Journal of Hematology & Oncology (Jun 2023)

Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study

  • Pierfrancesco Tassone,
  • Maria Teresa Di Martino,
  • Mariamena Arbitrio,
  • Lucia Fiorillo,
  • Nicoletta Staropoli,
  • Domenico Ciliberto,
  • Alessia Cordua,
  • Francesca Scionti,
  • Bernardo Bertucci,
  • Angela Salvino,
  • Mariangela Lopreiato,
  • Fredrik Thunarf,
  • Onofrio Cuomo,
  • Maria Cristina Zito,
  • Maria Rosanna De Fina,
  • Amelia Brescia,
  • Simona Gualtieri,
  • Caterina Riillo,
  • Francesco Manti,
  • Daniele Caracciolo,
  • Vito Barbieri,
  • Eugenio Donato Di Paola,
  • Adele Emanuela Di Francesco,
  • Pierosandro Tagliaferri

DOI
https://doi.org/10.1186/s13045-023-01468-8
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 12

Abstract

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Abstract Background We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. Methods In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0–2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). Results Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3–4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. Conclusions The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).

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