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)

Renal Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01613846
• Other study ID #: 16037 / AN 33/11
• Secondary ID: 2011-004396-36
• Status: Completed
• Phase: Phase 3
• First received: May 4, 2012
• Last updated: April 19, 2017
• Start date: May 2012

Study information

• Verified date: April 2017
• Source: Technische Universität München
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Other known NCT identifiers

• NCT02083094

Recruitment information / eligibility

• Status: Completed
• Enrollment: 544
• Est. primary completion date: October 30, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Renal Cell Carcinoma

Intervention

Drug:
• Sorafenib+Pazopanib
Sorafenib (first-line) followed by Pazopanib (second-line)
• Pazopanib+Sorafenib
Pazopanib (first-line) followed by Sorafenib (second-line)

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	A. ö. Bezirkskrankenhaus Kufstein	Kufstein
Austria	AKH Linz GmbH	Linz
Austria	LKH Salzburg	Salzburg
Germany	Universitätsklinikum Aachen, Urologische Klinik	Aachen
Germany	Gesundheitszentrum St. Marien GmbH	Amberg
Germany	Charite Campus Virchow Klinikum / Klein. Für Innere Med / Onkologie/Hämatologie	Berlin
Germany	Praxis für Urologie	Berlin
Germany	Gemeinschaftspraxis Pott / Tirier / Hannig - Onkologie	Bottrop
Germany	Urologie im Schlosscarrée Braunschweig	Braunschweig
Germany	Klinikum Bremen-Mitte gGmbH	Bremen
Germany	Bethanien Krankenhaus Chemnitz gGmbH	Chemnitz
Germany	Onkologische Gemeinschaftspraxis Dörfel/Göhler	Dresden
Germany	Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden	Dresden
Germany	Urologische Gemeinschaftspraxis	Duisburg
Germany	Krankenhaus Düren gGmbH	Düren
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Urologie Neandertal - Ortsübergreifende Gemeinschaftspraxis für Urologie	Erkrath
Germany	Waldkrankenhaus St. Marien	Erlangen
Germany	St.-Antonius-Hospital in Eschweiler / Klinik f. Hämatologie und Onkologie	Eschweiler
Germany	Hämato-onkologische Gemeinschaftspraxis	Essen
Germany	Onkozentrum Freiberg	Freiberg
Germany	Praxis für interdisziplinäre Onkologie & Hämatologie	Freiburg
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	MVZ Osthessen GmbH	Fulda
Germany	Gem.praxis Dres. J. Wilke, H. Wagner - Hämatol.u.intern.Onkol. am Klinikum Fürth	Fürth
Germany	Onkologische Schwerpunktpraxis	Goslar
Germany	Universitätsklinikum Göttingen	Göttingen
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	St. Antonius-Hospital Gronau GmbH	Gronau
Germany	Asklepios Klinik Altona	Hamburg
Germany	Onkologische Schwerpunktpraxis	Hamburg
Germany	Universitätsklinikum Heidelberg, Klinik für Urologie	Heidelberg
Germany	Urologie-Heinsberg	Heinsberg
Germany	Onkologische Praxis	Hildesheim
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	Universitätsklinikum Jena, Klinik für Urologie	Jena
Germany	Überörtliche Gemeinschaftspraxis	Köln
Germany	Praxis für Urologie	Lauenburg
Germany	Onkologische Schwerpunktpraxis Leer - Emden	Leer
Germany	MVZ Mitte/ MVZ Delitzsch GmbH	Leipzig
Germany	Urologische Facharztpraxis	Lutherstadt Eisleben
Germany	Universitätsklinikum Magdeburg A.ö.R	Magdeburg
Germany	Universitätsklinik Mannheim	Mannheim
Germany	Philips-Universität-Marburg, Urologie und Kinderurologie	Marburg
Germany	Praxis Markkleeberg	Markkleeberg
Germany	Kliniken Maria Hilf	Mönchengladbach
Germany	PUR/R Praxisklinik Urologie Rhein Rhur	Mühlheim
Germany	Klinikum r. d. Isar, Klinik für Urologie	München
Germany	Universitätsklinikum Münster , Klinik für Urologie	Münster
Germany	Eps- early phase solutions GmbH	Pößneck
Germany	Caritas Krankenhaus St. Josef	Regensburg
Germany	Universitätsklinikum Rostock	Rostock
Germany	Zentrum für Urologie und Onkologie	Rostock
Germany	Diakoniekrankenhaus Rotenburg (Wümme) gGmbH	Rotenburg (Wümme)
Germany	Klinikum Sindelfingen-Böblingen	Sindelfingen
Germany	Marienhospital / Innere Med III Onko Hämato Palliativm	Stuttgart
Germany	Eberhard-Karls-Universität Tübingen	Tübingen
Germany	Universitätsklinik Ulm	Ulm
Germany	Universitätsklinikum Ulm	Ulm
Germany	Praxis für Hämatologie und internistische Onkologie	Velbert
Germany	Klinikum Nordoberpfalz AG	Weiden
Germany	Gesellsch. z. Förd. Von Wissenschaft u.Qualitätssicherung i.d.ambul.Onkologie	Wiesbaden
Germany	Praxisgemeinschaft für Onkologie und Urologie	Wilhelmshaven
Germany	Gemeinschaftspraxis für Urologie	Wuppertal
Germany	Universitätsklinikum Würzburg	Würzburg
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	HAGA	Den Haag
Netherlands	Spaarne Ziekenhuis	Hoofddorp
Netherlands	TweeSteden Ziekenhuis	Tilburg
Netherlands	VieCuri Medical Center	Venlo

Sponsors (1)

Lead Sponsor	Collaborator
Technische Universität München

Countries where clinical trial is conducted

Austria,  Germany,  Netherlands, 

Outcome

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