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Open Access Research article

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

D Alan Anthoney1, Jay Naik1, Iain RJ MacPherson2, Donna Crawford2, John M Hartley3, Janet A Hartley3, Tomohisa Saito4, Masaichi Abe4, Keith Jones5, Masanori Miwa4, Christopher Twelves1* and TRJ Evans2

Author affiliations

1 St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, United Kingdom

2 University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, G12 OYN, United Kingdom

3 UCL Cancer Institute, Paul O’Gorman Building, University College London 72 Huntley Street, London, WC1E 6BT, United Kingdom

4 Chugai Pharmaceutical Co., Ltd, Nihonbashi Muromachi 2-1-1, Chuo-ku, Tokyo, 103-8324, Japan

5 Chugai Pharmaceuticals Europe Ltd. Turnham Green, London, W4 1NN, United Kingdom

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Citation and License

BMC Cancer 2012, 12:536  doi:10.1186/1471-2407-12-536

Published: 21 November 2012

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.

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).

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; diarrhoea 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.

Conclusions

TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage.

Trial registration

EU-CTR2006-001345-33

Keywords:
Pharmacodynamics; Pharmacogenomics; Pharmacokinetics; Phase I study; Safety profile; Topoisomerase-I inhibitor