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

  • PHASE I STUDIES
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Summary

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.

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Acknowledgments

We thank all of the staff who contributed to the care of the patients included in this study.

Conflict of interest

Cinthya Coronado, Eva M. Fernández-García, Carmen M. Kahatt, Jorge Luis Iglesias Dios, Pilar García Paramio and Bernardo Miguel-Lillo are employees of Pharma Mar.

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Authors and Affiliations

  1. AP-HP, Faculté de Medicine Paris Descartes, Hôpital Cochin, Paris, France

    Francois Goldwasser & Jerome Alexandre

  2. Pharma Mar, S.A, Madrid, Spain

    Cinthya Coronado, Eva M. Fernández-García, Carmen M. Kahatt, Pilar García Paramio, Jorge Luis Iglesias Dios & Bernardo Miguel-Lillo

  3. Hopital Beaujon, 100 Boulevard General Leclerc, 92118, Clichy, Cedex, France

    Sandrine Faivre & Eric Raymond

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  1. Francois Goldwasser
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Correspondence to Eric Raymond.

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Goldwasser, F., Faivre, S., Alexandre, J. et al. Phase I study of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine in patients with advanced malignancies. Invest New Drugs 32, 500–509 (2014). https://doi.org/10.1007/s10637-013-0060-7

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