Summary
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.
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Acknowledgements
We acknowledge the contribution of Sarah MacKenzie for medical writing support. We are grateful to the patients who participated in this trial, the many clinical research associates, nurses, and data managers for their help in patient recruitment, data management, and patient care during the conduct of this trial.
Disclosure
Employment or Leadership Position: H. Singer, PharmaMar; JL. Iglesias, PharmaMar; M. Cullell-Young, PharmaMar; Consultant or Advisory Role: P. Schöffski, PharmaMar; Stock Ownership: H. Singer, Zeltia Group; JL Iglesias, Zeltia Group; Honoraria: None; Research Funding: Patrick Schöffski, PharmaMar; Expert Testimony: Patrick Schöffski, PharmaMar; Other Remuneration: None.
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This work was supported by PharmaMar SA, Spain.
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Vilar, E., Grünwald, V., Schöffski, P. et al. A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors. Invest New Drugs 30, 299–305 (2012). https://doi.org/10.1007/s10637-010-9529-9
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DOI: https://doi.org/10.1007/s10637-010-9529-9