A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer.

Abstract

PURPOSE:

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.

STUDY DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: John Murren, Manuel Modiano, Shivaani Kummar, Caroline Clairmont, Merrill Egorin, Edward Chu, Mario Sznol
• Journal: Investigational new drugs (Invest New Drugs) Vol. 23 Issue 2 Pg. 123-35 (Mar 2005) ISSN: 0167-6997 [Print] United States
• PMID: 15744588 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydrazines
• Sulfonamides
• laromustine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Hydrazines (adverse effects, pharmacokinetics, therapeutic use)
• Infusions, Intravenous
• Male
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy)
• Sulfonamides (adverse effects, pharmacokinetics, therapeutic use)
• Thrombocytopenia (chemically induced)