Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S, Yuthavong Y (1993) Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrob Agents Chemother 37(5):1108–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lin AJ, Ager AL Jr, Klayman DL (1994) The antimalarial activity of dihydroartemisinin derivatives by transdermal application. Am J Trop Med Hyg 50(6):777–783

    Article  CAS  PubMed  Google Scholar 

  3. Lai H, Singh NP (1995) Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett 91:41–46

    Article  CAS  PubMed  Google Scholar 

  4. Moore Lai H, Li JR, Ren RL, McDougall JA, Singh NP, Choud CK (1995) Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 98:83–87

    Article  Google Scholar 

  5. Nakase I, Lai H, Singh NP, Sasaki T (2008) Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm 354:28–33

    Article  CAS  PubMed  Google Scholar 

  6. Hou J, Wang D, Zhang R, Wang H (2008) Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14(17):5519–5530

    Article  CAS  PubMed  Google Scholar 

  7. Efferth T, Briehl MM, Tome ME (2003) Role of antioxidant genes for the activity of artesunate against tumor cells. Int J Oncol 4:1231–1235

    Google Scholar 

  8. Chen HH, Zhou HJ, Fang X (2003) Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol Res 48(3):231–236

    Article  CAS  PubMed  Google Scholar 

  9. 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(9):1689–1700

    Article  CAS  PubMed  Google Scholar 

  10. Rinner B, Siegl V, Pürstner P, Efferth T, Brem B, Greger H, Pfragner R (2004) Activity of novel plant extracts against medullary thyroid carcinoma cells. Anticancer Res 24(2A):495–500

    PubMed  Google Scholar 

  11. Dell’Eva R, Pfeffer U, Vené 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

    Article  PubMed  Google Scholar 

  12. Nam W, Tak J, Ryu JK, Jung M, Yook JI, Kim HJ, Cha IH (2007) Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Head Neck 29(4):335–340

    Article  PubMed  Google Scholar 

  13. Zhou HJ, Wang WQ, Wu GD, Lee J, Li A (2007) Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol 47(2–3):131–138

    Article  CAS  PubMed  Google Scholar 

  14. 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(7):1045–1056

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  PubMed  PubMed Central  Google Scholar 

  16. Youns M, Efferth T, Reichling J, Fellenberg K, Bauer A, Hoheisel JD (2009) Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells. Biochem Pharmacol 78(3):273–283

    Article  CAS  PubMed  Google Scholar 

  17. Li S, Xue F, Cheng Z, Yang X, Wang S, Geng F, Pan L (2009) Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. Int J Hematol 90(4):513–521

    Article  CAS  PubMed  Google Scholar 

  18. Du JH, Zhang HD, Ma ZJ, Ji KM (2010) Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol 65(5):895–902

    Article  CAS  PubMed  Google Scholar 

  19. Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, Mayer B, Deubzer H, Witt O, Kreuter J, Doerr HW, Cinatl J, Cinatl J Jr (2010) Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol 79(2):130–136

    Article  CAS  PubMed  Google Scholar 

  20. Rasheed SA, Efferth T, Asangani IA, Allgayer H (2010) First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer 127(6):1475–1485

    Article  CAS  PubMed  Google Scholar 

  21. Sertel S, Eichhorn T, Simon CH, Plinkert PK, Johnson SW, Efferth T (2010) Pharmacogenomic identification of c-Myc/Max-regulated genes associated with cytotoxicity of artesunate towards human colon, ovarian and lung cancer cell lines. Molecules 15(4):2886–2910

    Article  CAS  PubMed  Google Scholar 

  22. Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR (2011) Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem 286(8):6587–6601

    Article  CAS  PubMed  Google Scholar 

  23. Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I (2011) Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways. Int J Oncol 39(1):279–285

    CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  25. 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(6):1599 – 603

    CAS  PubMed  Google Scholar 

  26. Mercer AE, Maggs JL, Sun XM, Cohen GM, Chadwick J, O’Neill PM, Park BK (2007) Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds. J Biol Chem 282:9372–9382

    Article  CAS  PubMed  Google Scholar 

  27. Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T (2008) Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res 68(11):4347–4351

    Article  CAS  PubMed  Google Scholar 

  28. Mercer AE, Copple IM, Maggs JL, O’Neill PM, Park BK (2011) The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials. J Biol Chem 286(2):987–996

    Article  CAS  PubMed  Google Scholar 

  29. Disbrow GL, Baege AC, Kierpiec KA, Yuan H, Centeno JA, Thibodeaux CA, Hartmann D, Schlegel R (2005) Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res 65(23):10854–10861

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Wang L, Chen T, Qu J, Wei X (2009) Quantitative analysis of caspase-3 activation by fitting fluorescence emission spectra in living cells. Micron 40(8):811–820

    Article  CAS  PubMed  Google Scholar 

  32. 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(6):1360–1365

    Article  CAS  PubMed  Google Scholar 

  33. Konkimalla VB, McCubrey JA, Efferth T (2009) The role of downstream signaling pathways of the epidermal growth factor receptor for Artesunate’s activity in cancer cells. Curr Cancer Drug Targ 9(1):72–80

    Article  CAS  Google Scholar 

  34. Chen H, Sun B, Wang S, Pan S, Gao Y, Bai X, Xue D (2010) Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-kappaB. J Cancer Res Clin Oncol 136(6):897–903

    Article  CAS  PubMed  Google Scholar 

  35. Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother Pharmacol 53:423–432

    Article  CAS  PubMed  Google Scholar 

  36. Anfosso L, Efferth T, Albini A, Pfeffer U (2006) Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenom J 6(4):269–278

    Article  CAS  Google Scholar 

  37. Sieber S, Gdynia G, Roth W, Bonavida B, Efferth T (2009) Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol 35(1):149–158

    CAS  PubMed  Google Scholar 

  38. Bhaw-Luximon A, Jhurry D (2017) Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives. Cancer Chemother Pharmacol 79(3):451–466

    Article  CAS  PubMed  Google Scholar 

  39. Hien TT, White NJ (1993) Qinghaosu Lancet 341:603–608

    Article  CAS  PubMed  Google Scholar 

  40. U.S. Army Medical Material Development Activity (2012) Intravenous Artesunate for Severe Malaria (IND No. 64,769), Investigator Brochure

  41. Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005) Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366:717–725

    Article  PubMed  Google Scholar 

  42. Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ (2003) Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 37:7–16

    Article  CAS  PubMed  Google Scholar 

  43. Leonardi E, Gilvary G, White NJ, Nosten F (2001) Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg 95:182–183

    Article  CAS  PubMed  Google Scholar 

  44. Barradell LB, Fitton A (1995) Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs 50(4):714–741

    Article  CAS  PubMed  Google Scholar 

  45. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G (2002) Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos 30(9):1005–1012

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. John F. Deeken
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongkun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marion Hartley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amrita K. Cheema
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brandon Smaglo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jimmy J. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aiwu Ruth He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Louis M. Weiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John L. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giuseppe Giaccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jim Luecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jay Y. Spiegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael J. Pishvaian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John F. Deeken.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Search

Navigation