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Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study

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An Erratum to this article was published on 19 April 2016

Abstract

Purpose

Artesunate (ART) has been used for a long time in the treatment of Plasmodium falciparum malaria and has been considered safe. The present phase I study aimed to determine the daily dose of ART that is well tolerated as add-on therapy in patients with breast cancer for 4 weeks of therapy. Ototoxicity could be a potential safety concern in settings different from malaria. Therefore, comprehensive audiological assessment was essential.

Methods

The ARTIC M33/2 study was a prospective, open, uncontrolled, monocentric phase I dose-escalation study to evaluate the safety and tolerability of ART in patients with advanced breast cancer. Patients received either 100, 150 or 200 mg oral ART daily for a test phase of 4 weeks as add-on therapy to their ongoing oncological treatment. For the investigation of the safety of ART for hearing, an audiological assessment was performed with each patient before the intake of ART and after 4 weeks of therapy.

Results

Twenty-three female patients were included in the study. During the test phase, four patients had adverse events (AEs) of the auditory system possibly related to the intake of ART. However, none of these AEs was classified as severe AE (SAE) and did not require treatment interruption. Four patients had AEs concerning the vestibular system (vertigo) during the test phase, one of which was classified as SAE. However, the SAE was fully reversible after discontinuation of ART.

Conclusion

None of the audiological results after 4 weeks of therapy with ART showed any dose-limiting auditory toxicity. However, audiological monitoring in further clinical studies with prolonged use of oral ART in doses up to 200 mg daily is warranted.

The ARTIC M33/2 study is registered at eudract.ema.europa.eu with the Number 2007-004432-23 and at clinicaltrials.gov with the Number NCT00764036.

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Fig. 1
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Notes

  1. This use of the tool BN20+ as screening instrument for frequent screening for safety monitoring was permitted by the EORTC.

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Acknowledgments

We thank Anthony Dayan for his preclinical toxicology assessment allowing the conduct of this study. This work was supported by H.W. and J. Hector Stiftung, Weinheim, Germany, HEIFAN (Heidelberger Förderverein der Ambulanz für Naturheilkunde) e. V., and Monika-Kutzner-Stiftung, Berlin, Germany. Study medication was kindly provided by Dafra Pharma International, Research and Development, Turnhout, Belgium.

Author contributions

M.K. analyzed data and wrote the main paper; C.v.H. designed and planned the study, was the principal investigator of the study, recruited the patients, as well as critically revised the paper; I.W-S designed and planned the study and critically revised the paper; S.H. collected and analyzed data; I.B. designed experiments and collected data; L.E. planned, consulted and reviewed biostatistical analysis; S.S. designed and performed experiments, analyzed data as well as wrote and critically revised the paper. All authors discussed the results and implications and commented on the manuscript at all stages as well as read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Miriam König, Sebastian Hoth, Ingo Baumann & Serkan Sertel

  2. Naturopathy and Integrative Medicine, Department of Gynecological Endocrinology and Reproductive Medicine, University Women’s Hospital, Heidelberg, Germany

    Cornelia von Hagens

  3. Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany

    Ingeborg Walter-Sack

  4. Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Lutz Edler

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  1. Miriam König
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Corresponding author

Correspondence to Serkan Sertel.

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Conflict of interest

No conflicts of interest are declared.

Ethical standards

The ARTIC M33/2 study obtained approval by the competent federal authority (BfArM Submission No. 4033804) and by the Ethical Committee of the Faculty of Medicine, Heidelberg University, Germany, registered as AFmu-495/2007 before start of recruitment. Written informed consent was obtained from each participant prior to screening. The study was performed in accordance with the Declaration of Helsinki (1964) and its later amendments and was registered with ClinicalTrials.gov number NCT00764036 and with EudraCT-Number 2007-004432-23.

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König, M., von Hagens, C., Hoth, S. et al. Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol 77, 413–427 (2016). https://doi.org/10.1007/s00280-016-2960-7

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