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Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas

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Summary

This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m2 and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m2 and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m2 and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m2 and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.

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Acknowledgments

The authors would like to acknowledge the work done by Martin Cullell-Young (medical writer, Pharma Mar S.A.) and Sonia Extremera (biostatistician, Pharma Mar S.A.) in the preparation of this manuscript.

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Authors and Affiliations

  1. Instituto Catalán de Oncología, Ctra. Gran Vía, s/n, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Ramón Salazar, Ana Oaknin & Beatriz Pardo

  2. Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, UK

    Ruth Plummer, Angela Robinson & Alan Hilary Calvert

  3. Pharma Mar S.A., Sociedad Unipersonal, Colmenar Viejo, Madrid, Spain

    Arturo Soto-Matos, Alejandro Yovine & Sergio Szyldergemajn

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  1. Ramón Salazar
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Correspondence to Ramón Salazar.

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Salazar, R., Plummer, R., Oaknin, A. et al. Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas. Invest New Drugs 29, 1406–1413 (2011). https://doi.org/10.1007/s10637-010-9488-1

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  • DOI: https://doi.org/10.1007/s10637-010-9488-1

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