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Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1

Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1
Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1
Background: 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.

Patients and methods: 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.

Results: eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 ?g/m2/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t1/2 = 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.

Conclusions: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 ?g/m2/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
1569-8041
Danson, S.J.
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Johnson, Peter W.M.
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Ward, T.H.
237feb66-8cb6-428b-8a52-05caca2de5d3
Dawson, M.
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Denneny, O.
dcef279b-f70b-4f37-9fbb-d68e08c8a7a5
Dickinson, G.
460e7601-1124-4194-90c5-af0650185a74
Aarons, L.
6f7e0ed7-a17d-41bf-83be-2fe5167840d0
Watson, A.
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Jowle, D.
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Cummings, J.
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Robson, L.
d8390e32-b483-43b0-9202-92bdc96c06ac
Halbert, G.
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Dive, C.
3be5ab4d-16b0-4023-a164-9f678267d4b4
Ranson, M.
cbd6ede8-fc49-45e0-ac6f-9118b98763a7
Danson, S.J.
8162cc02-62bb-4d7f-aaf8-100d29a78d81
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Ward, T.H.
237feb66-8cb6-428b-8a52-05caca2de5d3
Dawson, M.
7b6ce623-a614-4780-8fc3-c8a7f2d8fdd8
Denneny, O.
dcef279b-f70b-4f37-9fbb-d68e08c8a7a5
Dickinson, G.
460e7601-1124-4194-90c5-af0650185a74
Aarons, L.
6f7e0ed7-a17d-41bf-83be-2fe5167840d0
Watson, A.
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Jowle, D.
81eede35-09f5-4d24-88ab-258016319832
Cummings, J.
1d36bfc6-4917-42ef-a704-9cce9759fd72
Robson, L.
d8390e32-b483-43b0-9202-92bdc96c06ac
Halbert, G.
02f91a2f-df10-4031-a285-bf86c3b9f242
Dive, C.
3be5ab4d-16b0-4023-a164-9f678267d4b4
Ranson, M.
cbd6ede8-fc49-45e0-ac6f-9118b98763a7

Danson, S.J., Johnson, Peter W.M., Ward, T.H., Dawson, M., Denneny, O., Dickinson, G., Aarons, L., Watson, A., Jowle, D., Cummings, J., Robson, L., Halbert, G., Dive, C. and Ranson, M. (2011) Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. Annals of Oncology. (doi:10.1093/annonc/mdq638). (PMID:21378203)

Record type: Article

Abstract

Background: 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.

Patients and methods: 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.

Results: eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 ?g/m2/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t1/2 = 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.

Conclusions: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 ?g/m2/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

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Published date: 2011

Identifiers

Local EPrints ID: 180101
URI: http://eprints.soton.ac.uk/id/eprint/180101
ISSN: 1569-8041
PURE UUID: c2354e70-cc4f-4e2e-a7ca-102e0a9f3a3f
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974

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Date deposited: 05 Apr 2011 13:50
Last modified: 15 Mar 2024 02:58

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Contributors

Author: S.J. Danson
Author: T.H. Ward
Author: M. Dawson
Author: O. Denneny
Author: G. Dickinson
Author: L. Aarons
Author: A. Watson
Author: D. Jowle
Author: J. Cummings
Author: L. Robson
Author: G. Halbert
Author: C. Dive
Author: M. Ranson

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