S J Danson1, P Johnson2, T H Ward3, M Dawson3, O Denneny3, G Dickinson4, L Aarons4, A Watson2, D Jowle5, J Cummings3, L Robson6, G Halbert7, C Dive3, M Ranson8. 1. Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research. Electronic address: s.danson@sheffield.ac.uk. 2. Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton. 3. Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research. 4. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester. 5. Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester. 6. Cancer Research UK Drug Development Office, Cancer Research UK, London. 7. Cancer Research UK Formulation Unit, University of Strathclyde, Glasgow, UK. 8. Department of Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, Manchester; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research.
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 μg/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. CONCLUSIONS: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 μg/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.
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 μg/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. CONCLUSIONS: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 μg/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.
Authors: Brandon A Carter-Cooper; Steven Fletcher; Dana Ferraris; Eun Yong Choi; Dahlia Kronfli; Smaraki Dash; Phuc Truong; Edward A Sausville; Rena G Lapidus; Ashkan Emadi Journal: Bioorg Med Chem Lett Date: 2016-11-17 Impact factor: 2.823
Authors: Pramodkumar P Gupta; Virupaksha A Bastikar; Dalius Kuciauskas; Shanker Lal Kothari; Jonas Cicenas; Mindaugas Valius Journal: Med Oncol Date: 2017-09-06 Impact factor: 3.064