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Joerger, Markus; Stathis, Anastasios; Metaxas, Yannis; Hess, Dagmar; Mantiero, Mara; Mark, Michael; Volden, Matthias; Kaindl, Thomas; Engelhardt, Marc; Larger, Patrice; Lane, Heidi; Hafner, Peter; Levy, Nicole; Stuedeli, Silvia; Sessa, Cristiana; von Moos, Roger

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

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  • Medientyp: E-Artikel
  • Titel: A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors
  • Beteiligte: Joerger, Markus; Stathis, Anastasios; Metaxas, Yannis; Hess, Dagmar; Mantiero, Mara; Mark, Michael; Volden, Matthias; Kaindl, Thomas; Engelhardt, Marc; Larger, Patrice; Lane, Heidi; Hafner, Peter; Levy, Nicole; Stuedeli, Silvia; Sessa, Cristiana; von Moos, Roger
  • Erschienen: Springer Science and Business Media LLC, 2020
  • Erschienen in: Investigational New Drugs
  • Sprache: Englisch
  • DOI: 10.1007/s10637-019-00850-z
  • ISSN: 1573-0646; 0167-6997
  • Schlagwörter: Pharmacology (medical) ; Pharmacology ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Summary</jats:title><jats:p><jats:italic>Purpose</jats:italic> BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. <jats:italic>Methods</jats:italic> This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15–21 of cycle 2 to assess oral bioavailability. <jats:italic>Results</jats:italic> BAL101553 was well tolerated at doses up to ≤70 mg/m<jats:sup>2</jats:sup>. Three grade 3 DLTs occurred: hypotension (70 mg/m<jats:sup>2</jats:sup>), hyponatremia and neutropenia (both 90 mg/m<jats:sup>2</jats:sup>). The MTD for 48-h IV BAL101553 was 70 mg/m<jats:sup>2</jats:sup>. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the C<jats:sub>max</jats:sub> was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was &gt;80%. <jats:italic>Conclusions</jats:italic> Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.</jats:p>