laromustine and Thrombocytopenia

VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion.. The starting dose was 3 mg/m(2) every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m(2). Beyond 100 mg/m(2), dose increments were 25%. Initially, 1-2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related > or = grade 2 adverse event, all dose levels required assessment of 3-6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose.. Twenty-six patients in 13 dose levels ranging from 3-305 mg/m(2) were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m(2), six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes.. The MTD and recommended dose for phase II trials is 305 mg/m(2) every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Hydrazines; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Sulfonamides; Thrombocytopenia

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).. 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 approximately 33% 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.. 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.. VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Alkylating Agents; Area Under Curve; Humans; Hydrazines; Leukemia, Myeloid; Metabolic Clearance Rate; Middle Aged; Myelodysplastic Syndromes; Nausea; Sulfonamides; Survival Analysis; Thrombocytopenia; Treatment Outcome; Vomiting