Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

Demetri, G. D., Lo Russo, P., MacPherson, I. R.J. , Wang, D., Morgan, J. A., Brunton, V. G., Paliwal, P., Agarwal, S., Voi, M. and Evans, T.R. J. (2009) Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clinical Cancer Research, 15(9), pp. 6232-6240. (doi: 10.1158/1078-0432.CCR-09-0224)

Abstract

PURPOSE: 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. <br></br> EXPERIMENTAL DESIGN: 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. <br></br> RESULTS: 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.<br></br> CONCLUSION: 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.<br></br>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain and Evans, Professor Jeff
• Authors: Demetri, G. D., Lo Russo, P., MacPherson, I. R.J., Wang, D., Morgan, J. A., Brunton, V. G., Paliwal, P., Agarwal, S., Voi, M., and Evans, T.R. J.
• Subjects: R Medicine > RM Therapeutics. Pharmacology
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 29 September 2009
• Copyright Holders: Copyright © 2009 American Association for Cancer Research
• First Published: First published in Clinical Cancer Research 15(9):6232-6240
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.