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Phase I study of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine in patients with advanced malignancies

Abstract: OBJECTIVE
To determine the maximum tolerated dose and the recommended dose (RD) for phase II trials of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine.
METHODS
Open-label, dose-escalating, two-arm, uncontrolled, phase I study. Patients received carboplatin on Day (D) 1, followed by elisidepsin on D1 and D8, every 3 weeks, or gemcitabine on D1 and D15, followed by elisidepsin on D1 and D15, every 4 weeks. A pharmacokinetic analysis was done from blood samples collected during the first treatment infusion.
RESULTS
Fifteen patients were treated with carboplatin/elisidepsin at doses from 4 AUC/1.0 mg flat dose (FD) to 5 AUC/2.5 mg FD. Two patients had dose-limiting toxicities (DLTs) at 5 AUC/2.0 mg, a dose delay >2 weeks due to grade-2 ALT increase and grade-3 thrombocytopenia, and a D8 infusion omission due to grade-3 ALT increase. The RD was established at 4 AUC/1.0 mg. Toxicity consisted mainly of mild-moderate anorexia, fatigue, and nausea. Twenty-two patients were treated with gemcitabine/elisidepsin at doses from 1,000 mg*m2/1.0 mg FD to 1,250 mg*m2/7.5 mg FD. Two patients had DLTs at 1,250 mg*m2/7.5 mg, both a D15 dose omission due to grade-2 ALT increase. The RD was defined at 1,250 mg*m2/5.0 mg. Toxicity consisted mainly of mild-moderate fatigue, pruritus, erythema, and myalgia. No objective response was observed. No relevant pharmacokinetic interaction was detected.
CONCLUSION
Infra-optimal doses of elisidepsin and carboplatin and a lack of antitumor activity despite using active drug concentrations in combination with gemcitabine do not warrant further clinical development for these two combinations.

Full Reference: Goldwasser, Francois, Sandrine Faivre, Jerome Alexandre, Cinthya Coronado, Eva M. Fernandez-Garcia, Carmen M. Kahatt, Pilar Garcia Paramio, Jorge Luis Iglesias Dios, Bernardo Miguel-Lillo, and Eric Raymond. “Phase I Study of Elisidepsin (Irvalec(R)) in Combination with Carboplatin or Gemcitabine in Patients with Advanced Malignancies.” Investigational New Drugs 32, no. 3 (June 2014): 500–509. doi:10.1007/s10637-013-0060-7.

Link to full text: http://link.springer.com/article/10.1007%2Fs10637-013-0060-7

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