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

Elena Elez, Carlos Gomez-Roca, Arturo Soto Matos-Pita, Guillem Argiles, Thibaud Valentin, Cinthya Coronado, Jorge Iglesias, Teresa Macarulla, Sarah Betrian, Salvador Fudio, Katrin Zaragoza, Josep Tabernero, Jean Pierre Delord

    Research output: Contribution to journalArticleResearch

    6 Citations (Scopus)

    Abstract

    © 2018, Springer Science+Business Media, LLC, part of Springer Nature. 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.
    Original languageEnglish
    Pages (from-to)674-683
    JournalInvestigational New Drugs
    Volume37
    DOIs
    Publication statusPublished - 15 Aug 2019

    Keywords

    • First-in-human
    • Microtubule inhibitor
    • Phase I
    • Plocabulin
    • PM060184
    • Solid tumors

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