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

<p>Abstract</p> <p>Background</p> <p>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> <p>Methods</p> <p>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> <p>Results</p> <p>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 C_max from 1–10 mg/m². Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion.</p> <p>Conclusions</p> <p>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.</p> <p>Trial registration</p> <p>EU-CTR2006-001345-33</p>

Abstract licence: CC BY-NC-ND

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.