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

Abstract

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 performance status 0–1 with advanced refractory solid malignancies were enrolled. 14 patients were male and eight patients had colorectal adenocarcinoma. The MTD was 1,430 mcg/m2/day and the dose-limiting toxicity (DLT) was bone marrow suppression. DLT occurred in both patients treated at 1,905 mcg/m2/day: one developed grade 3 thrombocytopenia with haemorrhage and grade 3 anaemia; the other died from neutropenic sepsis. Other clinically significant drug-related toxicities included moderate phlebitis and fatigue. Plasma PK analysis on days 1 and 5 in cycle 1 showed rapid plasma clearance of RH1 (t1/2=12.3 mins) with AUC increasing proportionately with dose. The comet-X assay showed increases in DNA inter-stand cross-linking in peripheral blood lymphocytes treated at 200 mcg/m2/day or above. These cross-links were detectable within one hour of commencement of dosing and reached a maximum of 30%. DNA cross-linking after RH1 was seen in tumour samples, even with low levels of DTD. One patient was homozygous for the NQO1 polymorphism. No objective tumour responses were recorded. Conclusions: The MTD of 1,430 mcg/m2/day is the dose recommended for phase II clinical trials. Tested doses were associated with DNA cross-linking in both peripheral blood lymphocytes and tumour cells. No significant financial relationships to disclose.