Abstract
This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 mu g/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect.
RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 mu g/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.
| Language | English |
|---|---|
| Pages | 1653-1660 |
| Number of pages | 8 |
| Journal | Annals of Oncology |
| Volume | 22 |
| Issue number | 7 |
| Early online date | 4 Mar 2011 |
| DOIs | |
| Publication status | Published - Jul 2011 |
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Keywords
- chemotherapy
- DT-diaphorase
- pharmacodynamic
- pharmacokinetic
- phase I
- RH1
- nadph cytochrome-P450 reductase
- DNA cross-linking
- antitumor quinones
- cell-lines
- oxidoreductases
- NAD(P)H
- agent
- cytotoxicity
- activation
Cite this
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Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. / Danson, S. J.; Johnson, P.; Ward, T. H.; Dawson, M.; Denneny, O.; Dickinson, G.; Aarons, L.; Watson, A.; Jowle, D.; Cummings, J.; Robson, L.; Halbert, Gavin; Dive, C.; Ranson, M.
In: Annals of Oncology, Vol. 22, No. 7, 07.2011, p. 1653-1660.Research output: Contribution to journal › Article
TY - JOUR
T1 - Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1
AU - Danson, S. J.
AU - Johnson, P.
AU - Ward, T. H.
AU - Dawson, M.
AU - Denneny, O.
AU - Dickinson, G.
AU - Aarons, L.
AU - Watson, A.
AU - Jowle, D.
AU - Cummings, J.
AU - Robson, L.
AU - Halbert, Gavin
AU - Dive, C.
AU - Ranson, M.
PY - 2011/7
Y1 - 2011/7
N2 - This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 mu g/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect. RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 mu g/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.
AB - This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 mu g/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect. RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 mu g/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.
KW - chemotherapy
KW - DT-diaphorase
KW - pharmacodynamic
KW - pharmacokinetic
KW - phase I
KW - RH1
KW - nadph cytochrome-P450 reductase
KW - DNA cross-linking
KW - antitumor quinones
KW - cell-lines
KW - oxidoreductases
KW - NAD(P)H
KW - agent
KW - cytotoxicity
KW - activation
U2 - 10.1093/annonc/mdq638
DO - 10.1093/annonc/mdq638
M3 - Article
VL - 22
SP - 1653
EP - 1660
JO - Annals of Oncology
T2 - Annals of Oncology
JF - Annals of Oncology
SN - 1569-8041
IS - 7
ER -