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

Elena Elez1, Carlos Gomez-Roca2, Arturo Soto Matos-Pita3

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

Investigational New Drugs
|November 10, 2018
PubMed

Insights

Plocabulin, a novel marine-derived microtubule inhibitor, showed antitumor activity in advanced solid tumors. Peripheral sensory neuropathy was the main dose-limiting toxicity, necessitating further trials to optimize its use.

Area of Science:

  • Oncology
  • Pharmacology
  • Marine Biotechnology

Background:

  • Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor with antitumor properties.
  • This study assessed dose-limiting toxicities (DLT) to establish the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin.

Purpose of the Study:

  • To determine the MTD and RD of plocabulin in patients with advanced solid tumors.
  • To evaluate the safety and preliminary efficacy of plocabulin administered via infusion.

Main Methods:

  • Forty-four patients with advanced solid tumors received plocabulin using an accelerated titration design.
  • Plocabulin was administered as a 10-min infusion on Days 1, 8, and 15 every four weeks.
  • Dose escalation ranged from 1.3 mg/m² to 14.5 mg/m².

Main Results:

  • The MTD was determined to be 14.5 mg/m².
  • A recommended dose (RD) was not confirmed due to dose delays and omissions, resulting in low relative dose intensity (66%) at 12.0 mg/m².
  • The primary dose-limiting toxicity was grade 3 peripheral sensory neuropathy (PSN); other DLTs included tumor lysis syndrome, cardiac failure, and myalgia. Transient and manageable myelosuppression was observed.
  • Antitumor responses and disease stabilization were noted in various advanced solid tumors, with a 33% clinical benefit rate.

Conclusions:

  • Peripheral sensory neuropathy is the primary dose-limiting toxicity for plocabulin, consistent with its mechanism as a tubulin-binding agent.
  • Encouraging antitumor activity warrants further investigation with modified dosing schedules (e.g., D1&D8, D1-3 & D15-17) to optimize toxicity and identify the RD.
Keywords:
First-in-humanMicrotubule inhibitorPM060184Phase IPlocabulinSolid tumors

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