A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors
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To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.
Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.
Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m2. The MTD was 6.8 mg/m2, and the RD was 5.5 mg/m2. Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m2. DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m2 (n = 2 patients), 5.5 mg/m2 (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for >38 months, and 12 patients had disease stabilization (8 for ≥3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.
Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.
KeywordsAnti-proliferative Depsipeptide Kahalalide F Pharmacokinetics Phase I study
The authors are grateful to the patients who participated in this study and to their carers. The authors also acknowledge the study research teams who contributed to this study at both participating centers. The study was supported at the Beatson West of Scotland Cancer Centre by the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and by the Chief Scientist Office, Scotland.
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