A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

Abstract

Purpose: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS).Experimental Design: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m 2 was escalated by ϳ33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8.Results: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m 2 for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m 2 was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m 2 and 1 with acute myeloid leukemia treated with 600 mg/m 2 , achieved complete remission.Conclusions: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine

“…Cloretazine bears a functional resemblance to chloroethylnitrosoureas, such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), in that both agents generate chloroethylating and carbamoylating species; however, cloretazine was found to be more potent, more efficacious, and less toxic than BCNU in preclinical studies (2,5). Furthermore, cloretazine exhibited significant antileukemic activity alone and in combination with cytarabine (1-h-Darabinofuranosylcytosine) in acute myelogenous leukemia patients with relapsed/refractory disease in phase I and II clinical trials (6,7) and is currently in a pivotal phase III trial in acute myelogenous leukemia.…”

An in Vitro Evaluation of the Victim and Perpetrator Potential of the Anticancer Agent Laromustine (VNP40101M), Based on Reaction Phenotyping and Inhibition and Induction of Cytochrome P450 Enzymes

“…This process probably accounts for the considerably greater antineoplastic activity of laromustine relative to that of other sulfonylhydrazine alkylating agents, many of which generate 90CE like laromustine, but in contrast to laromustine do not generate methylisocyanate (Baumann et al, 2005). Laromustine displays anticancer activity against a broad spectrum of transplanted tumors (Finch et al, 2001) and exhibited antileukemic activity in initial clinical trials (Giles et al, 2004). Laromustine is being evaluated in clinical trials for the treatment of acute myelogenous leukemia and bone marrow transplant in patients with cancer.…”

Biotransformation and Rearrangement of Laromustine

“…It is thought that the antineoplastic effect of 90CE and related chloroethylating species augments the release of methylisocyanate and its inhibition of DNA repair by AGT, probably producing the significant improvement in antineoplastic activity of laromustine relative to the efficacy of other sulfonylhydrazine alkylating agents. Lomustine has shown anticancer activity against a broad spectrum of transplanted tumors (Finch et al, 2001) and exhibited antileukemic activity in initial clinical trials (Giles et al, 2004). The average human plasma C max for laromustine is approximately 25 mM (Nassar et al, 2009).…”