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First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors

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Summary

Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

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Acknowledgements

The authors wish to thank the patients, their families, and the clinical research teams for their time and trust, and for enabling this clinical trial and associated research.

Funding

This work was supported by Pharma Mar, S.A.

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Authors and Affiliations

  1. Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain

    Elena Elez, Guillem Argiles, Teresa Macarulla & Josep Tabernero

  2. Clinical Research Unit, Institut Claudius Regaud, IUCT- Oncopole, 1 avenue Joliot-Curie, Toulouse, 31059, France

    Carlos Gomez-Roca, Thibaud Valentin, Sarah Betrian & Jean-Pierre Delord

  3. Pharma Mar, S.A., Clinical R&D, Colmenar Viejo, Madrid, Spain

    Arturo Soto Matos-Pita, Cinthya Coronado, Jorge Iglesias, Salvador Fudio & Katrin Zaragoza

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  1. Elena Elez
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Corresponding author

Correspondence to Jean-Pierre Delord.

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Conflicts of interest

A Soto Matos-Pita, C Coronado, J Iglesias, S Fudio, and K Zaragoza are employees of Pharma Mar, S.A.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Elez, E., Gomez-Roca, C., Soto Matos-Pita, A. et al. First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors. Invest New Drugs 37, 674–683 (2019). https://doi.org/10.1007/s10637-018-0674-x

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  • DOI: https://doi.org/10.1007/s10637-018-0674-x

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