© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115
1 The Ottawa Hospital Regional Cancer Centre, Ottawa, Ontario, Canada
2 Centre Hospitalier Université de Montréal, Pavillon Notre-Dame, Montréal, Québec, Canada
3 NCIC Clinical Trials Group, Kingston, Ontario, Canada
4 MD Anderson Cancer Centre, Houston, Texas, USA
5 Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
6 Northeastern Ontario Oncology Program, Sudbury, Ontario, Canada
7 Pharma-Mar R&D, Colmenar Viejo, Madrid, Spain
*Correspondence to: Dr J. Maroun, Ottawa Hospital Regional Cancer Centre, 501 Smyth Road, Box #911, Ottawa, Ontario K1H 8L6, Canada. Tel: +1 (613) 737-7700 x70181; Fax: +1 (613) 247-3511; E-mail: jmaroun{at}ottawahospital.on.ca
Background: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.
Methods: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose.
Results: Thirty-seven patients were accrued on study. Doses ranged from 80 µg/m2 to 1500 µg/m2/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 µg/m2 and 1350 µg/m2/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 µg/m2 daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer.
Conclusions: Aplidine given at a dose of 1200 µg/m2 daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.
Key words: Aplidine, phase I clinical trial
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