Journal Article

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

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

2023

Overview

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).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Antitumor agents / Cancer / Cancer patients / Cancer Research / Clinical trials / Colorectal cancer / Colorectal carcinoma / Down-regulation / First-in-human clinical trials for cancer and blood disorders / Hematology / Humans / Medicine / Medicine & Public Health / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - therapeutic use / miR-221 / miRNA / miRNA therapeutics / Neoplasms - drug therapy / Non-coding RNA therapeutics / Oligonucleotides - therapeutic use / Oncology / Patients / Pharmacodynamics / Pharmacokinetics / Phosphorothioate / Protein expression / Proteins / PTEN protein / RNA therapeutics / Safety and security measures / Toxicity / Tumors / Urine