title: First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors.
abstract: This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m(2) (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m(2)). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m(2) (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.
authors.affiliation: Department of Medicine, University of Chicago, MC2115, 5841 South Maryland Avenue, Chicago, IL, 60637, USA, mratain@medicine.bsd.uchicago.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: David
authors.initials: D
authors.lastname: Geary
authors.forename: Samir D
authors.initials: SD
authors.lastname: Undevia
authors.forename: Cinthya
authors.initials: C
authors.lastname: Coronado
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Iglesias
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Bernardo
authors.initials: B
authors.lastname: Miguel-Lillo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C522358:elisidepsin