TY - JOUR
T1 - A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors
AU - Vilar, Eduardo
AU - Grünwald, Viktor
AU - Schöffski, Patrick
AU - Singer, Harald
AU - Salazar, Ramon
AU - Iglesias, Jose Luis
AU - Casado, Esther
AU - Cullell-Young, Martin
AU - Baselga, Jose
AU - Tabernero, Josep
N1 - Funding Information:
This work was supported by PharmaMar SA, Spain.
PY - 2012/2
Y1 - 2012/2
N2 - 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. Patients and 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/m 2/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m 2/day; all had grade 4 transaminase increases, one of whom (160 mg/m 2/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/m 2/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.
AB - 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. Patients and 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/m 2/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m 2/day; all had grade 4 transaminase increases, one of whom (160 mg/m 2/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/m 2/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.
KW - Dose escalation
KW - ES-285
KW - Pharmacokinetics
KW - Phase I
KW - Spisulosine
UR - http://www.scopus.com/inward/record.url?scp=84856510555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856510555&partnerID=8YFLogxK
U2 - 10.1007/s10637-010-9529-9
DO - 10.1007/s10637-010-9529-9
M3 - Article
C2 - 20820909
AN - SCOPUS:84856510555
SN - 0167-6997
VL - 30
SP - 299
EP - 305
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -