Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Anthoney, D.A. et al. (2012) Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses. BMC Cancer, 12(536), (doi: 10.1186/1471-2407-12-536)

Abstract

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain and Evans, Professor Jeff
• Authors: Anthoney, D.A., Naik, J., MacPherson, I.R.J., Crawford, D., Hartley, J.M., Hartley, J.A., Saito, T., Abe, M., Jones, K., Miwa, M., Twelves, C., and Evans, T.R.J.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer); R Medicine > RM Therapeutics. Pharmacology
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: BMC Cancer
• Publisher: BioMed Central Ltd.
• ISSN: 1471-2407
• Published Online: 21 November 2012
• Copyright Holders: Copyright © 2012 The Authors
• First Published: First published in BMC Cancer 12:536
• Publisher Policy: Reproduced under a Creative Commons License