PURPOSE: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. EXPERIMENTAL DESIGN: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. RESULTS: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). CONCLUSION: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
PURPOSE: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. EXPERIMENTAL DESIGN:Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. RESULTS: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). CONCLUSION: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
Authors: D R Budman; N J Meropol; B Reigner; P J Creaven; S M Lichtman; E Berghorn; J Behr; R J Gordon; B Osterwalder; T Griffin Journal: J Clin Oncol Date: 1998-05 Impact factor: 44.544
Authors: E Van Cutsem; C Verslype; P Beale; S Clarke; R Bugat; A Rakhit; S H Fettner; U Brennscheidt; A Feyereislova; J-P Delord Journal: Ann Oncol Date: 2007-11-06 Impact factor: 32.976
Authors: Mace L Rothenberg; Amit M Oza; Robert H Bigelow; Jordan D Berlin; John L Marshall; Ramesh K Ramanathan; Lowell L Hart; Sunil Gupta; Carlos A Garay; Brent G Burger; Nathalie Le Bail; Daniel G Haller Journal: J Clin Oncol Date: 2003-06-01 Impact factor: 44.544
Authors: David Cunningham; Yves Humblet; Salvatore Siena; David Khayat; Harry Bleiberg; Armando Santoro; Danny Bets; Matthias Mueser; Andreas Harstrick; Chris Verslype; Ian Chau; Eric Van Cutsem Journal: N Engl J Med Date: 2004-07-22 Impact factor: 91.245
Authors: Antoinette R Tan; Xiaowei Yang; Stephen M Hewitt; Arlene Berman; Erin R Lepper; Alex Sparreboom; Allyson L Parr; William D Figg; Catherine Chow; Seth M Steinberg; Stephen L Bacharach; Millie Whatley; Jorge A Carrasquillo; Jaime S Brahim; Seth A Ettenberg; Stan Lipkowitz; Sandra M Swain Journal: J Clin Oncol Date: 2004-08-01 Impact factor: 44.544
Authors: Joyce O'Shaughnessy; David Miles; Svetislava Vukelja; Vladimir Moiseyenko; Jean-Pierre Ayoub; Guadalupe Cervantes; Pierre Fumoleau; Stephen Jones; Wing-Yiu Lui; Louis Mauriac; Chris Twelves; Guy Van Hazel; Shailendra Verma; Robert Leonard Journal: J Clin Oncol Date: 2002-06-15 Impact factor: 44.544
Authors: Paulo M Hoff; Richard Pazdur; Yvonne Lassere; Susan Carter; Dvorit Samid; Diane Polito; James L Abbruzzese Journal: J Clin Oncol Date: 2004-06-01 Impact factor: 44.544
Authors: E Van Cutsem; P M Hoff; P Harper; R M Bukowski; D Cunningham; P Dufour; U Graeven; J Lokich; S Madajewicz; J A Maroun; J L Marshall; E P Mitchell; G Perez-Manga; P Rougier; W Schmiegel; J Schoelmerich; A Sobrero; R L Schilsky Journal: Br J Cancer Date: 2004-03-22 Impact factor: 7.640
Authors: Kunyan He; Qi Qi; Chi-Bun Chan; Ge Xiao; Xia Liu; Carol Tucker-Burden; Liya Wang; Hui Mao; Xiang Lu; Frank E McDonald; Hongbo Luo; Qi-Wen Fan; William A Weiss; Shi-Yong Sun; Daniel J Brat; Keqiang Ye Journal: Sci Signal Date: 2013-07-09 Impact factor: 8.192
Authors: Alan H Bryce; Ravi Rao; Jann Sarkaria; Joel M Reid; Yingwei Qi; Rui Qin; C David James; Robert B Jenkins; Joseph Boni; Charles Erlichman; Paul Haluska Journal: Invest New Drugs Date: 2011-09-01 Impact factor: 3.850
Authors: Wen Wee Ma; Joseph M Herman; Antonio Jimeno; Daniel Laheru; Wells A Messersmith; Christopher L Wolfgang; John L Cameron; Timothy M Pawlik; Ross C Donehower; Michelle A Rudek; Manuel Hidalgo Journal: Transl Oncol Date: 2010-12-01 Impact factor: 4.243
Authors: Colin D Weekes; Sujatha Nallapareddy; Michelle A Rudek; Alexis Norris-Kirby; Daniel Laheru; Antonio Jimeno; Ross C Donehower; Kathleen M Murphy; Manuel Hidalgo; Sharyn D Baker; Wells A Messersmith Journal: Invest New Drugs Date: 2010-03-23 Impact factor: 3.850
Authors: Elizabeth A Hopper-Borge; Rochelle E Nasto; Vladimir Ratushny; Louis M Weiner; Erica A Golemis; Igor Astsaturov Journal: Expert Opin Ther Targets Date: 2009-03 Impact factor: 6.902
Authors: Michelle A Rudek; Roisin M Connolly; Janelle M Hoskins; Elizabeth Garrett-Mayer; Stacie C Jeter; Deborah K Armstrong; John H Fetting; Vered Stearns; Laurie A Wright; Ming Zhao; Stanley P Watkins; Howard L McLeod; Nancy E Davidson; Antonio C Wolff Journal: Breast Cancer Res Treat Date: 2013-04-16 Impact factor: 4.872
Authors: L P Martin; M F Kozloff; R S Herbst; T A Samuel; S Kim; B Rosbrook; M Tortorici; Y Chen; J Tarazi; A J Olszanski; T Rado; A Starr; R B Cohen Journal: Br J Cancer Date: 2012-09-20 Impact factor: 7.640