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

Abstract

CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional 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 malignancies were treated. CB1954 was administered by i.v. 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/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.

• Authors: G Chung-Faye, D Palmer, D Anderson, J Clark, M Downes, J Baddeley, S Hussain, P I Murray, P Searle, L Seymour, P A Harris, D Ferry, D J Kerr
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 9 Pg. 2662-8 (Sep 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11555577 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Aziridines
• Prodrugs
• tretazicar
• Nitroreductases

Topics

• Abdominal Pain (chemically induced)
• Adenoviridae (genetics)
• Adult
• Aged
• Anorexia (chemically induced)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Aziridines (adverse effects, pharmacokinetics, therapeutic use)
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Fatigue (chemically induced)
• Female
• Gastrointestinal Neoplasms (genetics, metabolism, therapy)
• Genetic Vectors (administration & dosage)
• Humans
• Injections, Intraperitoneal
• Injections, Intravenous
• Male
• Middle Aged
• Nausea (chemically induced)
• Nitroreductases (genetics)
• Prodrugs (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Vomiting (chemically induced)