Open Access Highly Accessed Research article

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

Helmut Friess1*, Jan M Langrehr2, Helmut Oettle3, Jochen Raedle4, Marco Niedergethmann5, Christian Dittrich6, Dieter K Hossfeld7, Herbert Stöger8, Bart Neyns9, Peter Herzog10, Pascal Piedbois11, Frank Dobrowolski12, Werner Scheithauer13, Robert Hawkins14, Frieder Katz15, Peter Balcke16, Jan Vermorken17, Simon van Belle18, Neville Davidson19, Albert Abad Esteve20, Daniel Castellano21, Jörg Kleeff1, Adrien A Tempia-Caliera1, Andreas Kovar22 and Johannes Nippgen23

Author Affiliations

1 Department of General Surgery, University of Heidelberg, Heidelberg, Germany

2 Department of General and Transplantation Surgery, Charité, Virchow-Clinic, Berlin, Germany

3 Department of Hematology and Oncology, Charité, Virchow-Clinic, Berlin, Germany

4 Department of Medicine II, University of Frankfurt Hospital, Frankfurt am Main, Germany

5 Department of Surgery, University Hospital Mannheim, Mannheim, Germany

6 Ludwig Blotzmann-Institute for Applied Cancer Research (LBI-ACR Vienna), Kaiser Franz Josef-Spital, Vienna, Austria

7 Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

8 Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria

9 Department of Medical Oncology, Oncology Center, Vrije Universiteit Brussel, Brussels, Belgium

10 Department of Gastroenterology, Reinhardt Nieter Krankenhaus, Wilhelmshaven, Germany

11 Department of Medical Oncology, Henri Mondor Hospital, Creteil Cedex, France

12 Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dreseden, Germany

13 Department of Internal Medicine I, Division of Clinical Oncology, University Hospital of Vienna, Vienna, Austria

14 Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

15 Department of Medicine V, Clinic Darmstadt, Darmstadt, Germany

16 Department of Medicine, Clinic of the City of St. Poelten, St. Pölten, Austria

17 Department of Oncology, University Hospital Antwerpen, Edegem, Belgium

18 Department of Oncology, University Hospital Gent, Gent, Belgium

19 Department of Medicine, St John's Hospital, Chelmsford, Essex, UK

20 Department of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain

21 Department of Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain

22 Department of Pharmacology and Pharmacokinetics, Merck KGaA, Darmstadt, Germany

23 Medical Center of Excellence Oncology, Merck KGaA, Darmstadt, Germany

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BMC Cancer 2006, 6:285  doi:10.1186/1471-2407-6-285

Published: 11 December 2006

Abstract

Background

Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer.

Methods

A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients.

Results

Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa.

Conclusion

There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.