Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A phase I and pharmacokinetic study of its prodrug, CB1954

CB1954 [5-(azirdin-1-yl)-2,4-dinitrobenzamide] is converted by the bacteria l enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctiona l alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23 -78 years (median 62 years), with predominantly gastrointestinal malignanci es were treated. CB1954 was administered by Lv. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m(2). No significant toxicity was seen until 24 mg/m(2) (recommended i.v. dose). Dose-limiting toxicities (DL T) were diarrhea and hepatic toxicity, seen at 37.5 mg/m(2). DLT has not be en observed at the current i.p. dose of 24 mg/m(2). There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metab olism, and <5% of CB1954 was renally excreted. There was a nonlinear relati onship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m(2), the AUC was 5.8 muM/h. Intraperitoneal administra tion (24 mg/m(2)) achieved an AUC of 387 muM/h, giving a considerable regio nal advantage. In vitro, the AUC required to achieve the IC50 for CB1954, i n NTR-expressing cancer cells, ranges from 10-50 muM/h. Thus, CB1954 is wel l tolerated at a dose of 24 mg/m(2), and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now con ducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 ( 24 mg/m(2)) in patients with primary and secondary liver tumors.