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

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/m². 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 ≥ 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/m² were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m², 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.