A phase I and pharmacokinetic study of VNP40101M,a new alkylating agent,in patients with advanced or metastatic cancer |
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Authors: | John?Murren Manuel?Modiano Shivaani?Kummar Caroline?Clairmont Merrill?Egorin Edward?Chu Email author" target="_blank">Mario?SznolEmail author |
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Institution: | (1) From Yale-New Haven Cancer Center, New Haven, CT, USA;(2) Arizona Clinical Research Center, Tucson, AZ, USA;(3) West Haven Veterans, Administration Medical Center, West Haven, CT, USA;(4) University of Pittsburgh Cancer Institute, West Haven, CT, USA;(5) Vion Pharmaceuticals, Inc, West Haven, CT, USA;(6) Vion Pharmaceuticals, 4 Science Park, New Haven, 06511, CT, USA |
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Abstract: | 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.Supported by Vion Pharmaceuticals, Inc. |
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Keywords: | alkylating agents clinical pharmacology phase I clinical trial |
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