Final results of a phase I clinical trial of the bioreductive drug RH1

2514 Background: RH1 (2,5-diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benoquinone) is a novel bioreductive drug which is activated by the two electron reductase, DT-diaphorase (DTD) (NAD(P)H:quinone oxidoreductase). DTD is over-expressed in many tumors relative to normal tissue, especially lung, breast and colorectal tumors, so it is hoped that RH1 is selectively activated in such tumours with minimal normal tissue toxicity. Methods: Under the auspices of the CR-UK Drug Development Office, a dose escalation phase I trial of RH1 was performed at two centres. The primary objective was to establish the maximum tolerated dose (MTD) of RH1 given as a 10–30 minute infusion for 5 days every 3 weeks. Toxicity was assessed according to NCI CTC V2.0 criteria. Secondary objectives were to determine RH1 pharmacokinetics (PK), DNA cross-linking in peripheral blood lymphocytes and tumour cells, DTD activity in tumour, NQO1 polymorphism status and document any anti-tumour activity. Results: Eighteen patients of WHO perf...