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Annals of Oncology Advance Access published online on October 30, 2009
Annals of Oncology, doi:10.1093/annonc/mdp491
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors

P. Schmid1,*, P. Kiewe2, K. Possinger3, A. Korfel2, S. Lindemann4, M. Giurescu5, S. Reif6, H. Wiesinger6, E. Thiel2 and D. Kühnhardt3

1 Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, London, UK
2 Department of Oncology, Hematology and Transfusion Medicine, Charité Campus Benjamin Franklin
3 Department of Oncology and Hematology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin
4 Clinical Pharmacology
5 Global Medical Development Oncology
6 Clinical Pharmacokinetics, Bayer Schering Pharma AG, Berlin, Germany

* Correspondence to: Dr P. Schmid, Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK. Tel: +44-20-8846-1418; Fax: +44-20-8846-1433; E-mail: p.schmid{at}imperial.ac.uk

Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment.

Patients and methods: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6–29.4 mg/m2) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m2 dose) to assess the incidence of neuropathy with prolonged infusion.

Results: The MTD was established as 22.0 mg/m2. DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms.

Conclusions: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m2, once every 3 weeks.

chemotherapy, epothilones, first-in-human study, microtubule-stabilizing agent, phase I study, solid tumors

Received for publication July 7, 2009. Revision received August 27, 2009. Accepted for publication September 9, 2009.


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