TY - JOUR
T1 - A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies
AU - Deeken, John F.
AU - Wang, Hongkun
AU - Hartley, Marion
AU - Cheema, Amrita K.
AU - Smaglo, Brandon
AU - Hwang, Jimmy J.
AU - He, Aiwu Ruth
AU - Weiner, Louis M.
AU - Marshall, John L.
AU - Giaccone, Giuseppe
AU - Liu, Stephen
AU - Luecht, Jim
AU - Spiegel, Jay Y.
AU - Pishvaian, Michael J.
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Artesunate
KW - Clinical trial
KW - Phase I
KW - Solid tumors
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U2 - 10.1007/s00280-018-3533-8
DO - 10.1007/s00280-018-3533-8
M3 - Article
C2 - 29392450
AN - SCOPUS:85042511967
SN - 0344-5704
VL - 81
SP - 587
EP - 596
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 3
ER -