A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors
Vilar, Eduardo × Grünwald, Viktor Schöffski, Patrick Singer, Harald Salazar, Ramon Iglesias, Jose Luis Casado, Esther Cullell-Young, Martin Baselga, Jose Tabernero, Josep #
Investigational New Drugs vol:30 issue:1 pages:299-305
Background ES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug. Patients and methods Thirty patients from two centers were treated with a three-hour ES-285 intravenous infusion for five consecutive days, every 3 weeks. Eleven dose levels were explored. Results No dose-limiting toxicity (DLT) occurred from 2 to 81 mg/m(2)/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m(2)/day; all had grade 4 transaminase increases, one of whom (160 mg/m(2)/day) had concomitant grade 4 hepatitis and grade 3 bilirubin elevation. The MTD of this regimen was not reached due to early termination of the ES-285 phase I program, but was considered to be 80 to 100 mg/m(2)/day. Other toxicities included mild to moderate asthenia, nausea, vomiting, anemia, lymphopenia, and injection site reaction. Pharmacokinetic analyses showed dose proportionality on Days 1 and 5, a wide distribution and a long half-life. Seven patients (five with colorectal cancer) had stable disease (1.2-4.1 months), lasting for more than 3 months in three patients. Conclusions Liver enzyme elevations were dose limiting for ES-285 in this administration schedule. Low antitumor activity was observed.