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

• Published in: Investigational new drugs Vol. 33; no. 4; pp. 901 - 910
• Main Authors: Ratain, Mark J., Geary, David, Undevia, Samir D., Coronado, Cinthya, Alfaro, Vicente, Iglesias, Jorge L., Schilsky, Richard L., Miguel-Lillo, Bernardo
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-08-2015; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Alopecia; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Apoptosis; Baldness; Cancer; Cancer therapies; Cell death; Chemotherapy; Clinical trials; Cytotoxicity; Depsipeptides - administration & dosage; Depsipeptides - adverse effects; Depsipeptides - pharmacokinetics; Depsipeptides - therapeutic use; Disease; Drug dosages; Female; Gene expression; Humans; Male; Medicine; Medicine & Public Health; Melanoma; Mesothelioma; Metastasis; Middle Aged; Natural products; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Patients; Pharmacology/Toxicology; Phase I Studies; Prostate; Radiation therapy; Schedules; Studies; Tumors; Young Adult; United States > US; PM02734; Phase I; Dose-limiting toxicities; Cytotoxic; Antitumor
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-015-0247-1

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.