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Clinical Trial
. 2012 Nov 21:12:536.
doi: 10.1186/1471-2407-12-536.

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

D Alan Anthoney  1 , Jay Naik, Iain R J Macpherson, Donna Crawford, John M Hartley, Janet A Hartley, Tomohisa Saito, Masaichi Abe, Keith Jones, Masanori Miwa, Christopher Twelves, T R J Evans
Affiliations
Clinical Trial

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

D Alan Anthoney et al. BMC Cancer. .

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/m(2). MTD was 10 mg/m(2); DLTs at 12 (2/4 patients) and 10 mg/m(2) (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/m(2). 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.

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Figures

Figure 1
Figure 1
The fate of TP300, active form (TP3076) and its metabolite (TP3011).
Figure 2
Figure 2
Time-plasma concentration profile of TP300, TP3076 and TP3011. A: The plasma concentration profile of TP300. B: The plasma concentration profile of TP3076. C:The plasma concentration profile of TP3076. Square:1 mg/m2, Circle:2 mg/m2, Triangle (point up):4 mg/m2, Cross:6 mg/m2, X:8 mg/m2, Diamond:10 mg/m2, Triangle (point down):12 mg/m2.
Figure 3
Figure 3
Scatterplot of exposure against dose. A: The scatterplot of TP3076 Cmax. B: The scatterplot of TP3076 AUC. C: The scatterplot of TP3011 Cmax. D: The scatterplot of TP3011 AUC. E: The scatterplot of the sum of TP3076 and TP3011 Cmax. F: The scatterplot of the sum of TP3076 and TP3011 AUC.
Figure 4
Figure 4
Scatter plot of 1-Nadir/Pre-observation against AUC of TP3076+TP3011. Circle: Subject without DLT Double circle: Subject with DLT Solid line: Curve with sigmoid Emax model.
Figure 5
Figure 5
The boxplot of AUC by genotype; AOX1(c3404 A>G), UGT1A1*28 or CYP2D6. A:The boxplot of TP3076 AUC by AOX1(c3404 A>G). B:The boxplot of TP3011 AUC by AOX1(c3404 A>G). C:The boxplot of TP3076 AUC by UGT1A1 *28. D:The boxplot of TP3011 AUC by UGT1A1 *28. E:The boxplot of TP3076 AUC by CYP genotype. F:The boxplot of TP3011 AUC by CYP genotype. E: Extensive metabolizer. I:Intermediate metabolizer. P:Poor metabolizer.
Figure 6
Figure 6
Mean tail moment of COMET assay result over time by cohort. Square:1 mg/m2, Circle:2 mg/m2, Triangle (point up):4 mg/m2, Cross:6 mg/m2, X:8 mg/m2, Diamond:10 mg/m2, Triangle (point down):12 mg/m2 Dashed line: Overall mean.
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