Cancer Therapy : Clinical Phase I Dose-Escalation and Pharmacokinetic Study of Dasatinib in Patients with Advanced Solid Tumors

To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists.  In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing.  Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.  Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.  Dysregulated cell signaling through multiple kinases is associated with oncogenesis in many tumors. SRC family kinases (SFK), including SRC, YES, and FYN, are nonreceptor tyrosine kinases with a critical role in cellular proliferation. Together with YES and FYN, SRC has an ubiquitous distribution with particularly high levels in platelets, neurons, osteoclasts, and at epithelial cell-cell junctions (1, 2). Expression of the remaining SFKs is restricted primarily to hematopoietic cells. SFKs are basic components of the cell signaling machinery and are involved in pathways regulating growth, survival, motility, and adhesion (3). SFKs also promote several aspects of tumor progression and metastasis (4) and have a role in Authors' Affiliations: Ludwig Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Karmanos Cancer Institute, Detroit, Michigan; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; University of Edinburgh, Edinburgh, United Kingdom; and Bristol-Myers Squibb, Wallingford, Connecticut Received 1/29/09; revised 5/11/09; accepted 6/2/09; published OnlineFirst 9/29/09. Grant support: Bristol-Myers Squibb. G.D. Demetri was supported by The Virginia and Daniel K. Ludwig Trust for Cancer Research, the Pan-Mass Challenge of Paul's Posse and Leslie's Links, and the Russo Family GIST Research Fund. Editorial and writing support was provided by GardinerCaldwell US and funded by Bristol-Myers Squibb. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.  Previous presentations and preliminary abstract publications: (a) Evans TRJ, Morgan JA, van den Abbeele AD, et al. Phase I dose-escalation study of the SRC and multi-kinase inhibitor BMS-354825 in patients (pts) with GIST and other solid tumors. J Clin Oncol 2005;23(16S):200s, 3034 (poster presented at the American Society of Clinical Oncology, 2005). (b) Luo FR, Luo FR, Barrett Y, et al. Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003). J Clin Oncol 2006;24 (18S):132s, 3046. (c) Morgan JA, Demetri G, Wang D, et al. A phase I study of dasatinib, a SRC and multi-kinase inhibitor, in patients (pts) with GIST and other solid tumors.  Poster presented at the 18th European Organization for Research and Treatment of Cancer-National Cancer Institute-AACR International Conference on “Molecular Targets and Cancer Therapeutics” (7-10 November 2006, Prague). Requests for reprints: George D. Demetri, Ludwig Center, Dana-Farber Cancer Institute, 44 Binney Street, D1212, Boston, MA 02115.  ; E-mail: gdemetri@partners.org. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0224 6232 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Published Online First on September 29, 2009 as 10.1158/1078-0432.CCR-09-0224 Research. on April 15, 2017.  2009;  10.1158/1078-0432.CCR-09-0224