PURPOSE: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. RESULTS: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. CONCLUSIONS: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation.
PURPOSE: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. RESULTS: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. CONCLUSIONS: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation.
Authors: George D Demetri; Allan T van Oosterom; Christopher R Garrett; Martin E Blackstein; Manisha H Shah; Jaap Verweij; Grant McArthur; Ian R Judson; Michael C Heinrich; Jeffrey A Morgan; Jayesh Desai; Christopher D Fletcher; Suzanne George; Carlo L Bello; Xin Huang; Charles M Baum; Paolo G Casali Journal: Lancet Date: 2006-10-14 Impact factor: 79.321
Authors: Jayesh Desai; Leila Yassa; Ellen Marqusee; Suzanne George; Mary C Frates; Ming Hui Chen; Jeffrey A Morgan; Samuel S Dychter; P Reed Larsen; George D Demetri; Erik K Alexander Journal: Ann Intern Med Date: 2006-11-07 Impact factor: 25.391
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Authors: Eva Wardelmann; Sabine Merkelbach-Bruse; Katharina Pauls; Nadja Thomas; Hans-Ulrich Schildhaus; Thomas Heinicke; Nicola Speidel; Torsten Pietsch; Reinhard Buettner; Daniel Pink; Peter Reichardt; Peter Hohenberger Journal: Clin Cancer Res Date: 2006-03-15 Impact factor: 12.531
Authors: Deborah L White; Verity A Saunders; Phuong Dang; Jane Engler; Andrew C W Zannettino; Antony C Cambareri; Steven R Quinn; Paul W Manley; Timothy P Hughes Journal: Blood Date: 2006-04-04 Impact factor: 22.113
Authors: George D Demetri; Margaret von Mehren; Cristina R Antonescu; Ronald P DeMatteo; Kristen N Ganjoo; Robert G Maki; Peter W T Pisters; Chandrajit P Raut; Richard F Riedel; Scott Schuetze; Hema M Sundar; Jonathan C Trent; Jeffrey D Wayne Journal: J Natl Compr Canc Netw Date: 2010-04 Impact factor: 11.908