A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.
BACKGROUND
ES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug.


METHODS
Thirty patients from two centers were treated with a three-hour ES-285 intravenous infusion for five consecutive days, every 3 weeks. Eleven dose levels were explored.


RESULTS
No dose-limiting toxicity (DLT) occurred from 2 to 81 mg/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/day) had concomitant grade 4 hepatitis and grade 3 bilirubin elevation. The MTD of this regimen was not reached due to early termination of the ES-285 phase I program, but was considered to be 80 to 100 mg/m²/day. Other toxicities included mild to moderate asthenia, nausea, vomiting, anemia, lymphopenia, and injection site reaction. Pharmacokinetic analyses showed dose proportionality on Days 1 and 5, a wide distribution and a long half-life. Seven patients (five with colorectal cancer) had stable disease (1.2-4.1 months), lasting for more than 3 months in three patients.


CONCLUSIONS
Liver enzyme elevations were dose limiting for ES-285 in this administration schedule. Low antitumor activity was observed.
Vilar
Eduardo
E
Department of Medical Oncology, Vall d'Hebron University Hospital, Ps. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
Grünwald
Viktor
V
Schöffski
Patrick
P
Singer
Harald
H
Salazar
Ramon
R
Iglesias
Jose Luis
JL
Casado
Esther
E
Cullell-Young
Martin
M
Baselga
Jose
J
Tabernero
Josep
J
D000328:Adult; D000368:Aged; D000473:Alkanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005858:Germany; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013030:Spain; D016896:Treatment Outcome; D055815:Young Adult
D000473:Alkanes; D000970:Antineoplastic Agents; D008055:Lipids; C408363:spisulosine
Apoptosis. 2007 Feb;12(2):395-409
17191124
Mol Cancer Ther. 2009 Jun;8(6):1430-7
19509256
Pharmazie. 2006 Jan;61(1):21-4
16454201
Cancer Lett. 2000 Apr 28;152(1):23-9
10754202
Prog Mol Subcell Biol. 2006;43:363-79
17153351
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
J Mass Spectrom. 2003 May;38(5):548-54
12794877
PDA J Pharm Sci Technol. 2005 Jul-Aug;59(4):246-57
16218203
Eur J Pharmacol. 2008 Apr 28;584(2-3):237-45
18343365