A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors.

Abstract

PURPOSE:

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.

METHODS:

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.

RESULTS:

Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (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.

CONCLUSIONS:

Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.

• Authors: R Salazar, R J Jones, A Oaknin, D Crawford, C Cuadra, C Hopkins, M Gil, C Coronado, A Soto-Matos, M Cullell-Young, J L Iglesias Dios, T R J Evans
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 70 Issue 5 Pg. 673-81 (Nov 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22926637 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• elisidepsin
• Transaminases

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Depsipeptides (administration & dosage, adverse effects, pharmacokinetics)
• Disease Progression
• Dose-Response Relationship, Drug
• Female
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Transaminases (metabolism)
• Treatment Outcome