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A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

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Abstract

Purpose

The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).

Methods

Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.

Results

A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.

Conclusion

The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.

ClinicalTrials.gov Identifier

NCT02353026.

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Acknowledgements

We thank the patients and their families who participated in this trial. We thank Colonel Bryan Smith, at US Army Medical Materiel Development Activity (USAMMDA), who led the development of intravenous artesunate for the US Army. We thank Dr. Merrill Egorin for assistance in the design of the dosing regimen used in this study. Finally, we thank Dr. Robert Robey for assistance in aspects of data interpretation.

Funding

The project was partially supported by the Ruesch Center for the Cure of Gastrointestinal Cancers and Award Number P30CA051008 from the National Cancer Institute. Further support came from the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001409. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, the United States Army, or the United States Department of Defense.

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Authors and Affiliations

  1. Inova Schar Cancer Institute, Inova Health System, 3300 Gallows Road, Falls Church, VA, 22042, USA

    John F. Deeken

  2. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    Hongkun Wang, Marion Hartley, Amrita K. Cheema, Brandon Smaglo, Aiwu Ruth He, Louis M. Weiner, John L. Marshall, Giuseppe Giaccone, Stephen Liu, Jim Luecht, Jay Y. Spiegel & Michael J. Pishvaian

  3. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA

    Jimmy J. Hwang

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  1. John F. Deeken
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Corresponding author

Correspondence to John F. Deeken.

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Conflict of interest

Author John Deeken declares he has no conflict of interest. Author Hongkun Wang declares she has no conflict of interest. Author Marion Hartley declares she has no conflict of interest. Author Amrita K. Cheema declares she has no conflict of interest. Author Brandon Smaglo declares he has no conflict of interest. Author Jimmy J. Hwang declares he has no conflict of interest. Author Aiwu Ruth He declares she has no conflict of interest. Author Louis M. Weiner declares he has no conflict of interest. Author John L. Marshall declares he has no conflict of interest. Author Giuseppe Giaccone declares he has no conflict of interest. Author Stephen Liu declares he has no conflict of interest. Author Jim Luecht declares he has no conflict of interest. Author Jay Y. Spiegel declares he has no conflict of interest. Author Michael J. Pishvaian declares he has no conflict of interest.

Ethical approval

All procedures performed in studies 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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Deeken, J.F., Wang, H., Hartley, M. et al. A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol 81, 587–596 (2018). https://doi.org/10.1007/s00280-018-3533-8

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  • DOI: https://doi.org/10.1007/s00280-018-3533-8

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