BACKGROUND: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. METHODS: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. RESULTS: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. CONCLUSIONS: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.
BACKGROUND: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. METHODS: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. RESULTS: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. CONCLUSIONS: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.
Authors: Kathleen W Beekman; A Dimitrios Colevas; Kathleen Cooney; Robert Dipaola; Rodney L Dunn; Mitchell Gross; Evan T Keller; Kenneth J Pienta; Charles J Ryan; David Smith; Maha Hussain Journal: Clin Genitourin Cancer Date: 2006-03 Impact factor: 2.872
Authors: Fabienne Baffert; Tom Le; Barbara Sennino; Gavin Thurston; Calvin J Kuo; Dana Hu-Lowe; Donald M McDonald Journal: Am J Physiol Heart Circ Physiol Date: 2005-09-19 Impact factor: 4.733
Authors: Robert J Motzer; M Dror Michaelson; Bruce G Redman; Gary R Hudes; George Wilding; Robert A Figlin; Michelle S Ginsberg; Sindy T Kim; Charles M Baum; Samuel E DePrimo; Jim Z Li; Carlo L Bello; Charles P Theuer; Daniel J George; Brian I Rini Journal: J Clin Oncol Date: 2005-12-05 Impact factor: 44.544
Authors: F A L M Eskens; H Dumez; R Hoekstra; A Perschl; C Brindley; S Böttcher; W Wynendaele; J Drevs; J Verweij; A T van Oosterom Journal: Eur J Cancer Date: 2003-05 Impact factor: 9.162
Authors: H N Lode; T Moehler; R Xiang; A Jonczyk; S D Gillies; D A Cheresh; R A Reisfeld Journal: Proc Natl Acad Sci U S A Date: 1999-02-16 Impact factor: 11.205
Authors: David A Reardon; Karen L Fink; Tom Mikkelsen; Timothy F Cloughesy; Alison O'Neill; Scott Plotkin; Michael Glantz; Paula Ravin; Jeffrey J Raizer; Keith M Rich; David Schiff; William R Shapiro; Susan Burdette-Radoux; Edward J Dropcho; Sabine M Wittemer; Johannes Nippgen; Martin Picard; L Burt Nabors Journal: J Clin Oncol Date: 2008-11-03 Impact factor: 44.544
Authors: Patricia A Burke; Sally J DeNardo; Laird A Miers; Kathleen R Lamborn; Siegfried Matzku; Gerald L DeNardo Journal: Cancer Res Date: 2002-08-01 Impact factor: 12.701
Authors: Peter H O'Donnell; Sanja Karovic; Theodore G Karrison; Linda Janisch; Matthew R Levine; Pamela J Harris; Blase N Polite; Ezra E W Cohen; Gini F Fleming; Mark J Ratain; Michael L Maitland Journal: Clin Cancer Res Date: 2015-07-21 Impact factor: 12.531
Authors: Dong Hoon Shin; Hyo-Jong Lee; Hye-Young Min; Sun Phil Choi; Mi-Sook Lee; Jung Weon Lee; Faye M Johnson; Kapil Mehta; Scott M Lippman; Bonnie S Glisson; Ho-Young Lee Journal: J Natl Cancer Inst Date: 2013-10-03 Impact factor: 13.506
Authors: Katarzyna Szarc vel Szic; Ken Op de Beeck; Dariusz Ratman; An Wouters; Ilse M Beck; Ken Declerck; Karen Heyninck; Erik Fransen; Marc Bracke; Karolien De Bosscher; Filip Lardon; Guy Van Camp; Wim Vanden Berghe Journal: PLoS One Date: 2014-02-03 Impact factor: 3.240