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Investigational New Drugs

, Volume 23, Issue 2, pp 123–135 | Cite as

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

  • John Murren
  • Manuel Modiano
  • Shivaani Kummar
  • Caroline Clairmont
  • Merrill Egorin
  • Edward Chu
  • Mario Sznol
Article

Summary

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/m2 every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m2. Beyond 100 mg/m2, 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/m2 every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.

Key words

alkylating agents clinical pharmacology phase I clinical trial 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • John Murren
    • 1
  • Manuel Modiano
    • 2
  • Shivaani Kummar
    • 3
  • Caroline Clairmont
    • 5
  • Merrill Egorin
    • 4
  • Edward Chu
    • 3
  • Mario Sznol
    • 5
    • 6
  1. 1.From Yale-New Haven Cancer CenterNew HavenUSA
  2. 2.Arizona Clinical Research CenterTucsonUSA
  3. 3.West Haven VeteransAdministration Medical CenterWest HavenUSA
  4. 4.University of Pittsburgh Cancer InstituteWest HavenUSA
  5. 5.Vion Pharmaceuticals, IncWest HavenUSA
  6. 6.Vion PharmaceuticalsNew HavenUSA

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