TY - JOUR
T1 - A phase i study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors
AU - Gordon, Michael S.
AU - Ilaria, Robert
AU - De Alwis, Dinesh P.
AU - Mendelson, David S.
AU - McKane, Scott
AU - Wagner, Margaret M.
AU - Look, Katherine Y.
AU - Lorusso, Patricia M.
PY - 2013/1
Y1 - 2013/1
N2 - Purpose: To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent. Methods: In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg. Results: Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses. Conclusions: When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.
AB - Purpose: To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent. Methods: In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg. Results: Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses. Conclusions: When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.
KW - Dose escalation
KW - LY573636
KW - Phase I
KW - Solid tumors
KW - Tasisulam
UR - http://www.scopus.com/inward/record.url?scp=84872320891&partnerID=8YFLogxK
U2 - 10.1007/s00280-012-1917-8
DO - 10.1007/s00280-012-1917-8
M3 - Article
C2 - 23228983
AN - SCOPUS:84872320891
SN - 0344-5704
VL - 71
SP - 21
EP - 27
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
ER -