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.
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.


CONCLUSIONS
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.
Friess
Helmut
H
Department of General Surgery, University of Heidelberg, Heidelberg, Germany. helmut_friess@med.uni-heidelberg.de
Langrehr
Jan M
JM
Oettle
Helmut
H
Raedle
Jochen
J
Niedergethmann
Marco
M
Dittrich
Christian
C
Hossfeld
Dieter K
DK
Stöger
Herbert
H
Neyns
Bart
B
Herzog
Peter
P
Piedbois
Pascal
P
Dobrowolski
Frank
F
Scheithauer
Werner
W
Hawkins
Robert
R
Katz
Frieder
F
Balcke
Peter
P
Vermorken
Jan
J
van Belle
Simon
S
Davidson
Neville
N
Esteve
Albert Abad
AA
Castellano
Daniel
D
Kleeff
Jörg
J
Tempia-Caliera
Adrien A
AA
Kovar
Andreas
A
Nippgen
Johannes
J
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011788:Quality of Life; D012910:Snake Venoms / Q000627:therapeutic use* / Q000633:toxicity; D011795:Surveys and Questionnaires; D015996:Survival Rate; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D012910:Snake Venoms; D003841:Deoxycytidine; C422910:Cilengitide; D000093542:Gemcitabine