A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.

Abstract

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.

• Authors: Eduardo Vilar, Viktor Grünwald, Patrick Schöffski, Harald Singer, Ramon Salazar, Jose Luis Iglesias, Esther Casado, Martin Cullell-Young, Jose Baselga, Josep Tabernero
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 1 Pg. 299-305 (Feb 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 20820909 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Alkanes
• Antineoplastic Agents
• Lipids
• spisulosine

Topics

• Adult
• Aged
• Alkanes (administration & dosage, adverse effects, blood, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, adverse effects, blood, pharmacokinetics)
• Drug Administration Schedule
• Female
• Germany
• Half-Life
• Humans
• Infusions, Intravenous
• Lipids (administration & dosage, adverse effects, blood, pharmacokinetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Spain
• Treatment Outcome
• Young Adult