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ASP9853, an inhibitor of inducible nitric oxide synthase dimerization, in combination with docetaxel: preclinical investigation and a Phase I study in advanced solid tumors

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Abstract

Purpose

ASP9853 is an inhibitor of inducible nitric oxide (NO) synthase (iNOS) dimerization, which results in decreased NO production. Here, we report preclinical pharmacology of ASP9853 and the impact of ASP9853 in combination with a taxane on tumor volume in vivo. In addition, a Phase I open-label study of ASP9853 plus docetaxel was conducted to assess this combination in patients with advanced solid tumors.

Methods

The preclinical efficacy of ASP9853 in combination with a taxane was studied in tumor-bearing mice. In the clinic, patients with solid tumors that had progressed or failed to respond to previous therapies were treated with once–daily ASP9853 in combination with docetaxel once every 3 weeks to assess safety and tolerability and to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D) of the combination.

Results

ASP9853 in combination with docetaxel showed greater tumor growth inhibition than docetaxel alone against non-small lung cancer xenografts. Twenty patients were treated with ASP9853 and docetaxel. Five patients experienced neutropenic dose-limiting toxicities. Owing to overall toxicity that limited further dose escalation, the ASP9853 concentrations predicted for efficacy, based on the preclinical data, were not achieved. Due to toxicity and lack of clear efficacy, the study was terminated without determination of MTD or RP2D.

Conclusions

Inhibition of iNOS by ASP9853 in combination with docetaxel was not tolerable and resulted in the possible potentiation of neutropenia. Manipulation of the iNOS pathway, with or without chemotherapy, appears to be more complicated than initially expected.

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Acknowledgments

We would like to thank Michelle Utton-Mishra, Choice Healthcare Solutions, for medical writing assistance, funded by Astellas Pharma Inc.

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Authors and Affiliations

  1. Section of Hematology/Oncology, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA

    Jason J. Luke

  2. Yale Smilow Cancer Center, New Haven, CT, USA

    Patricia LoRusso

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Geoffrey I. Shapiro

  4. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Geoffrey I. Shapiro

  5. Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA

    Andrew Krivoshik, Robin Schuster, Takao Yamazaki, Allam Fakhoury & Carl Dmuchowski

  6. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, Japan

    Yukinori Arai

  7. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA

    Jeffrey R. Infante

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  1. Jason J. Luke
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  2. Patricia LoRusso
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Corresponding author

Correspondence to Jason J. Luke.

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Conflict of interest

J.L. has no COIs; P.L.R. has received consultancy/advisory fees from Astellas, Pfizer, Genetech and Astex; G.I.S. reports funding to the Dana-Farber Cancer Institute Early Drug Development Center for conduct of the study; J.I. has not COIs; A.K., R.S., T.Y., A.F. and C.D. are employees of Astellas Pharma Global Development, Inc.

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Luke, J.J., LoRusso, P., Shapiro, G.I. et al. ASP9853, an inhibitor of inducible nitric oxide synthase dimerization, in combination with docetaxel: preclinical investigation and a Phase I study in advanced solid tumors. Cancer Chemother Pharmacol 77, 549–558 (2016). https://doi.org/10.1007/s00280-016-2967-0

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  • DOI: https://doi.org/10.1007/s00280-016-2967-0

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