Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m−2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m−2. The maximum tolerated dose was 70 mg m−2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile

Cost reduction for aerospace engine components

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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 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. </jats:p