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Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2)

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Abstract

Purpose

The antimalarial drug artesunate (ART) is a promising candidate for cancer treatment as it displays anticancer effects in various models. While in short-term treatment of malaria, an excellent safety profile has been found for ART, the potential long-term treatment of cancer patients demands a phase I dose-finding clinical trial determining the daily ART dose which would be well tolerated as add-on therapy.

Methods

Patients with metastatic breast cancer were to receive either 100 or 150 or 200 mg oral ART daily as add-on to their guideline-based oncological therapy for a study period of four weeks with frequent clinical and laboratory monitoring until 4–8 weeks thereafter. According to the statistical design, recruitment was scheduled in groups of three patients in order not to miss a more than 33% frequency of dose-limiting adverse events (DL-AE) prior to dose escalation.

Results

Twenty-three patients were recruited, and all planned dose levels were applied. During the actual trial period of 4 ± 1 weeks, three patients experienced six DL-AEs altogether (leucopenia, neutropenia, asthenia, anemia) possibly related to ART (not exceeding 33% in any dose level).

Conclusions

Up to 200 mg/d (2.2–3.9 mg/kg/d) oral ART were safe and well tolerated; therefore, 200 mg/d are recommended for phase II/III trials. Safety monitoring should include reticulocytes, NTproBNP, as well as audiological and neurological exploration.

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References

  1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376

    Article  CAS  PubMed  Google Scholar 

  2. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N (2004) Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363:9–17

    Article  CAS  PubMed  Google Scholar 

  3. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G (2005) Artesunate in the treatment of metastatic uveal melanoma–first experiences. Oncol Rep 14:1599–1603

    CAS  PubMed  Google Scholar 

  4. Bethell D, Se Y, Lon C, Socheat D, Saunders D, Teja-Isavadharm P, Khemawoot P, Darapiseth S, Lin J, Sriwichai S, Kuntawungin W, Surasri S, Lee SJ, Sarim S, Tyner S, Smith B, Fukuda MM (2010) Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. Clin Infect Dis 51:e105–e114. doi:10.1086/657402

    Article  CAS  PubMed  Google Scholar 

  5. Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother Pharmacol 53:423–432. doi:10.1007/s00280-003-0751-4

    Article  CAS  PubMed  Google Scholar 

  6. Clark RL (2012) Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients. Birth Defects Res A Clin Mol Teratol 94:61–75. doi:10.1002/bdra.22868

    Article  CAS  PubMed  Google Scholar 

  7. Clark RL, White TE, Gaunt I, Winstanley P, Ward SA (2004) Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 71:380–394. doi:10.1002/bdrb.20027

    Article  CAS  PubMed  Google Scholar 

  8. Dayan AD (1998) Neurotoxicity and artemisinin compounds do the observations in animals justify limitation of clinical use? Med Trop (Mars) 58:32–37

    CAS  Google Scholar 

  9. Dell’Eva R, Pfeffer U, Vene R, Anfosso L, Forlani A, Albini A, Efferth T (2004) Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68:2359–2366. doi:10.1016/j.bcp.2004.08.021

    Article  PubMed  Google Scholar 

  10. Edler L, Burkholder I (2005) Overview of phase I trials. In: Crowley JC, Ankerst DP (eds) Handbook of statistics in clinical oncology. CRC Press, Boca Raton, pp 3–29

    Google Scholar 

  11. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR (2001) The anti-malarial artesunate is also active against cancer. Int J Oncol 18:767–773

    CAS  PubMed  Google Scholar 

  12. Efferth T, Giaisi M, Merling A, Krammer PH, Li-Weber M (2007) Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PLoS ONE 2:e693. doi:10.1371/journal.pone.0000693

    Article  PubMed  PubMed Central  Google Scholar 

  13. Efferth T, Ramirez T, Gebhart E, Halatsch ME (2004) Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774. Biochem Pharmacol 67:1689–1700

    Article  CAS  PubMed  Google Scholar 

  14. Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 64:382–394

    Article  CAS  PubMed  Google Scholar 

  15. Efferth T, Schottler U, Krishna S, Schmiedek P, Wenz F, Giordano FA (2016) Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature. Arch Toxicol. doi:10.1007/s00204-016-1810-z

    Google Scholar 

  16. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386. doi:10.1002/ijc.29210

    Article  CAS  PubMed  Google Scholar 

  17. Franco-Paredes C, Dismukes R, Nicolls D, Kozarsky PE (2005) Neurotoxicity due to antimalarial therapy associated with misdiagnosis of malaria. Clin Infect Dis 40:1710–1711. doi:10.1086/430180

    Article  PubMed  Google Scholar 

  18. Genovese RF, Newman DB, Brewer TG (2000) Behavioral and neural toxicity of the artemisinin antimalarial, arteether, but not artesunate and artelinate, in rats. Pharmacol Biochem Behav 67:37–44

    Article  CAS  PubMed  Google Scholar 

  19. Gordi T, Lepist EI (2004) Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett 147:99–107

    Article  CAS  PubMed  Google Scholar 

  20. Jiao Y, Ge CM, Meng QH, Cao JP, Tong J, Fan SJ (2007) Dihydroartemisinin is an inhibitor of ovarian cancer cell growth. Acta Pharmacol Sin 28:1045–1056. doi:10.1111/j.1745-7254.2007.00612.x

    Article  CAS  PubMed  Google Scholar 

  21. Kim SJ, Kim MS, Lee JW, Lee CH, Yoo H, Shin SH, Park MJ, Lee SH (2006) Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro. J Cancer Res Clin Oncol 132:129–135. doi:10.1007/s00432-005-0052-x

    Article  CAS  PubMed  Google Scholar 

  22. Koenig M, von Hagens C, Hoth S, Baumann I, Walter-Sack I, Edler L, Sertel S (2016) Erratum to: 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 77:1321. doi:10.1007/s00280-016-3023-9

    Article  Google Scholar 

  23. Koenig M, von Hagens C, Hoth S, Baumann I, Walter-Sack I, Edler L, Sertel S (2016) 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. doi:10.1007/s00280-016-2960-7

    Article  CAS  Google Scholar 

  24. Krishna S, Ganapathi S, Ster IC, Saeed ME, Cowan M, Finlayson C, Kovacsevics H, Jansen H, Kremsner PG, Efferth T, Kumar D (2015) A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer. EBioMedicine 2:82–90. doi:10.1016/j.ebiom.2014.11.010

    Article  PubMed  Google Scholar 

  25. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX (2007) Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 121:1360–1365. doi:10.1002/ijc.22804

    Article  CAS  PubMed  Google Scholar 

  26. Li Q, Xie LH, Johnson TO, Si Y, Haeberle AS, Weina PJ (2007) Toxicity evaluation of artesunate and artelinate in Plasmodium berghei-infected and uninfected rats. Trans R Soc Trop Med Hyg 101:104–112. doi:10.1016/j.trstmh.2006.04.010

    Article  CAS  PubMed  Google Scholar 

  27. Linde K, Witt CM, Streng A, Weidenhammer W, Wagenpfeil S, Brinkhaus B, Willich SN, Melchart D (2007) The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128:264–271. doi:10.1016/j.pain.2006.12.006

    Article  PubMed  Google Scholar 

  28. Lu H, Sheng R, Zhang C, Lee TY (2016) Comments regarding “Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature”. Arch Toxicol. doi:10.1007/s00204-016-1915-4

    Google Scholar 

  29. Miller LG, Panosian CB (1997) Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 336:1328. doi:10.1056/NEJM199705013361818

    Article  CAS  PubMed  Google Scholar 

  30. Panossian LA, Garga NI, Pelletier D (2005) Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 58:812–813. doi:10.1002/ana.20620

    Article  PubMed  Google Scholar 

  31. Reid BG, Stratton MS, Bowers S, Cavasin MA, Demos-Davies KM, Susano I, McKinsey TA (2016) Discovery of novel small molecule inhibitors of cardiac hypertrophy using high throughput, high content imaging. J Mol Cell Cardiol 97:106–113. doi:10.1016/j.yjmcc.2016.04.015

    Article  CAS  PubMed  Google Scholar 

  32. Reungpatthanaphong P, Mankhetkorn S (2002) Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biol Pharm Bull 25:1555–1561

    Article  CAS  PubMed  Google Scholar 

  33. Ribeiro IR, Olliaro P (1998) Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Med Trop (Mars) 58:50–53

    CAS  Google Scholar 

  34. Singh NP, Lai H (2001) Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 70:49–56

    Article  CAS  PubMed  Google Scholar 

  35. Singh NP, Verma KB (2002) Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Onc 10:279–280

    Article  Google Scholar 

  36. Sledge GW Jr (2016) Curing Metastatic Breast Cancer. J Oncol Prac 12:6–10. doi:10.1200/JOP.2015.008953

    Article  Google Scholar 

  37. Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27:25–61

    Article  CAS  PubMed  Google Scholar 

  38. Toovey S (2006) Are currently deployed artemisinins neurotoxic? Toxicol Lett 166:95–104. doi:10.1016/j.toxlet.2006.06.001

    Article  CAS  PubMed  Google Scholar 

  39. Uhl M, Schwab S, Efferth T (2016) Fatal liver and bone marrow toxicity by combination treatment of dichloroacetate and artesunate in a glioblastoma multiforme patient: case report and review of the literature. Front Oncol 6:204. doi:10.3389/fonc.2016.00204

    Article  PubMed  PubMed Central  Google Scholar 

  40. WHO (2006) Guideline for the treatment of malaria. WHO, Geneva

    Google Scholar 

  41. WHO (2015) Guidelines for the Treatment of Malaria, 3rd edn. WHO, Geneva

    Google Scholar 

  42. WHO (2001) The use of antimalarial drugs. Consultation report. World Health Organization, Geneva

    Google Scholar 

  43. Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, Xia XH, Li DQ (2008) Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao 6:134–138

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Planning and conduct of this investigator-initiated clinical study (IIT) was kindly supported by: A. Dayan contributed with his valuable toxicological expertise to answer the competent authority’s questions after submission of the protocol. I. Baumann planned audiological assessments, M. Eichbaum, F. Marmé, F. Schütz, A. Scharf, S. Hoth, and G. Richter gave helpful advice to the protocol, C. Klose planned and organized the data management. K. Staerck and A. Mallok critically reviewed patients’ informed consent. RJ Barrows, IB, and AS collected clinical data and were clinical consultants during the study. C. Zugck, P. Ehlermann, ME, FM, and P. Hallscheidt were clinical consultants during the study. C. Zemmel, AM, G. Zinser, and A. Schick-Schmitt organized patients’ care and collected and processed laboratory materials. We thank the nursing and medical staff of the gynecological department of the National Center for Tumor Diseases (NCT) Heidelberg, former oncological day-unit of the University Womens’ Hospital for patient-friendly care and study organization. B. Schurich and H. H. Otter contributed as monitors, J. Hajda as safety officer. C. v. Kalle, K. Linde, and U. Meyding-Lamadé contributed as members of the data safety monitoring board. Special thanks to the participating patients, their accompanying relatives, and their compliance with careful documentation and other time-consuming study procedures.

Author contributions

CvH, IWS, BSH, BAR, AS, TE, LE, ME, JO, and TS planned the study and contributed to the protocol. CvH (principal investigator) and AS (responsible oncologist throughout the whole study) enrolled patients. CvH, BSH, SeS, ME and MG examined patients and contributed clinical data. JM performed data analysis, reviewed by LE. CvH, IWS and LE wrote the first draft of the manuscript. All authors contributed to and approved the final manuscript.

Funding

This study was funded by H.W. & J. Hector Stiftung (Medizinprojekt M 33.2), Weinheim, HEIFAN (Heidelberger Förderverein der Ambulanz für Naturheilkunde) e.V. (parts of study staff costs from 2008 to 2012), Monika-Kutzner-Stiftung, Berlin (ARTIC M 33/2, Extensionsphase, approval August 25th, 2009), all in Germany, and the participating Departments. Study medication was provided by Dafra Pharma, Turnhout, Belgium.

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Authors and Affiliations

  1. Naturopathy and Integrative Medicine, Department of Gynecological Endocrinology and Reproductive Medicine, University Women’s Hospital Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany

    Cornelia von Hagens, Maren Goeckenjan, Julia Osburg & Thomas Strowitzki

  2. Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany

    Ingeborg Walter-Sack

  3. Department of Gynecology and Obstetrics, TU Dresden, Dresden, Germany

    Maren Goeckenjan

  4. Heidelberg School of Chinese Medicine, Heidelberg, Germany

    Julia Osburg

  5. Neuro-Center, University Hospital, Heidelberg, Germany

    Brigitte Storch-Hagenlocher

  6. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Heidelberg, Germany

    Serkan Sertel

  7. University Women’s Hospital, Heidelberg, Germany

    Michael Elsässer

  8. Department of Cardiology, University Hospital, Heidelberg, Germany

    Bjoern Andrew Remppis

  9. Heart and Vascular Centre, Bad Bevensen, Germany

    Bjoern Andrew Remppis

  10. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Lutz Edler

  11. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany

    Judith Munzinger

  12. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany

    Thomas Efferth

  13. National Center for Tumor Diseases, University-Hospital, Heidelberg, Germany

    Andreas Schneeweiss

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  1. Cornelia von Hagens
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  2. Ingeborg Walter-Sack
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  3. Maren Goeckenjan
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  7. Michael Elsässer
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  8. Bjoern Andrew Remppis
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  9. Lutz Edler
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  10. Judith Munzinger
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  11. Thomas Efferth
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  12. Andreas Schneeweiss
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  13. Thomas Strowitzki
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Corresponding author

Correspondence to Cornelia von Hagens.

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Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

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

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von Hagens, C., Walter-Sack, I., Goeckenjan, M. et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat 164, 359–369 (2017). https://doi.org/10.1007/s10549-017-4261-1

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  • DOI: https://doi.org/10.1007/s10549-017-4261-1

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