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Investigational New Drugs

, Volume 34, Issue 3, pp 329–337 | Cite as

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors

  • B. Milojkovic Kerklaan
  • S. Slater
  • M. Flynn
  • A. Greystoke
  • P. O. Witteveen
  • M. Megui-Roelvink
  • F. de Vos
  • E. Dean
  • L. Reyderman
  • L. Ottesen
  • M. Ranson
  • M. P. J. Lolkema
  • R. Plummer
  • R. Kristeleit
  • T. R. J. Evans
  • J. H. M. Schellens
PHASE I STUDIES

Summary

Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20–111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. Conclusions:Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response.

Keywords

E7820 Integrin-α2 Aromatic sulfonamide Maximum tolerated dose Food effect Pharmacokinetics 

Notes

Acknowledgments

The authors are grateful to the patients who participated in this study, their carers, and to the study teams at each participating site for their support of this study.

The study sites at Glasgow, Manchester, University College Hospital, London, and Newcastle are supported by Experimental Cancer Medicine Centre funding from Cancer Research UK, the Department of Health, and the Chief Scientist’s Office, Scotland.

Compliance with ethical standards

Conflict of interest

This work was supported by Eisai Inc.

L.Reyderman and L.Ottesen are employed by Eisai. Other authors have declared no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • B. Milojkovic Kerklaan
    • 1
  • S. Slater
    • 2
  • M. Flynn
    • 3
  • A. Greystoke
    • 4
  • P. O. Witteveen
    • 5
  • M. Megui-Roelvink
    • 1
  • F. de Vos
    • 5
  • E. Dean
    • 4
  • L. Reyderman
    • 6
  • L. Ottesen
    • 7
  • M. Ranson
    • 4
  • M. P. J. Lolkema
    • 5
    • 8
  • R. Plummer
    • 9
  • R. Kristeleit
    • 3
  • T. R. J. Evans
    • 2
  • J. H. M. Schellens
    • 1
    • 10
  1. 1.Department of Clinical Pharmacology, Division of Internal Medicine, Netherlands Cancer Institute – Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  2. 2.The Beatson West of Scotland Cancer CentreUniversity GlasgowGlasgowUK
  3. 3.University College London HospitalLondonUnited Kingdom
  4. 4.The Christie NHS Foundation Trust / University of ManchesterManchesterUK
  5. 5.Department of Medical Oncology, Cancer CenterUniversity Medical Centre UtrechtUtrechtThe Netherlands
  6. 6.Eisai IncWoodcliff LakeUSA
  7. 7.Eisai LtdHatfieldUK
  8. 8.Erasmus Medical Center Cancer Institute, Erasmus Medical CenterRotterdamThe Netherlands
  9. 9.Sir Bobby Robson Cancer Trials Research Centre NewcastleNewcastleUK
  10. 10.Utrecht Institute of Pharmaceutical Sciences (UIPS)Utrecht UniversityUtrechtThe Netherlands

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