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Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

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Abstract

Purpose

Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors.

Methods

The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response.

Results

An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment.

Conclusions

We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.

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Acknowledgments

The authors thank Scott Lawrence, Sonny Khin, Katherine Ferry-Galow, and Ravithat Putvatana, Leidos Biomedical Research, Inc., and Asako Nakamura, National Cancer Institute, for technical assistance with pharmacodynamic analyses during the course of these clinical trials. We also thank Mariam Konate, Capital Consulting Corporation, Andrea Regier Voth, Leidos Biomedical Research, Inc., and Joseph Shaw, Kelly Scientific, for medical writing support in the preparation of this manuscript.

Funding

This project was funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. Support was received from Contract N01CM-2011-0015, Grant UM1CA186690 (NIH/NCI). This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (BC 006161). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by Award P30CA047904. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA

    Shivaani Kummar, Alice Chen, Martin Gutierrez, Deborah Allen, Joseph M. Covey, Larry Rubinstein, Jerry Collins, Joseph Tomaszewski & James H. Doroshow

  2. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Thomas D. Pfister, Lihua Wang, William Yutzy, Yiping Zhang, Robert J. Kinders, Jiuping Ji & Ralph Parchment

  3. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Christophe Redon, William M. Bonner, Yves Pommier & James H. Doroshow

  4. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Julie L. Eiseman, Julianne L. Holleran & Jan H. Beumer

Authors
  1. Shivaani Kummar
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  2. Alice Chen
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  3. Martin Gutierrez
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  4. Thomas D. Pfister
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  5. Lihua Wang
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  6. Christophe Redon
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  7. William M. Bonner
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  8. William Yutzy
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  9. Yiping Zhang
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  10. Robert J. Kinders
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  11. Jiuping Ji
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  12. Deborah Allen
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  13. Joseph M. Covey
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  14. Julie L. Eiseman
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  15. Julianne L. Holleran
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  16. Jan H. Beumer
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  17. Larry Rubinstein
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  18. Jerry Collins
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  19. Joseph Tomaszewski
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  20. Ralph Parchment
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  21. Yves Pommier
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  22. James H. Doroshow
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Corresponding author

Correspondence to James H. Doroshow.

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Kummar, S., Chen, A., Gutierrez, M. et al. Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors. Cancer Chemother Pharmacol 78, 73–81 (2016). https://doi.org/10.1007/s00280-016-2998-6

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  • DOI: https://doi.org/10.1007/s00280-016-2998-6

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