Phase I Pharmacokinetic and Pharmacodynamic Study of the First-in-Class Spliceosome Inhibitor E7107 in Patients with Advanced Solid Tumors

Ferry Eskens, FJ Ramos, H (Hens) Burger, JP O'Brien, A Piera, Maja de Jonge, Y Mizui, Erik Wiemer, MJ Carreras, J Baselga, J Tabernero

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Purpose: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Experimental Design: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m(2) were explored. Results: Forty patients [24M/16F, median age 61 years (45-79)] were enrolled. At 4.5 mg/m(2), dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m(2), DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m(2), one patient experienced reversible grade 4 blurred vision. The maxi Conclusion: The MTD for E7107 using this schedule is 4.0 mg/m(2). Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. (C) 2013 AACR.
Original languageUndefined/Unknown
Pages (from-to)6296-6304
Number of pages9
JournalClinical Cancer Research
Issue number22
Publication statusPublished - 2013

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  • EMC MM-03-86-08

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