Abstract
BackgroundA 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.MethodsEligible 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).Results32 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.ConclusionsTP300 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 registrationEU-CTR2006-001345-33
Highlights
A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of the prodrug CH4556300 (TP300), a water soluble prodrug of the Topo-1 inhibitor topoisomerase inhibitor CH0793076 (TP3076), and active metabolite, TP3011
Toxicity Toxicity from TP300 was predominantly haematologic with neutropenia the DLT
Two/ four patients dosed at 12 mg/m2 experienced DLT: grade 4 febrile neutropenia (5 days duration) and grade 4 neutropenia (15 days)
Summary
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. Irinotecan hydrochloride is the most widely used topoisomerase-I inhibitor, approved for the treatment of patients with colorectal cancer previously treated with 5fluorouracil [2]. It has activity against a wide range of other cancers Irinotecan has, a number of properties that limit its usefulness It is metabolized enhance the clinical efficacy of this class of agents. TP3011 and TP3076 are equipotent as Topo-1 inhibitors, with IC50 in the sub-nanomolar range HCT-116 colorectal cancer cells in vitro [10]. There should, be less inter-individual variation in activation and toxicity with TP300 than with irinotecan; it would be expected that severe diarrhoea should not be an issue
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