FCCC LOGO Faculty Publications
Demetri GD , Casali PG , Blay JY , von Mehren M , Morgan JA , Bertulli R , Ray-Coquard I , Cassier P , Davey M , Borghaei H , Pink D , Debiec-Rychter M , Cheung W , Bailey SM , Veronese ML , Reichardt A , Fumagalli E , Reichardt P
A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors
Clinical Cancer Research. 2009 Sep;15(18) :5910-5916
PMID: 19723647    PMCID: PMC2861356    URL: https://www.ncbi.nlm.nih.gov/pubmed/19723647
Back to previous list
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. (Clin Cancer Res 2009;15(18):5910-6)
Demetri, George D. Casali, Paolo G. Blay, Jean-Yves von Mehren, Margaret Morgan, Jeffrey A. Bertulli, Rossella Ray-Coquard, Isabelle Cassier, Philippe Davey, Monica Borghaei, Hossein Pink, Daniel Debiec-Rychter, Maria Cheung, Wing Bailey, Stuart M. Veronese, Maria Luisa Reichardt, Annette Fumagalli, Elena Reichardt, Peter Novartis Pharmaceuticals Corporation ; Oncology Business Unit, Florham Park, NJ ; Virginia and Daniel K. Ludwig Trust for Cancer Research ; Stutman GIST Cancer Research Fund ; National Cancer Institute [P30 CA006927, CA106588]; Novartis Pharmaceuticals ; Pfizer, Inc. Grant support: Novartis Pharmaceuticals Corporation, Oncology Business Unit, Florham Park, NJ. G. Demetri received additional philanthropic support for this work from the following sources: The Virginia and Daniel K. Ludwig Trust for Cancer Research and the Stutman GIST Cancer Research Fund. M. von Mehren was supported by grant number P30 CA006927 and CA106588 from the National Cancer Institute. The following authors received funding from Novartis Pharmaceuticals: G. Demetri, E. Fumagalli, P.G. Casali, P. Reichardt, M. von Mehren, and J.Y. Blay. The following authors received funding from Pfizer, Inc., for other projects: G. Demetri, E. Fumagalli, and P.G. Casali. 31 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 496oa