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Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 5, pp 911–921 | Cite as

Phase I study of combined indomethacin and platinum-based chemotherapy to reduce platinum-induced fatty acids

  • Daphne L. van der Velden
  • Geert A. Cirkel
  • Julia M. Houthuijzen
  • E. van Werkhoven
  • Jeanine M. L. Roodhart
  • Laura G. M. Daenen
  • Sovann Kaing
  • Johan Gerrits
  • Nanda M. Verhoeven-Duif
  • Cecile Grootscholten
  • Henk Boot
  • Cristisiana Sessa
  • Haiko J. Bloemendal
  • Filip Y. De Vos
  • Emile E. Voest
Original Article

Abstract

Purpose

Chemotherapy-resistance remains a major obstacle to effective anti-cancer treatment. We previously showed that platinum analogs cause the release of two fatty acids. These platinum-induced fatty acids (PIFAs) induced complete chemoresistance in mice, whereas co-administration of a COX-1 inhibitor, indomethacin, prevented PIFA release and significantly enhanced chemosensitivity. To assess the safety of combining indomethacin with platinum-based chemotherapy, and to explore its efficacy and associated PIFA levels, a multi-center phase I trial was conducted.

Methods

The study was comprised of two arms: oxaliplatin plus capecitabine (CAPOX, arm I) and cisplatin plus gemcitabine, capecitabine or 5FU (arm II) in patients for whom these regimens were indicated as standard care. Indomethacin was escalated from 25 to 75 mg TID, using a standard 3 × 3 design per arm, and was administered orally 8 days around chemo-infusion from cycle two onwards. PIFA levels were measured before and after treatment initiation, with and without indomethacin.

Results

Thirteen patients were enrolled, of which ten were evaluable for safety analyses. In arm I, no dose-limiting toxicities were observed, and all indomethacin dose levels were well-tolerated. Partial responses were observed in three patients (30%). Indomethacin lowered plasma levels of 12-S-hydroxy-5,8,10-heptadecatrienoic acid (12-S-HHT), whereas 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) levels were not affected. Only one patient was included in arm II; renal toxicity led to closure of this cohort.

Conclusions

Combined indomethacin and CAPOX treatment is safe and reduces the concentrations of 12-S-HHT, which may be associated with improved chemosensitivity. The recommended phase II dose is 75 mg indomethacin TID given 8 days surrounding standard dosed CAPOX.

Keywords

Chemotherapy resistance Mesenchymal stem cells Platinum-induced fatty acids Indomethacin Oxaliplatin 

Notes

Acknowledgements

This work was supported by a Grant from the Dutch Cancer Society (KWF), Grant number UU 2012-5712, and received financial support rom the Swiss Advisory Board for Research EOC for study monitoring. The authors gratefully acknowledge the support of all four participating sites, and all study participants.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Daphne L. van der Velden
    • 1
  • Geert A. Cirkel
    • 2
  • Julia M. Houthuijzen
    • 3
  • E. van Werkhoven
    • 4
  • Jeanine M. L. Roodhart
    • 5
  • Laura G. M. Daenen
    • 5
  • Sovann Kaing
    • 1
  • Johan Gerrits
    • 6
  • Nanda M. Verhoeven-Duif
    • 6
  • Cecile Grootscholten
    • 7
  • Henk Boot
    • 7
  • Cristisiana Sessa
    • 8
  • Haiko J. Bloemendal
    • 2
  • Filip Y. De Vos
    • 5
  • Emile E. Voest
    • 1
  1. 1.Division of Molecular Oncology and ImmunologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Division of Medical OncologyMeander Medical CenterAmersfoortThe Netherlands
  3. 3.Division of Molecular PathologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Biometrics DepartmentNetherlands Cancer InstituteAmsterdamThe Netherlands
  5. 5.Division of Medical OncologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  6. 6.Section Metabolic Diagnostics, Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  7. 7.Division of Medical OncologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  8. 8.Division of Medical OncologyOncology Institute of Southern SwitzerlandBellinzonaSwitzerland

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