Article
Phase II Study of First Line Sorafenib (BAY 43-9006) in Patients with Locally Advanced and/or Metastatic Pancreatic Cancer – a Study of the Central European Society for Anticancer Drug Research - EWIV (CESAR)
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Authors
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Max E. Scheulen
- Central European Society for Anticancer Drug Research - EWIV, Wien, Österreich , Essen, Deutschland
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Klaus Mross
- Klinik für Tumorbiologie, Freiburg
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Christian Dittrich
- LBI-ACR VIEnna und ACR-ITR VIEnna, Kaiser Franz Josef-Spital, Österreich
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Andreas Hochhaus
- III. Medizinische Klinik, Universitätsklinikum Mannheim, Universität Heidelberg
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Rudolf Morant
- Zentrum für Tumordiagnostik und Prävention, St. Gallen, Schweiz
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Dieter Köberle
- Abteilung Medizinische Onkologie, Kantonsspital, St. Gallen, Schweiz
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Jürgen Krauß
- Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen
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Annette Frost
- Klinik für Tumorbiologie, Freiburg
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Christian Flashar
- Abteilung für Hämatologie und Onkologie, Marienhospital Herne, Ruhruniversität Bochum
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Lutz Edler
- Deutsches Krebsforschungszentrum Heidelberg
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Urban Scheuring
- Bayer Vital GmbH, Leverkusen
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Dirk Strumberg
- Abteilung für Hämatologie und Onkologie, Marienhospital Herne, Ruhruniversität Bochum
| Published: | March 20, 2006 |
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Outline
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Background: Sorafenib (BAY 43-9006) is a novel orally active multi-kinase inhibitor with anti-angiogenic and anti-proliferative activity by blocking both the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-ß. Previous single-agent phase I studies showed that sorafenib is well tolerated, with manageable and reversible side effects, most commonly hand-foot skin (HFS) reaction, rash, fatigue, and diarrhea. This phase II study was conducted to investigate the activity of sorafenib in previously untreated patients (pts) with locally advanced and/or metastatic pancreatic cancer (PC).
Methods: Pts received sorafenib 400 mg bid by continuous oral dosing. Pts without prior systemic therapy for advanced disease and at least one uni-dimensional measurable lesion according to the RECIST-criteria were eligible for study entry. The primary objective was the proportion of evaluable patients with time to progression (PP-TTP12) of ≥ 12 weeks. A minimum of 37 evaluable pts (those completing at least 4 weeks [one cycle] of sorafenib therapy) were required to detect an increase in PP-TTP12 from 10 to 30% in a one stage design. Secondary endpoints were overall response, overall survival, toxicity according to Common Toxicity Criteria (CTC v3.0) and drug safety.
Results: A total of 47 pts with PC was enrolled between August 2004 and January 2005. One pt had to be excluded because of lack of a target lesion. The PP-TTP12 in the full analysis set of 46 pts was 26.1% (12 pts, 95%CI 14.3-41.1%) with one PR (not-confirmed) and 11 SD until 12 weeks. The null hypothesis PP-TTP12 ≤ 10% was rejected in a one-sided binominal test with p = 0.0015. Thus, this phase II trial concludes a significant effect and demonstrates efficacy with respect to the primary objective. Median TTP was 6.3 wks (5.9-11.9 wks) with a 12-week rate of 30.1% (18.8-48.2%) and median survival was 21.7 wks (14.6-39.3 wks). All 47 pts are evaluable for toxicity and adverse events (AE). There were 19 grade 3&4 AE including two with definite relation to treatment (one hand-foot syndrome, one diarrhea).
Conclusion: Sorafenib demonstrates activity with respect to PP-TTP12 in pts with PC and has only mild toxicity on long-term continuous oral administration. Thus, further investigations in future trials are necessary.
