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.
Similar content being viewed by others
References
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
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
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
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
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
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
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
Dayan AD (1998) Neurotoxicity and artemisinin compounds do the observations in animals justify limitation of clinical use? Med Trop (Mars) 58:32–37
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
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
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
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
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
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
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
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
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
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
Gordi T, Lepist EI (2004) Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett 147:99–107
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
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
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
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
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
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
Li Q, **e 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
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
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
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
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
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
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
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
Singh NP, Lai H (2001) Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 70:49–56
Singh NP, Verma KB (2002) Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Onc 10:279–280
Sledge GW Jr (2016) Curing Metastatic Breast Cancer. J Oncol Prac 12:6–10. doi:10.1200/JOP.2015.008953
Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27:25–61
Toovey S (2006) Are currently deployed artemisinins neurotoxic? Toxicol Lett 166:95–104. doi:10.1016/j.toxlet.2006.06.001
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
WHO (2006) Guideline for the treatment of malaria. WHO, Geneva
WHO (2015) Guidelines for the Treatment of Malaria, 3rd edn. WHO, Geneva
WHO (2001) The use of antimalarial drugs. Consultation report. World Health Organization, Geneva
Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, **a XH, Li DQ (2008) Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. Zhong ** Yi Jie He Xue Bao 6:134–138
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-017-4261-1