindelfingen-Böblingen
city: Stuttgart
country: Germany
facility: Marienhospital / Innere Med III Onko Hämato Palliativm
city: Tübingen
country: Germany
facility: Eberhard-Karls-Universität Tübingen
city: Ulm
country: Germany
facility: Universitätsklinik Ulm
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Velbert
country: Germany
facility: Praxis für Hämatologie und internistische Onkologie
city: Weiden
country: Germany
facility: Klinikum Nordoberpfalz AG
city: Wiesbaden
country: Germany
facility: Gesellsch. z. Förd. Von Wissenschaft u.Qualitätssicherung i.d.ambul.Onkologie
city: Wilhelmshaven
country: Germany
facility: Praxisgemeinschaft für Onkologie und Urologie
city: Wuppertal
country: Germany
facility: Gemeinschaftspraxis für Urologie
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: HAGA
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
city: Tilburg
country: Netherlands
facility: TweeSteden Ziekenhuis
city: Venlo
country: Netherlands
facility: VieCuri Medical Center
Study officials:
affiliation: Klinikum rechts der Isar, TU München
name: Jürgen E. Gschwend, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.