Cancer Chemotherapy and Pharmacology (2018) 81:587–596
A phase I study of intravenous artesunate in patients with advanced
solid tumor malignancies
John F. Deeken
· Hongkun Wang
· Marion Hartley
· Amrita K. Cheema
· Brandon Smaglo
· Jimmy J. Hwang
Aiwu Ruth He
· Louis M. Weiner
· John L. Marshall
· Giuseppe Giaccone
· Stephen Liu
· Jim Luecht
Jay Y. Spiegel
· Michael J. Pishvaian
Received: 4 December 2017 / Accepted: 26 January 2018 / Published online: 1 February 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Purpose The artemisinin class of anti-malarial drugs has shown signiﬁcant anti-cancer activity in pre-clinical models. Pro-
posed 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), hyper-
sensitivity 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.
Keywords Phase I · Artesunate · Clinical trial · Solid tumors
Artemisinin is a peroxide-containing sesquiterpene lactone
derived from the Chinese medicinal plant Artemisia annua
(qinghaosu) , and has been used for centuries in tradi-
tional Chinese folk medicine. Since the 1970s, it has been
puriﬁed and used successfully as an anti-malarial medication
with few serious side-eﬀects .
In its original form, artemisinin has a low solubility.
Chemical modiﬁcations have produced a number of solu-
ble, potent analogs, now in clinical use. The various arte-
misinins in clinical use diﬀer according to substituents at
position C-10. Dihydroartemisinin (DHA) is the most potent
compound in this class, but has poor water solubility and
is thus not available parentally. Artesunate, the hemisucci-
nate ester of dihydroartemisinin, is water-soluble and can be
Results were presented at the 2015 American Society of Clinical
Oncology (ASCO) Annual Meetings.
* John F. Deeken
Inova Schar Cancer Institute, Inova Health System, 3300
Gallows Road, Falls Church, VA 22042, USA
Lombardi Comprehensive Cancer Center, Georgetown
University Medical Center, Washington, DC, USA
Levine Cancer Institute, Carolinas HealthCare System,
Charlotte, NC, USA