Investigational new drugs · 2010
A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Vilar Eduardo, Grünwald Viktor, Schöffski Patrick, Singer Harald, Salazar Ramon, Iglesias Jose Luis, Casado Esther, Cullell-Young Martin, Baselga Jose, Tabernero Josep
Аннотация
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/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/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/m²/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.
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/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/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/m²/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.