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Investigational New Drugs

, Volume 32, Issue 3, pp 436–444 | Cite as

A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors

  • D. S. Hong
  • R. Kurzrock
  • A. Naing
  • J. J. Wheler
  • G. S. Falchook
  • J. S. Schiffman
  • N. Faulkner
  • M. J. Pilat
  • J. O’Brien
  • P. LoRusso
PHASE I STUDIES

Summary

The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m2. Twenty-six patients were enrolled in the study. At 5.7 mg/m2, two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1–3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m2 with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m2. The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m2 and 4.3 mg/m2, respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6–13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

Keywords

Advanced solid tumors E7107 Pharmacodynamic Pharmacokinetic Phase I 

Notes

Acknowledgments

We gratefully acknowledge the participating patients, their families, and study investigators for their invaluable contribution. Editorial support was provided by Deborah McGregor, PhD, of Complete Medical Communications, funded by Eisai Inc., and Jo Ann of the Department of Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas. This study was funded by Eisai Inc.

Authors’ contributions

All authors were involved in the writing, review, and/or revision of the manuscript, and have approved the manuscript for submission. D. Hong and P. LoRusso were principal investigators for the study and were involved in the development of the methodology, the acquisition of data, and the analysis and interpretation of the results. R. Kurzrock, A. Naing, J. Wheler, G. Falchook, J. Schiffman, N. Faulkner, and M. J. Pilat were involved in the acquisition of data. J. O’Brien was involved in the development of the methodology, and the analysis and interpretation of the results.

Financial support

This study was funded by Eisai Inc.

Conflicts of interest

D. S. Hong received research grant funding from Eisai for this study. J. O’Brien is affiliated with Eisai Inc., NJ, USA. The remaining authors have no conflicts of interest to declare.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • D. S. Hong
    • 1
  • R. Kurzrock
    • 1
  • A. Naing
    • 1
  • J. J. Wheler
    • 1
  • G. S. Falchook
    • 1
  • J. S. Schiffman
    • 1
  • N. Faulkner
    • 2
  • M. J. Pilat
    • 2
  • J. O’Brien
    • 3
  • P. LoRusso
    • 2
  1. 1.University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Barbara Ann Karmanos Cancer CenterDetroitUSA
  3. 3.Eisai IncWoodcliff LakeUSA

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