Abstract
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. 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. 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 maximum tolerated dose (MTD) is 4.0 mg/m(2). No complete or partial responses during treatment were observed; one patient at 4.0 mg/m(2) had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. 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.
Highlights
Protein-encoding genes of the human genome are composed of multiple exons interrupted by introns
Eight patients presented disease control for more than 3 months. This is the first clinical study that has been conducted with the spliceosome inhibitor E7107
Because it was a phase I study, the most emphasis was put on the analysis of safety and tolerability, whereas extensive pharmacologic research was done aiming at an optimal assessment of the pharmacokinetic and pharmacodynamic behavior
Summary
Protein-encoding genes of the human genome are composed of multiple exons interrupted by introns. Exon and intron sequences are converted into single precursor messenger ribonucleic acid (pre-mRNA). In a process called "splicing," intron sequences are removed from pre-mRNA and exons are fused together, resulting in the formation of mature mRNA, which is processed further and subsequently transported out of the nucleus into the cellular cytoplasm to be translated into proteins. Most genes give rise to multiple spliced transcripts by a process called alternative splicing. These various transcripts contain different combinations of exons, leading to different mRNA variants and the synthesis of different proteins. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, is the main cellular machinery guiding splicing.
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