Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses
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
Citation and License
BMC Cancer 2012, 12:536 doi:10.1186/1471-2407-12-536Published: 21 November 2012
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.
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).
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.
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.