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

作者：Schmid P^*; Kiewe P; Possinger K; Korfel A; Lindemann S; Giurescu M; Reif S; Wiesinger H; Thiel E; Kuehnhardt D

来源：Annals of Oncology, 2010, 21(3): 633-639.

DOI：10.1093/annonc/mdp491

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

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/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53-or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion.
Results: The MTD was established as 22.0 mg/m(2). 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/m(2), once every 3 weeks.

• 出版日期2010-3